Clinical Review

Since publication of initial findings of the Women’s Health Initiative (WHI) in 2002, use of systemic menopausal hormone therapy (HT) has declined by some 80% among US women.¹ Against this backdrop, this year’s Menopause Update highlights the “hot off the press” updated position statement on menopausal HT from The North American Menopause Society (NAMS), summarized by Dr. JoAnn V. Pinkerton. Although this guidance is chock full of practical, evidence-based guidance, the take-home message that Dr. Pinkerton and I would like to leave readers of OBG Management with is that for women with bothersome menopausal symptoms aged in their 50s or within 10 years of the onset of menopause who are free of contraindications, use of systemic HT is appropriate.

Related Article:
Dr. Andrew M. Kaunitz on prescribing systemic HT to older women

Although menopausal vasomotor and related symptoms improve as women age, in untreated women, vulvovaginal atrophy (VVA, also known as genitourinary syndrome of menopause, or GSM) tends to progress, causing vaginal dryness and sexual dysfunction, among other symptoms. When symptomatic GSM represents the only indication for treatment, low-dose local vaginal estrogen, ospemifene, or dehydroepiandrosterone (DHEA; prasterone) is safe and effective. However, as with systemic HT, specific treatments for GSM are substantially underutilized.² The current package labeling for low-dose vaginal estrogen deters many appropriate candidates from using this safe, effective treatment. In this Update, Dr. JoAnn E. Manson reviews the rationale for updating this labeling as well as recent efforts to accomplish the task.

Read about updated NAMS guidelines on HT

Guidelines on HT have been updated by The North American Menopause Society

The 2017 hormone therapy position statement of The North American Menopause Society [published online ahead of print June 2017]. Menopause.

The North American Menopause Society Hormone Therapy (HT) Position Statement Advisory Panel, composed of more than 20 experts in menopausal women's HT, including clinicians, researchers, and epidemiologists, reviewed the 2012 HT Position Statement, evaluated prior and new literature and used levels of evidence to identify the quality of the evidence and strength of the recommendations and to find consensus for the guidelines. The following information comes from the NAMS 2017 Hormone Therapy Position Statement.³

What are the major findings?

HT is the most effective treatment for vasomotor symptoms (VMS) and GSM and has been shown to prevent bone loss and fracture. Risks of HT may differ for women depending on type, dose, duration, route of administration, and timing of initiation and whether or not a progestogen is needed. Treatment should be individualized using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation about benefits and risks of continuing or discontinuing HT.

For women who are younger than age 60 or within 10 years of menopause and have no contraindication, the clearest benefit of HT is for the treatment of VMS and prevention of bone loss in those at elevated risk.

The clinical guidelines were presented to NAMS audience at the 2016 annual clinical meeting, where NAMS recommended "determining the most appropriate type, dose, formulation, and duration of HT."⁴

When to initiate HT and duration of use

In its now-published 2017 guidelines on HT, NAMS affirms the safety and efficacy of HT for symptomatic menopausal women or those at high risk for bone loss who are under age 60 or within 10 years of menopause. NAMS encourages practitioners to employ shared decision making with their patients to find the appropriate type, dose, formulation, and duration of HT, making individualized decisions based on evidence-based information, the unique health risks of women, and with periodic reassessment.

In the clinical guidelines presented in the 2016 NAMS annual meeting,⁴ key recommendations taken from the 2017 Hormone Therapy Position Statement³ include the following: For women who are aged younger than 60 years or within 10 years of menopause and have no contraindications, the benefit/risk ratio appears favorable for treatment of bothersome VMS and in those at elevated risk for bone loss or fracture.

For women who initiate HT more than 10 years from menopause or after age 60, this benefit/risk ratio appears less favorable because of greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia.

What about extended use of hormone therapy? There is no evidence to support routine discontinuation of HT after age 65. Decisions about longer durations of HT should be individualized and considered for indications such as persistent VMS or bone loss, with shared decision making, documentation, and periodic reevaluation. Longer duration is more favorable for estrogen therapy than for estrogen-progestin therapy, based on the Women's Health Initiative (WHI) randomized controlled trials.⁵

What about only vaginal symptoms? For bothersome GSM not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended and can be continued as long as indicated since there is minimal systemic absorption of estrogen, with serum levels remaining within the normal postmenopausal range.^6,7 For women with estrogen sensitive cancer, oncologists should be included in decision making, particularly for women on aromatase inhibitors.

Considerations for special populations Early menopause. For women with hypoestrogenism, primary ovarian insufficiency, or premature surgical menopause without contraindications, HT is recommended until at least the median age of menopause (52 years), as studies suggest that benefits outweigh the risks for effects on bone, heart, cognition, GSM, sexual function, and mood.⁸

Family history of breast cancer. Observational evidence suggests that use of HT does not further alter the risk for breast cancer in women with a family history of breast cancer. Family history is one risk, among others, that should be assessed when counseling women regarding HT.

Women who are BRCA-positive without breast cancer. For women who are BRCA-positive (higher genetic risk of breast cancer, primarily estrogen-receptor-negative), and have undergone surgical menopause (bilateral salpingo-oophorectomy), the benefits of estrogen to decrease health risks caused by premature loss of estrogen need to be considered on an individual basis.⁹ On the basis of limited observational studies, consider offering systemic HT until the median age of menopause (52 years) with longer use individualized.³

Related Article:
Is menopausal hormone therapy safe when your patient carries a BRCA mutation?

Survivors of endometrial and breast cancer with bothersome VMS. For women with prior estrogen-sensitive cancers, non-HTs should be considered first, particularly those agents studied through randomized controlled trials in this population and found to be effective. If systemic estrogen is considered for persistent symptoms after non-HT or complementary options have been unsuccessful, decisions should be made for compelling reasons and after detailed counseling, with shared decision making and in conjunction with their oncologist.³ 

Bothersome GSM. On the basis of limited observational data, there appears to be minimal to no demonstrated elevation in risk for recurrence of endometrial or breast cancer using low-dose vaginal estrogen,^3,10 but decisions should be made in conjunction with an oncologist.

Related Article:
Focus on treating genital atrophy symptoms
 

The importance of relaying the new guidelines to patients

It is important for clinicians to talk to women about their menopausal symptoms and their options for relief of symptoms or prevention of bone loss. Discussion should take into account age and time from menopause, include evidence-based information^11-13 about benefits and risks of different types of therapy, and employ shared decision making to choose the most appropriate therapy to maximize benefits and minimize risks for the individual woman.

Following the WHI initial release in 2002, both women and providers became fearful of HT and believed media hype and celebrities that compounded bioidentical HT was safer than FDA-approved HTs. However, compounded products lack safety and efficacy data, are not monitored or regulated by the FDA, and have unique risks associated with compounding, including concerns about sterility, impurities, and overdosing or underdosing, which could increase cancer risk.³

Read about modifying low-dose vaginal estrogen’s black box warning

Physicians continue to underwhelmingly prescribe low-dose vaginal estrogen for GSM 

Kingsberg SA, Krychman M, Graham S, Bernick B, Mirkin S. The Women's EMPOWER survey: identifying women's perceptions on vulvar and vaginal atrophy and its treatment. J Sex Med. 2017;14(3):413-424.

GSM is seriously underrecognized and undertreated.^2,8,14 It has a major impact on women's lives--a silent epidemic affecting women's quality of life, sexual health, interpersonal relationships, and even physical health in terms of increased risk of urinary tract infections and urinary symptoms. Unfortunately, patients are reluctant to mention the problem to their clinicians, and they do not clearly recognize it as a medical condition that has available treatment options. Clinicians also rarely receive adequate training in the management of this condition and how to discuss it with their patients. Given busy schedules and time constraints, addressing this topic often falls through the cracks, representing a missed opportunity for helping our patients with safe and effective treatments. In a recent study by Kingsberg and colleagues, an astoundingly low percentageof women with GSM symptoms received treatment. 

Details of the study

The study authors evaluated women's perceptions of GSM and available treatment options. US women aged 45 and older who reported GSM symptoms were surveyed. Of 1,858 women with a median age of 58 (range, 45-90), the study authors found that 50% had never used any treatment; 25% used over-the-counter medications; 18% were former users of GSM treatments; and 7% currently used prescribed GSM therapies.

When GSM was discussed, women were more likely than their clinicians to initiate the conversation. The main reason for women not mentioning their symptoms was the perception that GSM symptoms were a natural and inevitable part of aging. Hormonal products were perceived by women as having several downsides, including risk of systemic absorption, messiness of local creams, and the need to reuse an applicator. Overall, clinicians recommended vaginal estrogen therapy to only 23% and oral HTs to 18% of women.

The results of the study are consistent with results of earlier surveys of menopausal women. Although the survey included nearly 2,000 women, it has the potential for selection biases inherent to most Internet-based surveys. In addition, the respondents tended to be white and have higher socieconomic status, with limited representation from other groups.

Calls for the current boxed warning to be revised

GSM is highly prevalent among postmenopausal women; the condition has adverse effects on quality of life and sexual health.^2,8,14 Safe and effective treatments are available but are underutilized.^1,8,15,16 A current boxed warning appears on low-dose vaginal estrogen--class labeling that appears on all medications in the class of estrogen or HT, regardless of dose or route of administration. These warnings are based on findings from the WHI and other studies of systemic estrogen or estrogen plus progestin, which demonstrated a complex pattern of risks and benefits of HT (including increased risk of venous thrombosis or pulmonary embolism, stroke, and breast cancer [with estrogen plus progestin]).

These findings, however, do not appear to be relevant to low-dose vaginal estrogen, given minimal if any systemic absorption and much lower blood levels of hormones than found with systemic HT. Blood levels of estradiol with low-dose vaginal estrogen remain in the normal postmenopausal range, compared to several-fold elevations in hormone levels with systemic HT.^8,15,16 Additionally, observational studies of low-dose vaginal estrogen, as well as short-term randomized clinical trials, show no evidence of an increased risk of venous thromboembolic events, heart disease, stroke, breast cancer, or dementia--the listed possible adverse effects in the boxed warning. The current warning is based on extrapolating findings from systemic HT, which is inappropriate and not evidence-based for low-dose vaginal estrogen.¹⁵

The inappropriate boxed warning contributes to the problem of undertreatment of GSM in women by discouraging clinicians from prescribing the medication and dissuading patients from taking it even after purchase. Testimonials from many clinicians caring for these women have underscored that women will fill their prescription, but after seeing the boxed warning will often become alarmed and decide not to take the medication. Clinicians reported that patients often say at their next appointment: "No, I never took it. I got very scared when I saw the boxed warning." As a result, clinicians often have to spend a great deal of time explaining the limitations of, and lack of evidence for, the boxed warning on low-dose vaginal estrogen.

Related Article:
2016 Update on menopause
 

Recommended label revisions

A modified label, without a boxed warning, would be safer for women because the key messages would not be obscured by the large amount of irrelevant information. Our Working Group recommended that the label explain that the listed risks were found in studies of systemic HT and their relevance to low-dose vaginal estrogen is unknown. The Group also recommended that warning text should be added in bold font to advise  patients to seek medical attention if they have vaginal bleeding or spotting while taking the medication. In addition, patients who have a history of breast cancer or other hormone-sensitive cancer should discuss the use of the medication with their oncologist.   

Status update on efforts to revise label. A citizen's petition was filed in the Spring of 2016, with signatures from more than 600 clinicians and patients and representatives of medical and professional organizations endorsing a more appropriate evidence-based label for low-dose vaginal estrogen. The FDA is continuing to review and deliberate on these issues but has not yet made a final decision.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Since publication of initial findings of the Women’s Health Initiative (WHI) in 2002, use of systemic menopausal hormone therapy (HT) has declined by some 80% among US women.¹ Against this backdrop, this year’s Menopause Update highlights the “hot off the press” updated position statement on menopausal HT from The North American Menopause Society (NAMS), summarized by Dr. JoAnn V. Pinkerton. Although this guidance is chock full of practical, evidence-based guidance, the take-home message that Dr. Pinkerton and I would like to leave readers of OBG Management with is that for women with bothersome menopausal symptoms aged in their 50s or within 10 years of the onset of menopause who are free of contraindications, use of systemic HT is appropriate.

Related Article:
Dr. Andrew M. Kaunitz on prescribing systemic HT to older women

Although menopausal vasomotor and related symptoms improve as women age, in untreated women, vulvovaginal atrophy (VVA, also known as genitourinary syndrome of menopause, or GSM) tends to progress, causing vaginal dryness and sexual dysfunction, among other symptoms. When symptomatic GSM represents the only indication for treatment, low-dose local vaginal estrogen, ospemifene, or dehydroepiandrosterone (DHEA; prasterone) is safe and effective. However, as with systemic HT, specific treatments for GSM are substantially underutilized.² The current package labeling for low-dose vaginal estrogen deters many appropriate candidates from using this safe, effective treatment. In this Update, Dr. JoAnn E. Manson reviews the rationale for updating this labeling as well as recent efforts to accomplish the task.

Read about updated NAMS guidelines on HT

Guidelines on HT have been updated by The North American Menopause Society

The 2017 hormone therapy position statement of The North American Menopause Society [published online ahead of print June 2017]. Menopause.

The North American Menopause Society Hormone Therapy (HT) Position Statement Advisory Panel, composed of more than 20 experts in menopausal women's HT, including clinicians, researchers, and epidemiologists, reviewed the 2012 HT Position Statement, evaluated prior and new literature and used levels of evidence to identify the quality of the evidence and strength of the recommendations and to find consensus for the guidelines. The following information comes from the NAMS 2017 Hormone Therapy Position Statement.³

What are the major findings?

HT is the most effective treatment for vasomotor symptoms (VMS) and GSM and has been shown to prevent bone loss and fracture. Risks of HT may differ for women depending on type, dose, duration, route of administration, and timing of initiation and whether or not a progestogen is needed. Treatment should be individualized using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation about benefits and risks of continuing or discontinuing HT.

For women who are younger than age 60 or within 10 years of menopause and have no contraindication, the clearest benefit of HT is for the treatment of VMS and prevention of bone loss in those at elevated risk.

The clinical guidelines were presented to NAMS audience at the 2016 annual clinical meeting, where NAMS recommended "determining the most appropriate type, dose, formulation, and duration of HT."⁴

When to initiate HT and duration of use

In its now-published 2017 guidelines on HT, NAMS affirms the safety and efficacy of HT for symptomatic menopausal women or those at high risk for bone loss who are under age 60 or within 10 years of menopause. NAMS encourages practitioners to employ shared decision making with their patients to find the appropriate type, dose, formulation, and duration of HT, making individualized decisions based on evidence-based information, the unique health risks of women, and with periodic reassessment.

In the clinical guidelines presented in the 2016 NAMS annual meeting,⁴ key recommendations taken from the 2017 Hormone Therapy Position Statement³ include the following: For women who are aged younger than 60 years or within 10 years of menopause and have no contraindications, the benefit/risk ratio appears favorable for treatment of bothersome VMS and in those at elevated risk for bone loss or fracture.

For women who initiate HT more than 10 years from menopause or after age 60, this benefit/risk ratio appears less favorable because of greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia.

What about extended use of hormone therapy? There is no evidence to support routine discontinuation of HT after age 65. Decisions about longer durations of HT should be individualized and considered for indications such as persistent VMS or bone loss, with shared decision making, documentation, and periodic reevaluation. Longer duration is more favorable for estrogen therapy than for estrogen-progestin therapy, based on the Women's Health Initiative (WHI) randomized controlled trials.⁵

What about only vaginal symptoms? For bothersome GSM not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended and can be continued as long as indicated since there is minimal systemic absorption of estrogen, with serum levels remaining within the normal postmenopausal range.^6,7 For women with estrogen sensitive cancer, oncologists should be included in decision making, particularly for women on aromatase inhibitors.

Considerations for special populations Early menopause. For women with hypoestrogenism, primary ovarian insufficiency, or premature surgical menopause without contraindications, HT is recommended until at least the median age of menopause (52 years), as studies suggest that benefits outweigh the risks for effects on bone, heart, cognition, GSM, sexual function, and mood.⁸

Family history of breast cancer. Observational evidence suggests that use of HT does not further alter the risk for breast cancer in women with a family history of breast cancer. Family history is one risk, among others, that should be assessed when counseling women regarding HT.

Women who are BRCA-positive without breast cancer. For women who are BRCA-positive (higher genetic risk of breast cancer, primarily estrogen-receptor-negative), and have undergone surgical menopause (bilateral salpingo-oophorectomy), the benefits of estrogen to decrease health risks caused by premature loss of estrogen need to be considered on an individual basis.⁹ On the basis of limited observational studies, consider offering systemic HT until the median age of menopause (52 years) with longer use individualized.³

Related Article:
Is menopausal hormone therapy safe when your patient carries a BRCA mutation?

Survivors of endometrial and breast cancer with bothersome VMS. For women with prior estrogen-sensitive cancers, non-HTs should be considered first, particularly those agents studied through randomized controlled trials in this population and found to be effective. If systemic estrogen is considered for persistent symptoms after non-HT or complementary options have been unsuccessful, decisions should be made for compelling reasons and after detailed counseling, with shared decision making and in conjunction with their oncologist.³ 

Bothersome GSM. On the basis of limited observational data, there appears to be minimal to no demonstrated elevation in risk for recurrence of endometrial or breast cancer using low-dose vaginal estrogen,^3,10 but decisions should be made in conjunction with an oncologist.

Related Article:
Focus on treating genital atrophy symptoms
 

The importance of relaying the new guidelines to patients

It is important for clinicians to talk to women about their menopausal symptoms and their options for relief of symptoms or prevention of bone loss. Discussion should take into account age and time from menopause, include evidence-based information^11-13 about benefits and risks of different types of therapy, and employ shared decision making to choose the most appropriate therapy to maximize benefits and minimize risks for the individual woman.

Following the WHI initial release in 2002, both women and providers became fearful of HT and believed media hype and celebrities that compounded bioidentical HT was safer than FDA-approved HTs. However, compounded products lack safety and efficacy data, are not monitored or regulated by the FDA, and have unique risks associated with compounding, including concerns about sterility, impurities, and overdosing or underdosing, which could increase cancer risk.³

Read about modifying low-dose vaginal estrogen’s black box warning

Physicians continue to underwhelmingly prescribe low-dose vaginal estrogen for GSM 

Kingsberg SA, Krychman M, Graham S, Bernick B, Mirkin S. The Women's EMPOWER survey: identifying women's perceptions on vulvar and vaginal atrophy and its treatment. J Sex Med. 2017;14(3):413-424.

GSM is seriously underrecognized and undertreated.^2,8,14 It has a major impact on women's lives--a silent epidemic affecting women's quality of life, sexual health, interpersonal relationships, and even physical health in terms of increased risk of urinary tract infections and urinary symptoms. Unfortunately, patients are reluctant to mention the problem to their clinicians, and they do not clearly recognize it as a medical condition that has available treatment options. Clinicians also rarely receive adequate training in the management of this condition and how to discuss it with their patients. Given busy schedules and time constraints, addressing this topic often falls through the cracks, representing a missed opportunity for helping our patients with safe and effective treatments. In a recent study by Kingsberg and colleagues, an astoundingly low percentageof women with GSM symptoms received treatment. 

Details of the study

The study authors evaluated women's perceptions of GSM and available treatment options. US women aged 45 and older who reported GSM symptoms were surveyed. Of 1,858 women with a median age of 58 (range, 45-90), the study authors found that 50% had never used any treatment; 25% used over-the-counter medications; 18% were former users of GSM treatments; and 7% currently used prescribed GSM therapies.

When GSM was discussed, women were more likely than their clinicians to initiate the conversation. The main reason for women not mentioning their symptoms was the perception that GSM symptoms were a natural and inevitable part of aging. Hormonal products were perceived by women as having several downsides, including risk of systemic absorption, messiness of local creams, and the need to reuse an applicator. Overall, clinicians recommended vaginal estrogen therapy to only 23% and oral HTs to 18% of women.

The results of the study are consistent with results of earlier surveys of menopausal women. Although the survey included nearly 2,000 women, it has the potential for selection biases inherent to most Internet-based surveys. In addition, the respondents tended to be white and have higher socieconomic status, with limited representation from other groups.

Calls for the current boxed warning to be revised

GSM is highly prevalent among postmenopausal women; the condition has adverse effects on quality of life and sexual health.^2,8,14 Safe and effective treatments are available but are underutilized.^1,8,15,16 A current boxed warning appears on low-dose vaginal estrogen--class labeling that appears on all medications in the class of estrogen or HT, regardless of dose or route of administration. These warnings are based on findings from the WHI and other studies of systemic estrogen or estrogen plus progestin, which demonstrated a complex pattern of risks and benefits of HT (including increased risk of venous thrombosis or pulmonary embolism, stroke, and breast cancer [with estrogen plus progestin]).

These findings, however, do not appear to be relevant to low-dose vaginal estrogen, given minimal if any systemic absorption and much lower blood levels of hormones than found with systemic HT. Blood levels of estradiol with low-dose vaginal estrogen remain in the normal postmenopausal range, compared to several-fold elevations in hormone levels with systemic HT.^8,15,16 Additionally, observational studies of low-dose vaginal estrogen, as well as short-term randomized clinical trials, show no evidence of an increased risk of venous thromboembolic events, heart disease, stroke, breast cancer, or dementia--the listed possible adverse effects in the boxed warning. The current warning is based on extrapolating findings from systemic HT, which is inappropriate and not evidence-based for low-dose vaginal estrogen.¹⁵

The inappropriate boxed warning contributes to the problem of undertreatment of GSM in women by discouraging clinicians from prescribing the medication and dissuading patients from taking it even after purchase. Testimonials from many clinicians caring for these women have underscored that women will fill their prescription, but after seeing the boxed warning will often become alarmed and decide not to take the medication. Clinicians reported that patients often say at their next appointment: "No, I never took it. I got very scared when I saw the boxed warning." As a result, clinicians often have to spend a great deal of time explaining the limitations of, and lack of evidence for, the boxed warning on low-dose vaginal estrogen.

Related Article:
2016 Update on menopause
 

Recommended label revisions

A modified label, without a boxed warning, would be safer for women because the key messages would not be obscured by the large amount of irrelevant information. Our Working Group recommended that the label explain that the listed risks were found in studies of systemic HT and their relevance to low-dose vaginal estrogen is unknown. The Group also recommended that warning text should be added in bold font to advise  patients to seek medical attention if they have vaginal bleeding or spotting while taking the medication. In addition, patients who have a history of breast cancer or other hormone-sensitive cancer should discuss the use of the medication with their oncologist.   

Status update on efforts to revise label. A citizen's petition was filed in the Spring of 2016, with signatures from more than 600 clinicians and patients and representatives of medical and professional organizations endorsing a more appropriate evidence-based label for low-dose vaginal estrogen. The FDA is continuing to review and deliberate on these issues but has not yet made a final decision.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Since publication of initial findings of the Women’s Health Initiative (WHI) in 2002, use of systemic menopausal hormone therapy (HT) has declined by some 80% among US women.¹ Against this backdrop, this year’s Menopause Update highlights the “hot off the press” updated position statement on menopausal HT from The North American Menopause Society (NAMS), summarized by Dr. JoAnn V. Pinkerton. Although this guidance is chock full of practical, evidence-based guidance, the take-home message that Dr. Pinkerton and I would like to leave readers of OBG Management with is that for women with bothersome menopausal symptoms aged in their 50s or within 10 years of the onset of menopause who are free of contraindications, use of systemic HT is appropriate.

Related Article:
Dr. Andrew M. Kaunitz on prescribing systemic HT to older women

Although menopausal vasomotor and related symptoms improve as women age, in untreated women, vulvovaginal atrophy (VVA, also known as genitourinary syndrome of menopause, or GSM) tends to progress, causing vaginal dryness and sexual dysfunction, among other symptoms. When symptomatic GSM represents the only indication for treatment, low-dose local vaginal estrogen, ospemifene, or dehydroepiandrosterone (DHEA; prasterone) is safe and effective. However, as with systemic HT, specific treatments for GSM are substantially underutilized.² The current package labeling for low-dose vaginal estrogen deters many appropriate candidates from using this safe, effective treatment. In this Update, Dr. JoAnn E. Manson reviews the rationale for updating this labeling as well as recent efforts to accomplish the task.

Read about updated NAMS guidelines on HT

Guidelines on HT have been updated by The North American Menopause Society

The 2017 hormone therapy position statement of The North American Menopause Society [published online ahead of print June 2017]. Menopause.

The North American Menopause Society Hormone Therapy (HT) Position Statement Advisory Panel, composed of more than 20 experts in menopausal women's HT, including clinicians, researchers, and epidemiologists, reviewed the 2012 HT Position Statement, evaluated prior and new literature and used levels of evidence to identify the quality of the evidence and strength of the recommendations and to find consensus for the guidelines. The following information comes from the NAMS 2017 Hormone Therapy Position Statement.³

What are the major findings?

HT is the most effective treatment for vasomotor symptoms (VMS) and GSM and has been shown to prevent bone loss and fracture. Risks of HT may differ for women depending on type, dose, duration, route of administration, and timing of initiation and whether or not a progestogen is needed. Treatment should be individualized using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation about benefits and risks of continuing or discontinuing HT.

For women who are younger than age 60 or within 10 years of menopause and have no contraindication, the clearest benefit of HT is for the treatment of VMS and prevention of bone loss in those at elevated risk.

The clinical guidelines were presented to NAMS audience at the 2016 annual clinical meeting, where NAMS recommended "determining the most appropriate type, dose, formulation, and duration of HT."⁴

When to initiate HT and duration of use

In its now-published 2017 guidelines on HT, NAMS affirms the safety and efficacy of HT for symptomatic menopausal women or those at high risk for bone loss who are under age 60 or within 10 years of menopause. NAMS encourages practitioners to employ shared decision making with their patients to find the appropriate type, dose, formulation, and duration of HT, making individualized decisions based on evidence-based information, the unique health risks of women, and with periodic reassessment.

In the clinical guidelines presented in the 2016 NAMS annual meeting,⁴ key recommendations taken from the 2017 Hormone Therapy Position Statement³ include the following: For women who are aged younger than 60 years or within 10 years of menopause and have no contraindications, the benefit/risk ratio appears favorable for treatment of bothersome VMS and in those at elevated risk for bone loss or fracture.

For women who initiate HT more than 10 years from menopause or after age 60, this benefit/risk ratio appears less favorable because of greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia.

What about extended use of hormone therapy? There is no evidence to support routine discontinuation of HT after age 65. Decisions about longer durations of HT should be individualized and considered for indications such as persistent VMS or bone loss, with shared decision making, documentation, and periodic reevaluation. Longer duration is more favorable for estrogen therapy than for estrogen-progestin therapy, based on the Women's Health Initiative (WHI) randomized controlled trials.⁵

What about only vaginal symptoms? For bothersome GSM not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended and can be continued as long as indicated since there is minimal systemic absorption of estrogen, with serum levels remaining within the normal postmenopausal range.^6,7 For women with estrogen sensitive cancer, oncologists should be included in decision making, particularly for women on aromatase inhibitors.

Considerations for special populations Early menopause. For women with hypoestrogenism, primary ovarian insufficiency, or premature surgical menopause without contraindications, HT is recommended until at least the median age of menopause (52 years), as studies suggest that benefits outweigh the risks for effects on bone, heart, cognition, GSM, sexual function, and mood.⁸

Family history of breast cancer. Observational evidence suggests that use of HT does not further alter the risk for breast cancer in women with a family history of breast cancer. Family history is one risk, among others, that should be assessed when counseling women regarding HT.

Women who are BRCA-positive without breast cancer. For women who are BRCA-positive (higher genetic risk of breast cancer, primarily estrogen-receptor-negative), and have undergone surgical menopause (bilateral salpingo-oophorectomy), the benefits of estrogen to decrease health risks caused by premature loss of estrogen need to be considered on an individual basis.⁹ On the basis of limited observational studies, consider offering systemic HT until the median age of menopause (52 years) with longer use individualized.³

Related Article:
Is menopausal hormone therapy safe when your patient carries a BRCA mutation?

Survivors of endometrial and breast cancer with bothersome VMS. For women with prior estrogen-sensitive cancers, non-HTs should be considered first, particularly those agents studied through randomized controlled trials in this population and found to be effective. If systemic estrogen is considered for persistent symptoms after non-HT or complementary options have been unsuccessful, decisions should be made for compelling reasons and after detailed counseling, with shared decision making and in conjunction with their oncologist.³ 

Bothersome GSM. On the basis of limited observational data, there appears to be minimal to no demonstrated elevation in risk for recurrence of endometrial or breast cancer using low-dose vaginal estrogen,^3,10 but decisions should be made in conjunction with an oncologist.

Related Article:
Focus on treating genital atrophy symptoms
 

The importance of relaying the new guidelines to patients

It is important for clinicians to talk to women about their menopausal symptoms and their options for relief of symptoms or prevention of bone loss. Discussion should take into account age and time from menopause, include evidence-based information^11-13 about benefits and risks of different types of therapy, and employ shared decision making to choose the most appropriate therapy to maximize benefits and minimize risks for the individual woman.

Following the WHI initial release in 2002, both women and providers became fearful of HT and believed media hype and celebrities that compounded bioidentical HT was safer than FDA-approved HTs. However, compounded products lack safety and efficacy data, are not monitored or regulated by the FDA, and have unique risks associated with compounding, including concerns about sterility, impurities, and overdosing or underdosing, which could increase cancer risk.³

Read about modifying low-dose vaginal estrogen’s black box warning

Physicians continue to underwhelmingly prescribe low-dose vaginal estrogen for GSM 

Kingsberg SA, Krychman M, Graham S, Bernick B, Mirkin S. The Women's EMPOWER survey: identifying women's perceptions on vulvar and vaginal atrophy and its treatment. J Sex Med. 2017;14(3):413-424.

GSM is seriously underrecognized and undertreated.^2,8,14 It has a major impact on women's lives--a silent epidemic affecting women's quality of life, sexual health, interpersonal relationships, and even physical health in terms of increased risk of urinary tract infections and urinary symptoms. Unfortunately, patients are reluctant to mention the problem to their clinicians, and they do not clearly recognize it as a medical condition that has available treatment options. Clinicians also rarely receive adequate training in the management of this condition and how to discuss it with their patients. Given busy schedules and time constraints, addressing this topic often falls through the cracks, representing a missed opportunity for helping our patients with safe and effective treatments. In a recent study by Kingsberg and colleagues, an astoundingly low percentageof women with GSM symptoms received treatment. 

Details of the study

The study authors evaluated women's perceptions of GSM and available treatment options. US women aged 45 and older who reported GSM symptoms were surveyed. Of 1,858 women with a median age of 58 (range, 45-90), the study authors found that 50% had never used any treatment; 25% used over-the-counter medications; 18% were former users of GSM treatments; and 7% currently used prescribed GSM therapies.

When GSM was discussed, women were more likely than their clinicians to initiate the conversation. The main reason for women not mentioning their symptoms was the perception that GSM symptoms were a natural and inevitable part of aging. Hormonal products were perceived by women as having several downsides, including risk of systemic absorption, messiness of local creams, and the need to reuse an applicator. Overall, clinicians recommended vaginal estrogen therapy to only 23% and oral HTs to 18% of women.

The results of the study are consistent with results of earlier surveys of menopausal women. Although the survey included nearly 2,000 women, it has the potential for selection biases inherent to most Internet-based surveys. In addition, the respondents tended to be white and have higher socieconomic status, with limited representation from other groups.

Calls for the current boxed warning to be revised

GSM is highly prevalent among postmenopausal women; the condition has adverse effects on quality of life and sexual health.^2,8,14 Safe and effective treatments are available but are underutilized.^1,8,15,16 A current boxed warning appears on low-dose vaginal estrogen--class labeling that appears on all medications in the class of estrogen or HT, regardless of dose or route of administration. These warnings are based on findings from the WHI and other studies of systemic estrogen or estrogen plus progestin, which demonstrated a complex pattern of risks and benefits of HT (including increased risk of venous thrombosis or pulmonary embolism, stroke, and breast cancer [with estrogen plus progestin]).

These findings, however, do not appear to be relevant to low-dose vaginal estrogen, given minimal if any systemic absorption and much lower blood levels of hormones than found with systemic HT. Blood levels of estradiol with low-dose vaginal estrogen remain in the normal postmenopausal range, compared to several-fold elevations in hormone levels with systemic HT.^8,15,16 Additionally, observational studies of low-dose vaginal estrogen, as well as short-term randomized clinical trials, show no evidence of an increased risk of venous thromboembolic events, heart disease, stroke, breast cancer, or dementia--the listed possible adverse effects in the boxed warning. The current warning is based on extrapolating findings from systemic HT, which is inappropriate and not evidence-based for low-dose vaginal estrogen.¹⁵

The inappropriate boxed warning contributes to the problem of undertreatment of GSM in women by discouraging clinicians from prescribing the medication and dissuading patients from taking it even after purchase. Testimonials from many clinicians caring for these women have underscored that women will fill their prescription, but after seeing the boxed warning will often become alarmed and decide not to take the medication. Clinicians reported that patients often say at their next appointment: "No, I never took it. I got very scared when I saw the boxed warning." As a result, clinicians often have to spend a great deal of time explaining the limitations of, and lack of evidence for, the boxed warning on low-dose vaginal estrogen.

Related Article:
2016 Update on menopause
 

Recommended label revisions

A modified label, without a boxed warning, would be safer for women because the key messages would not be obscured by the large amount of irrelevant information. Our Working Group recommended that the label explain that the listed risks were found in studies of systemic HT and their relevance to low-dose vaginal estrogen is unknown. The Group also recommended that warning text should be added in bold font to advise  patients to seek medical attention if they have vaginal bleeding or spotting while taking the medication. In addition, patients who have a history of breast cancer or other hormone-sensitive cancer should discuss the use of the medication with their oncologist.   

Status update on efforts to revise label. A citizen's petition was filed in the Spring of 2016, with signatures from more than 600 clinicians and patients and representatives of medical and professional organizations endorsing a more appropriate evidence-based label for low-dose vaginal estrogen. The FDA is continuing to review and deliberate on these issues but has not yet made a final decision.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Managing diabetes is a complex undertaking, with an extensive regimen of self-care—including regular exercise, meal planning, blood glucose monitoring, medication scheduling, and multiple visits—that is critically linked to glycemic control and the prevention of complications. Incorporating all of these elements into daily life can be daunting.^1-3

In fact, nearly half of US adults with diabetes fail to meet the recommended targets.⁴ This leads to frustration, which often manifests in psychosocial problems that further hamper efforts to manage the ­disease.^5-10 The most notable is a psychosocial disorder known as diabetes distress, which affects close to 45% of persons with diabetes.^11,12

It is important to note that diabetes distress is not a psychiatric disorder; rather, it is a broad affective reaction to the stress of living with this chronic and complex disease.^13-15 By negatively affecting adherence to a self-care regimen, diabetes distress contributes to worsening glycemic control and increasing morbidity.^16-18

Recognizing that about 80% of those with diabetes are treated in primary care settings, this review is intended to call your attention to diabetes distress, alert you to brief screening tools that can easily be incorporated into clinic visits, and offer guidance in matching proposed interventions to the aspects of diabetes self-management that cause patients the greatest distress.¹⁹

DIABETES DISTRESS: WHAT IT IS, WHAT IT'S NOT

For patients with type 2 diabetes, diabetes distress centers around four main issues

• Frustration with the demands of self-care
• Apprehension about the future and the possibility of developing serious complications
• Concern about both the quality and the cost of required medical care
• Perceived lack of support from family and/or friends.^11,12,20

As mentioned earlier, diabetes distress is not a psychiatric condition and should not be confused with major depressive disorder (MDD). Here’s help in telling the difference.

For starters, a diagnosis of depression is symptom-based.¹³ MDD requires the presence of at least five of the nine symptoms defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth ed. (DSM-5)—eg, persistent feelings of worthlessness or guilt, sleep disturbances, lack of interest in normal activities—for at least two weeks.²¹ What’s more, the diagnostic criteria for MDD do not specify a cause or disease process. Nor do they distinguish between a pathological response and an expected reaction to a stressful life event.²² Further, depression measures reflect symptoms (eg, hyperglycemia), as well as stressful experiences resulting from diabetes self-care, which may contribute to the high rate of false positives or incorrect diagnoses of MDD and missed diagnoses of diabetes distress.²³

Unlike MDD, diabetes distress has a specific cause—diabetes—and can best be understood as an emotional response to a demanding health condition.¹³ And, because the source of the problem is identified, diabetes distress can be treated with specific interventions targeting the areas causing the highest levels of stress.

When a psychiatric condition and diabetes distress overlap

MDD, anxiety disorders, and diabetes distress are all common in patients with diabetes, and the co-occurrence of a psychiatric disorder and diabetes distress is high.^24,25Thus, it is important not only to identify cases of diabetes distress but also to consider comorbid depression and/or anxiety in patients with diabetes distress.

More often, though, it is the other way around, according to the Distress and Depression in Diabetes (3D) study. The researchers recently found that 84% of patients with moderate or high diabetes distress did not fulfill the criteria for MDD, but that 67% of diabetes patients with MDD also had moderate or high diabetes distress.^13,15,17,25

The data highlight the importance of screening patients with a dual diagnosis of diabetes and MDD for diabetes distress. Keep in mind that persons diagnosed with diabetes distress and a comorbid psychiatric condition may require more complex and intensive treatment than those with either diabetes distress or MDD alone.²⁵

SCREENING FOR DIABETES DISTRESS

Diabetes distress can be easily assessed using one of several patient-reported outcome measures. Six validated measures, ranging in length from one to 28 questions, are designed for use in primary care (see Table).^26-30 Some of the measures are easily accessible online; others require a subscription to MEDLINE.

Problem Areas in Diabetes (PAID). There are three versions of PAID—a 20-item screen assessing a broad range of feelings related to living with diabetes and its treatment, a five-item version (PAID-5) with high rates of sensitivity (95%) and specificity (89%), and a single-item test (PAID-1) that is highly correlated with the longer version.^26,27

Diabetes Distress Scale (DDS). This tool is available in a 17-item measure assessing diabetes distress as it relates to the emotional burden, physician-related distress, regimen-related distress, and interpersonal distress.²⁸ DDS is also available in a short form (DDS-2) with two items and a 28-item scale specifically for patients with type 1 diabetes.^29,30 T1-DDS, the only diabetes distress measure focused on this particular patient population, assesses the seven sources of distress found to be common among adults with type 1 diabetes: powerlessness, negative social perceptions, physician distress, friend/family distress, hypoglycemia distress, management distress, and eating distress.

Studies have shown that not only do those with type 1 diabetes experience different stressors compared with their type 2 counterparts, but also that they tend to experience distress differently. For patients with type 1 diabetes, for example, powerlessness ranked as the highest source of distress, followed by eating distress and hypoglycemia distress. These sources of distress differ from the regimen distress, emotional burden, interpersonal distress, and physician distress identified by those with type 2 diabetes.³⁰

HOW TO RESPOND TO DIABETES DISTRESS

Diabetes distress is easier to identify than to successfully treat. Few validated treatments for diabetes distress exist and, to our knowledge, only two studies have assessed interventions aimed at reduction of such distress.^31,32

The REDEEM trial recruited adults with type 2 diabetes and diabetes distress to participate in a 12-month randomized controlled trial (RCT).³¹ The trial had three arms, comparing the effectiveness of a computer-assisted self-management (CASM) program alone, a CASM program plus in-person diabetes distress­–specific problem-solving therapy, and a computer-assisted minimally supportive intervention. The main outcomes included diabetes distress (using the DDS scale and subscales), self-management behaviors, and A1C.

Participants in all three arms showed significant reductions in total diabetes distress and improvements in self-management behaviors, with no significant differences among the groups. No differences in A1C were found. However, those in the CASM program plus distress-specific therapy arm showed a larger reduction in regimen distress compared with the other two groups.³¹

The DIAMOS trial recruited adults who had type 1 or type 2 diabetes, diabetes distress, and subclinical depressive symptoms for a two-arm RCT.³² One group underwent cognitive behavioral interventions, while the controls had standard group-based diabetes education. The main outcomes included diabetes distress (measured via the PAID scale), depressive symptoms, well-being, diabetes self-care, diabetes acceptance, satisfaction with diabetes treatment, A1C, and subclinical inflammation.

The intervention group showed greater improvement in diabetes distress and depressive symptoms compared with the control group, but no differences in well-being, self-care, treatment satisfaction, A1C, or subclinical inflammation were observed.³²

Both studies support the use of problem-solving therapy and cognitive behavioral interventions for patients with diabetes distress. Future research should evaluate the effectiveness of these interventions in the primary care setting.

What else to offer when challenges mount?

Diabetes is a progressive disease, and most patients experience multiple challenges over time. These typically include complications and comorbidities, physical limitations, polypharmacy, hypoglycemia, and cognitive impairment, as well as changes in everything from medication and lifestyle to insurance coverage and social support.^33,34 All increase the risk for diabetes distress, as well as related psychiatric conditions.

Aging and diabetes are independent risk factors for cognitive impairment, for example, and the presence of both increases this risk.³⁵ What’s more, diabetes alone is associated with poorer executive function, the higher-level cognitive processes that allow individuals to engage in independent, purposeful, and flexible goal-related behaviors.^36-38 Both poor cognitive function and impaired executive function interfere with the ability to perform self-care behaviors such as adjusting insulin doses, drawing insulin into a syringe, or dialing an insulin dose with an insulin pen.³⁹ This in turn can lead to frustration and increase the likelihood of moderate to high diabetes distress.

Assessing diabetes distress in patients with cognitive impairment, poor executive functioning, or other psychological limitations is particularly difficult, however, as no diabetes distress measures take such deficits into account. Thus, primary care providers without expertise in neuropsychology should consider referring patients with such problems to specialists for assessment.

The progressive nature of diabetes also highlights the need for primary care providers to periodically screen for diabetes distress and engage in ongoing discussions about what type of care is best for individual patients, and why. When developing or updating treatment plans and making recommendations, it is crucial to consider the impact the treatment would likely have on the patient’s physical and mental health and to explicitly inquire about and acknowledge his or her values and preferences for care.^40-44

It is also important to remain aware of socioeconomic changes—in employment, insurance coverage, and living situations, for example—which are not addressed in the screening tools.

Moderate to high diabetes distress scores, as well as individual items patients identify as “very serious” problems, represent clinical red flags that should be the focus of careful discussion during a medical visit. Patients with moderate to high distress should be referred to a therapist trained in cognitive behavioral therapy or problem-solving therapy. Clinicians who lack access to such resources can incorporate cognitive behavioral and problem-solving techniques into patient discussions. (See “Directing Help Where It’s Most Needed.”) All patients should be referred to a certified diabetes educator—a key component of diabetes care.^45,46

Managing diabetes is a complex undertaking, with an extensive regimen of self-care—including regular exercise, meal planning, blood glucose monitoring, medication scheduling, and multiple visits—that is critically linked to glycemic control and the prevention of complications. Incorporating all of these elements into daily life can be daunting.^1-3

In fact, nearly half of US adults with diabetes fail to meet the recommended targets.⁴ This leads to frustration, which often manifests in psychosocial problems that further hamper efforts to manage the ­disease.^5-10 The most notable is a psychosocial disorder known as diabetes distress, which affects close to 45% of persons with diabetes.^11,12

It is important to note that diabetes distress is not a psychiatric disorder; rather, it is a broad affective reaction to the stress of living with this chronic and complex disease.^13-15 By negatively affecting adherence to a self-care regimen, diabetes distress contributes to worsening glycemic control and increasing morbidity.^16-18

Recognizing that about 80% of those with diabetes are treated in primary care settings, this review is intended to call your attention to diabetes distress, alert you to brief screening tools that can easily be incorporated into clinic visits, and offer guidance in matching proposed interventions to the aspects of diabetes self-management that cause patients the greatest distress.¹⁹

DIABETES DISTRESS: WHAT IT IS, WHAT IT'S NOT

For patients with type 2 diabetes, diabetes distress centers around four main issues

• Frustration with the demands of self-care
• Apprehension about the future and the possibility of developing serious complications
• Concern about both the quality and the cost of required medical care
• Perceived lack of support from family and/or friends.^11,12,20

As mentioned earlier, diabetes distress is not a psychiatric condition and should not be confused with major depressive disorder (MDD). Here’s help in telling the difference.

For starters, a diagnosis of depression is symptom-based.¹³ MDD requires the presence of at least five of the nine symptoms defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth ed. (DSM-5)—eg, persistent feelings of worthlessness or guilt, sleep disturbances, lack of interest in normal activities—for at least two weeks.²¹ What’s more, the diagnostic criteria for MDD do not specify a cause or disease process. Nor do they distinguish between a pathological response and an expected reaction to a stressful life event.²² Further, depression measures reflect symptoms (eg, hyperglycemia), as well as stressful experiences resulting from diabetes self-care, which may contribute to the high rate of false positives or incorrect diagnoses of MDD and missed diagnoses of diabetes distress.²³

Unlike MDD, diabetes distress has a specific cause—diabetes—and can best be understood as an emotional response to a demanding health condition.¹³ And, because the source of the problem is identified, diabetes distress can be treated with specific interventions targeting the areas causing the highest levels of stress.

When a psychiatric condition and diabetes distress overlap

MDD, anxiety disorders, and diabetes distress are all common in patients with diabetes, and the co-occurrence of a psychiatric disorder and diabetes distress is high.^24,25Thus, it is important not only to identify cases of diabetes distress but also to consider comorbid depression and/or anxiety in patients with diabetes distress.

More often, though, it is the other way around, according to the Distress and Depression in Diabetes (3D) study. The researchers recently found that 84% of patients with moderate or high diabetes distress did not fulfill the criteria for MDD, but that 67% of diabetes patients with MDD also had moderate or high diabetes distress.^13,15,17,25

The data highlight the importance of screening patients with a dual diagnosis of diabetes and MDD for diabetes distress. Keep in mind that persons diagnosed with diabetes distress and a comorbid psychiatric condition may require more complex and intensive treatment than those with either diabetes distress or MDD alone.²⁵

SCREENING FOR DIABETES DISTRESS

Diabetes distress can be easily assessed using one of several patient-reported outcome measures. Six validated measures, ranging in length from one to 28 questions, are designed for use in primary care (see Table).^26-30 Some of the measures are easily accessible online; others require a subscription to MEDLINE.

Problem Areas in Diabetes (PAID). There are three versions of PAID—a 20-item screen assessing a broad range of feelings related to living with diabetes and its treatment, a five-item version (PAID-5) with high rates of sensitivity (95%) and specificity (89%), and a single-item test (PAID-1) that is highly correlated with the longer version.^26,27

Diabetes Distress Scale (DDS). This tool is available in a 17-item measure assessing diabetes distress as it relates to the emotional burden, physician-related distress, regimen-related distress, and interpersonal distress.²⁸ DDS is also available in a short form (DDS-2) with two items and a 28-item scale specifically for patients with type 1 diabetes.^29,30 T1-DDS, the only diabetes distress measure focused on this particular patient population, assesses the seven sources of distress found to be common among adults with type 1 diabetes: powerlessness, negative social perceptions, physician distress, friend/family distress, hypoglycemia distress, management distress, and eating distress.

Studies have shown that not only do those with type 1 diabetes experience different stressors compared with their type 2 counterparts, but also that they tend to experience distress differently. For patients with type 1 diabetes, for example, powerlessness ranked as the highest source of distress, followed by eating distress and hypoglycemia distress. These sources of distress differ from the regimen distress, emotional burden, interpersonal distress, and physician distress identified by those with type 2 diabetes.³⁰

HOW TO RESPOND TO DIABETES DISTRESS

Diabetes distress is easier to identify than to successfully treat. Few validated treatments for diabetes distress exist and, to our knowledge, only two studies have assessed interventions aimed at reduction of such distress.^31,32

The REDEEM trial recruited adults with type 2 diabetes and diabetes distress to participate in a 12-month randomized controlled trial (RCT).³¹ The trial had three arms, comparing the effectiveness of a computer-assisted self-management (CASM) program alone, a CASM program plus in-person diabetes distress­–specific problem-solving therapy, and a computer-assisted minimally supportive intervention. The main outcomes included diabetes distress (using the DDS scale and subscales), self-management behaviors, and A1C.

Participants in all three arms showed significant reductions in total diabetes distress and improvements in self-management behaviors, with no significant differences among the groups. No differences in A1C were found. However, those in the CASM program plus distress-specific therapy arm showed a larger reduction in regimen distress compared with the other two groups.³¹

The DIAMOS trial recruited adults who had type 1 or type 2 diabetes, diabetes distress, and subclinical depressive symptoms for a two-arm RCT.³² One group underwent cognitive behavioral interventions, while the controls had standard group-based diabetes education. The main outcomes included diabetes distress (measured via the PAID scale), depressive symptoms, well-being, diabetes self-care, diabetes acceptance, satisfaction with diabetes treatment, A1C, and subclinical inflammation.

The intervention group showed greater improvement in diabetes distress and depressive symptoms compared with the control group, but no differences in well-being, self-care, treatment satisfaction, A1C, or subclinical inflammation were observed.³²

Both studies support the use of problem-solving therapy and cognitive behavioral interventions for patients with diabetes distress. Future research should evaluate the effectiveness of these interventions in the primary care setting.

What else to offer when challenges mount?

Diabetes is a progressive disease, and most patients experience multiple challenges over time. These typically include complications and comorbidities, physical limitations, polypharmacy, hypoglycemia, and cognitive impairment, as well as changes in everything from medication and lifestyle to insurance coverage and social support.^33,34 All increase the risk for diabetes distress, as well as related psychiatric conditions.

Aging and diabetes are independent risk factors for cognitive impairment, for example, and the presence of both increases this risk.³⁵ What’s more, diabetes alone is associated with poorer executive function, the higher-level cognitive processes that allow individuals to engage in independent, purposeful, and flexible goal-related behaviors.^36-38 Both poor cognitive function and impaired executive function interfere with the ability to perform self-care behaviors such as adjusting insulin doses, drawing insulin into a syringe, or dialing an insulin dose with an insulin pen.³⁹ This in turn can lead to frustration and increase the likelihood of moderate to high diabetes distress.

Assessing diabetes distress in patients with cognitive impairment, poor executive functioning, or other psychological limitations is particularly difficult, however, as no diabetes distress measures take such deficits into account. Thus, primary care providers without expertise in neuropsychology should consider referring patients with such problems to specialists for assessment.

The progressive nature of diabetes also highlights the need for primary care providers to periodically screen for diabetes distress and engage in ongoing discussions about what type of care is best for individual patients, and why. When developing or updating treatment plans and making recommendations, it is crucial to consider the impact the treatment would likely have on the patient’s physical and mental health and to explicitly inquire about and acknowledge his or her values and preferences for care.^40-44

It is also important to remain aware of socioeconomic changes—in employment, insurance coverage, and living situations, for example—which are not addressed in the screening tools.

Moderate to high diabetes distress scores, as well as individual items patients identify as “very serious” problems, represent clinical red flags that should be the focus of careful discussion during a medical visit. Patients with moderate to high distress should be referred to a therapist trained in cognitive behavioral therapy or problem-solving therapy. Clinicians who lack access to such resources can incorporate cognitive behavioral and problem-solving techniques into patient discussions. (See “Directing Help Where It’s Most Needed.”) All patients should be referred to a certified diabetes educator—a key component of diabetes care.^45,46

Managing diabetes is a complex undertaking, with an extensive regimen of self-care—including regular exercise, meal planning, blood glucose monitoring, medication scheduling, and multiple visits—that is critically linked to glycemic control and the prevention of complications. Incorporating all of these elements into daily life can be daunting.^1-3

In fact, nearly half of US adults with diabetes fail to meet the recommended targets.⁴ This leads to frustration, which often manifests in psychosocial problems that further hamper efforts to manage the ­disease.^5-10 The most notable is a psychosocial disorder known as diabetes distress, which affects close to 45% of persons with diabetes.^11,12

It is important to note that diabetes distress is not a psychiatric disorder; rather, it is a broad affective reaction to the stress of living with this chronic and complex disease.^13-15 By negatively affecting adherence to a self-care regimen, diabetes distress contributes to worsening glycemic control and increasing morbidity.^16-18

Recognizing that about 80% of those with diabetes are treated in primary care settings, this review is intended to call your attention to diabetes distress, alert you to brief screening tools that can easily be incorporated into clinic visits, and offer guidance in matching proposed interventions to the aspects of diabetes self-management that cause patients the greatest distress.¹⁹

DIABETES DISTRESS: WHAT IT IS, WHAT IT'S NOT

For patients with type 2 diabetes, diabetes distress centers around four main issues

• Frustration with the demands of self-care
• Apprehension about the future and the possibility of developing serious complications
• Concern about both the quality and the cost of required medical care
• Perceived lack of support from family and/or friends.^11,12,20

As mentioned earlier, diabetes distress is not a psychiatric condition and should not be confused with major depressive disorder (MDD). Here’s help in telling the difference.

For starters, a diagnosis of depression is symptom-based.¹³ MDD requires the presence of at least five of the nine symptoms defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth ed. (DSM-5)—eg, persistent feelings of worthlessness or guilt, sleep disturbances, lack of interest in normal activities—for at least two weeks.²¹ What’s more, the diagnostic criteria for MDD do not specify a cause or disease process. Nor do they distinguish between a pathological response and an expected reaction to a stressful life event.²² Further, depression measures reflect symptoms (eg, hyperglycemia), as well as stressful experiences resulting from diabetes self-care, which may contribute to the high rate of false positives or incorrect diagnoses of MDD and missed diagnoses of diabetes distress.²³

Unlike MDD, diabetes distress has a specific cause—diabetes—and can best be understood as an emotional response to a demanding health condition.¹³ And, because the source of the problem is identified, diabetes distress can be treated with specific interventions targeting the areas causing the highest levels of stress.

When a psychiatric condition and diabetes distress overlap

MDD, anxiety disorders, and diabetes distress are all common in patients with diabetes, and the co-occurrence of a psychiatric disorder and diabetes distress is high.^24,25Thus, it is important not only to identify cases of diabetes distress but also to consider comorbid depression and/or anxiety in patients with diabetes distress.

More often, though, it is the other way around, according to the Distress and Depression in Diabetes (3D) study. The researchers recently found that 84% of patients with moderate or high diabetes distress did not fulfill the criteria for MDD, but that 67% of diabetes patients with MDD also had moderate or high diabetes distress.^13,15,17,25

The data highlight the importance of screening patients with a dual diagnosis of diabetes and MDD for diabetes distress. Keep in mind that persons diagnosed with diabetes distress and a comorbid psychiatric condition may require more complex and intensive treatment than those with either diabetes distress or MDD alone.²⁵

SCREENING FOR DIABETES DISTRESS

Diabetes distress can be easily assessed using one of several patient-reported outcome measures. Six validated measures, ranging in length from one to 28 questions, are designed for use in primary care (see Table).^26-30 Some of the measures are easily accessible online; others require a subscription to MEDLINE.

Problem Areas in Diabetes (PAID). There are three versions of PAID—a 20-item screen assessing a broad range of feelings related to living with diabetes and its treatment, a five-item version (PAID-5) with high rates of sensitivity (95%) and specificity (89%), and a single-item test (PAID-1) that is highly correlated with the longer version.^26,27

Diabetes Distress Scale (DDS). This tool is available in a 17-item measure assessing diabetes distress as it relates to the emotional burden, physician-related distress, regimen-related distress, and interpersonal distress.²⁸ DDS is also available in a short form (DDS-2) with two items and a 28-item scale specifically for patients with type 1 diabetes.^29,30 T1-DDS, the only diabetes distress measure focused on this particular patient population, assesses the seven sources of distress found to be common among adults with type 1 diabetes: powerlessness, negative social perceptions, physician distress, friend/family distress, hypoglycemia distress, management distress, and eating distress.

Studies have shown that not only do those with type 1 diabetes experience different stressors compared with their type 2 counterparts, but also that they tend to experience distress differently. For patients with type 1 diabetes, for example, powerlessness ranked as the highest source of distress, followed by eating distress and hypoglycemia distress. These sources of distress differ from the regimen distress, emotional burden, interpersonal distress, and physician distress identified by those with type 2 diabetes.³⁰

HOW TO RESPOND TO DIABETES DISTRESS

Diabetes distress is easier to identify than to successfully treat. Few validated treatments for diabetes distress exist and, to our knowledge, only two studies have assessed interventions aimed at reduction of such distress.^31,32

The REDEEM trial recruited adults with type 2 diabetes and diabetes distress to participate in a 12-month randomized controlled trial (RCT).³¹ The trial had three arms, comparing the effectiveness of a computer-assisted self-management (CASM) program alone, a CASM program plus in-person diabetes distress­–specific problem-solving therapy, and a computer-assisted minimally supportive intervention. The main outcomes included diabetes distress (using the DDS scale and subscales), self-management behaviors, and A1C.

Participants in all three arms showed significant reductions in total diabetes distress and improvements in self-management behaviors, with no significant differences among the groups. No differences in A1C were found. However, those in the CASM program plus distress-specific therapy arm showed a larger reduction in regimen distress compared with the other two groups.³¹

The DIAMOS trial recruited adults who had type 1 or type 2 diabetes, diabetes distress, and subclinical depressive symptoms for a two-arm RCT.³² One group underwent cognitive behavioral interventions, while the controls had standard group-based diabetes education. The main outcomes included diabetes distress (measured via the PAID scale), depressive symptoms, well-being, diabetes self-care, diabetes acceptance, satisfaction with diabetes treatment, A1C, and subclinical inflammation.

The intervention group showed greater improvement in diabetes distress and depressive symptoms compared with the control group, but no differences in well-being, self-care, treatment satisfaction, A1C, or subclinical inflammation were observed.³²

Both studies support the use of problem-solving therapy and cognitive behavioral interventions for patients with diabetes distress. Future research should evaluate the effectiveness of these interventions in the primary care setting.

What else to offer when challenges mount?

Diabetes is a progressive disease, and most patients experience multiple challenges over time. These typically include complications and comorbidities, physical limitations, polypharmacy, hypoglycemia, and cognitive impairment, as well as changes in everything from medication and lifestyle to insurance coverage and social support.^33,34 All increase the risk for diabetes distress, as well as related psychiatric conditions.

Aging and diabetes are independent risk factors for cognitive impairment, for example, and the presence of both increases this risk.³⁵ What’s more, diabetes alone is associated with poorer executive function, the higher-level cognitive processes that allow individuals to engage in independent, purposeful, and flexible goal-related behaviors.^36-38 Both poor cognitive function and impaired executive function interfere with the ability to perform self-care behaviors such as adjusting insulin doses, drawing insulin into a syringe, or dialing an insulin dose with an insulin pen.³⁹ This in turn can lead to frustration and increase the likelihood of moderate to high diabetes distress.

Assessing diabetes distress in patients with cognitive impairment, poor executive functioning, or other psychological limitations is particularly difficult, however, as no diabetes distress measures take such deficits into account. Thus, primary care providers without expertise in neuropsychology should consider referring patients with such problems to specialists for assessment.

The progressive nature of diabetes also highlights the need for primary care providers to periodically screen for diabetes distress and engage in ongoing discussions about what type of care is best for individual patients, and why. When developing or updating treatment plans and making recommendations, it is crucial to consider the impact the treatment would likely have on the patient’s physical and mental health and to explicitly inquire about and acknowledge his or her values and preferences for care.^40-44

It is also important to remain aware of socioeconomic changes—in employment, insurance coverage, and living situations, for example—which are not addressed in the screening tools.

Moderate to high diabetes distress scores, as well as individual items patients identify as “very serious” problems, represent clinical red flags that should be the focus of careful discussion during a medical visit. Patients with moderate to high distress should be referred to a therapist trained in cognitive behavioral therapy or problem-solving therapy. Clinicians who lack access to such resources can incorporate cognitive behavioral and problem-solving techniques into patient discussions. (See “Directing Help Where It’s Most Needed.”) All patients should be referred to a certified diabetes educator—a key component of diabetes care.^45,46

IN THIS ARTICLE

• Diagnosis
• Treatment/management
• Physcial signs suggestive of CVID in patients with appropriate history
• Case outcome

A 60-year-old woman with a recent history of air and cruise ship travel presented with symptoms consistent with acute sinusitis. She had a 34–pack-year history of cigarette smoking but had quit at age 50. Her medical history was significant for hypothyroidism, hypertension, coronary artery disease, mild asthma, and COPD. Past surgical history included coronary artery bypass, abdominal hysterectomy, and cholecystectomy. Her medications included inhaled bronchodilators, thyroxin, hydrochlorothiazide, nitrates, ß-blockers, and calcium channel blockers.

Over the next five years, she presented with frequent episodes of respiratory illness for which she received multiple courses of antibiotics, inhaled bronchodilators, and oral as well as inhaled corticosteroids. She consequently became increasingly sensitized to multiple antibiotic classes and was frequently hospitalized for the treatment of her respiratory illnesses.

Common variable immunodeficiency disorders (collectively known as CVID) are the most common clinically significant immunodeficiency diseases among adults.¹ Manifesting clinically as frequent, unusually severe or recalcitrant bacterial infections of the ear, sinus, respiratory tree, and/or gastrointestinal tract, CVID is genetically induced.² Additionally, these disorders can predispose individuals to autoimmune conditions and to cancers involving B lymphocytes.³ Often thought to be a disease of younger people, CVID can occur across the age span.⁴

The immune dysfunction that characterizes CVID is believed to result from underlying genetic defects that affect the differentiation of B cells, leading to faulty immunoglobulin (Ig) synthesis. Recent advances that allow the detection of multiple novel susceptibility loci for CVID have dramatically increased our understanding of the pathophysiology and pathogenesis of this disorder.⁵ These advances are being used to refine the diagnostic parameters of CVID and in the future may help clinicians tailor treatment protocols to specific genetic defects.^5,6

Although considered rare, CVID is often unrecognized; the incidence is likely much higher than the current estimates of 1:10,000 to 1:50,000.⁷ About 13% to 23% of individuals with chronic sinusitis are thought to be affected by CVID.⁸ While it is most commonly diagnosed during the second and third decades of life, it can be diagnosed at any time during the lifespan.⁴ A high burden of disease is associated with this disorder, as hospitalizations and costly, aggressive treatment regimens are needed to manage the resultant bacterial infections and sequelae.²

Increased awareness of CVID among primary care providers is needed to assure prompt diagnosis and to avoid unnecessary complications associated with delayed treatment. The diagnostic workup is complex, and referral to immunology for specific diagnosis and treatment is strongly advised. Recognition is the first step, and primary care providers must include primary immunodeficiency disorders, including CVID, in their differential to avert a missed diagnosis and to ensure optimal treatment.⁹

CLINICAL MANIFESTATIONS/PATIENT HISTORY

Frequent and severe infections are a hallmark of CVID. The most common types of infections seen in CVID are sinusitis, conjunctivitis, otitis media, bronchitis, pneumonia, and gastroenteritis.¹⁰ These primary bacterial infections can disseminate, causing septicemia and/or central nervous system infection.¹¹ The usual infectious pathogens are encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, but atypical infections due to organisms such as Pneumocystis carinii and Mycoplasma pneumoniae also occur in some patients.^12,13

Although the majority of CVID cases occur sporadically, family history is helpful in securing the correct diagnosis.¹⁵ Known immunodeficiency, unusual susceptibility to infections, autoimmune diseases, hematologic malignancy, or death caused by infection in other family members should increase the provider’s index of suspicion for CVID.¹⁶

Many genetic defects have been implicated in CVID, yet the wide phenotypic expression found even in persons with similar genetic profiles implies that CVID has a complex genetic transmission pattern.¹⁵ Known or suspected consanguinity in parents or grandparents increases the risk for CVID.⁶

Although these family history elements occur infrequently, they increase the likelihood of severe opportunistic infection, which can cause organ damage or even death.^1,17 Being alert for these elements of family history can help to avoid delays in diagnosis and treatment and eventual organ damage.²

DIFFERENTIAL DIAGNOSIS

When considering the differential diagnosis for the primary features of CVID, other etiologies that should be considered include allergies, environmental exposures, uncontrolled gastroesophageal reflux disease, structural abnormalities of the upper respiratory tract, and celiac disease.^5,10,18,19 Far less common but still worthy of consideration are other genetic conditions, such as primary ciliary dyskinesia, cystic fibrosis, thymic dysfunction or carcinoma, and protein-losing enteropathies.^20,21

A number of conditions can cause immunosuppression. Transient reductions in serum Ig levels can occur in the presence of serious infections.²² Long-term, high-dose use of some medications, such as corticosteroids, or use of anticonvulsants may reduce antibody availability. Chronic illnesses, malignancy, and malnutrition can also play a role in immunosuppression.¹⁹ CVID shares features with a large number of primary immune diseases, and these as well as other causes of hypogammaglobulinemia must be excluded before the diagnosis of CVID can be made.¹

DIAGNOSIS

While infectious disease is a common reason patients seek medical care, few patients presenting with one will have CVID. Nevertheless, immunologic evaluations should be performed and appropriate referral to an immunology specialist is strongly recommended when more than one severe infection arises in a year’s time; when a pattern of severe or unusual infections presents over a period of time; when bronchiectasis is present; or when infections do not resolve with conventional treatment.¹⁶ In addition, the physical findings noted in the Table, when combined with a history of recurrent infections, autoimmune disorders, or lymphocytic malignancy, should prompt evaluation for CVID.^10,16,18,23

The diagnosis of CVID requires testing for low serum levels of total IgG, IgG subclasses, IgA, and IgM. In CVID, IgG and IgA levels will be reduced, and occasionally IgM levels will also be diminished.²⁴ Unless an active infection is present, there will be no change in the patient’s routine blood tests, such as the complete blood count and total complement levels.

The diagnosis is also based on demonstration of a deficient antibody response to protein (tetanus) and polysaccharide (pneumonia) vaccine antigens.²¹ A minimal reaction to these vaccines should prompt referral to an immunology specialist for additional testing and a plan of care.²⁵ However, whenever the index of suspicion for CVID is high, prompt referral to immunology should not be delayed to perform further testing.¹⁶

TREATMENT/MANAGEMENT

IgG replacement therapy, which treats the underlying pathophysiology of CVID by supplementing one of the deficient antibodies, is the standard treatment for CVID. IgG is considered a blood product since it is made from human plasma. Patients may experience untoward reactions to IgG replacement therapy, similar to transfusion reactions; such reactions commonly include back pain, low-grade fever, muscle and joint discomfort, and fatigue. These unpleasant effects can be minimized with the prophylactic use of antihistamines, antipyretics, or even glucocorticoids.²⁶

Although IgG replacement therapy has high upfront costs, it increases patients’ well-being considerably by preventing multiple or recurrent infections and the resultant hospitalizations for antibiotic therapy.²⁷ Home infusion of IgG can minimize costs as well as increase patient autonomy.²⁸ With home infusions, IgG is administered via a multisite subcutaneous route using a slow-infusion mechanical pump. Subcutaneous infusions generally take four to six hours, depending on the number of sites used. Some patients can infuse while they sleep, which increases patient satisfaction with the treatment.²⁷

Infections in persons with CVID can be severe and may lead to organ-system compromise, requiring aggressive therapy aimed at supporting the function of the affected organ systems. For example, patients with CVID can develop unrelenting vomiting and diarrhea, which may require inpatient admission for rehydration and stabilization until the infection can be treated adequately.³²

Treatment options remain limited for the subset of CVID patients who develop severe complications, such as interstitial lung disease or neoplasms. These complications are associated with a significant increase in patient mortality, and allogeneic hematopoietic stem cell transplantation may be indicated for patients who develop them. This potentially curative treatment is being explored in ongoing research trials.³³

PATIENT EDUCATION

Scrupulous hand hygiene, careful avoidance of infectious exposures, watchful food handling and preparation, and lifestyle choices that support good general health are key elements of self-care for patients who have CVID. Preventive measures serve this population well by helping to reduce some of the complications of this serious disease.

Patients with CVID should understand keys aspects regarding its diagnosis, treatment, and prognosis. Specifically, they should know that people who have CVID are born missing some of the body’s immune defenses, which increases their risk for infection, especially of the sinuses, lungs, and gut. Sometimes it takes years to make this diagnosis, because it is a rare cause of common symptoms.

The patient was referred to immunology, and a diagnosis of CVID was made. She was successfully treated with subcutaneous IgG replacement therapy. She died due to overwhelming sepsis after an episode of pneumonia at age 84.

CONCLUSION

The secret to prompt detection of CVID is adding it to the differential diagnosis of recurrent infections. Timely recognition and appropriate referral prevent serious complications, since successful treatment options are available.

Special thanks to Doug Bartelt, DNP, APNP, NP-C.

IN THIS ARTICLE

• Diagnosis
• Treatment/management
• Physcial signs suggestive of CVID in patients with appropriate history
• Case outcome

A 60-year-old woman with a recent history of air and cruise ship travel presented with symptoms consistent with acute sinusitis. She had a 34–pack-year history of cigarette smoking but had quit at age 50. Her medical history was significant for hypothyroidism, hypertension, coronary artery disease, mild asthma, and COPD. Past surgical history included coronary artery bypass, abdominal hysterectomy, and cholecystectomy. Her medications included inhaled bronchodilators, thyroxin, hydrochlorothiazide, nitrates, ß-blockers, and calcium channel blockers.

Over the next five years, she presented with frequent episodes of respiratory illness for which she received multiple courses of antibiotics, inhaled bronchodilators, and oral as well as inhaled corticosteroids. She consequently became increasingly sensitized to multiple antibiotic classes and was frequently hospitalized for the treatment of her respiratory illnesses.

Common variable immunodeficiency disorders (collectively known as CVID) are the most common clinically significant immunodeficiency diseases among adults.¹ Manifesting clinically as frequent, unusually severe or recalcitrant bacterial infections of the ear, sinus, respiratory tree, and/or gastrointestinal tract, CVID is genetically induced.² Additionally, these disorders can predispose individuals to autoimmune conditions and to cancers involving B lymphocytes.³ Often thought to be a disease of younger people, CVID can occur across the age span.⁴

The immune dysfunction that characterizes CVID is believed to result from underlying genetic defects that affect the differentiation of B cells, leading to faulty immunoglobulin (Ig) synthesis. Recent advances that allow the detection of multiple novel susceptibility loci for CVID have dramatically increased our understanding of the pathophysiology and pathogenesis of this disorder.⁵ These advances are being used to refine the diagnostic parameters of CVID and in the future may help clinicians tailor treatment protocols to specific genetic defects.^5,6

Although considered rare, CVID is often unrecognized; the incidence is likely much higher than the current estimates of 1:10,000 to 1:50,000.⁷ About 13% to 23% of individuals with chronic sinusitis are thought to be affected by CVID.⁸ While it is most commonly diagnosed during the second and third decades of life, it can be diagnosed at any time during the lifespan.⁴ A high burden of disease is associated with this disorder, as hospitalizations and costly, aggressive treatment regimens are needed to manage the resultant bacterial infections and sequelae.²

Increased awareness of CVID among primary care providers is needed to assure prompt diagnosis and to avoid unnecessary complications associated with delayed treatment. The diagnostic workup is complex, and referral to immunology for specific diagnosis and treatment is strongly advised. Recognition is the first step, and primary care providers must include primary immunodeficiency disorders, including CVID, in their differential to avert a missed diagnosis and to ensure optimal treatment.⁹

CLINICAL MANIFESTATIONS/PATIENT HISTORY

Frequent and severe infections are a hallmark of CVID. The most common types of infections seen in CVID are sinusitis, conjunctivitis, otitis media, bronchitis, pneumonia, and gastroenteritis.¹⁰ These primary bacterial infections can disseminate, causing septicemia and/or central nervous system infection.¹¹ The usual infectious pathogens are encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, but atypical infections due to organisms such as Pneumocystis carinii and Mycoplasma pneumoniae also occur in some patients.^12,13

Although the majority of CVID cases occur sporadically, family history is helpful in securing the correct diagnosis.¹⁵ Known immunodeficiency, unusual susceptibility to infections, autoimmune diseases, hematologic malignancy, or death caused by infection in other family members should increase the provider’s index of suspicion for CVID.¹⁶

Many genetic defects have been implicated in CVID, yet the wide phenotypic expression found even in persons with similar genetic profiles implies that CVID has a complex genetic transmission pattern.¹⁵ Known or suspected consanguinity in parents or grandparents increases the risk for CVID.⁶

Although these family history elements occur infrequently, they increase the likelihood of severe opportunistic infection, which can cause organ damage or even death.^1,17 Being alert for these elements of family history can help to avoid delays in diagnosis and treatment and eventual organ damage.²

DIFFERENTIAL DIAGNOSIS

When considering the differential diagnosis for the primary features of CVID, other etiologies that should be considered include allergies, environmental exposures, uncontrolled gastroesophageal reflux disease, structural abnormalities of the upper respiratory tract, and celiac disease.^5,10,18,19 Far less common but still worthy of consideration are other genetic conditions, such as primary ciliary dyskinesia, cystic fibrosis, thymic dysfunction or carcinoma, and protein-losing enteropathies.^20,21

A number of conditions can cause immunosuppression. Transient reductions in serum Ig levels can occur in the presence of serious infections.²² Long-term, high-dose use of some medications, such as corticosteroids, or use of anticonvulsants may reduce antibody availability. Chronic illnesses, malignancy, and malnutrition can also play a role in immunosuppression.¹⁹ CVID shares features with a large number of primary immune diseases, and these as well as other causes of hypogammaglobulinemia must be excluded before the diagnosis of CVID can be made.¹

DIAGNOSIS

While infectious disease is a common reason patients seek medical care, few patients presenting with one will have CVID. Nevertheless, immunologic evaluations should be performed and appropriate referral to an immunology specialist is strongly recommended when more than one severe infection arises in a year’s time; when a pattern of severe or unusual infections presents over a period of time; when bronchiectasis is present; or when infections do not resolve with conventional treatment.¹⁶ In addition, the physical findings noted in the Table, when combined with a history of recurrent infections, autoimmune disorders, or lymphocytic malignancy, should prompt evaluation for CVID.^10,16,18,23

The diagnosis of CVID requires testing for low serum levels of total IgG, IgG subclasses, IgA, and IgM. In CVID, IgG and IgA levels will be reduced, and occasionally IgM levels will also be diminished.²⁴ Unless an active infection is present, there will be no change in the patient’s routine blood tests, such as the complete blood count and total complement levels.

The diagnosis is also based on demonstration of a deficient antibody response to protein (tetanus) and polysaccharide (pneumonia) vaccine antigens.²¹ A minimal reaction to these vaccines should prompt referral to an immunology specialist for additional testing and a plan of care.²⁵ However, whenever the index of suspicion for CVID is high, prompt referral to immunology should not be delayed to perform further testing.¹⁶

TREATMENT/MANAGEMENT

IgG replacement therapy, which treats the underlying pathophysiology of CVID by supplementing one of the deficient antibodies, is the standard treatment for CVID. IgG is considered a blood product since it is made from human plasma. Patients may experience untoward reactions to IgG replacement therapy, similar to transfusion reactions; such reactions commonly include back pain, low-grade fever, muscle and joint discomfort, and fatigue. These unpleasant effects can be minimized with the prophylactic use of antihistamines, antipyretics, or even glucocorticoids.²⁶

Although IgG replacement therapy has high upfront costs, it increases patients’ well-being considerably by preventing multiple or recurrent infections and the resultant hospitalizations for antibiotic therapy.²⁷ Home infusion of IgG can minimize costs as well as increase patient autonomy.²⁸ With home infusions, IgG is administered via a multisite subcutaneous route using a slow-infusion mechanical pump. Subcutaneous infusions generally take four to six hours, depending on the number of sites used. Some patients can infuse while they sleep, which increases patient satisfaction with the treatment.²⁷

Infections in persons with CVID can be severe and may lead to organ-system compromise, requiring aggressive therapy aimed at supporting the function of the affected organ systems. For example, patients with CVID can develop unrelenting vomiting and diarrhea, which may require inpatient admission for rehydration and stabilization until the infection can be treated adequately.³²

Treatment options remain limited for the subset of CVID patients who develop severe complications, such as interstitial lung disease or neoplasms. These complications are associated with a significant increase in patient mortality, and allogeneic hematopoietic stem cell transplantation may be indicated for patients who develop them. This potentially curative treatment is being explored in ongoing research trials.³³

PATIENT EDUCATION

Scrupulous hand hygiene, careful avoidance of infectious exposures, watchful food handling and preparation, and lifestyle choices that support good general health are key elements of self-care for patients who have CVID. Preventive measures serve this population well by helping to reduce some of the complications of this serious disease.

Patients with CVID should understand keys aspects regarding its diagnosis, treatment, and prognosis. Specifically, they should know that people who have CVID are born missing some of the body’s immune defenses, which increases their risk for infection, especially of the sinuses, lungs, and gut. Sometimes it takes years to make this diagnosis, because it is a rare cause of common symptoms.

The patient was referred to immunology, and a diagnosis of CVID was made. She was successfully treated with subcutaneous IgG replacement therapy. She died due to overwhelming sepsis after an episode of pneumonia at age 84.

CONCLUSION

The secret to prompt detection of CVID is adding it to the differential diagnosis of recurrent infections. Timely recognition and appropriate referral prevent serious complications, since successful treatment options are available.

Special thanks to Doug Bartelt, DNP, APNP, NP-C.

IN THIS ARTICLE

• Diagnosis
• Treatment/management
• Physcial signs suggestive of CVID in patients with appropriate history
• Case outcome

A 60-year-old woman with a recent history of air and cruise ship travel presented with symptoms consistent with acute sinusitis. She had a 34–pack-year history of cigarette smoking but had quit at age 50. Her medical history was significant for hypothyroidism, hypertension, coronary artery disease, mild asthma, and COPD. Past surgical history included coronary artery bypass, abdominal hysterectomy, and cholecystectomy. Her medications included inhaled bronchodilators, thyroxin, hydrochlorothiazide, nitrates, ß-blockers, and calcium channel blockers.

Over the next five years, she presented with frequent episodes of respiratory illness for which she received multiple courses of antibiotics, inhaled bronchodilators, and oral as well as inhaled corticosteroids. She consequently became increasingly sensitized to multiple antibiotic classes and was frequently hospitalized for the treatment of her respiratory illnesses.

Common variable immunodeficiency disorders (collectively known as CVID) are the most common clinically significant immunodeficiency diseases among adults.¹ Manifesting clinically as frequent, unusually severe or recalcitrant bacterial infections of the ear, sinus, respiratory tree, and/or gastrointestinal tract, CVID is genetically induced.² Additionally, these disorders can predispose individuals to autoimmune conditions and to cancers involving B lymphocytes.³ Often thought to be a disease of younger people, CVID can occur across the age span.⁴

The immune dysfunction that characterizes CVID is believed to result from underlying genetic defects that affect the differentiation of B cells, leading to faulty immunoglobulin (Ig) synthesis. Recent advances that allow the detection of multiple novel susceptibility loci for CVID have dramatically increased our understanding of the pathophysiology and pathogenesis of this disorder.⁵ These advances are being used to refine the diagnostic parameters of CVID and in the future may help clinicians tailor treatment protocols to specific genetic defects.^5,6

Although considered rare, CVID is often unrecognized; the incidence is likely much higher than the current estimates of 1:10,000 to 1:50,000.⁷ About 13% to 23% of individuals with chronic sinusitis are thought to be affected by CVID.⁸ While it is most commonly diagnosed during the second and third decades of life, it can be diagnosed at any time during the lifespan.⁴ A high burden of disease is associated with this disorder, as hospitalizations and costly, aggressive treatment regimens are needed to manage the resultant bacterial infections and sequelae.²

Increased awareness of CVID among primary care providers is needed to assure prompt diagnosis and to avoid unnecessary complications associated with delayed treatment. The diagnostic workup is complex, and referral to immunology for specific diagnosis and treatment is strongly advised. Recognition is the first step, and primary care providers must include primary immunodeficiency disorders, including CVID, in their differential to avert a missed diagnosis and to ensure optimal treatment.⁹

CLINICAL MANIFESTATIONS/PATIENT HISTORY

Frequent and severe infections are a hallmark of CVID. The most common types of infections seen in CVID are sinusitis, conjunctivitis, otitis media, bronchitis, pneumonia, and gastroenteritis.¹⁰ These primary bacterial infections can disseminate, causing septicemia and/or central nervous system infection.¹¹ The usual infectious pathogens are encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, but atypical infections due to organisms such as Pneumocystis carinii and Mycoplasma pneumoniae also occur in some patients.^12,13

Although the majority of CVID cases occur sporadically, family history is helpful in securing the correct diagnosis.¹⁵ Known immunodeficiency, unusual susceptibility to infections, autoimmune diseases, hematologic malignancy, or death caused by infection in other family members should increase the provider’s index of suspicion for CVID.¹⁶

Many genetic defects have been implicated in CVID, yet the wide phenotypic expression found even in persons with similar genetic profiles implies that CVID has a complex genetic transmission pattern.¹⁵ Known or suspected consanguinity in parents or grandparents increases the risk for CVID.⁶

Although these family history elements occur infrequently, they increase the likelihood of severe opportunistic infection, which can cause organ damage or even death.^1,17 Being alert for these elements of family history can help to avoid delays in diagnosis and treatment and eventual organ damage.²

DIFFERENTIAL DIAGNOSIS

When considering the differential diagnosis for the primary features of CVID, other etiologies that should be considered include allergies, environmental exposures, uncontrolled gastroesophageal reflux disease, structural abnormalities of the upper respiratory tract, and celiac disease.^5,10,18,19 Far less common but still worthy of consideration are other genetic conditions, such as primary ciliary dyskinesia, cystic fibrosis, thymic dysfunction or carcinoma, and protein-losing enteropathies.^20,21

A number of conditions can cause immunosuppression. Transient reductions in serum Ig levels can occur in the presence of serious infections.²² Long-term, high-dose use of some medications, such as corticosteroids, or use of anticonvulsants may reduce antibody availability. Chronic illnesses, malignancy, and malnutrition can also play a role in immunosuppression.¹⁹ CVID shares features with a large number of primary immune diseases, and these as well as other causes of hypogammaglobulinemia must be excluded before the diagnosis of CVID can be made.¹

DIAGNOSIS

While infectious disease is a common reason patients seek medical care, few patients presenting with one will have CVID. Nevertheless, immunologic evaluations should be performed and appropriate referral to an immunology specialist is strongly recommended when more than one severe infection arises in a year’s time; when a pattern of severe or unusual infections presents over a period of time; when bronchiectasis is present; or when infections do not resolve with conventional treatment.¹⁶ In addition, the physical findings noted in the Table, when combined with a history of recurrent infections, autoimmune disorders, or lymphocytic malignancy, should prompt evaluation for CVID.^10,16,18,23

The diagnosis of CVID requires testing for low serum levels of total IgG, IgG subclasses, IgA, and IgM. In CVID, IgG and IgA levels will be reduced, and occasionally IgM levels will also be diminished.²⁴ Unless an active infection is present, there will be no change in the patient’s routine blood tests, such as the complete blood count and total complement levels.

The diagnosis is also based on demonstration of a deficient antibody response to protein (tetanus) and polysaccharide (pneumonia) vaccine antigens.²¹ A minimal reaction to these vaccines should prompt referral to an immunology specialist for additional testing and a plan of care.²⁵ However, whenever the index of suspicion for CVID is high, prompt referral to immunology should not be delayed to perform further testing.¹⁶

TREATMENT/MANAGEMENT

IgG replacement therapy, which treats the underlying pathophysiology of CVID by supplementing one of the deficient antibodies, is the standard treatment for CVID. IgG is considered a blood product since it is made from human plasma. Patients may experience untoward reactions to IgG replacement therapy, similar to transfusion reactions; such reactions commonly include back pain, low-grade fever, muscle and joint discomfort, and fatigue. These unpleasant effects can be minimized with the prophylactic use of antihistamines, antipyretics, or even glucocorticoids.²⁶

Although IgG replacement therapy has high upfront costs, it increases patients’ well-being considerably by preventing multiple or recurrent infections and the resultant hospitalizations for antibiotic therapy.²⁷ Home infusion of IgG can minimize costs as well as increase patient autonomy.²⁸ With home infusions, IgG is administered via a multisite subcutaneous route using a slow-infusion mechanical pump. Subcutaneous infusions generally take four to six hours, depending on the number of sites used. Some patients can infuse while they sleep, which increases patient satisfaction with the treatment.²⁷

Infections in persons with CVID can be severe and may lead to organ-system compromise, requiring aggressive therapy aimed at supporting the function of the affected organ systems. For example, patients with CVID can develop unrelenting vomiting and diarrhea, which may require inpatient admission for rehydration and stabilization until the infection can be treated adequately.³²

Treatment options remain limited for the subset of CVID patients who develop severe complications, such as interstitial lung disease or neoplasms. These complications are associated with a significant increase in patient mortality, and allogeneic hematopoietic stem cell transplantation may be indicated for patients who develop them. This potentially curative treatment is being explored in ongoing research trials.³³

PATIENT EDUCATION

Scrupulous hand hygiene, careful avoidance of infectious exposures, watchful food handling and preparation, and lifestyle choices that support good general health are key elements of self-care for patients who have CVID. Preventive measures serve this population well by helping to reduce some of the complications of this serious disease.

Patients with CVID should understand keys aspects regarding its diagnosis, treatment, and prognosis. Specifically, they should know that people who have CVID are born missing some of the body’s immune defenses, which increases their risk for infection, especially of the sinuses, lungs, and gut. Sometimes it takes years to make this diagnosis, because it is a rare cause of common symptoms.

The patient was referred to immunology, and a diagnosis of CVID was made. She was successfully treated with subcutaneous IgG replacement therapy. She died due to overwhelming sepsis after an episode of pneumonia at age 84.

CONCLUSION

The secret to prompt detection of CVID is adding it to the differential diagnosis of recurrent infections. Timely recognition and appropriate referral prevent serious complications, since successful treatment options are available.

Special thanks to Doug Bartelt, DNP, APNP, NP-C.

BY JEFF BAUER

Use of a blood collection system that diverts and sequesters the initial 1.5 to 2 mL of blood was associated with a significant decrease in blood culture contamination compared to standard practice, according to an open-label trial conducted at a single ED. The results were published online in the journal Clinical Infectious Diseases.

An estimated 0.6% to 6% of blood cultures are contaminated. Some blood cultures may become contaminated by skin fragments colonized with bacteria that are dislodged during venipuncture. Such false-positive results lead to increased costs and harm associated with unnecessary additional testing and treatment.

Researchers at the University of Nebraska Medical Center evaluated a novel sterile blood collection system, the SteriPath initial specimen diversion device (ISDD), to determine if it could reduce contamination rates by diverting and excluding the initial portion of collected blood. Investigators evaluated 1,808 blood cultures from 904 adult ED patients at an urban 689-bed university hospital. The patients’ mean age was 59 years, and 55% were male. For each patient, the first 20-mL blood sample was obtained using a standard procedure in which blood was drawn into a syringe and then injected into blood culture vials. A second 20-mL sample was obtained using the ISDD; the initial 1.5 to 2 mL of blood was diverted into a holding chamber, and the rest of the sample was directed into the blood culture vials. A culture was determined to be contaminated if one or more of several skin-residing organisms, including coagulase-negative staphylococci, Propionibacterium species, Micrococcus species, viridans group streptococci, Corynebacterium species, or Bacillus species, was recovered from only one of the paired cultures.

Compared to standard practice, use of the ISDD was associated with a significant reduction in blood culture contamination. Overall, two of the 904 samples (0.22%) collected with the ISDD were contaminated, compared to 16 of the 904 samples (1.78%) collected via standard practice (P = .001). Sensitivity was not affected by use of the ISDD; true septicemia was observed in 65 of 904 samples (7.2%) collected via ISDD and 69 of 904 samples (7.6%) collected via standard procedure (P = .41).

Rupp ME, Cavalieri RJ, Marolf C, Lyden E. Reduction in blood culture contamination through use of initial specimen diversion device. Clin Infect Dis. 2017 Apr 3. [Epub ahead of print]. doi:10.1093/cid/cix304.

FDA: Fluoroquinolone Use Not Linked to Retinal Detachment, Aortic Problems

LUCAS FRANKI

FRONTLINE MEDICAL NEWS

The Food and Drug Administration (FDA) has found no evidence of a link between fluoroquinolone antibiotic use and retinal detachment or aortic aneurysm and dissection, according to a new Drug Safety Communication update on potential serious, disabling adverse effects of oral and injectable fluoroquinolones.

Fluoroquinolones are used to treat acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections.

In a Safety Communication published May 12, 2016, the FDA noted that serious adverse effects were possible from fluoroquinolone usage and that fluoroquinolones should be prescribed only when no other treatment options are possible. Serious adverse effects associated with fluoroquinolone use include hallucination, depression, suicidal thoughts, tendinitis and tendon rupture, a pins-and-needles feeling in the arms and legs, joint pain and swelling, skin rash, and severe diarrhea.

After reviewing patient cases and study findings, the FDA said the evidence did not support an association between fluoroquinolone use and potential retinal or aortic dangers, according to its May 10, 2017, Drug Safety Communication update.

“We will continue to assess safety issues with fluoroquinolones, and will update the public if additional actions are needed,” the FDA said in a statement.

US Food and Drug Administration. FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. May 10, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm. Accessed May 25, 2017.

Intravenous tPA Increases Risk of Mortality in Children With Acute Ischemic Stroke

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

Intravenous thrombolysis with tissue plasminogen activator (tPA) is associated with adverse outcomes, including an increased risk of death, in children with acute ischemic stroke, based on a review of cases from the 2006-2010 Nationwide Inpatient Survey.

Of 20,587 patients ages 0 to 17 years who were included in the survey, 198 received an intervention, including tPA in 169 patients, intra-arterial thrombectomy (IAT) in five patients, and both tPA and IAT in 24 patients. The overall mortality rate was 7.8%, but in those who received tPA, it was 13.8%, compared with 7.7% in those who did not, Kathryn Ess, MD, of Rush University Medical Center, Chicago, reported at the annual meeting of the American Academy of Neurology. No deaths occurred in those who underwent only IAT, said Dr Ess.

Other outcomes were also worse for those who received tPA. For example, untreated patients were more likely to be discharged home than were tPA-treated patients (67.8% vs 47.5%), and intracerebral hemorrhage was more common in treated vs untreated patients (10.1% vs 3.8%). Costs for treated patients averaged $200,346 vs $123,015 for untreated patients.

Children included in the review had a mean age of 6 years, 43.9% were girls, and 47.7% were white. Treated patients were older (10 years vs 5.9 years), and comorbidities included Moyamoya disease in 12.4% of patients, cardiac valvular disease in 6.6%, and sickle cell disease in 6.5%. Those who received tPA had a higher prevalence of procoagulable conditions (15.2% vs 2%). Of note, the higher prevalence of intracerebral hemorrhage in treated patients was not explained by Moyamoya or sickle cell disease, as patients with those comorbidities were less likely than those without those conditions to receive treatment, Dr Ess said.

Though limited by the retrospective study design, small numbers of treated patients, a lack of data on stroke severity or functional outcomes, and the inclusion of data from years before newer thrombectomy devices became available, the findings highlight concerns about the safety and efficacy of tPA in children with ischemic stroke, she said, noting that few studies have looked at the utility of tPA with or without IAT in the pediatric population.

“Studies of the efficacy of ischemic stroke treatment in adults can’t necessarily be extrapolated to children,” she said, adding that this is especially true given the difference in etiologies of pediatric acute ischemic stroke.

Indeed, the findings underscore “the age-old adage that children are not just little adults,” said Andrew Southerland, MD, of the University of Virginia, Charlottesville, who was the discussant for the session. “We need prospective clinical trials in children,” he said.

HCV Seroconversion Rate 0.1% After Occupational Exposure

BIANCA NOGRADY

FRONTLINE MEDICAL NEWS

An analysis of 13 years of accidental occupational exposures to hepatitis C virus (HCV)-contaminated fluids or instruments has revealed a seroconversion rate of just 0.1%, significantly lower than that previously reported in the literature. This finding is from a longitudinal analysis of data from a prospectively maintained database of 1,361 occupational injuries involving HCV-positive source that occurred between 2002 and 2015 conducted by Francesco M. Egro, MD, and his colleagues from the University of Pittsburgh Medical Center. Results were published online in the American Journal of Infection Control.

The two incidents of seroconversion occurred in patients who were exposed to blood from an HCV-positive patient via percutaneous injuries to the thumb from a hollow-bore needle, representing an overall seroconversion rate of 0.1%. In both cases, the source patients whose blood was involved were not coinfected with hepatitis B virus or human immunodeficiency virus.

Researchers also conducted a review of literature on needlestick injuries and occupational exposure to HCV-infected blood and fluids; from this review, they calculated an overall seroconversion rate average of 0.7%, with an average rate of 0.8% for percutaneous exposures. The review did not include mucomembranous exposure, as there were not enough data.

In this study, 65% of exposures were caused by percutaneous injuries and 34% were caused by mucocutaneous injuries; the cause of the remaining 1% was uncertain.

The hand was the most common site of injury (63%), followed by the face and neck (28%), and the arm, foot, leg, or trunk (4%). There was no record of the anatomical location of the injury in 5% of cases.

In nearly three-quarters of cases, blood was the source of exposure, while blood-containing saliva accounted for 3% of cases. The remaining 24% of cases were linked to other fluids, such as peritoneal fluid, tracheal secretions, amniotic fluid, bloody irrigation fluid, and blood-containing feces.

“The risk of transmission after exposure to HCV-positive patients’ fluids or tissues other than blood is expected to be low, but has not been formally quantified,” the authors wrote. “Although there have been reports of HCV seroconversion after human bites and after punching a HCV-positive individual in the teeth, percutaneous exposures to the blood of a HCV-positive source remain the most common cause of occupational HCV transmission.”

While the rate of seroconversion was low, the authors encouraged prompt reporting, testing, and follow-up of exposed individuals.

Egro FM, Nwaiwu CA, Smith S, Harper JD, Spiess AM. Seroconversion rates among health care workers exposed to hepatitis C virus-contaminated body fluids: The University of Pittsburgh 13-year experience. Am J Infect Control. 2017 Apr 24. [Epub ahead of print]. doi:10.1016/j.ajic.2017.03.011.

BY JEFF BAUER

Use of a blood collection system that diverts and sequesters the initial 1.5 to 2 mL of blood was associated with a significant decrease in blood culture contamination compared to standard practice, according to an open-label trial conducted at a single ED. The results were published online in the journal Clinical Infectious Diseases.

An estimated 0.6% to 6% of blood cultures are contaminated. Some blood cultures may become contaminated by skin fragments colonized with bacteria that are dislodged during venipuncture. Such false-positive results lead to increased costs and harm associated with unnecessary additional testing and treatment.

Researchers at the University of Nebraska Medical Center evaluated a novel sterile blood collection system, the SteriPath initial specimen diversion device (ISDD), to determine if it could reduce contamination rates by diverting and excluding the initial portion of collected blood. Investigators evaluated 1,808 blood cultures from 904 adult ED patients at an urban 689-bed university hospital. The patients’ mean age was 59 years, and 55% were male. For each patient, the first 20-mL blood sample was obtained using a standard procedure in which blood was drawn into a syringe and then injected into blood culture vials. A second 20-mL sample was obtained using the ISDD; the initial 1.5 to 2 mL of blood was diverted into a holding chamber, and the rest of the sample was directed into the blood culture vials. A culture was determined to be contaminated if one or more of several skin-residing organisms, including coagulase-negative staphylococci, Propionibacterium species, Micrococcus species, viridans group streptococci, Corynebacterium species, or Bacillus species, was recovered from only one of the paired cultures.

Compared to standard practice, use of the ISDD was associated with a significant reduction in blood culture contamination. Overall, two of the 904 samples (0.22%) collected with the ISDD were contaminated, compared to 16 of the 904 samples (1.78%) collected via standard practice (P = .001). Sensitivity was not affected by use of the ISDD; true septicemia was observed in 65 of 904 samples (7.2%) collected via ISDD and 69 of 904 samples (7.6%) collected via standard procedure (P = .41).

Rupp ME, Cavalieri RJ, Marolf C, Lyden E. Reduction in blood culture contamination through use of initial specimen diversion device. Clin Infect Dis. 2017 Apr 3. [Epub ahead of print]. doi:10.1093/cid/cix304.

FDA: Fluoroquinolone Use Not Linked to Retinal Detachment, Aortic Problems

LUCAS FRANKI

FRONTLINE MEDICAL NEWS

The Food and Drug Administration (FDA) has found no evidence of a link between fluoroquinolone antibiotic use and retinal detachment or aortic aneurysm and dissection, according to a new Drug Safety Communication update on potential serious, disabling adverse effects of oral and injectable fluoroquinolones.

Fluoroquinolones are used to treat acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections.

In a Safety Communication published May 12, 2016, the FDA noted that serious adverse effects were possible from fluoroquinolone usage and that fluoroquinolones should be prescribed only when no other treatment options are possible. Serious adverse effects associated with fluoroquinolone use include hallucination, depression, suicidal thoughts, tendinitis and tendon rupture, a pins-and-needles feeling in the arms and legs, joint pain and swelling, skin rash, and severe diarrhea.

After reviewing patient cases and study findings, the FDA said the evidence did not support an association between fluoroquinolone use and potential retinal or aortic dangers, according to its May 10, 2017, Drug Safety Communication update.

“We will continue to assess safety issues with fluoroquinolones, and will update the public if additional actions are needed,” the FDA said in a statement.

US Food and Drug Administration. FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. May 10, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm. Accessed May 25, 2017.

Intravenous tPA Increases Risk of Mortality in Children With Acute Ischemic Stroke

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

Intravenous thrombolysis with tissue plasminogen activator (tPA) is associated with adverse outcomes, including an increased risk of death, in children with acute ischemic stroke, based on a review of cases from the 2006-2010 Nationwide Inpatient Survey.

Of 20,587 patients ages 0 to 17 years who were included in the survey, 198 received an intervention, including tPA in 169 patients, intra-arterial thrombectomy (IAT) in five patients, and both tPA and IAT in 24 patients. The overall mortality rate was 7.8%, but in those who received tPA, it was 13.8%, compared with 7.7% in those who did not, Kathryn Ess, MD, of Rush University Medical Center, Chicago, reported at the annual meeting of the American Academy of Neurology. No deaths occurred in those who underwent only IAT, said Dr Ess.

Other outcomes were also worse for those who received tPA. For example, untreated patients were more likely to be discharged home than were tPA-treated patients (67.8% vs 47.5%), and intracerebral hemorrhage was more common in treated vs untreated patients (10.1% vs 3.8%). Costs for treated patients averaged $200,346 vs $123,015 for untreated patients.

Children included in the review had a mean age of 6 years, 43.9% were girls, and 47.7% were white. Treated patients were older (10 years vs 5.9 years), and comorbidities included Moyamoya disease in 12.4% of patients, cardiac valvular disease in 6.6%, and sickle cell disease in 6.5%. Those who received tPA had a higher prevalence of procoagulable conditions (15.2% vs 2%). Of note, the higher prevalence of intracerebral hemorrhage in treated patients was not explained by Moyamoya or sickle cell disease, as patients with those comorbidities were less likely than those without those conditions to receive treatment, Dr Ess said.

Though limited by the retrospective study design, small numbers of treated patients, a lack of data on stroke severity or functional outcomes, and the inclusion of data from years before newer thrombectomy devices became available, the findings highlight concerns about the safety and efficacy of tPA in children with ischemic stroke, she said, noting that few studies have looked at the utility of tPA with or without IAT in the pediatric population.

“Studies of the efficacy of ischemic stroke treatment in adults can’t necessarily be extrapolated to children,” she said, adding that this is especially true given the difference in etiologies of pediatric acute ischemic stroke.

Indeed, the findings underscore “the age-old adage that children are not just little adults,” said Andrew Southerland, MD, of the University of Virginia, Charlottesville, who was the discussant for the session. “We need prospective clinical trials in children,” he said.

HCV Seroconversion Rate 0.1% After Occupational Exposure

BIANCA NOGRADY

FRONTLINE MEDICAL NEWS

An analysis of 13 years of accidental occupational exposures to hepatitis C virus (HCV)-contaminated fluids or instruments has revealed a seroconversion rate of just 0.1%, significantly lower than that previously reported in the literature. This finding is from a longitudinal analysis of data from a prospectively maintained database of 1,361 occupational injuries involving HCV-positive source that occurred between 2002 and 2015 conducted by Francesco M. Egro, MD, and his colleagues from the University of Pittsburgh Medical Center. Results were published online in the American Journal of Infection Control.

The two incidents of seroconversion occurred in patients who were exposed to blood from an HCV-positive patient via percutaneous injuries to the thumb from a hollow-bore needle, representing an overall seroconversion rate of 0.1%. In both cases, the source patients whose blood was involved were not coinfected with hepatitis B virus or human immunodeficiency virus.

Researchers also conducted a review of literature on needlestick injuries and occupational exposure to HCV-infected blood and fluids; from this review, they calculated an overall seroconversion rate average of 0.7%, with an average rate of 0.8% for percutaneous exposures. The review did not include mucomembranous exposure, as there were not enough data.

In this study, 65% of exposures were caused by percutaneous injuries and 34% were caused by mucocutaneous injuries; the cause of the remaining 1% was uncertain.

The hand was the most common site of injury (63%), followed by the face and neck (28%), and the arm, foot, leg, or trunk (4%). There was no record of the anatomical location of the injury in 5% of cases.

In nearly three-quarters of cases, blood was the source of exposure, while blood-containing saliva accounted for 3% of cases. The remaining 24% of cases were linked to other fluids, such as peritoneal fluid, tracheal secretions, amniotic fluid, bloody irrigation fluid, and blood-containing feces.

“The risk of transmission after exposure to HCV-positive patients’ fluids or tissues other than blood is expected to be low, but has not been formally quantified,” the authors wrote. “Although there have been reports of HCV seroconversion after human bites and after punching a HCV-positive individual in the teeth, percutaneous exposures to the blood of a HCV-positive source remain the most common cause of occupational HCV transmission.”

While the rate of seroconversion was low, the authors encouraged prompt reporting, testing, and follow-up of exposed individuals.

Egro FM, Nwaiwu CA, Smith S, Harper JD, Spiess AM. Seroconversion rates among health care workers exposed to hepatitis C virus-contaminated body fluids: The University of Pittsburgh 13-year experience. Am J Infect Control. 2017 Apr 24. [Epub ahead of print]. doi:10.1016/j.ajic.2017.03.011.

BY JEFF BAUER

Use of a blood collection system that diverts and sequesters the initial 1.5 to 2 mL of blood was associated with a significant decrease in blood culture contamination compared to standard practice, according to an open-label trial conducted at a single ED. The results were published online in the journal Clinical Infectious Diseases.

An estimated 0.6% to 6% of blood cultures are contaminated. Some blood cultures may become contaminated by skin fragments colonized with bacteria that are dislodged during venipuncture. Such false-positive results lead to increased costs and harm associated with unnecessary additional testing and treatment.

Researchers at the University of Nebraska Medical Center evaluated a novel sterile blood collection system, the SteriPath initial specimen diversion device (ISDD), to determine if it could reduce contamination rates by diverting and excluding the initial portion of collected blood. Investigators evaluated 1,808 blood cultures from 904 adult ED patients at an urban 689-bed university hospital. The patients’ mean age was 59 years, and 55% were male. For each patient, the first 20-mL blood sample was obtained using a standard procedure in which blood was drawn into a syringe and then injected into blood culture vials. A second 20-mL sample was obtained using the ISDD; the initial 1.5 to 2 mL of blood was diverted into a holding chamber, and the rest of the sample was directed into the blood culture vials. A culture was determined to be contaminated if one or more of several skin-residing organisms, including coagulase-negative staphylococci, Propionibacterium species, Micrococcus species, viridans group streptococci, Corynebacterium species, or Bacillus species, was recovered from only one of the paired cultures.

Compared to standard practice, use of the ISDD was associated with a significant reduction in blood culture contamination. Overall, two of the 904 samples (0.22%) collected with the ISDD were contaminated, compared to 16 of the 904 samples (1.78%) collected via standard practice (P = .001). Sensitivity was not affected by use of the ISDD; true septicemia was observed in 65 of 904 samples (7.2%) collected via ISDD and 69 of 904 samples (7.6%) collected via standard procedure (P = .41).

Rupp ME, Cavalieri RJ, Marolf C, Lyden E. Reduction in blood culture contamination through use of initial specimen diversion device. Clin Infect Dis. 2017 Apr 3. [Epub ahead of print]. doi:10.1093/cid/cix304.

FDA: Fluoroquinolone Use Not Linked to Retinal Detachment, Aortic Problems

LUCAS FRANKI

FRONTLINE MEDICAL NEWS

The Food and Drug Administration (FDA) has found no evidence of a link between fluoroquinolone antibiotic use and retinal detachment or aortic aneurysm and dissection, according to a new Drug Safety Communication update on potential serious, disabling adverse effects of oral and injectable fluoroquinolones.

Fluoroquinolones are used to treat acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections.

In a Safety Communication published May 12, 2016, the FDA noted that serious adverse effects were possible from fluoroquinolone usage and that fluoroquinolones should be prescribed only when no other treatment options are possible. Serious adverse effects associated with fluoroquinolone use include hallucination, depression, suicidal thoughts, tendinitis and tendon rupture, a pins-and-needles feeling in the arms and legs, joint pain and swelling, skin rash, and severe diarrhea.

After reviewing patient cases and study findings, the FDA said the evidence did not support an association between fluoroquinolone use and potential retinal or aortic dangers, according to its May 10, 2017, Drug Safety Communication update.

“We will continue to assess safety issues with fluoroquinolones, and will update the public if additional actions are needed,” the FDA said in a statement.

US Food and Drug Administration. FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. May 10, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm. Accessed May 25, 2017.

Intravenous tPA Increases Risk of Mortality in Children With Acute Ischemic Stroke

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

Intravenous thrombolysis with tissue plasminogen activator (tPA) is associated with adverse outcomes, including an increased risk of death, in children with acute ischemic stroke, based on a review of cases from the 2006-2010 Nationwide Inpatient Survey.

Of 20,587 patients ages 0 to 17 years who were included in the survey, 198 received an intervention, including tPA in 169 patients, intra-arterial thrombectomy (IAT) in five patients, and both tPA and IAT in 24 patients. The overall mortality rate was 7.8%, but in those who received tPA, it was 13.8%, compared with 7.7% in those who did not, Kathryn Ess, MD, of Rush University Medical Center, Chicago, reported at the annual meeting of the American Academy of Neurology. No deaths occurred in those who underwent only IAT, said Dr Ess.

Other outcomes were also worse for those who received tPA. For example, untreated patients were more likely to be discharged home than were tPA-treated patients (67.8% vs 47.5%), and intracerebral hemorrhage was more common in treated vs untreated patients (10.1% vs 3.8%). Costs for treated patients averaged $200,346 vs $123,015 for untreated patients.

Children included in the review had a mean age of 6 years, 43.9% were girls, and 47.7% were white. Treated patients were older (10 years vs 5.9 years), and comorbidities included Moyamoya disease in 12.4% of patients, cardiac valvular disease in 6.6%, and sickle cell disease in 6.5%. Those who received tPA had a higher prevalence of procoagulable conditions (15.2% vs 2%). Of note, the higher prevalence of intracerebral hemorrhage in treated patients was not explained by Moyamoya or sickle cell disease, as patients with those comorbidities were less likely than those without those conditions to receive treatment, Dr Ess said.

Though limited by the retrospective study design, small numbers of treated patients, a lack of data on stroke severity or functional outcomes, and the inclusion of data from years before newer thrombectomy devices became available, the findings highlight concerns about the safety and efficacy of tPA in children with ischemic stroke, she said, noting that few studies have looked at the utility of tPA with or without IAT in the pediatric population.

“Studies of the efficacy of ischemic stroke treatment in adults can’t necessarily be extrapolated to children,” she said, adding that this is especially true given the difference in etiologies of pediatric acute ischemic stroke.

Indeed, the findings underscore “the age-old adage that children are not just little adults,” said Andrew Southerland, MD, of the University of Virginia, Charlottesville, who was the discussant for the session. “We need prospective clinical trials in children,” he said.

HCV Seroconversion Rate 0.1% After Occupational Exposure

BIANCA NOGRADY

FRONTLINE MEDICAL NEWS

An analysis of 13 years of accidental occupational exposures to hepatitis C virus (HCV)-contaminated fluids or instruments has revealed a seroconversion rate of just 0.1%, significantly lower than that previously reported in the literature. This finding is from a longitudinal analysis of data from a prospectively maintained database of 1,361 occupational injuries involving HCV-positive source that occurred between 2002 and 2015 conducted by Francesco M. Egro, MD, and his colleagues from the University of Pittsburgh Medical Center. Results were published online in the American Journal of Infection Control.

The two incidents of seroconversion occurred in patients who were exposed to blood from an HCV-positive patient via percutaneous injuries to the thumb from a hollow-bore needle, representing an overall seroconversion rate of 0.1%. In both cases, the source patients whose blood was involved were not coinfected with hepatitis B virus or human immunodeficiency virus.

Researchers also conducted a review of literature on needlestick injuries and occupational exposure to HCV-infected blood and fluids; from this review, they calculated an overall seroconversion rate average of 0.7%, with an average rate of 0.8% for percutaneous exposures. The review did not include mucomembranous exposure, as there were not enough data.

In this study, 65% of exposures were caused by percutaneous injuries and 34% were caused by mucocutaneous injuries; the cause of the remaining 1% was uncertain.

The hand was the most common site of injury (63%), followed by the face and neck (28%), and the arm, foot, leg, or trunk (4%). There was no record of the anatomical location of the injury in 5% of cases.

In nearly three-quarters of cases, blood was the source of exposure, while blood-containing saliva accounted for 3% of cases. The remaining 24% of cases were linked to other fluids, such as peritoneal fluid, tracheal secretions, amniotic fluid, bloody irrigation fluid, and blood-containing feces.

“The risk of transmission after exposure to HCV-positive patients’ fluids or tissues other than blood is expected to be low, but has not been formally quantified,” the authors wrote. “Although there have been reports of HCV seroconversion after human bites and after punching a HCV-positive individual in the teeth, percutaneous exposures to the blood of a HCV-positive source remain the most common cause of occupational HCV transmission.”

While the rate of seroconversion was low, the authors encouraged prompt reporting, testing, and follow-up of exposed individuals.

Egro FM, Nwaiwu CA, Smith S, Harper JD, Spiess AM. Seroconversion rates among health care workers exposed to hepatitis C virus-contaminated body fluids: The University of Pittsburgh 13-year experience. Am J Infect Control. 2017 Apr 24. [Epub ahead of print]. doi:10.1016/j.ajic.2017.03.011.

Illustration: Kimberly Martens for OBG Management

CASE: Transgender man consults gynecologist for fertility options

A 36-year-old transgender man considering the possibility of having his own biological children presents to the gynecology office to discuss hysterectomy as gender dysphoria treatment as well as his fertility preservation options. He has never had a gynecologic examination. Since age 24, he has been on testosterone therapy. Although his menses initially ceased, each month over the past 2 years he has had breakthrough spotting lasting 2 to 4 days, sometimes accompanied by pelvic pain and cramping. These symptoms have caused him distress and anxiety, which have led to his missing work 1 to 3 days each month. On presentation, he appears anxious and makes little eye contact. His girlfriend of 6 years has come in with him and is very supportive.

Over the past decade, transgender health care has moved to the forefront of the medical conversation. At many prominent medical centers across the United States, clinicians are forming multidisciplinary teams to help improve the health care of this patient population. Outcomes are being studied, and the literature is becoming more robust.

People tend to think of transgender women—male-assigned persons who self-identify as female—as the typical prototype for transgender people, but this focus is skewed in both society and the medical community. Transgender men—female-assigned persons who self-identify as male—remain underrepresented, mostly because they want to stay “under the radar,” especially with respect to medical care and, more specifically, routine gynecologic care.

Although the transgender woman has unique health needs and may present to a gynecologist for care after gender-affirmationsurgery, the transgender man’s many health care needs and their subtleties can be addressed only by a gynecologist. In this article, I review these intricacies of care to help increase clinician comfort in treating these patients.

Why transgender patients may delay seeking health care

Transgender patients remain underserved because of the health care barriers they encounter. Factors contributing to poor access include lack of health insurance, inability to pay for services, clinician insensitivity and hostility, and fear of exposure of transgender status during health care encounters.¹ In a recent large survey study, 30% of transgender respondents indicated that they delayed or did not seek medical care as a result of discrimination, and those who had needed to teach their clinicians about transgenderism were 4 times more likely to postpone or not seek care.²

In a 2015 survey of ObGyns’ current knowledge and practice regarding LGBT (lesbian, gay, bisexual, transgender) care, only one-third of respondents indicated they were comfortable caring for transgender patients.³ In addition, only one-third indicated being knowledgeable about the steps transgender patients must take to transition to their self-identified gender, and less than half were familiar with the recommendations for the routine health maintenance and screening of these patients.

Much of this discomfort derives from the lack of incorporation of LGBT-specific topics in medical curricula. In 2011, Obedin-Maliver and colleagues found that, at 176 US and Canadian allopathic and osteopathic medical schools, the median time dedicated to LGBT health care needs and related topics was unsatisfactory.⁴ This deficiency is slowly being reduced with changes in the curricula of many health care specialties. In ObGyn residency programs, for example, transgender-specific questions have been added to annual in-service examinations. The hope is that, as education initiatives improve, clinicians will become more comfortable caring for gender-minority patients, who with improved access to care will no longer need to seek subspecialists in transgender services.

Read about the need for gyn exams, managing benign disorders, and cervical cancer screening

Considerations for the gynecologic visit and examination

Transgender men visit the gynecology office for many reasons, including routine gynecologic care and health maintenance, care for acute and chronic gynecologic conditions (abnormal bleeding, pelvic pain, vaginitis), evaluation and management of pelvic floor disorders, consultation on hysterectomy for gender transition, and fertility counseling.

However, transgender men who reach their third, fourth, or fifth decade without having had a pelvic examination cite many reasons for avoiding the gynecology office. Most commonly, gynecologic visits and genital examination can severely exacerbate these patients’ gender dysphoria. In addition, many patients who do not engage in penetrative vaginal sex think their health risks are so low that they can forgo or delay pelvic exams. Patients who have stopped menstruating while on testosterone therapy may think there is no need for routine gynecologic care. Other reasons for avoiding pelvic exams are pain and traumatic sexual memories.⁵

Related Article:
Four pillars of a successful practice: 4. Motivate your staff

Transgender men need to receive the regular guideline-recommended pelvic exams and screenings used for cisgender women. (Cisgender refers to a person whose sense of gender identity corresponds with their birth sex.) We need to educate patients in this regard and to discuss several issues before performing an examination. First, take a thorough history and avoid making assumptions about sexual orientation and sex practices. Some patients have penetrative vaginal intercourse with either men or women. For some patients, the exam may cause dysphoria symptoms, and we need to validate patients’ fears. Discussing these issues ahead of time helps patients get used to the idea of undergoing an exam and assures them that the clinician is experienced in performing these exams for transgender men. In my practice, we explain the exam’s purpose (screening or diagnosis) and importance. We also counsel patients that they may experience some normal, and temporary, spotting after the exam. For those who experience severe dysphoria with vaginal bleeding of any kind, we acknowledge that postexam spotting may cause some anxiety. Patients with severe anxiety before the exam may be premedicated with an anxiolytic agent as long as someone can transport them to and from the office.

The bimanual exam should be performed with care and efficiency and with the patient given as much control as possible. In most cases, we ask patients to undress only from the waist down, and their genitals stay covered. Patients uncomfortable in stirrups are asked to show us the position that suits them best, and we try to accommodate them. Although speed is a goal, remember that many patients are nulliparous, have had limited or no vaginal penetration, or are on testosterone and have significant vaginal dryness. Use the smallest speculum possible, a pediatric or long and narrow adult speculum, and apply lubricant copiously. Pre-exam application of topical lidocaine jelly to the introitus can help reduce pain. To help a patient relax the pelvic floor muscles and habituate to the presence of a foreign object in the vagina, start the exam by inserting a single digit. In addition, ask the patient about speculum placement inside the vagina: Does he want to place the speculum himself or guide the clinician’s hand? Open the speculum only as much as needed to adequately visualize the cervix and then remove it with care.

Managing benign gynecologic disorders

The same algorithms are used to evaluate abnormal bleeding in all patients, but the differential diagnosis expands for those on testosterone therapy. Testosterone may no longer be suppressing their cycles, and abnormal bleeding could simply be the return of menses, which would present as regular cyclic bleeding. Increasing the testosterone dosing or changing the testosterone formulation may help, and the gynecologist should discuss these options with the patient’s prescribing clinician. In addition, progesterone in any form (for example, medroxyprogesterone acetate 5 to 30 mg daily) can be added to testosterone regimens to help suppress menses. The levonorgestrel-releasing intrauterine device (LNG-IUD) can be very effective, but placement can induce anxiety, and some patients decline this treatment option.

In patients with intermenstrual spotting, assess the vagina for atrophy. Both over-the-counter vaginal moisturizers and DHEA (dehydroepiandrosterone) suppositories (1% compounded) can help treat atrophy, but not all patients are comfortable using them. Most patients decline vaginal estrogen products for symptomatic vaginal atrophy even though the systemic effects are minimal.

The historic literature suggests that female-to-male patients’ long-term exposure to androgens leads to atrophic changes in the endometrium and myometrium, and clinical studies of menopausal women who take exogenous androgens have confirmed this effect.⁶ However, new data point to a different histologic scenario. A recent study found a possible association between long-term testosterone use in transgender men of reproductive age and a low proliferative active endometrium, as well as hypertrophic changes in the myometrium.⁷ The causes may be peripheral aromatization of androgens and expression and up-regulation of androgen receptors within the endometrial stroma and myometrial cells.⁸ Given these emerging data and anecdotal cases reported by clinicians who perform hysterectomies for transgender men, imaging and tissue sampling should be used to evaluate abnormal uterine bleeding, particularly in patients previously amenorrheic on testosterone. Be aware that transvaginal ultrasound or endometrial biopsy are challenging procedures for these patients. Counsel patients to ensure that they adhere to follow-up.

Related Article:
2017 Update on cervical disease

The ongoing need for cervical cancer screening

The concept of “original gender surveillance” was presented in a 2-case series of transgender men with uterine and cervical cancer that might have been detected earlier with better screening and routine care.⁹ There is no evidence, however, that long-term high-dose androgen therapy causes endometrial or cervical cancer,¹⁰ and the data on endometrial cancer in patients on cross-sex hormone therapy are limited such that a causal relationship between testosterone and these malignancies cannot be established.^9,11–14

The rate of unsatisfactory Pap smears is higher in transgender men than in cisgender women. The difference was anecdotally noted by clinicians who routinely cared for transgender patients over time and was confirmed with a retrospective chart review.¹⁵

Peitzmeier and colleagues reviewed the records of 233 transgender men and 3,625 cisgender women with Pap tests performed at an urban community health center over 6 years.¹⁵ The transgender cohort, with its prevalence rate of 10%, was 10 times more likely to have an unsatisfactory or inadequate Pap smear. Moreover, the transgender patients were more likely to have longer latency to follow-up for a repeat Pap test. In addition, testosterone therapy was more likely associated with inadequate Pap smears, and time on testosterone therapy was associated with higher odds of Pap smear inadequacy. Besides the exogenous hormone therapy, clinician comfort level and experience may have contributed to the high prevalence of inadequate Pap smears.

As mentioned earlier, it is important to become comfortable performing pelvic exams for transgender men and to prepare patients for the possibility that a Pap smear might be inadequate, making a follow-up visit and repeat Pap test necessary.¹⁶

Read about hysterectomy, oophorectomy, and vaginectomy choices

Consultation for hysterectomy: Perioperative considerations

Transgender men may undergo hysterectomy, oophorectomy, and/or vaginectomy. The TABLE summarizes the indications and perioperative considerations for each procedure.

Some transgender men undergo hysterectomy for benign gynecologic disease. Counseling and perioperative planning are the same for these patients as for cisgender women, although some of the considerations discussed here remain important.

Other patients undergo hysterectomy as part of transitioning to their self-affirmed gender. The World Professional Association for Transgender Health (WPATH) Standards of Care should be used to guide counseling and treatment.¹⁷ These guidelines were designed as a framework for performing hysterectomy and other gender-affirming procedures. According to the WPATH standards, the criteria for hysterectomy and oophorectomy are:

• 2 referral letters from qualified mental health professionals
• well-documented persistent gender dysphoria
• capacity to make fully informed decisions and to consent to treatment
• age of majority in given country
• good control of any concurrent medical or mental health concerns, and
• hormone therapy for 12 continuous months, as appropriate to gender goals, unless the patient has a medical contraindication or is otherwise unable or unwilling to take hormones.

As the guidelines emphasize, these criteria do not apply to patients undergoing either procedure for medical indications other than gender dysphoria.

Hysterectomy approach. Most surgeons perform gender-affirming hysterectomies laparoscopically. Many clinicians hesitate to perform these hysterectomies vaginally, as the patients are often nulliparous. In general, the best operative route is the one the surgeon feels most comfortable performing safely and efficiently. For a nulliparous patient with minimal pelvic organ descensus and a narrow pelvis, the laparoscopic approach is reasonable. A recent study in a small cohort of transgender men found that vaginal hysterectomy was successful in only 1 in 4 patients.¹⁸ Nevertheless, the American College of Obstetricians and Gynecologists (ACOG) recommends vaginal hysterectomy, when appropriate, for limiting complications and morbidity while maximizing cost-effectiveness.¹⁹ Although data are limited, vaginal hysterectomy seems feasible and should be considered in a subset of patients who pre‑sent for gender-affirming hysterectomy.

Related Article:
Total laparoscopic versus laparoscopic supracervical hysterectomy

The oophorectomy debate

Oophorectomy concurrent with hysterectomy remains a topic of debate among gynecologists who perform hysterectomy for gender transition. Some clinicians think gonadectomy poses a significant risk for bone health compromise at an early age. The long-term effects of testosterone on bone have not been well studied. Although bone metabolism is thought to increase over the short term, there are no major changes in bone density over the long term. In fact, in the setting of long-term testosterone therapy, cortical bone was found to be larger in transgender men than in cisgender women.²⁰ The issue is for patients who stop taking exogenous testosterone after oophorectomy. This subset of patients has not been well studied but clearly needs bone health surveillance and supplementation.

Another concern about oophorectomy is its effect on fertility. Because it is important to discuss fertility-preserving options, during consultation for a hysterectomy I spend a large portion of time addressing fertility goals. Patients who want to become a parent but do not want to carry a child (they want a current or future partner or surrogate to carry) are candidates for hysterectomy; those who do not want a genetic child are candidates for oophorectomy; and those who do not want to preserve their fertility (or have already ended it) and who meet the WPATH criteria for surgery are candidates for oophorectomy concurrent with hysterectomy. The discussion can be particularly challenging with young transgender men, since their ability to project their family planning goals may be compromised by their gender dysphoria. Clinicians can counsel patients about another option: isolated hysterectomy with subsequent staged oophorectomy.

Similar to cisgender women with polycystic ovary syndrome, transgender men on exogenous testosterone therapy are at risk for ovarian cysts,⁷ which can cause pain and should be evaluated and managed. As mentioned, these patients may find it difficult to visit a gynecologist and tolerate a vaginal examination, and many fear presenting to an emergency room, as they will need to disclose their transgender status and risk being discriminated against or, worse, not being triaged or cared for properly. Patients should be thoroughly counseled about the risks and benefits of having oophorectomy performed concurrently with hysterectomy.

Related Article:
Vaginal hysterectomy with basic instrumentation

The question of vaginectomy

Patients and clinicians often ask about concurrent vaginectomy procedures. In some cases, patients with severe gender dysphoria and absence of penetrative vaginal activity request excision or obliteration of the vagina. There is no standard of care, however. Vaginectomy can be done transvaginally or abdominally: open, laparoscopically, or robotically. It therefore should be performed by surgeons experienced in the procedure. Patients should be advised that a portion of the vaginal epithelium is sometimes used for certain phalloplasty procedures and that, if they are considering genital reconstruction in the future, it may be beneficial to preserve the vagina until that time.

There are no guidelines on stopping or continuing testosterone therapy perioperatively. Some clinicians are concerned about possible venous thromboembolic events related to perioperative use of testosterone, but there are no data supporting increased risk. The risk of postoperative vaginal cuff bleeding in patients on and off testosterone has not been well studied. Since patients who stop taking testosterone may develop severe mood swings and malaise, they should be counseled on recognizing and managing such changes. There are also no data on the risk of vaginal cuff dehiscence in this patient population. Testosterone usually causes the vagina to become very atrophic, so proper closure should be ensured to avoid cuff evisceration. In my practice, the vaginal cuff is closed in 2 layers using at least 1 layer of delayed absorbable suture.

Read about addressing fertility, contraception, OB care, and your role

Addressing fertility, contraception, and obstetric care

Most transgender men are able to conceive a child.²¹ Data in this area, however, are sparse. Most of the literature on reproductive health in this patient population is focused on human immunodeficiency virus (HIV) and other sexually transmitted infections.²² Nevertheless, patient-physician dialogue on fertility and reproductive health has increased since more patients started seeking surgical transition services (likely a result of improved coverage for these surgeries). In addition, we are learning more about patients’ ability and desire to conceive after long-term use of cross-sex hormone therapy. The importance of this dialogue is becoming apparent. One survey study found that more than half of the transgender men who had undergone affirmation surgery wanted to become parents.²³

Before initiating cross-sex hormone therapy or before undergoing hysterectomy and/or oophorectomy, patients must be counseled about their fertility options. Testosterone may affect fertility and fecundity, but there are case reports of successful pregnancy after discontinuation of testosterone.²¹ Reproductive endocrinology and fertility specialists have begun to recognize the importance of fertility preservation in this patient population and to apply the principles of oncofertility care beyond patients with cancer. In a 2015 opinion paper on access to fertility services by transgender persons, the Ethics Committee of the American Society for Reproductive Medicine focused on this population’s unique fertility needs.²⁴ Currently, oocyte and embryo cryopreservation are options for transgender men planning to start cross-sex hormones or undergo surgery.²⁵ Other methods being investigated may become options in the future.²⁵

There are even fewer data on transgender men’s contraceptive needs. Many clinicians mistakenly think these patients are at low risk for pregnancy. Some patients have male partners and engage in penetrative penile-vaginal intercourse; others are not on testosterone therapy; and still others, despite taking testosterone, are not always amenorrheic and may be ovulating. In a small cross-sectional study, Light and colleagues found that 12% of transgender men who were surveyed after conceiving had been amenorrheic on testosterone therapy, and 24% of these pregnancies were not planned.²¹

In a study by Cipres and colleagues, half of the 26 transgender men were considered at risk for pregnancy: These patients still had a uterus, not all were on testosterone, not all on testosterone were amenorrheic, they were having vaginal intercourse with cisgender men, and none were using condoms or other contraception.²⁶ The authors noted several potential underlying reasons for poor counseling on contraceptive needs: patients feel stigmatized, clinicians assume these patients are not candidates for “female” hormone therapy, patients fear these modalities may feminize them and compromise their affirmed identities, patients poorly understand how testosterone works and have mistaken ideas about its contraceptive properties, and clinician discomfort with broaching fertility and reproductive health discussions.

Data are also limited on pregnancy in transgender men. We do know that clinicians are not well equipped to help patients during the peripartum period and better resources are needed.²¹ Gender dysphoria can worsen during and immediately after pregnancy, and patients may be at significant risk for postpartum depression. More research is needed.

Related Article:
Care of the transgender patient: What is the gynecologist's role?

Gynecologists play key role in transgender care

Transgender men’s unique health care needs can be addressed only by gynecologists.It is important to become comfortable with and educated about these needs and their subtleties. This starts with understanding transgender patients’ gender dysphoria associated with the gynecologic visit and examination. Learning more about these patients and their needs will improve health care delivery.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Illustration: Kimberly Martens for OBG Management

CASE: Transgender man consults gynecologist for fertility options

A 36-year-old transgender man considering the possibility of having his own biological children presents to the gynecology office to discuss hysterectomy as gender dysphoria treatment as well as his fertility preservation options. He has never had a gynecologic examination. Since age 24, he has been on testosterone therapy. Although his menses initially ceased, each month over the past 2 years he has had breakthrough spotting lasting 2 to 4 days, sometimes accompanied by pelvic pain and cramping. These symptoms have caused him distress and anxiety, which have led to his missing work 1 to 3 days each month. On presentation, he appears anxious and makes little eye contact. His girlfriend of 6 years has come in with him and is very supportive.

Over the past decade, transgender health care has moved to the forefront of the medical conversation. At many prominent medical centers across the United States, clinicians are forming multidisciplinary teams to help improve the health care of this patient population. Outcomes are being studied, and the literature is becoming more robust.

People tend to think of transgender women—male-assigned persons who self-identify as female—as the typical prototype for transgender people, but this focus is skewed in both society and the medical community. Transgender men—female-assigned persons who self-identify as male—remain underrepresented, mostly because they want to stay “under the radar,” especially with respect to medical care and, more specifically, routine gynecologic care.

Although the transgender woman has unique health needs and may present to a gynecologist for care after gender-affirmationsurgery, the transgender man’s many health care needs and their subtleties can be addressed only by a gynecologist. In this article, I review these intricacies of care to help increase clinician comfort in treating these patients.

Why transgender patients may delay seeking health care

Transgender patients remain underserved because of the health care barriers they encounter. Factors contributing to poor access include lack of health insurance, inability to pay for services, clinician insensitivity and hostility, and fear of exposure of transgender status during health care encounters.¹ In a recent large survey study, 30% of transgender respondents indicated that they delayed or did not seek medical care as a result of discrimination, and those who had needed to teach their clinicians about transgenderism were 4 times more likely to postpone or not seek care.²

In a 2015 survey of ObGyns’ current knowledge and practice regarding LGBT (lesbian, gay, bisexual, transgender) care, only one-third of respondents indicated they were comfortable caring for transgender patients.³ In addition, only one-third indicated being knowledgeable about the steps transgender patients must take to transition to their self-identified gender, and less than half were familiar with the recommendations for the routine health maintenance and screening of these patients.

Much of this discomfort derives from the lack of incorporation of LGBT-specific topics in medical curricula. In 2011, Obedin-Maliver and colleagues found that, at 176 US and Canadian allopathic and osteopathic medical schools, the median time dedicated to LGBT health care needs and related topics was unsatisfactory.⁴ This deficiency is slowly being reduced with changes in the curricula of many health care specialties. In ObGyn residency programs, for example, transgender-specific questions have been added to annual in-service examinations. The hope is that, as education initiatives improve, clinicians will become more comfortable caring for gender-minority patients, who with improved access to care will no longer need to seek subspecialists in transgender services.

Read about the need for gyn exams, managing benign disorders, and cervical cancer screening

Considerations for the gynecologic visit and examination

Transgender men visit the gynecology office for many reasons, including routine gynecologic care and health maintenance, care for acute and chronic gynecologic conditions (abnormal bleeding, pelvic pain, vaginitis), evaluation and management of pelvic floor disorders, consultation on hysterectomy for gender transition, and fertility counseling.

However, transgender men who reach their third, fourth, or fifth decade without having had a pelvic examination cite many reasons for avoiding the gynecology office. Most commonly, gynecologic visits and genital examination can severely exacerbate these patients’ gender dysphoria. In addition, many patients who do not engage in penetrative vaginal sex think their health risks are so low that they can forgo or delay pelvic exams. Patients who have stopped menstruating while on testosterone therapy may think there is no need for routine gynecologic care. Other reasons for avoiding pelvic exams are pain and traumatic sexual memories.⁵

Related Article:
Four pillars of a successful practice: 4. Motivate your staff

Transgender men need to receive the regular guideline-recommended pelvic exams and screenings used for cisgender women. (Cisgender refers to a person whose sense of gender identity corresponds with their birth sex.) We need to educate patients in this regard and to discuss several issues before performing an examination. First, take a thorough history and avoid making assumptions about sexual orientation and sex practices. Some patients have penetrative vaginal intercourse with either men or women. For some patients, the exam may cause dysphoria symptoms, and we need to validate patients’ fears. Discussing these issues ahead of time helps patients get used to the idea of undergoing an exam and assures them that the clinician is experienced in performing these exams for transgender men. In my practice, we explain the exam’s purpose (screening or diagnosis) and importance. We also counsel patients that they may experience some normal, and temporary, spotting after the exam. For those who experience severe dysphoria with vaginal bleeding of any kind, we acknowledge that postexam spotting may cause some anxiety. Patients with severe anxiety before the exam may be premedicated with an anxiolytic agent as long as someone can transport them to and from the office.

The bimanual exam should be performed with care and efficiency and with the patient given as much control as possible. In most cases, we ask patients to undress only from the waist down, and their genitals stay covered. Patients uncomfortable in stirrups are asked to show us the position that suits them best, and we try to accommodate them. Although speed is a goal, remember that many patients are nulliparous, have had limited or no vaginal penetration, or are on testosterone and have significant vaginal dryness. Use the smallest speculum possible, a pediatric or long and narrow adult speculum, and apply lubricant copiously. Pre-exam application of topical lidocaine jelly to the introitus can help reduce pain. To help a patient relax the pelvic floor muscles and habituate to the presence of a foreign object in the vagina, start the exam by inserting a single digit. In addition, ask the patient about speculum placement inside the vagina: Does he want to place the speculum himself or guide the clinician’s hand? Open the speculum only as much as needed to adequately visualize the cervix and then remove it with care.

Managing benign gynecologic disorders

The same algorithms are used to evaluate abnormal bleeding in all patients, but the differential diagnosis expands for those on testosterone therapy. Testosterone may no longer be suppressing their cycles, and abnormal bleeding could simply be the return of menses, which would present as regular cyclic bleeding. Increasing the testosterone dosing or changing the testosterone formulation may help, and the gynecologist should discuss these options with the patient’s prescribing clinician. In addition, progesterone in any form (for example, medroxyprogesterone acetate 5 to 30 mg daily) can be added to testosterone regimens to help suppress menses. The levonorgestrel-releasing intrauterine device (LNG-IUD) can be very effective, but placement can induce anxiety, and some patients decline this treatment option.

In patients with intermenstrual spotting, assess the vagina for atrophy. Both over-the-counter vaginal moisturizers and DHEA (dehydroepiandrosterone) suppositories (1% compounded) can help treat atrophy, but not all patients are comfortable using them. Most patients decline vaginal estrogen products for symptomatic vaginal atrophy even though the systemic effects are minimal.

The historic literature suggests that female-to-male patients’ long-term exposure to androgens leads to atrophic changes in the endometrium and myometrium, and clinical studies of menopausal women who take exogenous androgens have confirmed this effect.⁶ However, new data point to a different histologic scenario. A recent study found a possible association between long-term testosterone use in transgender men of reproductive age and a low proliferative active endometrium, as well as hypertrophic changes in the myometrium.⁷ The causes may be peripheral aromatization of androgens and expression and up-regulation of androgen receptors within the endometrial stroma and myometrial cells.⁸ Given these emerging data and anecdotal cases reported by clinicians who perform hysterectomies for transgender men, imaging and tissue sampling should be used to evaluate abnormal uterine bleeding, particularly in patients previously amenorrheic on testosterone. Be aware that transvaginal ultrasound or endometrial biopsy are challenging procedures for these patients. Counsel patients to ensure that they adhere to follow-up.

Related Article:
2017 Update on cervical disease

The ongoing need for cervical cancer screening

The concept of “original gender surveillance” was presented in a 2-case series of transgender men with uterine and cervical cancer that might have been detected earlier with better screening and routine care.⁹ There is no evidence, however, that long-term high-dose androgen therapy causes endometrial or cervical cancer,¹⁰ and the data on endometrial cancer in patients on cross-sex hormone therapy are limited such that a causal relationship between testosterone and these malignancies cannot be established.^9,11–14

The rate of unsatisfactory Pap smears is higher in transgender men than in cisgender women. The difference was anecdotally noted by clinicians who routinely cared for transgender patients over time and was confirmed with a retrospective chart review.¹⁵

Peitzmeier and colleagues reviewed the records of 233 transgender men and 3,625 cisgender women with Pap tests performed at an urban community health center over 6 years.¹⁵ The transgender cohort, with its prevalence rate of 10%, was 10 times more likely to have an unsatisfactory or inadequate Pap smear. Moreover, the transgender patients were more likely to have longer latency to follow-up for a repeat Pap test. In addition, testosterone therapy was more likely associated with inadequate Pap smears, and time on testosterone therapy was associated with higher odds of Pap smear inadequacy. Besides the exogenous hormone therapy, clinician comfort level and experience may have contributed to the high prevalence of inadequate Pap smears.

As mentioned earlier, it is important to become comfortable performing pelvic exams for transgender men and to prepare patients for the possibility that a Pap smear might be inadequate, making a follow-up visit and repeat Pap test necessary.¹⁶

Read about hysterectomy, oophorectomy, and vaginectomy choices

Consultation for hysterectomy: Perioperative considerations

Transgender men may undergo hysterectomy, oophorectomy, and/or vaginectomy. The TABLE summarizes the indications and perioperative considerations for each procedure.

Some transgender men undergo hysterectomy for benign gynecologic disease. Counseling and perioperative planning are the same for these patients as for cisgender women, although some of the considerations discussed here remain important.

Other patients undergo hysterectomy as part of transitioning to their self-affirmed gender. The World Professional Association for Transgender Health (WPATH) Standards of Care should be used to guide counseling and treatment.¹⁷ These guidelines were designed as a framework for performing hysterectomy and other gender-affirming procedures. According to the WPATH standards, the criteria for hysterectomy and oophorectomy are:

• 2 referral letters from qualified mental health professionals
• well-documented persistent gender dysphoria
• capacity to make fully informed decisions and to consent to treatment
• age of majority in given country
• good control of any concurrent medical or mental health concerns, and
• hormone therapy for 12 continuous months, as appropriate to gender goals, unless the patient has a medical contraindication or is otherwise unable or unwilling to take hormones.

As the guidelines emphasize, these criteria do not apply to patients undergoing either procedure for medical indications other than gender dysphoria.

Hysterectomy approach. Most surgeons perform gender-affirming hysterectomies laparoscopically. Many clinicians hesitate to perform these hysterectomies vaginally, as the patients are often nulliparous. In general, the best operative route is the one the surgeon feels most comfortable performing safely and efficiently. For a nulliparous patient with minimal pelvic organ descensus and a narrow pelvis, the laparoscopic approach is reasonable. A recent study in a small cohort of transgender men found that vaginal hysterectomy was successful in only 1 in 4 patients.¹⁸ Nevertheless, the American College of Obstetricians and Gynecologists (ACOG) recommends vaginal hysterectomy, when appropriate, for limiting complications and morbidity while maximizing cost-effectiveness.¹⁹ Although data are limited, vaginal hysterectomy seems feasible and should be considered in a subset of patients who pre‑sent for gender-affirming hysterectomy.

Related Article:
Total laparoscopic versus laparoscopic supracervical hysterectomy

The oophorectomy debate

Oophorectomy concurrent with hysterectomy remains a topic of debate among gynecologists who perform hysterectomy for gender transition. Some clinicians think gonadectomy poses a significant risk for bone health compromise at an early age. The long-term effects of testosterone on bone have not been well studied. Although bone metabolism is thought to increase over the short term, there are no major changes in bone density over the long term. In fact, in the setting of long-term testosterone therapy, cortical bone was found to be larger in transgender men than in cisgender women.²⁰ The issue is for patients who stop taking exogenous testosterone after oophorectomy. This subset of patients has not been well studied but clearly needs bone health surveillance and supplementation.

Another concern about oophorectomy is its effect on fertility. Because it is important to discuss fertility-preserving options, during consultation for a hysterectomy I spend a large portion of time addressing fertility goals. Patients who want to become a parent but do not want to carry a child (they want a current or future partner or surrogate to carry) are candidates for hysterectomy; those who do not want a genetic child are candidates for oophorectomy; and those who do not want to preserve their fertility (or have already ended it) and who meet the WPATH criteria for surgery are candidates for oophorectomy concurrent with hysterectomy. The discussion can be particularly challenging with young transgender men, since their ability to project their family planning goals may be compromised by their gender dysphoria. Clinicians can counsel patients about another option: isolated hysterectomy with subsequent staged oophorectomy.

Similar to cisgender women with polycystic ovary syndrome, transgender men on exogenous testosterone therapy are at risk for ovarian cysts,⁷ which can cause pain and should be evaluated and managed. As mentioned, these patients may find it difficult to visit a gynecologist and tolerate a vaginal examination, and many fear presenting to an emergency room, as they will need to disclose their transgender status and risk being discriminated against or, worse, not being triaged or cared for properly. Patients should be thoroughly counseled about the risks and benefits of having oophorectomy performed concurrently with hysterectomy.

Related Article:
Vaginal hysterectomy with basic instrumentation

The question of vaginectomy

Patients and clinicians often ask about concurrent vaginectomy procedures. In some cases, patients with severe gender dysphoria and absence of penetrative vaginal activity request excision or obliteration of the vagina. There is no standard of care, however. Vaginectomy can be done transvaginally or abdominally: open, laparoscopically, or robotically. It therefore should be performed by surgeons experienced in the procedure. Patients should be advised that a portion of the vaginal epithelium is sometimes used for certain phalloplasty procedures and that, if they are considering genital reconstruction in the future, it may be beneficial to preserve the vagina until that time.

There are no guidelines on stopping or continuing testosterone therapy perioperatively. Some clinicians are concerned about possible venous thromboembolic events related to perioperative use of testosterone, but there are no data supporting increased risk. The risk of postoperative vaginal cuff bleeding in patients on and off testosterone has not been well studied. Since patients who stop taking testosterone may develop severe mood swings and malaise, they should be counseled on recognizing and managing such changes. There are also no data on the risk of vaginal cuff dehiscence in this patient population. Testosterone usually causes the vagina to become very atrophic, so proper closure should be ensured to avoid cuff evisceration. In my practice, the vaginal cuff is closed in 2 layers using at least 1 layer of delayed absorbable suture.

Read about addressing fertility, contraception, OB care, and your role

Addressing fertility, contraception, and obstetric care

Most transgender men are able to conceive a child.²¹ Data in this area, however, are sparse. Most of the literature on reproductive health in this patient population is focused on human immunodeficiency virus (HIV) and other sexually transmitted infections.²² Nevertheless, patient-physician dialogue on fertility and reproductive health has increased since more patients started seeking surgical transition services (likely a result of improved coverage for these surgeries). In addition, we are learning more about patients’ ability and desire to conceive after long-term use of cross-sex hormone therapy. The importance of this dialogue is becoming apparent. One survey study found that more than half of the transgender men who had undergone affirmation surgery wanted to become parents.²³

Before initiating cross-sex hormone therapy or before undergoing hysterectomy and/or oophorectomy, patients must be counseled about their fertility options. Testosterone may affect fertility and fecundity, but there are case reports of successful pregnancy after discontinuation of testosterone.²¹ Reproductive endocrinology and fertility specialists have begun to recognize the importance of fertility preservation in this patient population and to apply the principles of oncofertility care beyond patients with cancer. In a 2015 opinion paper on access to fertility services by transgender persons, the Ethics Committee of the American Society for Reproductive Medicine focused on this population’s unique fertility needs.²⁴ Currently, oocyte and embryo cryopreservation are options for transgender men planning to start cross-sex hormones or undergo surgery.²⁵ Other methods being investigated may become options in the future.²⁵

There are even fewer data on transgender men’s contraceptive needs. Many clinicians mistakenly think these patients are at low risk for pregnancy. Some patients have male partners and engage in penetrative penile-vaginal intercourse; others are not on testosterone therapy; and still others, despite taking testosterone, are not always amenorrheic and may be ovulating. In a small cross-sectional study, Light and colleagues found that 12% of transgender men who were surveyed after conceiving had been amenorrheic on testosterone therapy, and 24% of these pregnancies were not planned.²¹

In a study by Cipres and colleagues, half of the 26 transgender men were considered at risk for pregnancy: These patients still had a uterus, not all were on testosterone, not all on testosterone were amenorrheic, they were having vaginal intercourse with cisgender men, and none were using condoms or other contraception.²⁶ The authors noted several potential underlying reasons for poor counseling on contraceptive needs: patients feel stigmatized, clinicians assume these patients are not candidates for “female” hormone therapy, patients fear these modalities may feminize them and compromise their affirmed identities, patients poorly understand how testosterone works and have mistaken ideas about its contraceptive properties, and clinician discomfort with broaching fertility and reproductive health discussions.

Data are also limited on pregnancy in transgender men. We do know that clinicians are not well equipped to help patients during the peripartum period and better resources are needed.²¹ Gender dysphoria can worsen during and immediately after pregnancy, and patients may be at significant risk for postpartum depression. More research is needed.

Related Article:
Care of the transgender patient: What is the gynecologist's role?

Gynecologists play key role in transgender care

Transgender men’s unique health care needs can be addressed only by gynecologists.It is important to become comfortable with and educated about these needs and their subtleties. This starts with understanding transgender patients’ gender dysphoria associated with the gynecologic visit and examination. Learning more about these patients and their needs will improve health care delivery.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Illustration: Kimberly Martens for OBG Management

CASE: Transgender man consults gynecologist for fertility options

A 36-year-old transgender man considering the possibility of having his own biological children presents to the gynecology office to discuss hysterectomy as gender dysphoria treatment as well as his fertility preservation options. He has never had a gynecologic examination. Since age 24, he has been on testosterone therapy. Although his menses initially ceased, each month over the past 2 years he has had breakthrough spotting lasting 2 to 4 days, sometimes accompanied by pelvic pain and cramping. These symptoms have caused him distress and anxiety, which have led to his missing work 1 to 3 days each month. On presentation, he appears anxious and makes little eye contact. His girlfriend of 6 years has come in with him and is very supportive.

Over the past decade, transgender health care has moved to the forefront of the medical conversation. At many prominent medical centers across the United States, clinicians are forming multidisciplinary teams to help improve the health care of this patient population. Outcomes are being studied, and the literature is becoming more robust.

People tend to think of transgender women—male-assigned persons who self-identify as female—as the typical prototype for transgender people, but this focus is skewed in both society and the medical community. Transgender men—female-assigned persons who self-identify as male—remain underrepresented, mostly because they want to stay “under the radar,” especially with respect to medical care and, more specifically, routine gynecologic care.

Although the transgender woman has unique health needs and may present to a gynecologist for care after gender-affirmationsurgery, the transgender man’s many health care needs and their subtleties can be addressed only by a gynecologist. In this article, I review these intricacies of care to help increase clinician comfort in treating these patients.

Why transgender patients may delay seeking health care

Transgender patients remain underserved because of the health care barriers they encounter. Factors contributing to poor access include lack of health insurance, inability to pay for services, clinician insensitivity and hostility, and fear of exposure of transgender status during health care encounters.¹ In a recent large survey study, 30% of transgender respondents indicated that they delayed or did not seek medical care as a result of discrimination, and those who had needed to teach their clinicians about transgenderism were 4 times more likely to postpone or not seek care.²

In a 2015 survey of ObGyns’ current knowledge and practice regarding LGBT (lesbian, gay, bisexual, transgender) care, only one-third of respondents indicated they were comfortable caring for transgender patients.³ In addition, only one-third indicated being knowledgeable about the steps transgender patients must take to transition to their self-identified gender, and less than half were familiar with the recommendations for the routine health maintenance and screening of these patients.

Much of this discomfort derives from the lack of incorporation of LGBT-specific topics in medical curricula. In 2011, Obedin-Maliver and colleagues found that, at 176 US and Canadian allopathic and osteopathic medical schools, the median time dedicated to LGBT health care needs and related topics was unsatisfactory.⁴ This deficiency is slowly being reduced with changes in the curricula of many health care specialties. In ObGyn residency programs, for example, transgender-specific questions have been added to annual in-service examinations. The hope is that, as education initiatives improve, clinicians will become more comfortable caring for gender-minority patients, who with improved access to care will no longer need to seek subspecialists in transgender services.

Read about the need for gyn exams, managing benign disorders, and cervical cancer screening

Considerations for the gynecologic visit and examination

Transgender men visit the gynecology office for many reasons, including routine gynecologic care and health maintenance, care for acute and chronic gynecologic conditions (abnormal bleeding, pelvic pain, vaginitis), evaluation and management of pelvic floor disorders, consultation on hysterectomy for gender transition, and fertility counseling.

However, transgender men who reach their third, fourth, or fifth decade without having had a pelvic examination cite many reasons for avoiding the gynecology office. Most commonly, gynecologic visits and genital examination can severely exacerbate these patients’ gender dysphoria. In addition, many patients who do not engage in penetrative vaginal sex think their health risks are so low that they can forgo or delay pelvic exams. Patients who have stopped menstruating while on testosterone therapy may think there is no need for routine gynecologic care. Other reasons for avoiding pelvic exams are pain and traumatic sexual memories.⁵

Related Article:
Four pillars of a successful practice: 4. Motivate your staff

Transgender men need to receive the regular guideline-recommended pelvic exams and screenings used for cisgender women. (Cisgender refers to a person whose sense of gender identity corresponds with their birth sex.) We need to educate patients in this regard and to discuss several issues before performing an examination. First, take a thorough history and avoid making assumptions about sexual orientation and sex practices. Some patients have penetrative vaginal intercourse with either men or women. For some patients, the exam may cause dysphoria symptoms, and we need to validate patients’ fears. Discussing these issues ahead of time helps patients get used to the idea of undergoing an exam and assures them that the clinician is experienced in performing these exams for transgender men. In my practice, we explain the exam’s purpose (screening or diagnosis) and importance. We also counsel patients that they may experience some normal, and temporary, spotting after the exam. For those who experience severe dysphoria with vaginal bleeding of any kind, we acknowledge that postexam spotting may cause some anxiety. Patients with severe anxiety before the exam may be premedicated with an anxiolytic agent as long as someone can transport them to and from the office.

The bimanual exam should be performed with care and efficiency and with the patient given as much control as possible. In most cases, we ask patients to undress only from the waist down, and their genitals stay covered. Patients uncomfortable in stirrups are asked to show us the position that suits them best, and we try to accommodate them. Although speed is a goal, remember that many patients are nulliparous, have had limited or no vaginal penetration, or are on testosterone and have significant vaginal dryness. Use the smallest speculum possible, a pediatric or long and narrow adult speculum, and apply lubricant copiously. Pre-exam application of topical lidocaine jelly to the introitus can help reduce pain. To help a patient relax the pelvic floor muscles and habituate to the presence of a foreign object in the vagina, start the exam by inserting a single digit. In addition, ask the patient about speculum placement inside the vagina: Does he want to place the speculum himself or guide the clinician’s hand? Open the speculum only as much as needed to adequately visualize the cervix and then remove it with care.

Managing benign gynecologic disorders

The same algorithms are used to evaluate abnormal bleeding in all patients, but the differential diagnosis expands for those on testosterone therapy. Testosterone may no longer be suppressing their cycles, and abnormal bleeding could simply be the return of menses, which would present as regular cyclic bleeding. Increasing the testosterone dosing or changing the testosterone formulation may help, and the gynecologist should discuss these options with the patient’s prescribing clinician. In addition, progesterone in any form (for example, medroxyprogesterone acetate 5 to 30 mg daily) can be added to testosterone regimens to help suppress menses. The levonorgestrel-releasing intrauterine device (LNG-IUD) can be very effective, but placement can induce anxiety, and some patients decline this treatment option.

In patients with intermenstrual spotting, assess the vagina for atrophy. Both over-the-counter vaginal moisturizers and DHEA (dehydroepiandrosterone) suppositories (1% compounded) can help treat atrophy, but not all patients are comfortable using them. Most patients decline vaginal estrogen products for symptomatic vaginal atrophy even though the systemic effects are minimal.

The historic literature suggests that female-to-male patients’ long-term exposure to androgens leads to atrophic changes in the endometrium and myometrium, and clinical studies of menopausal women who take exogenous androgens have confirmed this effect.⁶ However, new data point to a different histologic scenario. A recent study found a possible association between long-term testosterone use in transgender men of reproductive age and a low proliferative active endometrium, as well as hypertrophic changes in the myometrium.⁷ The causes may be peripheral aromatization of androgens and expression and up-regulation of androgen receptors within the endometrial stroma and myometrial cells.⁸ Given these emerging data and anecdotal cases reported by clinicians who perform hysterectomies for transgender men, imaging and tissue sampling should be used to evaluate abnormal uterine bleeding, particularly in patients previously amenorrheic on testosterone. Be aware that transvaginal ultrasound or endometrial biopsy are challenging procedures for these patients. Counsel patients to ensure that they adhere to follow-up.

Related Article:
2017 Update on cervical disease

The ongoing need for cervical cancer screening

The concept of “original gender surveillance” was presented in a 2-case series of transgender men with uterine and cervical cancer that might have been detected earlier with better screening and routine care.⁹ There is no evidence, however, that long-term high-dose androgen therapy causes endometrial or cervical cancer,¹⁰ and the data on endometrial cancer in patients on cross-sex hormone therapy are limited such that a causal relationship between testosterone and these malignancies cannot be established.^9,11–14

The rate of unsatisfactory Pap smears is higher in transgender men than in cisgender women. The difference was anecdotally noted by clinicians who routinely cared for transgender patients over time and was confirmed with a retrospective chart review.¹⁵

Peitzmeier and colleagues reviewed the records of 233 transgender men and 3,625 cisgender women with Pap tests performed at an urban community health center over 6 years.¹⁵ The transgender cohort, with its prevalence rate of 10%, was 10 times more likely to have an unsatisfactory or inadequate Pap smear. Moreover, the transgender patients were more likely to have longer latency to follow-up for a repeat Pap test. In addition, testosterone therapy was more likely associated with inadequate Pap smears, and time on testosterone therapy was associated with higher odds of Pap smear inadequacy. Besides the exogenous hormone therapy, clinician comfort level and experience may have contributed to the high prevalence of inadequate Pap smears.

As mentioned earlier, it is important to become comfortable performing pelvic exams for transgender men and to prepare patients for the possibility that a Pap smear might be inadequate, making a follow-up visit and repeat Pap test necessary.¹⁶

Read about hysterectomy, oophorectomy, and vaginectomy choices

Consultation for hysterectomy: Perioperative considerations

Transgender men may undergo hysterectomy, oophorectomy, and/or vaginectomy. The TABLE summarizes the indications and perioperative considerations for each procedure.

Some transgender men undergo hysterectomy for benign gynecologic disease. Counseling and perioperative planning are the same for these patients as for cisgender women, although some of the considerations discussed here remain important.

Other patients undergo hysterectomy as part of transitioning to their self-affirmed gender. The World Professional Association for Transgender Health (WPATH) Standards of Care should be used to guide counseling and treatment.¹⁷ These guidelines were designed as a framework for performing hysterectomy and other gender-affirming procedures. According to the WPATH standards, the criteria for hysterectomy and oophorectomy are:

• 2 referral letters from qualified mental health professionals
• well-documented persistent gender dysphoria
• capacity to make fully informed decisions and to consent to treatment
• age of majority in given country
• good control of any concurrent medical or mental health concerns, and
• hormone therapy for 12 continuous months, as appropriate to gender goals, unless the patient has a medical contraindication or is otherwise unable or unwilling to take hormones.

As the guidelines emphasize, these criteria do not apply to patients undergoing either procedure for medical indications other than gender dysphoria.

Hysterectomy approach. Most surgeons perform gender-affirming hysterectomies laparoscopically. Many clinicians hesitate to perform these hysterectomies vaginally, as the patients are often nulliparous. In general, the best operative route is the one the surgeon feels most comfortable performing safely and efficiently. For a nulliparous patient with minimal pelvic organ descensus and a narrow pelvis, the laparoscopic approach is reasonable. A recent study in a small cohort of transgender men found that vaginal hysterectomy was successful in only 1 in 4 patients.¹⁸ Nevertheless, the American College of Obstetricians and Gynecologists (ACOG) recommends vaginal hysterectomy, when appropriate, for limiting complications and morbidity while maximizing cost-effectiveness.¹⁹ Although data are limited, vaginal hysterectomy seems feasible and should be considered in a subset of patients who pre‑sent for gender-affirming hysterectomy.

Related Article:
Total laparoscopic versus laparoscopic supracervical hysterectomy

The oophorectomy debate

Oophorectomy concurrent with hysterectomy remains a topic of debate among gynecologists who perform hysterectomy for gender transition. Some clinicians think gonadectomy poses a significant risk for bone health compromise at an early age. The long-term effects of testosterone on bone have not been well studied. Although bone metabolism is thought to increase over the short term, there are no major changes in bone density over the long term. In fact, in the setting of long-term testosterone therapy, cortical bone was found to be larger in transgender men than in cisgender women.²⁰ The issue is for patients who stop taking exogenous testosterone after oophorectomy. This subset of patients has not been well studied but clearly needs bone health surveillance and supplementation.

Another concern about oophorectomy is its effect on fertility. Because it is important to discuss fertility-preserving options, during consultation for a hysterectomy I spend a large portion of time addressing fertility goals. Patients who want to become a parent but do not want to carry a child (they want a current or future partner or surrogate to carry) are candidates for hysterectomy; those who do not want a genetic child are candidates for oophorectomy; and those who do not want to preserve their fertility (or have already ended it) and who meet the WPATH criteria for surgery are candidates for oophorectomy concurrent with hysterectomy. The discussion can be particularly challenging with young transgender men, since their ability to project their family planning goals may be compromised by their gender dysphoria. Clinicians can counsel patients about another option: isolated hysterectomy with subsequent staged oophorectomy.

Similar to cisgender women with polycystic ovary syndrome, transgender men on exogenous testosterone therapy are at risk for ovarian cysts,⁷ which can cause pain and should be evaluated and managed. As mentioned, these patients may find it difficult to visit a gynecologist and tolerate a vaginal examination, and many fear presenting to an emergency room, as they will need to disclose their transgender status and risk being discriminated against or, worse, not being triaged or cared for properly. Patients should be thoroughly counseled about the risks and benefits of having oophorectomy performed concurrently with hysterectomy.

Related Article:
Vaginal hysterectomy with basic instrumentation

The question of vaginectomy

Patients and clinicians often ask about concurrent vaginectomy procedures. In some cases, patients with severe gender dysphoria and absence of penetrative vaginal activity request excision or obliteration of the vagina. There is no standard of care, however. Vaginectomy can be done transvaginally or abdominally: open, laparoscopically, or robotically. It therefore should be performed by surgeons experienced in the procedure. Patients should be advised that a portion of the vaginal epithelium is sometimes used for certain phalloplasty procedures and that, if they are considering genital reconstruction in the future, it may be beneficial to preserve the vagina until that time.

There are no guidelines on stopping or continuing testosterone therapy perioperatively. Some clinicians are concerned about possible venous thromboembolic events related to perioperative use of testosterone, but there are no data supporting increased risk. The risk of postoperative vaginal cuff bleeding in patients on and off testosterone has not been well studied. Since patients who stop taking testosterone may develop severe mood swings and malaise, they should be counseled on recognizing and managing such changes. There are also no data on the risk of vaginal cuff dehiscence in this patient population. Testosterone usually causes the vagina to become very atrophic, so proper closure should be ensured to avoid cuff evisceration. In my practice, the vaginal cuff is closed in 2 layers using at least 1 layer of delayed absorbable suture.

Read about addressing fertility, contraception, OB care, and your role

Addressing fertility, contraception, and obstetric care

Most transgender men are able to conceive a child.²¹ Data in this area, however, are sparse. Most of the literature on reproductive health in this patient population is focused on human immunodeficiency virus (HIV) and other sexually transmitted infections.²² Nevertheless, patient-physician dialogue on fertility and reproductive health has increased since more patients started seeking surgical transition services (likely a result of improved coverage for these surgeries). In addition, we are learning more about patients’ ability and desire to conceive after long-term use of cross-sex hormone therapy. The importance of this dialogue is becoming apparent. One survey study found that more than half of the transgender men who had undergone affirmation surgery wanted to become parents.²³

Before initiating cross-sex hormone therapy or before undergoing hysterectomy and/or oophorectomy, patients must be counseled about their fertility options. Testosterone may affect fertility and fecundity, but there are case reports of successful pregnancy after discontinuation of testosterone.²¹ Reproductive endocrinology and fertility specialists have begun to recognize the importance of fertility preservation in this patient population and to apply the principles of oncofertility care beyond patients with cancer. In a 2015 opinion paper on access to fertility services by transgender persons, the Ethics Committee of the American Society for Reproductive Medicine focused on this population’s unique fertility needs.²⁴ Currently, oocyte and embryo cryopreservation are options for transgender men planning to start cross-sex hormones or undergo surgery.²⁵ Other methods being investigated may become options in the future.²⁵

There are even fewer data on transgender men’s contraceptive needs. Many clinicians mistakenly think these patients are at low risk for pregnancy. Some patients have male partners and engage in penetrative penile-vaginal intercourse; others are not on testosterone therapy; and still others, despite taking testosterone, are not always amenorrheic and may be ovulating. In a small cross-sectional study, Light and colleagues found that 12% of transgender men who were surveyed after conceiving had been amenorrheic on testosterone therapy, and 24% of these pregnancies were not planned.²¹

In a study by Cipres and colleagues, half of the 26 transgender men were considered at risk for pregnancy: These patients still had a uterus, not all were on testosterone, not all on testosterone were amenorrheic, they were having vaginal intercourse with cisgender men, and none were using condoms or other contraception.²⁶ The authors noted several potential underlying reasons for poor counseling on contraceptive needs: patients feel stigmatized, clinicians assume these patients are not candidates for “female” hormone therapy, patients fear these modalities may feminize them and compromise their affirmed identities, patients poorly understand how testosterone works and have mistaken ideas about its contraceptive properties, and clinician discomfort with broaching fertility and reproductive health discussions.

Data are also limited on pregnancy in transgender men. We do know that clinicians are not well equipped to help patients during the peripartum period and better resources are needed.²¹ Gender dysphoria can worsen during and immediately after pregnancy, and patients may be at significant risk for postpartum depression. More research is needed.

Related Article:
Care of the transgender patient: What is the gynecologist's role?

Gynecologists play key role in transgender care

Transgender men’s unique health care needs can be addressed only by gynecologists.It is important to become comfortable with and educated about these needs and their subtleties. This starts with understanding transgender patients’ gender dysphoria associated with the gynecologic visit and examination. Learning more about these patients and their needs will improve health care delivery.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Pyogenic flexor tenosynovitis (PFT) is a common closed space infection of the flexor tendon sheaths of the hand and remains one of the most challenging problems encountered in orthopedic and hand surgery (Figure 1). PFT also is known as septic flexor tenosynovitis and suppurative flexor tenosynovitis.

Kanavel¹ initially described 4 cardinal signs that characterize infection of the flexor tendon sheath: symmetric fusiform swelling of the entire digit, exquisite tenderness to palpation along the course of the tendon sheath, semiflexed posture at rest, and pain with attempted passive extension of the digit. The prevalence of this infection ranges from 2.5% to 9.4%.² Once the infection is established in a patient, it can cause significant morbidity and disability and produce an economic burden. It can also present a significant treatment dilemma for the treating surgeon, as there is no standardized protocol for managing this common but challenging hand infection. For treatment, many surgeons combine surgical decompression, sheath irrigation, and empiric intravenous (IV) antibiotic administration. However, despite prompt treatment, and regardless of the protocol used, complication rates as high as 38% have been reported.³ Moreover, even after infection eradication, a significant proportion of patients continue to have pain, swelling, stiffness, loss of composite flexion, weakness, and recurrence that potentially requires amputation.

1. What Causes Pyogenic Flexor Tenosynovitis?

PFT can result from hematogenous spread, but local inoculation by a laceration, a puncture, or a bite also is common^4-7 (Figure 1). As a consequence of these mechanisms of injury, the most common source of PFT is skin flora. Staphylococcus aureus has been found in up to 75% of positive cultures in several studies.^2,5,6,8,9 Methicillin-resistant S aureus (MRSA) has been found in up to 29% of cases, and the incidence continues to increase, particularly in urban areas.^2,9-12 Other common bacteria are Staphylococcus epidermidis, β-hemolytic Streptococcus species, and Pseudomonas aeruginosa.^5,6,10 Infection by more than 1 species of bacteria is also fairly prevalent. Of 62 patients in a study, 38% had infections with 1 organism, and 62% with 2 or more.⁶ Twenty-six percent of cultures grew mixed anaerobic and aerobic organisms.⁶ PFT is seldom caused by Eikenella corrodens from a human bite or Pasteurella multocida from an animal bite.¹⁰ Other rare causes of PFT are Listeria monocytogenes¹³ and Clostridium difficile from a gastrointestinal source.¹⁴Neisseria gonorrhea can cause acute tenosynovitis, usually in the setting of disseminated gonococcal infection.^15,16 Also reported is mycobacterial tenosynovitis, most commonly caused by Mycobacterium kansasii and Mycobacterium marinum.¹⁷

2. Which Antibiotics Are Best Suited to Empirical Management of PFT?

Management of PFT, regardless of the pathogen, includes prompt administration of empiric IV antibiotics, usually followed by surgical drainage.^7,18-20 While cultures are being tested, antibiotics should be selected—including antibiotics for empiric coverage against common gram-positive organisms, including Staphylococcus and Streptococcus species.¹² The Centers for Disease Control and Prevention recommends empiric coverage for MRSA if the local prevalence exceeds 10% to 15%. Recommended empiric antibiotics are trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin (both oral) and clindamycin, vancomycin, and daptomycin (all IV).

In addition, institutional and local antibiotic resistance patterns of bacteria should guide treatment and antibiotic selection. First-generation cephalosporins have long been the cornerstone of treatment for infections caused by S aureus, but increasing methicillin resistance has reduced their role in the treatment, particularly the empiric treatment, of MRSA infections. Methicillin resistance first appeared as nosocomial S aureus infections in 1961, only 1 year after the introduction of the semisynthetic penicillin class that includes methicillin. Over the past 2 decades, MRSA has emerged in the community in otherwise young and healthy individuals with no healthcare-associated risk factors. Fortunately, several readily available antibiotics have maintained their efficacy in managing these “community-acquired” MRSA hand infections. TMP-SMX provides adequate coverage for MRSA and is a relatively inexpensive medication, and clindamycin is an equally effective and cost-effective alternative.

Presumptive antibiotics should also cover gram-negative rods and anaerobes, including Clostridium species, especially in immunocompromised patients.^7,9 These patients may require additional antibiotics for presumptive coverage of other rarer bacterial causes, especially when unique mechanisms of injury (eg, aquatic injury, farm injury) are involved. Once culture results are ready, antibiotic regimens should be narrowed to cover the specific organisms identified.

3. What Are the Timing and Indications for Surgery?

Nonoperative treatment may be appropriate for PFT patients who present early, typically within 48 hours after penetrating trauma to the hand.²¹ In a 4-patient series, Neviaser and Gunther¹⁹ successfully treated PFT nonoperatively, with IV antibiotics, splinting, and elevation. During nonoperative treatment, the affected hand should be regularly examined. If this treatment is to be successful, clinical symptoms should improve within 48 hours; if they do not, surgical irrigation and débridement should be performed.

Regardless of timing and type of irrigation, surgical treatment remains the treatment of choice for the majority of PFT cases. Michon²² developed a 3-tier PFT classification system that is based on intraoperative findings (Table).

4. What Are the Surgical Techniques for PFT Drainage?

Several surgical methods have been developed to decompress and irrigate the flexor sheaths of the hand. However, debates about optimal timing of surgical intervention, surgery type (open surgery or closed catheter irrigation only), and irrigation method continue.

Open Irrigation and Débridement

Open irrigation and débridement procedures were originally described for surgical management of PFT.¹ Midaxial and palmar (Bruner zigzag) incisions can be used to expose and open the entire sheath for complete drainage and washout. Both incisions afford good access to the flexor sheath, but the midaxial approach may provide more coverage of the sheath after surgery. Open irrigation and débridement is the treatment of choice for the most advanced cases of PFT and for atypical or chronic tenosynovial infections.^4,23,24 The Bruner zigzag incision affords ease of surgical dissection, extension, and more exposure of the flexor tendon sheath at the expense of possible difficulty in closure or flap necrosis in the setting of a swollen digit. Alternatively, the midaxial incision has the advantage of a large, more robust skin flap for more reliable closure.

Closed Tendon Sheath Irrigation

In 1943, Dickson-Wright²⁵ first described catheter irrigation of tendon sheath infections. Later, Neviaser⁴ described this technique in detail. A proximal incision is made over the metacarpal neck. The tendon sheath is cut transversely at the proximal edge of the A1 pulley. An angiocatheter is inserted 1 cm to 2 cm antegrade into the flexor tendon sheath. Then, a distal midaxial incision is made dorsal to the neurovascular bundle at the level of the distal interphalangeal joint on the ulnar aspect of the finger or the radial aspect of the thumb. The distal edge of the flexor sheath is exposed and resected distal to the distal-most pulley. A Penrose drain can be threaded into the tendon sheath beneath the A4 pulley to keep the wound open and allow for fluid drainage. The sheath is flushed gently in the operating room. After surgery, intermittent bedside irrigation can be continued on the floor.

Neviaser⁴ reported excellent initial results with this technique; 18 of 20 patients regained complete active and passive range of motion (ROM) by 1 week after surgery. Similarly, Juliano and Eglseder,²⁶ using a similar method, reported 100% excellent results for mild PFT and 88.4% excellent results for more severe infection.

Gutowski and colleagues²³ reviewed 47 PFT cases to determine if there is a difference in outcomes between PFT treated with open irrigation and débridement and PFT treated with closed catheter irrigation. Between these groups, they found no significant differences in early postoperative outcomes, including resolution of infection, need for additional surgery, and hospital length of stay.

There are also many differing opinions regarding the best irrigation method. Some authors have asserted that normal saline is sufficient,^4,5,23 and others that local antibiotics provide added benefit.^27-29 Recently, Draeger and colleagues³⁰ reported promising results with local injection of antibiotics into the tendon sheath and the addition of locally administered corticosteroids in the treatment of PFT in an animal model.

Continuous Closed Irrigation

A continuous closed irrigation system with inlet and outlet tubes has yielded successful results.^8,31,32 This system consists of 2 fenestrated tubes placed within the infected space, with the tip of the smaller caliber inlet tube positioned just inside the larger outlet tube. Advantages of this system include the patient’s ability to participate in hand therapy with the system in place and avoidance of pain caused by the high pressures involved in intermittent closed irrigation. Duration of this system has ranged from 2 days to 3 weeks, and results have been good.^5,8

Postoperative Irrigation

Use of postoperative irrigation on the floor or at home is controversial, as leaving an indwelling catheter in the tendon sheath can lead to complications. Catheters may increase digital stiffness by decreasing the patient’s ability to participate in therapy or may cause additional injury and irritation to the sheath itself if left in place too long. Lille and colleagues⁶ retrospectively compared the results of intraoperative closed tendon sheath irrigation alone with those of intraoperative and postoperative closed tendon sheath irrigation. There were no significant differences in mean hospital length of stay, follow-up complication rates, or postoperative ROM—which suggests that postoperative intermittent or continuous irrigation is not necessary.

Our Preferred Technique

We recommend a palmar approach that begins with outlining a Bruner zigzag incision along the entire finger. Then, only the distal-most and proximal-most incision lines are opened, thereby exposing the A5 and A1 pulleys, respectively (Figure 2).

5. What Are the Long-Term Outcomes of PFT?

The principal complication associated with PFT is stiffness with loss of ROM, which can be caused by flexor tendon adhesions, joint capsular thickening, or destruction of the sheath and pulley system.²⁴ In several studies, up to one-fourth of patients with PFT did not obtain full ROM, despite adequate treatment.^4-6,27 Therefore, full active ROM exercises should be initiated immediately after surgery to counteract the development of stiffness.

The most severe complication of PFT is amputation of the affected digit (Figures 3A, 3B).

Conclusion

PFT is a common hand infection that can cause significant morbidity. Early treatment is crucial: this requires use of IV antibiotics, or surgical irrigation and débridement in more advanced cases. However, despite prompt and thorough treatment, severe infection can lead to long-term impaired function and even amputation of the affected digit. More research is needed to determine optimal timing and technique for surgical intervention and to elucidate the role of local antibiotics and corticosteroids in treating this infection and potentially preventing the morbid outcomes we currently see.

Am J Orthop. 2017;46(3):E207-E212. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Pyogenic flexor tenosynovitis (PFT) is a common closed space infection of the flexor tendon sheaths of the hand and remains one of the most challenging problems encountered in orthopedic and hand surgery (Figure 1). PFT also is known as septic flexor tenosynovitis and suppurative flexor tenosynovitis.

Kanavel¹ initially described 4 cardinal signs that characterize infection of the flexor tendon sheath: symmetric fusiform swelling of the entire digit, exquisite tenderness to palpation along the course of the tendon sheath, semiflexed posture at rest, and pain with attempted passive extension of the digit. The prevalence of this infection ranges from 2.5% to 9.4%.² Once the infection is established in a patient, it can cause significant morbidity and disability and produce an economic burden. It can also present a significant treatment dilemma for the treating surgeon, as there is no standardized protocol for managing this common but challenging hand infection. For treatment, many surgeons combine surgical decompression, sheath irrigation, and empiric intravenous (IV) antibiotic administration. However, despite prompt treatment, and regardless of the protocol used, complication rates as high as 38% have been reported.³ Moreover, even after infection eradication, a significant proportion of patients continue to have pain, swelling, stiffness, loss of composite flexion, weakness, and recurrence that potentially requires amputation.

1. What Causes Pyogenic Flexor Tenosynovitis?

PFT can result from hematogenous spread, but local inoculation by a laceration, a puncture, or a bite also is common^4-7 (Figure 1). As a consequence of these mechanisms of injury, the most common source of PFT is skin flora. Staphylococcus aureus has been found in up to 75% of positive cultures in several studies.^2,5,6,8,9 Methicillin-resistant S aureus (MRSA) has been found in up to 29% of cases, and the incidence continues to increase, particularly in urban areas.^2,9-12 Other common bacteria are Staphylococcus epidermidis, β-hemolytic Streptococcus species, and Pseudomonas aeruginosa.^5,6,10 Infection by more than 1 species of bacteria is also fairly prevalent. Of 62 patients in a study, 38% had infections with 1 organism, and 62% with 2 or more.⁶ Twenty-six percent of cultures grew mixed anaerobic and aerobic organisms.⁶ PFT is seldom caused by Eikenella corrodens from a human bite or Pasteurella multocida from an animal bite.¹⁰ Other rare causes of PFT are Listeria monocytogenes¹³ and Clostridium difficile from a gastrointestinal source.¹⁴Neisseria gonorrhea can cause acute tenosynovitis, usually in the setting of disseminated gonococcal infection.^15,16 Also reported is mycobacterial tenosynovitis, most commonly caused by Mycobacterium kansasii and Mycobacterium marinum.¹⁷

2. Which Antibiotics Are Best Suited to Empirical Management of PFT?

Management of PFT, regardless of the pathogen, includes prompt administration of empiric IV antibiotics, usually followed by surgical drainage.^7,18-20 While cultures are being tested, antibiotics should be selected—including antibiotics for empiric coverage against common gram-positive organisms, including Staphylococcus and Streptococcus species.¹² The Centers for Disease Control and Prevention recommends empiric coverage for MRSA if the local prevalence exceeds 10% to 15%. Recommended empiric antibiotics are trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin (both oral) and clindamycin, vancomycin, and daptomycin (all IV).

In addition, institutional and local antibiotic resistance patterns of bacteria should guide treatment and antibiotic selection. First-generation cephalosporins have long been the cornerstone of treatment for infections caused by S aureus, but increasing methicillin resistance has reduced their role in the treatment, particularly the empiric treatment, of MRSA infections. Methicillin resistance first appeared as nosocomial S aureus infections in 1961, only 1 year after the introduction of the semisynthetic penicillin class that includes methicillin. Over the past 2 decades, MRSA has emerged in the community in otherwise young and healthy individuals with no healthcare-associated risk factors. Fortunately, several readily available antibiotics have maintained their efficacy in managing these “community-acquired” MRSA hand infections. TMP-SMX provides adequate coverage for MRSA and is a relatively inexpensive medication, and clindamycin is an equally effective and cost-effective alternative.

Presumptive antibiotics should also cover gram-negative rods and anaerobes, including Clostridium species, especially in immunocompromised patients.^7,9 These patients may require additional antibiotics for presumptive coverage of other rarer bacterial causes, especially when unique mechanisms of injury (eg, aquatic injury, farm injury) are involved. Once culture results are ready, antibiotic regimens should be narrowed to cover the specific organisms identified.

3. What Are the Timing and Indications for Surgery?

Nonoperative treatment may be appropriate for PFT patients who present early, typically within 48 hours after penetrating trauma to the hand.²¹ In a 4-patient series, Neviaser and Gunther¹⁹ successfully treated PFT nonoperatively, with IV antibiotics, splinting, and elevation. During nonoperative treatment, the affected hand should be regularly examined. If this treatment is to be successful, clinical symptoms should improve within 48 hours; if they do not, surgical irrigation and débridement should be performed.

Regardless of timing and type of irrigation, surgical treatment remains the treatment of choice for the majority of PFT cases. Michon²² developed a 3-tier PFT classification system that is based on intraoperative findings (Table).

4. What Are the Surgical Techniques for PFT Drainage?

Several surgical methods have been developed to decompress and irrigate the flexor sheaths of the hand. However, debates about optimal timing of surgical intervention, surgery type (open surgery or closed catheter irrigation only), and irrigation method continue.

Open Irrigation and Débridement

Open irrigation and débridement procedures were originally described for surgical management of PFT.¹ Midaxial and palmar (Bruner zigzag) incisions can be used to expose and open the entire sheath for complete drainage and washout. Both incisions afford good access to the flexor sheath, but the midaxial approach may provide more coverage of the sheath after surgery. Open irrigation and débridement is the treatment of choice for the most advanced cases of PFT and for atypical or chronic tenosynovial infections.^4,23,24 The Bruner zigzag incision affords ease of surgical dissection, extension, and more exposure of the flexor tendon sheath at the expense of possible difficulty in closure or flap necrosis in the setting of a swollen digit. Alternatively, the midaxial incision has the advantage of a large, more robust skin flap for more reliable closure.

Closed Tendon Sheath Irrigation

In 1943, Dickson-Wright²⁵ first described catheter irrigation of tendon sheath infections. Later, Neviaser⁴ described this technique in detail. A proximal incision is made over the metacarpal neck. The tendon sheath is cut transversely at the proximal edge of the A1 pulley. An angiocatheter is inserted 1 cm to 2 cm antegrade into the flexor tendon sheath. Then, a distal midaxial incision is made dorsal to the neurovascular bundle at the level of the distal interphalangeal joint on the ulnar aspect of the finger or the radial aspect of the thumb. The distal edge of the flexor sheath is exposed and resected distal to the distal-most pulley. A Penrose drain can be threaded into the tendon sheath beneath the A4 pulley to keep the wound open and allow for fluid drainage. The sheath is flushed gently in the operating room. After surgery, intermittent bedside irrigation can be continued on the floor.

Neviaser⁴ reported excellent initial results with this technique; 18 of 20 patients regained complete active and passive range of motion (ROM) by 1 week after surgery. Similarly, Juliano and Eglseder,²⁶ using a similar method, reported 100% excellent results for mild PFT and 88.4% excellent results for more severe infection.

Gutowski and colleagues²³ reviewed 47 PFT cases to determine if there is a difference in outcomes between PFT treated with open irrigation and débridement and PFT treated with closed catheter irrigation. Between these groups, they found no significant differences in early postoperative outcomes, including resolution of infection, need for additional surgery, and hospital length of stay.

There are also many differing opinions regarding the best irrigation method. Some authors have asserted that normal saline is sufficient,^4,5,23 and others that local antibiotics provide added benefit.^27-29 Recently, Draeger and colleagues³⁰ reported promising results with local injection of antibiotics into the tendon sheath and the addition of locally administered corticosteroids in the treatment of PFT in an animal model.

Continuous Closed Irrigation

A continuous closed irrigation system with inlet and outlet tubes has yielded successful results.^8,31,32 This system consists of 2 fenestrated tubes placed within the infected space, with the tip of the smaller caliber inlet tube positioned just inside the larger outlet tube. Advantages of this system include the patient’s ability to participate in hand therapy with the system in place and avoidance of pain caused by the high pressures involved in intermittent closed irrigation. Duration of this system has ranged from 2 days to 3 weeks, and results have been good.^5,8

Postoperative Irrigation

Use of postoperative irrigation on the floor or at home is controversial, as leaving an indwelling catheter in the tendon sheath can lead to complications. Catheters may increase digital stiffness by decreasing the patient’s ability to participate in therapy or may cause additional injury and irritation to the sheath itself if left in place too long. Lille and colleagues⁶ retrospectively compared the results of intraoperative closed tendon sheath irrigation alone with those of intraoperative and postoperative closed tendon sheath irrigation. There were no significant differences in mean hospital length of stay, follow-up complication rates, or postoperative ROM—which suggests that postoperative intermittent or continuous irrigation is not necessary.

Our Preferred Technique

We recommend a palmar approach that begins with outlining a Bruner zigzag incision along the entire finger. Then, only the distal-most and proximal-most incision lines are opened, thereby exposing the A5 and A1 pulleys, respectively (Figure 2).

5. What Are the Long-Term Outcomes of PFT?

The principal complication associated with PFT is stiffness with loss of ROM, which can be caused by flexor tendon adhesions, joint capsular thickening, or destruction of the sheath and pulley system.²⁴ In several studies, up to one-fourth of patients with PFT did not obtain full ROM, despite adequate treatment.^4-6,27 Therefore, full active ROM exercises should be initiated immediately after surgery to counteract the development of stiffness.

The most severe complication of PFT is amputation of the affected digit (Figures 3A, 3B).

Conclusion

PFT is a common hand infection that can cause significant morbidity. Early treatment is crucial: this requires use of IV antibiotics, or surgical irrigation and débridement in more advanced cases. However, despite prompt and thorough treatment, severe infection can lead to long-term impaired function and even amputation of the affected digit. More research is needed to determine optimal timing and technique for surgical intervention and to elucidate the role of local antibiotics and corticosteroids in treating this infection and potentially preventing the morbid outcomes we currently see.

Am J Orthop. 2017;46(3):E207-E212. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Pyogenic flexor tenosynovitis (PFT) is a common closed space infection of the flexor tendon sheaths of the hand and remains one of the most challenging problems encountered in orthopedic and hand surgery (Figure 1). PFT also is known as septic flexor tenosynovitis and suppurative flexor tenosynovitis.

Kanavel¹ initially described 4 cardinal signs that characterize infection of the flexor tendon sheath: symmetric fusiform swelling of the entire digit, exquisite tenderness to palpation along the course of the tendon sheath, semiflexed posture at rest, and pain with attempted passive extension of the digit. The prevalence of this infection ranges from 2.5% to 9.4%.² Once the infection is established in a patient, it can cause significant morbidity and disability and produce an economic burden. It can also present a significant treatment dilemma for the treating surgeon, as there is no standardized protocol for managing this common but challenging hand infection. For treatment, many surgeons combine surgical decompression, sheath irrigation, and empiric intravenous (IV) antibiotic administration. However, despite prompt treatment, and regardless of the protocol used, complication rates as high as 38% have been reported.³ Moreover, even after infection eradication, a significant proportion of patients continue to have pain, swelling, stiffness, loss of composite flexion, weakness, and recurrence that potentially requires amputation.

1. What Causes Pyogenic Flexor Tenosynovitis?

PFT can result from hematogenous spread, but local inoculation by a laceration, a puncture, or a bite also is common^4-7 (Figure 1). As a consequence of these mechanisms of injury, the most common source of PFT is skin flora. Staphylococcus aureus has been found in up to 75% of positive cultures in several studies.^2,5,6,8,9 Methicillin-resistant S aureus (MRSA) has been found in up to 29% of cases, and the incidence continues to increase, particularly in urban areas.^2,9-12 Other common bacteria are Staphylococcus epidermidis, β-hemolytic Streptococcus species, and Pseudomonas aeruginosa.^5,6,10 Infection by more than 1 species of bacteria is also fairly prevalent. Of 62 patients in a study, 38% had infections with 1 organism, and 62% with 2 or more.⁶ Twenty-six percent of cultures grew mixed anaerobic and aerobic organisms.⁶ PFT is seldom caused by Eikenella corrodens from a human bite or Pasteurella multocida from an animal bite.¹⁰ Other rare causes of PFT are Listeria monocytogenes¹³ and Clostridium difficile from a gastrointestinal source.¹⁴Neisseria gonorrhea can cause acute tenosynovitis, usually in the setting of disseminated gonococcal infection.^15,16 Also reported is mycobacterial tenosynovitis, most commonly caused by Mycobacterium kansasii and Mycobacterium marinum.¹⁷

2. Which Antibiotics Are Best Suited to Empirical Management of PFT?

Management of PFT, regardless of the pathogen, includes prompt administration of empiric IV antibiotics, usually followed by surgical drainage.^7,18-20 While cultures are being tested, antibiotics should be selected—including antibiotics for empiric coverage against common gram-positive organisms, including Staphylococcus and Streptococcus species.¹² The Centers for Disease Control and Prevention recommends empiric coverage for MRSA if the local prevalence exceeds 10% to 15%. Recommended empiric antibiotics are trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin (both oral) and clindamycin, vancomycin, and daptomycin (all IV).

In addition, institutional and local antibiotic resistance patterns of bacteria should guide treatment and antibiotic selection. First-generation cephalosporins have long been the cornerstone of treatment for infections caused by S aureus, but increasing methicillin resistance has reduced their role in the treatment, particularly the empiric treatment, of MRSA infections. Methicillin resistance first appeared as nosocomial S aureus infections in 1961, only 1 year after the introduction of the semisynthetic penicillin class that includes methicillin. Over the past 2 decades, MRSA has emerged in the community in otherwise young and healthy individuals with no healthcare-associated risk factors. Fortunately, several readily available antibiotics have maintained their efficacy in managing these “community-acquired” MRSA hand infections. TMP-SMX provides adequate coverage for MRSA and is a relatively inexpensive medication, and clindamycin is an equally effective and cost-effective alternative.

Presumptive antibiotics should also cover gram-negative rods and anaerobes, including Clostridium species, especially in immunocompromised patients.^7,9 These patients may require additional antibiotics for presumptive coverage of other rarer bacterial causes, especially when unique mechanisms of injury (eg, aquatic injury, farm injury) are involved. Once culture results are ready, antibiotic regimens should be narrowed to cover the specific organisms identified.

3. What Are the Timing and Indications for Surgery?

Nonoperative treatment may be appropriate for PFT patients who present early, typically within 48 hours after penetrating trauma to the hand.²¹ In a 4-patient series, Neviaser and Gunther¹⁹ successfully treated PFT nonoperatively, with IV antibiotics, splinting, and elevation. During nonoperative treatment, the affected hand should be regularly examined. If this treatment is to be successful, clinical symptoms should improve within 48 hours; if they do not, surgical irrigation and débridement should be performed.

Regardless of timing and type of irrigation, surgical treatment remains the treatment of choice for the majority of PFT cases. Michon²² developed a 3-tier PFT classification system that is based on intraoperative findings (Table).

4. What Are the Surgical Techniques for PFT Drainage?

Several surgical methods have been developed to decompress and irrigate the flexor sheaths of the hand. However, debates about optimal timing of surgical intervention, surgery type (open surgery or closed catheter irrigation only), and irrigation method continue.

Open Irrigation and Débridement

Open irrigation and débridement procedures were originally described for surgical management of PFT.¹ Midaxial and palmar (Bruner zigzag) incisions can be used to expose and open the entire sheath for complete drainage and washout. Both incisions afford good access to the flexor sheath, but the midaxial approach may provide more coverage of the sheath after surgery. Open irrigation and débridement is the treatment of choice for the most advanced cases of PFT and for atypical or chronic tenosynovial infections.^4,23,24 The Bruner zigzag incision affords ease of surgical dissection, extension, and more exposure of the flexor tendon sheath at the expense of possible difficulty in closure or flap necrosis in the setting of a swollen digit. Alternatively, the midaxial incision has the advantage of a large, more robust skin flap for more reliable closure.

Closed Tendon Sheath Irrigation

In 1943, Dickson-Wright²⁵ first described catheter irrigation of tendon sheath infections. Later, Neviaser⁴ described this technique in detail. A proximal incision is made over the metacarpal neck. The tendon sheath is cut transversely at the proximal edge of the A1 pulley. An angiocatheter is inserted 1 cm to 2 cm antegrade into the flexor tendon sheath. Then, a distal midaxial incision is made dorsal to the neurovascular bundle at the level of the distal interphalangeal joint on the ulnar aspect of the finger or the radial aspect of the thumb. The distal edge of the flexor sheath is exposed and resected distal to the distal-most pulley. A Penrose drain can be threaded into the tendon sheath beneath the A4 pulley to keep the wound open and allow for fluid drainage. The sheath is flushed gently in the operating room. After surgery, intermittent bedside irrigation can be continued on the floor.

Neviaser⁴ reported excellent initial results with this technique; 18 of 20 patients regained complete active and passive range of motion (ROM) by 1 week after surgery. Similarly, Juliano and Eglseder,²⁶ using a similar method, reported 100% excellent results for mild PFT and 88.4% excellent results for more severe infection.

Gutowski and colleagues²³ reviewed 47 PFT cases to determine if there is a difference in outcomes between PFT treated with open irrigation and débridement and PFT treated with closed catheter irrigation. Between these groups, they found no significant differences in early postoperative outcomes, including resolution of infection, need for additional surgery, and hospital length of stay.

There are also many differing opinions regarding the best irrigation method. Some authors have asserted that normal saline is sufficient,^4,5,23 and others that local antibiotics provide added benefit.^27-29 Recently, Draeger and colleagues³⁰ reported promising results with local injection of antibiotics into the tendon sheath and the addition of locally administered corticosteroids in the treatment of PFT in an animal model.

Continuous Closed Irrigation

A continuous closed irrigation system with inlet and outlet tubes has yielded successful results.^8,31,32 This system consists of 2 fenestrated tubes placed within the infected space, with the tip of the smaller caliber inlet tube positioned just inside the larger outlet tube. Advantages of this system include the patient’s ability to participate in hand therapy with the system in place and avoidance of pain caused by the high pressures involved in intermittent closed irrigation. Duration of this system has ranged from 2 days to 3 weeks, and results have been good.^5,8

Postoperative Irrigation

Use of postoperative irrigation on the floor or at home is controversial, as leaving an indwelling catheter in the tendon sheath can lead to complications. Catheters may increase digital stiffness by decreasing the patient’s ability to participate in therapy or may cause additional injury and irritation to the sheath itself if left in place too long. Lille and colleagues⁶ retrospectively compared the results of intraoperative closed tendon sheath irrigation alone with those of intraoperative and postoperative closed tendon sheath irrigation. There were no significant differences in mean hospital length of stay, follow-up complication rates, or postoperative ROM—which suggests that postoperative intermittent or continuous irrigation is not necessary.

Our Preferred Technique

We recommend a palmar approach that begins with outlining a Bruner zigzag incision along the entire finger. Then, only the distal-most and proximal-most incision lines are opened, thereby exposing the A5 and A1 pulleys, respectively (Figure 2).

5. What Are the Long-Term Outcomes of PFT?

The principal complication associated with PFT is stiffness with loss of ROM, which can be caused by flexor tendon adhesions, joint capsular thickening, or destruction of the sheath and pulley system.²⁴ In several studies, up to one-fourth of patients with PFT did not obtain full ROM, despite adequate treatment.^4-6,27 Therefore, full active ROM exercises should be initiated immediately after surgery to counteract the development of stiffness.

The most severe complication of PFT is amputation of the affected digit (Figures 3A, 3B).

Conclusion

PFT is a common hand infection that can cause significant morbidity. Early treatment is crucial: this requires use of IV antibiotics, or surgical irrigation and débridement in more advanced cases. However, despite prompt and thorough treatment, severe infection can lead to long-term impaired function and even amputation of the affected digit. More research is needed to determine optimal timing and technique for surgical intervention and to elucidate the role of local antibiotics and corticosteroids in treating this infection and potentially preventing the morbid outcomes we currently see.

Am J Orthop. 2017;46(3):E207-E212. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

From the University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract

• Objective: To review the evidence on interventions for managing cancer-related fatigue (CRF) and provide evidence-based guidance on approaches to its management.
• Methods: Nonsystematic review of the literature.
• Results: Several theories have been proposed to explain the biology of CRF, but there is no single clear mechanism that can be targeted for therapy. The approach to patients begins with screening for fatigue and assessing its intensity, followed by a thorough history and examination to determine whether any reversible medical conditions are contributing to fatigue. Management of underlying medical comorbidities may help some patients. For patients whose fatigue persists, pharmacologic and nonpharmacologic treatment options are available. Pharmacologic options include psychostimulants, such as methylphenidate and modafinil, and corticosteroids. Nonpharmacologic approaches include exercise, cognitive behavior therapy, yoga, acupuncture, and tai chi.
• Conclusion: We recommend an individualized approach, often with a combination of the available options. Patients need to be evaluated periodically to assess their fatigue, and since cancer-related fatigue affects survivors, long-term follow-up is needed.

Key words: fatigue; cancer; pro-inflammatory cytokines; nonpharmacologic; psychostimulants.

Fatigue is a common distressing effect of cancer [1].It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2].” Differences between CRF and fatigue reported by individuals without cancer are that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, ranging between 25% and 99% [2,3]. This variability may be secondary to methods used for screening fatigue and characteristics of the patient groups. In this article, we discuss recognition of CRF and approaches to its management.

Pathophysiology

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of more than 1 mechanism contributing to fatigue in an individual patient.

Central Nervous System Disturbances

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores [4]. Higher levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF [5]. However, there is not enough evidence at this time to support central nervous system disturbance as the main contributing factor to fatigue in cancer patients.

Circadian Rhythm Dysregulation

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways [2]. Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors [6]. These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

Inhibition of Hypothalamic–Pituitary–Adrenal Axis

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis [6]. The inhibition of the HPA axis may occur with higher levels of serotonin as well [7]. The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue [8]. Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue [2].

Skeletal Muscle Effect

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction [9]. ATP infusion improved muscle strength in one trial, but this was not confirmed in another trial [10,11]. Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls [12]. This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles [13,14].

Pro-inflammatory Cytokines

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma [15]. IL-6 was also associated with increased fatigue in breast cancer survivors [16]. Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy [17]. Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients [18,19]. Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients [20]. Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF [21].

Other Hypotheses

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support [22], genetic alterations in immune pathway [23], epigenetic changes [24], accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation [25], elevated vascular endothelial growth factor levels [26], and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction [13] all have been postulated to cause CRF.

Approach to Evaluation and Treatment

Screening

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to underrecognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue [2]. Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials [27]. A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF [2]. This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors [28]. The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue [29,30]. The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day [31]. The 9-item BFI is often used in clinical trials [29]. It measures the severity of fatigue over the previous 24 hours and has been validated in non-English speaking patients [32].

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which measures general, physical, mental, and emotional fatigue domains as well as activity and compares them with those of individuals without cancer [33,34]. The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments [35].

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales [36]. Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic re-evaluation, and moderate and severe fatigue need further evaluation and management [37].

Primary Evaluation

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living [37]. Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse which may cause poor sleep and fatigue.

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below.

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels [38]. Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or autoimmune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes [39]. Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond [40]. Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL [41].

Sleep disturbance. Poor sleep is common in fatigued cancer survivors [42]. Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuroendocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue [43]. Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep [44]. Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep [45]. Melatonin agonists are approved for insomnia in the United states, but not in Europe [46].

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men [47].

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster [48]. A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating of one of these symptoms without addressing other symptoms is not effective [49]. Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy—such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue [50].

Management

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time [51,52]. When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients [53].

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy [54]. CBT interventions that optimize sleep quality may improve fatigue [55]. More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials (RCTs) showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF [56].

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations [57]. Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship [58]. Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve cardiorespiratory fitness, muscle strength, and body composition [57]. Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended not only for younger patients, but also in the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors [59]. In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone [60]. This effect was also shown in an RCT of 160 patients with stage 0 to III breast cancer undergoing radiation therapy [61]. The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits in the physical fatigue but not the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week [62]. An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes [63]. Patients withcomorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy [37]. Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life [64,65]. We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training [66]. Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life [67].

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors [68]. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit not only physical fatigue, but also cognitive fatigue [69]. DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF [70]. More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months [71]. Additional research is needed in this area.

Acupuncture. An RCT in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue [72]. However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue [73]. Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done, with mixed results, and additional research is needed [74]. Currently, there are not sufficient data to recommend any of these modalities.

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF [75–77], but RCTs have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of non-pharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment [37].

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. RCTs of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF [78]. Likewise, in an analysis of 5 RCTs, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo [79]. However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease [80]. Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically [81]. In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner [82]. However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment [83]. Also, other RCTs in patients undergoing adjuvant chemotherapy for breast cancer [84] and patients receiving radiation therapy for brain tumors [85] failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm [86]. Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation [87]. A placebo effect was also noted in patients with multiple myeloma [88] and patients with primary brain tumors [89]. In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue [90]. In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7) [91]. This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional RCTs are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF [37].

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines [92]. In a RCT evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo [93]. A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo [94]. Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis [37].

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups [95].

Antidepressants have failed to demonstrate benefit in CRF without depression [8]. However, if a patient has both fatigue and depression, antidepressants may help [96]. A selective serotonin receptor inhibitor is recommended as a first-line antidepressant [97]. Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF [74]. The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF [98].

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo [99]. Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects [100]. Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy [101]. Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Re-evaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms [28]. Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

Conclusion

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: Bryan Tutt provided editorial assistance.

Corresponding author: Carmelita P. Escalante, MD, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030, [email protected].

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract

• Objective: To review the evidence on interventions for managing cancer-related fatigue (CRF) and provide evidence-based guidance on approaches to its management.
• Methods: Nonsystematic review of the literature.
• Results: Several theories have been proposed to explain the biology of CRF, but there is no single clear mechanism that can be targeted for therapy. The approach to patients begins with screening for fatigue and assessing its intensity, followed by a thorough history and examination to determine whether any reversible medical conditions are contributing to fatigue. Management of underlying medical comorbidities may help some patients. For patients whose fatigue persists, pharmacologic and nonpharmacologic treatment options are available. Pharmacologic options include psychostimulants, such as methylphenidate and modafinil, and corticosteroids. Nonpharmacologic approaches include exercise, cognitive behavior therapy, yoga, acupuncture, and tai chi.
• Conclusion: We recommend an individualized approach, often with a combination of the available options. Patients need to be evaluated periodically to assess their fatigue, and since cancer-related fatigue affects survivors, long-term follow-up is needed.

Key words: fatigue; cancer; pro-inflammatory cytokines; nonpharmacologic; psychostimulants.

Fatigue is a common distressing effect of cancer [1].It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2].” Differences between CRF and fatigue reported by individuals without cancer are that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, ranging between 25% and 99% [2,3]. This variability may be secondary to methods used for screening fatigue and characteristics of the patient groups. In this article, we discuss recognition of CRF and approaches to its management.

Pathophysiology

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of more than 1 mechanism contributing to fatigue in an individual patient.

Central Nervous System Disturbances

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores [4]. Higher levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF [5]. However, there is not enough evidence at this time to support central nervous system disturbance as the main contributing factor to fatigue in cancer patients.

Circadian Rhythm Dysregulation

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways [2]. Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors [6]. These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

Inhibition of Hypothalamic–Pituitary–Adrenal Axis

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis [6]. The inhibition of the HPA axis may occur with higher levels of serotonin as well [7]. The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue [8]. Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue [2].

Skeletal Muscle Effect

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction [9]. ATP infusion improved muscle strength in one trial, but this was not confirmed in another trial [10,11]. Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls [12]. This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles [13,14].

Pro-inflammatory Cytokines

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma [15]. IL-6 was also associated with increased fatigue in breast cancer survivors [16]. Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy [17]. Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients [18,19]. Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients [20]. Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF [21].

Other Hypotheses

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support [22], genetic alterations in immune pathway [23], epigenetic changes [24], accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation [25], elevated vascular endothelial growth factor levels [26], and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction [13] all have been postulated to cause CRF.

Approach to Evaluation and Treatment

Screening

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to underrecognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue [2]. Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials [27]. A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF [2]. This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors [28]. The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue [29,30]. The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day [31]. The 9-item BFI is often used in clinical trials [29]. It measures the severity of fatigue over the previous 24 hours and has been validated in non-English speaking patients [32].

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which measures general, physical, mental, and emotional fatigue domains as well as activity and compares them with those of individuals without cancer [33,34]. The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments [35].

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales [36]. Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic re-evaluation, and moderate and severe fatigue need further evaluation and management [37].

Primary Evaluation

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living [37]. Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse which may cause poor sleep and fatigue.

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below.

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels [38]. Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or autoimmune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes [39]. Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond [40]. Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL [41].

Sleep disturbance. Poor sleep is common in fatigued cancer survivors [42]. Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuroendocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue [43]. Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep [44]. Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep [45]. Melatonin agonists are approved for insomnia in the United states, but not in Europe [46].

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men [47].

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster [48]. A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating of one of these symptoms without addressing other symptoms is not effective [49]. Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy—such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue [50].

Management

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time [51,52]. When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients [53].

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy [54]. CBT interventions that optimize sleep quality may improve fatigue [55]. More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials (RCTs) showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF [56].

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations [57]. Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship [58]. Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve cardiorespiratory fitness, muscle strength, and body composition [57]. Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended not only for younger patients, but also in the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors [59]. In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone [60]. This effect was also shown in an RCT of 160 patients with stage 0 to III breast cancer undergoing radiation therapy [61]. The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits in the physical fatigue but not the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week [62]. An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes [63]. Patients withcomorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy [37]. Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life [64,65]. We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training [66]. Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life [67].

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors [68]. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit not only physical fatigue, but also cognitive fatigue [69]. DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF [70]. More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months [71]. Additional research is needed in this area.

Acupuncture. An RCT in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue [72]. However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue [73]. Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done, with mixed results, and additional research is needed [74]. Currently, there are not sufficient data to recommend any of these modalities.

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF [75–77], but RCTs have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of non-pharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment [37].

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. RCTs of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF [78]. Likewise, in an analysis of 5 RCTs, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo [79]. However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease [80]. Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically [81]. In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner [82]. However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment [83]. Also, other RCTs in patients undergoing adjuvant chemotherapy for breast cancer [84] and patients receiving radiation therapy for brain tumors [85] failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm [86]. Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation [87]. A placebo effect was also noted in patients with multiple myeloma [88] and patients with primary brain tumors [89]. In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue [90]. In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7) [91]. This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional RCTs are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF [37].

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines [92]. In a RCT evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo [93]. A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo [94]. Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis [37].

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups [95].

Antidepressants have failed to demonstrate benefit in CRF without depression [8]. However, if a patient has both fatigue and depression, antidepressants may help [96]. A selective serotonin receptor inhibitor is recommended as a first-line antidepressant [97]. Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF [74]. The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF [98].

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo [99]. Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects [100]. Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy [101]. Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Re-evaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms [28]. Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

Conclusion

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: Bryan Tutt provided editorial assistance.

Corresponding author: Carmelita P. Escalante, MD, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030, [email protected].

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract

• Objective: To review the evidence on interventions for managing cancer-related fatigue (CRF) and provide evidence-based guidance on approaches to its management.
• Methods: Nonsystematic review of the literature.
• Results: Several theories have been proposed to explain the biology of CRF, but there is no single clear mechanism that can be targeted for therapy. The approach to patients begins with screening for fatigue and assessing its intensity, followed by a thorough history and examination to determine whether any reversible medical conditions are contributing to fatigue. Management of underlying medical comorbidities may help some patients. For patients whose fatigue persists, pharmacologic and nonpharmacologic treatment options are available. Pharmacologic options include psychostimulants, such as methylphenidate and modafinil, and corticosteroids. Nonpharmacologic approaches include exercise, cognitive behavior therapy, yoga, acupuncture, and tai chi.
• Conclusion: We recommend an individualized approach, often with a combination of the available options. Patients need to be evaluated periodically to assess their fatigue, and since cancer-related fatigue affects survivors, long-term follow-up is needed.

Key words: fatigue; cancer; pro-inflammatory cytokines; nonpharmacologic; psychostimulants.

Fatigue is a common distressing effect of cancer [1].It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2].” Differences between CRF and fatigue reported by individuals without cancer are that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, ranging between 25% and 99% [2,3]. This variability may be secondary to methods used for screening fatigue and characteristics of the patient groups. In this article, we discuss recognition of CRF and approaches to its management.

Pathophysiology

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of more than 1 mechanism contributing to fatigue in an individual patient.

Central Nervous System Disturbances

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores [4]. Higher levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF [5]. However, there is not enough evidence at this time to support central nervous system disturbance as the main contributing factor to fatigue in cancer patients.

Circadian Rhythm Dysregulation

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways [2]. Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors [6]. These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

Inhibition of Hypothalamic–Pituitary–Adrenal Axis

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis [6]. The inhibition of the HPA axis may occur with higher levels of serotonin as well [7]. The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue [8]. Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue [2].

Skeletal Muscle Effect

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction [9]. ATP infusion improved muscle strength in one trial, but this was not confirmed in another trial [10,11]. Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls [12]. This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles [13,14].

Pro-inflammatory Cytokines

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma [15]. IL-6 was also associated with increased fatigue in breast cancer survivors [16]. Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy [17]. Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients [18,19]. Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients [20]. Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF [21].

Other Hypotheses

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support [22], genetic alterations in immune pathway [23], epigenetic changes [24], accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation [25], elevated vascular endothelial growth factor levels [26], and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction [13] all have been postulated to cause CRF.

Approach to Evaluation and Treatment

Screening

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to underrecognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue [2]. Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials [27]. A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF [2]. This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors [28]. The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue [29,30]. The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day [31]. The 9-item BFI is often used in clinical trials [29]. It measures the severity of fatigue over the previous 24 hours and has been validated in non-English speaking patients [32].

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which measures general, physical, mental, and emotional fatigue domains as well as activity and compares them with those of individuals without cancer [33,34]. The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments [35].

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales [36]. Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic re-evaluation, and moderate and severe fatigue need further evaluation and management [37].

Primary Evaluation

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living [37]. Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse which may cause poor sleep and fatigue.

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below.

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels [38]. Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or autoimmune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes [39]. Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond [40]. Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL [41].

Sleep disturbance. Poor sleep is common in fatigued cancer survivors [42]. Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuroendocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue [43]. Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep [44]. Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep [45]. Melatonin agonists are approved for insomnia in the United states, but not in Europe [46].

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men [47].

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster [48]. A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating of one of these symptoms without addressing other symptoms is not effective [49]. Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy—such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue [50].

Management

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time [51,52]. When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients [53].

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy [54]. CBT interventions that optimize sleep quality may improve fatigue [55]. More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials (RCTs) showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF [56].

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations [57]. Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship [58]. Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve cardiorespiratory fitness, muscle strength, and body composition [57]. Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended not only for younger patients, but also in the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors [59]. In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone [60]. This effect was also shown in an RCT of 160 patients with stage 0 to III breast cancer undergoing radiation therapy [61]. The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits in the physical fatigue but not the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week [62]. An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes [63]. Patients withcomorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy [37]. Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life [64,65]. We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training [66]. Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life [67].

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors [68]. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit not only physical fatigue, but also cognitive fatigue [69]. DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF [70]. More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months [71]. Additional research is needed in this area.

Acupuncture. An RCT in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue [72]. However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue [73]. Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done, with mixed results, and additional research is needed [74]. Currently, there are not sufficient data to recommend any of these modalities.

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF [75–77], but RCTs have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of non-pharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment [37].

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. RCTs of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF [78]. Likewise, in an analysis of 5 RCTs, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo [79]. However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease [80]. Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically [81]. In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner [82]. However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment [83]. Also, other RCTs in patients undergoing adjuvant chemotherapy for breast cancer [84] and patients receiving radiation therapy for brain tumors [85] failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm [86]. Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation [87]. A placebo effect was also noted in patients with multiple myeloma [88] and patients with primary brain tumors [89]. In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue [90]. In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7) [91]. This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional RCTs are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF [37].

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines [92]. In a RCT evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo [93]. A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo [94]. Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis [37].

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups [95].

Antidepressants have failed to demonstrate benefit in CRF without depression [8]. However, if a patient has both fatigue and depression, antidepressants may help [96]. A selective serotonin receptor inhibitor is recommended as a first-line antidepressant [97]. Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF [74]. The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF [98].

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo [99]. Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects [100]. Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy [101]. Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Re-evaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms [28]. Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

Conclusion

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: Bryan Tutt provided editorial assistance.

Corresponding author: Carmelita P. Escalante, MD, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030, [email protected].

Financial disclosures: None.

Take-Home Points

• Arthroplasty is a rarely utilized and, therefore, a rarely reported treatment for distal femur fractures.
• Arthroplasty carries certain advantages over fixation, including earlier weight-bearing, a benefit for elderly individuals.
• Arthroplasty is more often described in situations of comminution, often necessitating constrained prostheses.
• It is not unreasonable to utilize arthroplasty in extra-articular fractures in poor-quality bone, which can take the form of unconstrained prosthesis and supplemental fixation.

• The true complication rate is unclear, given that the few papers reporting high complication rates were in sicker populations.

Distal femur fractures (DFFs) in the elderly historically were difficult to treat because of osteoporotic bone, comminution, and intra-articular involvement. DFFs in minimally ambulatory patients were once treated nonoperatively, with traction or immobilization,^1,2 but surgery is now considered for displaced and unstable fractures, even in myelopathic and nonambulatory patients, to provide pain relief, ease mobility, and decrease the risks associated with prolonged bed rest.¹ Options are constantly evolving, but poor knee function, malunion, nonunion, prolonged immobilization, implant failure, and high morbidity and mortality rates have been reported in several studies regardless of fixation method.

Arthritis after DFF has been reported at rates of 36% to 50% by long-term follow-up.^3-5 However, total knee arthroplasty (TKA) for posttraumatic arthritis is more complex because of scarring, arthrofibrosis, malunion, nonunion, and the frequent need for hardware removal. These cases have a higher incidence of infection, aseptic loosening, stiffness,⁶ and skin necrosis.⁷ Primary TKA is a rarely used treatment for acute DFF. Several authors have recommended primary TKA for patients with intra-articular DFFs and preexisting osteoarthritis or rheumatoid arthritis, severe comminution, or poor bone stock.^7-22 Compared with open reduction and internal fixation (ORIF), primary TKA may allow for earlier mobility and weight-bearing and thereby reduce the rates of complications (eg, respiratory failure, deep vein thrombosis, pulmonary embolism) associated with prolonged immobilization.²³As the literature on TKA for acute DFF is scant, and to our knowledge there are no clear indications or guidelines, we performed a systematic review to determine whether TKA has been successful in relieving pain and restoring knee function. In this article, we discuss the indications, implant options, technical considerations, complications, and results (eg, range of motion [ROM], ambulatory status) associated with these procedures.

Methods

On December 1, 2015, we searched the major databases Medline, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library for articles published since 1950. In our searches, we used the conjoint term knee arthroplasty with femur fracture, and knee replacement with femur fracture. Specifically, we queried: ((“knee replacement” OR “knee arthroplasty”) AND (intercondylar OR supracondylar OR femoral OR femur) AND fracture) NOT arthrodesis NOT periprosthetic NOT “posttraumatic arthritis” NOT osteotomy. We also hand-searched the current website of JBJS [Journal of Bone and Joint Surgery] Case Connector, a major case-report repository that was launched in 2011 but is not currently indexed by Medline.

All citations were imported to RefWorks for management and for removal of duplicates. Each article underwent screening and review by Dr. Chen and Dr. Li. Articles were included if titles were relevant to arthroplasty as treatment for acute (within 1 month) DFF. Articles and cases were excluded if they were reviews, published in languages other than English, animal studies, studies regarding nonacute (>3 months or nonunion) DFFs or periprosthetic fractures, or studies that considered only treatments other than TKA (ie, plate osteosynthesis).

Full-text publications were obtained and independently reviewed by Dr. Chen and Dr. Li for relevance and satisfaction of inclusion criteria. Disagreements were resolved by discussion. Given the rarity of publications on the treatment, all study designs from level I to level IV were included.

The same 2 reviewers extracted the data into prearranged summary tables. Data included study size, patient demographics, AO/OTA (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association) fracture type either reported or assessed by description and imaging (33A, extra-articular; 33B, partial articular with 1 intact condyle; 33C, complete articular with both condyles involved), baseline comorbidity, implant used and fracture treatment (if separate from arthroplasty), postoperative regimen, respective outcomes, and complication rates.

Results

We identified 728 articles: 389 through Medline, 294 through EMBASE, and 45 through the Cochrane Library (Figure 1).

The current evidence regarding primary TKA for acute DFF is primarily level IV (Table 1). Only 1 level III study¹⁶ compared TKA with ORIF. Three case series^11,19,24 met our inclusion criteria (Table 1, Table 2). In addition, 5 case series involved patients who met our criteria, but these studies did not separately report results for DFFs and proximal tibia fractures,^9,20-22 or separately for acute fractures and nonunions or ORIF failures.⁸

Discussion

DFFs in the elderly historically were difficult to treat. Reported outcomes are largely favorable, but, even with newer plate designs, catastrophic failures still occur in the absence of bony union.^26,27 After ORIF, patients’ weight-bearing is often restricted for 12 weeks or longer²⁸—a protocol that is undesirable in elderly patients, especially given that the rate of mortality 1 year after these fractures has been found to be as high as 25%.²⁹

Arthroplasty for DFFs—performed either with ORIF, or independently with a constrained implant—is a documented treatment modality, but the evidence is poor, and results have been mixed. Patients who received hinged TKA with major fracture resection had higher complication rates.^8,11,22,24 However, the problems were mostly medical, not associated with surgical technique. Appleton and colleagues²⁴ found a higher than expected 1-year mortality rate, 41%, but used an unhealthy baseline population (44% cognitive impairment, 17% nonambulatory before injury).Although Boureau and colleagues²² found a 1-year mortality rate of 30%, only 1 in 10 deaths was attributable to a perioperative complication. Among the remaining cases involving resection and megaprostheses for previously ambulatory patients, only 1 perioperative death was recorded (Table 2).^11,12,16,18 Therefore, the risks associated with patients’ baseline health and ambulatory status must be weighed against the benefits of aggressive arthroplasty.

An overwhelming majority of 33C fractures were treated with megaprostheses—a finding perhaps attributable to the higher likelihood that patients with osteoporosis have intra-articular, comminuted injuries. In addition, surgeons may have been more likely to indicate 33C fractures for joint replacement, whereas 33A and 33B patterns were more amenable to fracture fixation.^17,18 Interestingly, few type B fractures (0 in primary analysis and only 9 of 67 cases in Table 3) were treated with megaprostheses. In these situations, 1 condyle and ligamentous constraint remain intact, reducing the need for a constrained implant.

There were no reports of atraumatic or aseptic loosening, though use of rotating platforms with linked prostheses helps minimize this complication. Also surprising is the lack of nonunions in any of the reviewed studies, as nonunion is one of the most devastating complications of ORIF. Only 1 superficial and 2 deep infections were reported in all of the literature—representing 1.8% of all cases, which is comparable to the rate for elective primary TKA.³⁰In elderly patients with significant comorbidities, the main surgical goals are to minimize operative time and reduce time to mobility. It is therefore imperative to keep in mind that arthroplasty is elective. However, functional results of primary TKA for DFF may be more encouraging for healthier patients, as many can achieve satisfactory ROM and early weight-bearing. Therefore, TKA for DFF may benefit healthy and ambulatory patients in the setting of intra-articular comminution. Whether this treatment affects mortality rates remains to be seen.

There were several limitations to this study. First, the literature on the topic is scant. Second, exclusion criteria were kept lax to allow for inclusion of all treatments. This came at a cost to internal validity, given the heterogeneous population and differences in comorbidities between studies. Fracture classification was inconsistent as well: Although AO/OTA classification was dominant, descriptive classifications were used in several cases^7,10,12 (these descriptions, however, were sufficient for assigning equivalent AO/OTA classes). Details on preoperative functional status and comorbidity status and on postoperative protocols were also limited, though ROM and ambulatory status were provided in most studies. Last, most of these studies were single case reports or case series, so there may be reporting bias in the body of the literature, as reflected in the discrepancies between encouraging case reports and concerning case series with longer follow-up. Such bias can be avoided with larger, controlled sampling and adequate follow-up.

TKA should be considered for acute DFF in patients who have knee arthritis and are able to tolerate the physiological load of the surgery. In the choice of implant design, several factors should be considered, including bone quality, articular involvement, degree of comminution, and ligamentous injury. Unconstrained knee designs should be considered in cases in which the fracture pattern appears stable and the collateral ligaments are intact (eg, 33A and 33BB fractures). Megaprostheses, which may allow for immediate weight-bearing but require considerable bone resection, would be beneficial in 33C fractures and in fractures with ligamentous compromise. However, their complication rates are unclear, and comparative studies are needed to investigate whether the rates are higher for these patients than for patients treated more traditionally.

Am J Orthop. 2017;46(3):E163-E171. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Arthroplasty is a rarely utilized and, therefore, a rarely reported treatment for distal femur fractures.
• Arthroplasty carries certain advantages over fixation, including earlier weight-bearing, a benefit for elderly individuals.
• Arthroplasty is more often described in situations of comminution, often necessitating constrained prostheses.
• It is not unreasonable to utilize arthroplasty in extra-articular fractures in poor-quality bone, which can take the form of unconstrained prosthesis and supplemental fixation.

• The true complication rate is unclear, given that the few papers reporting high complication rates were in sicker populations.

Distal femur fractures (DFFs) in the elderly historically were difficult to treat because of osteoporotic bone, comminution, and intra-articular involvement. DFFs in minimally ambulatory patients were once treated nonoperatively, with traction or immobilization,^1,2 but surgery is now considered for displaced and unstable fractures, even in myelopathic and nonambulatory patients, to provide pain relief, ease mobility, and decrease the risks associated with prolonged bed rest.¹ Options are constantly evolving, but poor knee function, malunion, nonunion, prolonged immobilization, implant failure, and high morbidity and mortality rates have been reported in several studies regardless of fixation method.

Arthritis after DFF has been reported at rates of 36% to 50% by long-term follow-up.^3-5 However, total knee arthroplasty (TKA) for posttraumatic arthritis is more complex because of scarring, arthrofibrosis, malunion, nonunion, and the frequent need for hardware removal. These cases have a higher incidence of infection, aseptic loosening, stiffness,⁶ and skin necrosis.⁷ Primary TKA is a rarely used treatment for acute DFF. Several authors have recommended primary TKA for patients with intra-articular DFFs and preexisting osteoarthritis or rheumatoid arthritis, severe comminution, or poor bone stock.^7-22 Compared with open reduction and internal fixation (ORIF), primary TKA may allow for earlier mobility and weight-bearing and thereby reduce the rates of complications (eg, respiratory failure, deep vein thrombosis, pulmonary embolism) associated with prolonged immobilization.²³As the literature on TKA for acute DFF is scant, and to our knowledge there are no clear indications or guidelines, we performed a systematic review to determine whether TKA has been successful in relieving pain and restoring knee function. In this article, we discuss the indications, implant options, technical considerations, complications, and results (eg, range of motion [ROM], ambulatory status) associated with these procedures.

Methods

On December 1, 2015, we searched the major databases Medline, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library for articles published since 1950. In our searches, we used the conjoint term knee arthroplasty with femur fracture, and knee replacement with femur fracture. Specifically, we queried: ((“knee replacement” OR “knee arthroplasty”) AND (intercondylar OR supracondylar OR femoral OR femur) AND fracture) NOT arthrodesis NOT periprosthetic NOT “posttraumatic arthritis” NOT osteotomy. We also hand-searched the current website of JBJS [Journal of Bone and Joint Surgery] Case Connector, a major case-report repository that was launched in 2011 but is not currently indexed by Medline.

All citations were imported to RefWorks for management and for removal of duplicates. Each article underwent screening and review by Dr. Chen and Dr. Li. Articles were included if titles were relevant to arthroplasty as treatment for acute (within 1 month) DFF. Articles and cases were excluded if they were reviews, published in languages other than English, animal studies, studies regarding nonacute (>3 months or nonunion) DFFs or periprosthetic fractures, or studies that considered only treatments other than TKA (ie, plate osteosynthesis).

Full-text publications were obtained and independently reviewed by Dr. Chen and Dr. Li for relevance and satisfaction of inclusion criteria. Disagreements were resolved by discussion. Given the rarity of publications on the treatment, all study designs from level I to level IV were included.

The same 2 reviewers extracted the data into prearranged summary tables. Data included study size, patient demographics, AO/OTA (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association) fracture type either reported or assessed by description and imaging (33A, extra-articular; 33B, partial articular with 1 intact condyle; 33C, complete articular with both condyles involved), baseline comorbidity, implant used and fracture treatment (if separate from arthroplasty), postoperative regimen, respective outcomes, and complication rates.

Results

We identified 728 articles: 389 through Medline, 294 through EMBASE, and 45 through the Cochrane Library (Figure 1).

The current evidence regarding primary TKA for acute DFF is primarily level IV (Table 1). Only 1 level III study¹⁶ compared TKA with ORIF. Three case series^11,19,24 met our inclusion criteria (Table 1, Table 2). In addition, 5 case series involved patients who met our criteria, but these studies did not separately report results for DFFs and proximal tibia fractures,^9,20-22 or separately for acute fractures and nonunions or ORIF failures.⁸

Discussion

DFFs in the elderly historically were difficult to treat. Reported outcomes are largely favorable, but, even with newer plate designs, catastrophic failures still occur in the absence of bony union.^26,27 After ORIF, patients’ weight-bearing is often restricted for 12 weeks or longer²⁸—a protocol that is undesirable in elderly patients, especially given that the rate of mortality 1 year after these fractures has been found to be as high as 25%.²⁹

Arthroplasty for DFFs—performed either with ORIF, or independently with a constrained implant—is a documented treatment modality, but the evidence is poor, and results have been mixed. Patients who received hinged TKA with major fracture resection had higher complication rates.^8,11,22,24 However, the problems were mostly medical, not associated with surgical technique. Appleton and colleagues²⁴ found a higher than expected 1-year mortality rate, 41%, but used an unhealthy baseline population (44% cognitive impairment, 17% nonambulatory before injury).Although Boureau and colleagues²² found a 1-year mortality rate of 30%, only 1 in 10 deaths was attributable to a perioperative complication. Among the remaining cases involving resection and megaprostheses for previously ambulatory patients, only 1 perioperative death was recorded (Table 2).^11,12,16,18 Therefore, the risks associated with patients’ baseline health and ambulatory status must be weighed against the benefits of aggressive arthroplasty.

An overwhelming majority of 33C fractures were treated with megaprostheses—a finding perhaps attributable to the higher likelihood that patients with osteoporosis have intra-articular, comminuted injuries. In addition, surgeons may have been more likely to indicate 33C fractures for joint replacement, whereas 33A and 33B patterns were more amenable to fracture fixation.^17,18 Interestingly, few type B fractures (0 in primary analysis and only 9 of 67 cases in Table 3) were treated with megaprostheses. In these situations, 1 condyle and ligamentous constraint remain intact, reducing the need for a constrained implant.

There were no reports of atraumatic or aseptic loosening, though use of rotating platforms with linked prostheses helps minimize this complication. Also surprising is the lack of nonunions in any of the reviewed studies, as nonunion is one of the most devastating complications of ORIF. Only 1 superficial and 2 deep infections were reported in all of the literature—representing 1.8% of all cases, which is comparable to the rate for elective primary TKA.³⁰In elderly patients with significant comorbidities, the main surgical goals are to minimize operative time and reduce time to mobility. It is therefore imperative to keep in mind that arthroplasty is elective. However, functional results of primary TKA for DFF may be more encouraging for healthier patients, as many can achieve satisfactory ROM and early weight-bearing. Therefore, TKA for DFF may benefit healthy and ambulatory patients in the setting of intra-articular comminution. Whether this treatment affects mortality rates remains to be seen.

There were several limitations to this study. First, the literature on the topic is scant. Second, exclusion criteria were kept lax to allow for inclusion of all treatments. This came at a cost to internal validity, given the heterogeneous population and differences in comorbidities between studies. Fracture classification was inconsistent as well: Although AO/OTA classification was dominant, descriptive classifications were used in several cases^7,10,12 (these descriptions, however, were sufficient for assigning equivalent AO/OTA classes). Details on preoperative functional status and comorbidity status and on postoperative protocols were also limited, though ROM and ambulatory status were provided in most studies. Last, most of these studies were single case reports or case series, so there may be reporting bias in the body of the literature, as reflected in the discrepancies between encouraging case reports and concerning case series with longer follow-up. Such bias can be avoided with larger, controlled sampling and adequate follow-up.

TKA should be considered for acute DFF in patients who have knee arthritis and are able to tolerate the physiological load of the surgery. In the choice of implant design, several factors should be considered, including bone quality, articular involvement, degree of comminution, and ligamentous injury. Unconstrained knee designs should be considered in cases in which the fracture pattern appears stable and the collateral ligaments are intact (eg, 33A and 33BB fractures). Megaprostheses, which may allow for immediate weight-bearing but require considerable bone resection, would be beneficial in 33C fractures and in fractures with ligamentous compromise. However, their complication rates are unclear, and comparative studies are needed to investigate whether the rates are higher for these patients than for patients treated more traditionally.

Am J Orthop. 2017;46(3):E163-E171. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Arthroplasty is a rarely utilized and, therefore, a rarely reported treatment for distal femur fractures.
• Arthroplasty carries certain advantages over fixation, including earlier weight-bearing, a benefit for elderly individuals.
• Arthroplasty is more often described in situations of comminution, often necessitating constrained prostheses.
• It is not unreasonable to utilize arthroplasty in extra-articular fractures in poor-quality bone, which can take the form of unconstrained prosthesis and supplemental fixation.

• The true complication rate is unclear, given that the few papers reporting high complication rates were in sicker populations.

Distal femur fractures (DFFs) in the elderly historically were difficult to treat because of osteoporotic bone, comminution, and intra-articular involvement. DFFs in minimally ambulatory patients were once treated nonoperatively, with traction or immobilization,^1,2 but surgery is now considered for displaced and unstable fractures, even in myelopathic and nonambulatory patients, to provide pain relief, ease mobility, and decrease the risks associated with prolonged bed rest.¹ Options are constantly evolving, but poor knee function, malunion, nonunion, prolonged immobilization, implant failure, and high morbidity and mortality rates have been reported in several studies regardless of fixation method.

Arthritis after DFF has been reported at rates of 36% to 50% by long-term follow-up.^3-5 However, total knee arthroplasty (TKA) for posttraumatic arthritis is more complex because of scarring, arthrofibrosis, malunion, nonunion, and the frequent need for hardware removal. These cases have a higher incidence of infection, aseptic loosening, stiffness,⁶ and skin necrosis.⁷ Primary TKA is a rarely used treatment for acute DFF. Several authors have recommended primary TKA for patients with intra-articular DFFs and preexisting osteoarthritis or rheumatoid arthritis, severe comminution, or poor bone stock.^7-22 Compared with open reduction and internal fixation (ORIF), primary TKA may allow for earlier mobility and weight-bearing and thereby reduce the rates of complications (eg, respiratory failure, deep vein thrombosis, pulmonary embolism) associated with prolonged immobilization.²³As the literature on TKA for acute DFF is scant, and to our knowledge there are no clear indications or guidelines, we performed a systematic review to determine whether TKA has been successful in relieving pain and restoring knee function. In this article, we discuss the indications, implant options, technical considerations, complications, and results (eg, range of motion [ROM], ambulatory status) associated with these procedures.

Methods

On December 1, 2015, we searched the major databases Medline, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library for articles published since 1950. In our searches, we used the conjoint term knee arthroplasty with femur fracture, and knee replacement with femur fracture. Specifically, we queried: ((“knee replacement” OR “knee arthroplasty”) AND (intercondylar OR supracondylar OR femoral OR femur) AND fracture) NOT arthrodesis NOT periprosthetic NOT “posttraumatic arthritis” NOT osteotomy. We also hand-searched the current website of JBJS [Journal of Bone and Joint Surgery] Case Connector, a major case-report repository that was launched in 2011 but is not currently indexed by Medline.

All citations were imported to RefWorks for management and for removal of duplicates. Each article underwent screening and review by Dr. Chen and Dr. Li. Articles were included if titles were relevant to arthroplasty as treatment for acute (within 1 month) DFF. Articles and cases were excluded if they were reviews, published in languages other than English, animal studies, studies regarding nonacute (>3 months or nonunion) DFFs or periprosthetic fractures, or studies that considered only treatments other than TKA (ie, plate osteosynthesis).

Full-text publications were obtained and independently reviewed by Dr. Chen and Dr. Li for relevance and satisfaction of inclusion criteria. Disagreements were resolved by discussion. Given the rarity of publications on the treatment, all study designs from level I to level IV were included.

The same 2 reviewers extracted the data into prearranged summary tables. Data included study size, patient demographics, AO/OTA (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association) fracture type either reported or assessed by description and imaging (33A, extra-articular; 33B, partial articular with 1 intact condyle; 33C, complete articular with both condyles involved), baseline comorbidity, implant used and fracture treatment (if separate from arthroplasty), postoperative regimen, respective outcomes, and complication rates.

Results

We identified 728 articles: 389 through Medline, 294 through EMBASE, and 45 through the Cochrane Library (Figure 1).

The current evidence regarding primary TKA for acute DFF is primarily level IV (Table 1). Only 1 level III study¹⁶ compared TKA with ORIF. Three case series^11,19,24 met our inclusion criteria (Table 1, Table 2). In addition, 5 case series involved patients who met our criteria, but these studies did not separately report results for DFFs and proximal tibia fractures,^9,20-22 or separately for acute fractures and nonunions or ORIF failures.⁸

Discussion

DFFs in the elderly historically were difficult to treat. Reported outcomes are largely favorable, but, even with newer plate designs, catastrophic failures still occur in the absence of bony union.^26,27 After ORIF, patients’ weight-bearing is often restricted for 12 weeks or longer²⁸—a protocol that is undesirable in elderly patients, especially given that the rate of mortality 1 year after these fractures has been found to be as high as 25%.²⁹

Arthroplasty for DFFs—performed either with ORIF, or independently with a constrained implant—is a documented treatment modality, but the evidence is poor, and results have been mixed. Patients who received hinged TKA with major fracture resection had higher complication rates.^8,11,22,24 However, the problems were mostly medical, not associated with surgical technique. Appleton and colleagues²⁴ found a higher than expected 1-year mortality rate, 41%, but used an unhealthy baseline population (44% cognitive impairment, 17% nonambulatory before injury).Although Boureau and colleagues²² found a 1-year mortality rate of 30%, only 1 in 10 deaths was attributable to a perioperative complication. Among the remaining cases involving resection and megaprostheses for previously ambulatory patients, only 1 perioperative death was recorded (Table 2).^11,12,16,18 Therefore, the risks associated with patients’ baseline health and ambulatory status must be weighed against the benefits of aggressive arthroplasty.

An overwhelming majority of 33C fractures were treated with megaprostheses—a finding perhaps attributable to the higher likelihood that patients with osteoporosis have intra-articular, comminuted injuries. In addition, surgeons may have been more likely to indicate 33C fractures for joint replacement, whereas 33A and 33B patterns were more amenable to fracture fixation.^17,18 Interestingly, few type B fractures (0 in primary analysis and only 9 of 67 cases in Table 3) were treated with megaprostheses. In these situations, 1 condyle and ligamentous constraint remain intact, reducing the need for a constrained implant.

There were no reports of atraumatic or aseptic loosening, though use of rotating platforms with linked prostheses helps minimize this complication. Also surprising is the lack of nonunions in any of the reviewed studies, as nonunion is one of the most devastating complications of ORIF. Only 1 superficial and 2 deep infections were reported in all of the literature—representing 1.8% of all cases, which is comparable to the rate for elective primary TKA.³⁰In elderly patients with significant comorbidities, the main surgical goals are to minimize operative time and reduce time to mobility. It is therefore imperative to keep in mind that arthroplasty is elective. However, functional results of primary TKA for DFF may be more encouraging for healthier patients, as many can achieve satisfactory ROM and early weight-bearing. Therefore, TKA for DFF may benefit healthy and ambulatory patients in the setting of intra-articular comminution. Whether this treatment affects mortality rates remains to be seen.

There were several limitations to this study. First, the literature on the topic is scant. Second, exclusion criteria were kept lax to allow for inclusion of all treatments. This came at a cost to internal validity, given the heterogeneous population and differences in comorbidities between studies. Fracture classification was inconsistent as well: Although AO/OTA classification was dominant, descriptive classifications were used in several cases^7,10,12 (these descriptions, however, were sufficient for assigning equivalent AO/OTA classes). Details on preoperative functional status and comorbidity status and on postoperative protocols were also limited, though ROM and ambulatory status were provided in most studies. Last, most of these studies were single case reports or case series, so there may be reporting bias in the body of the literature, as reflected in the discrepancies between encouraging case reports and concerning case series with longer follow-up. Such bias can be avoided with larger, controlled sampling and adequate follow-up.

TKA should be considered for acute DFF in patients who have knee arthritis and are able to tolerate the physiological load of the surgery. In the choice of implant design, several factors should be considered, including bone quality, articular involvement, degree of comminution, and ligamentous injury. Unconstrained knee designs should be considered in cases in which the fracture pattern appears stable and the collateral ligaments are intact (eg, 33A and 33BB fractures). Megaprostheses, which may allow for immediate weight-bearing but require considerable bone resection, would be beneficial in 33C fractures and in fractures with ligamentous compromise. However, their complication rates are unclear, and comparative studies are needed to investigate whether the rates are higher for these patients than for patients treated more traditionally.

Am J Orthop. 2017;46(3):E163-E171. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

IN THIS ARTICLE

• Staging endometriosis
• Medications for treating endometriosis
• Complications

Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity (ie, endometrial implants), most commonly found on the ovaries. Although its pathophysiology is not completely understood, the disease is associated with dysmenorrhea, dyspareunia, and infertility.^1,2 Endometriosis is an estrogen-dependent disorder, predominantly affecting women of childbearing age. It occurs in 10% to 15% of the general female population, but prevalence is even higher (35% to 50%) among women who experience pelvic pain and/or infertility.^1-4 Although endometriosis mainly affects women in their mid-to-late 20s, it can also manifest in adolescence.^3,5 Nearly half of all adolescents with intractable dysmenorrhea are diagnosed with endometriosis.⁵

ETIOLOGY

The etiology of endometriosis, while not completely understood, is likely multifactorial. Factors that may influence its development include gene expression, tissue response to hormones, neuronal tissue involvement, lack of protective factors, inflammation, and cellular oxidative stress.^6,7

Several theories regarding the etiology of endometriosis have been proposed; the most widely accepted is the transplantation theory, which suggests that endometriosis results from retrograde flow of menstrual tissue through the fallopian tubes. During menstruation, fragments of the endometrium are driven through the fallopian tubes and into the pelvic cavity, where they can implant onto the pelvic structures, leading to further growth and invasion.^2,6,8 Women who have polymenorrhea, prolonged menses, and early menarche therefore have an increased risk for endometriosis.⁸ This theory does not account for the fact that although nearly 90% of women have some elements of retrograde menstrual flow, only a fraction of them develop endometriosis.⁶

Two other plausible explanations are the coelomic metaplasia and embryonic rest theories. In the coelomic metaplasia theory, the mesothelium (coelomic epithelium)—which encases the ovaries—invaginates into the ovaries and undergoes a metaplastic change to endometrial tissue. This could explain the development of endometriosis in patients with the congenital malformation Müllerian agenesis. In the embryonic rest theory, Müllerian remnants in the rectovaginal area, left behind by the Müllerian duct system, have the potential to differentiate into endometrial tissue.^2,5,6,8

Another theory involving lymphatic or hematologic spread has been proposed, which would explain the presence of endometrial implants at sites distant from the uterus (eg, the pleural cavity and brain). However, this theory is not widely understood.⁶

The two most recent hypotheses on endometriosis are associated with an abnormal immune system and a possible genetic predisposition. The peritoneal fluid of women with endometriosis has different levels of prostanoids, cytokines, growth factors, and interleukins than that of women who do not have the condition. It is uncertain whether the relationship between peritoneal fluid changes and endometriosis is causal.⁶ A genetic correlation has been suggested, based on an increased prevalence of endometriosis in women with an affected first-degree relative; in a case-control study on family incidence of endometriosis, 5.9% to 9.6% of first-degree relatives and 1.3% of second-degree relatives were affected.⁹ The Oxford Endometriosis Gene (OXEGENE) study is currently investigating susceptible loci for endometriosis genes, which could provide a better understanding of the disease process.⁶

CLINICAL PRESENTATION

The most common symptoms of endometriosis are dysmenorrhea, deep dyspareunia, chronic pelvic pain, and infertility, but 20% to 25% of affected women are asymptomatic.^4,10,11 Pelvic pain in women most often heralds onset of menses and worsens during menstruation.¹ Other symptoms include back pain, dyschezia, dysuria, nausea, lethargy, and chronic fatigue.^4,8,10

Endometriosis is concomitant with infertility; endometrial adhesions that attach to pelvic organs cause distortion of pelvic structures and impaired ovum release and pick-up, and are believed to reduce fecundity. Additionally, women with endometriosis have low ovarian reserve and low-quality oocytes.^6,8 Altered chemical elements (ie, prostanoids, cytokines, growth factors, and interleukins) may also contribute to endometrial-related infertility; intrapelvic growth factors could affect the fallopian tubes or pelvic environment, and thus the oocytes in a similar fashion.⁶

In adolescents, endometriosis can present as cyclic or acyclic pain; severe dysmenorrhea; dysmenorrhea that responds poorly to medications (eg, oral contraceptive pills [OCPs] or NSAIDs); and prolonged menstruation with premenstrual spotting.¹

The physical exam may reveal tender nodules in the posterior vaginal fornix; cervical motion tenderness; a fixed uterus, cervix, or adnexa; uterine motion tenderness; thickening, pain, tenderness, or nodularity of the uterosacral ligament; or tender adnexal masses due to endometriomas.^8,10

PATHOLOGIC CHARACTERISTICS AND STAGING

Gross pathology of endometriosis varies based on duration of disease and depth of implants or lesions. Implants range from punctate foci to small stellate patches that vary in color but typically measure less than 2 cm. They manifest most commonly in the ovaries, followed by the anterior and posterior cul-de-sac, posterior broad ligament, and uterosacral ligament. Implants can also be located on the uterus, fallopian tubes, sigmoid colon, ureter, small intestine, lungs, and brain (see Figure).³

Due to recurrent cyclic hemorrhage within a deep implant, endometriomas typically appear in the ovaries, entirely replacing normal ovarian tissue. Endometriomas are composed of dark, thick, degenerated blood products that result in a brown cyst—hence their designation as chocolate cysts. Microscopically, they are comprised of endometrial glands, stroma, and sometimes smooth muscle.³

Staging of endometriosis is determined by the volume, depth, location, and size of the implants (see Table 1). It is important to note that staging does not necessarily reflect symptom severity.¹²

DIAGNOSIS

There are several approaches to the diagnostic evaluation of endometriosis, all of which should be guided by the clinical presentation and physical examination. Clinical characteristics can be nonspecific and highly variable, warranting more reliable diagnostic methods.

Laparoscopy is the diagnostic gold standard for endometriosis, and biopsy of implants revealing endometrial tissue is confirmatory. Less invasive diagnostic methods include ultrasound and MRI—but without confirmatory histologic sampling, these only yield a presumptive diagnosis.

With ultrasonography, a transvaginal approach should be taken. While endometriomas have a variety of presentations on ultrasound, most appear as a homogenous, hypoechoic, focal lesion within the ovary. MRI has greater specificity than ultrasound for diagnosis of endometriomas. However, “shading,” or loss of signal, within an endometrioma is a feature commonly found on MRI.³

Other tests that aid in the diagnosis, but are not definitive, include sedimentation rate and tumor marker CA-125. These are both commonly elevated in patients with endometriosis. Measurement of CA-125 is helpful for identifying patients with infertility and severe endometriosis, who would therefore benefit from early surgical intervention.⁸

TREATMENT

There is no permanent cure for endometriosis; treatment entails nonsurgical and surgical approaches to symptom resolution. Treatment is directed by the patient’s desire to maintain fertility.

Conservative treatment of pelvic pain with NSAIDs is a common approach. Progestins are also used to treat pelvic pain; they create an acyclic, hypo-estrogenic environment by blocking ovarian estrogen secretion and subsequent endometrial cell proliferation. In addition to alleviating pain, progestins also prevent disease recurrence after surgery.^2,13 Options include combination OCPs, levonorgestrel intrauterine devices, medroxyprogesterone acetate, and etonogestrel implants. Combination OCPs and medroxyprogesterone acetate are considered to be firstline treatment.⁸

Gonadotropin-releasing hormone agonists (GnRH-a), such as leuprolide acetate, and androgenic agents, such as danocrine, are also indicated for relief of pain resulting from biopsy-confirmed endometriosis. Danocrine has been shown to ameliorate pain in up to 92% of patients.^3,8 Other unconventional treatment modalities include aromatase inhibitors, selective estrogen receptor modulators, anti-inflammatory agents, and immunomodulators.² For an outline of the medication choices and their mechanisms of action, see Table 2.

Surgery, or ablation of the implants, is another viable treatment option; it can be performed via laparoscopy or laparotomy. Although the success rate is high, implants recur in 28% of patients 18 months after surgery and in 40% of patients after nine years; 40% to 50% of patients have adhesion recurrence.³

Patients who have concomitant infertility can be treated with advanced reproductive techniques, including intrauterine insemination and ovarian hyperstimulation. The monthly fecundity rate with such techniques is 9% to 18%.³ Laparoscopic surgery with ablation of endometrial implants may increase fertility in patients with endometriosis.⁸

Hysterectomy and bilateral salpingo-oophorectomy are definitive treatment options reserved for patients with intractable pain and those who do not wish to maintain fertility.^3,8 Recurrent symptoms occur in 10% of patients 10 years after hysterectomy with bilateral salpingectomy, compared with 62% of those who have hysterectomy alone.⁸ Complete surgical removal of endometriomas, and ovary if affected, can reduce risk for epithelial ovarian cancer in the future.²

COMPLICATIONS

Adhesions are a common complication of endometriosis. Ultrasound can be used for diagnosis and to determine whether pelvic organs are fixed (ie, fixed retroverted uterus). MRI may also be used; adhesions appear as “speculated low-signal-intensity stranding that obscures organ interfaces.”³ Other suggestive findings on MRI include posterior displacement of the pelvic organs, elevation of the posterior vaginal fornix, hydrosalpinx, loculated fluid collections, and angulated bowel loops.³

Malignant transformation is rare, affecting fewer than 1% of patients with endometriosis. Most malignancies arise from ovarian endometriosis and can be related to unopposed estrogen therapy; they are typically large and have a solid component. The most common endometriosis-related malignant neoplasm is endometrioid carcinoma, followed by clear-cell carcinoma.³

CONCLUSION

Patients with endometriosis often present with complaints such as dysmenorrhea, deep dyspareunia, and chronic pelvic pain, but surgical and histologic findings indicate that symptom severity does not necessarily equate to disease severity. Definitive diagnosis requires an invasive surgical procedure.

In the absence of a cure, endometriosis treatment focuses on symptom control and improvement in quality of life. Familiarity with the disease process and knowledge of treatment options will help health care providers achieve this goal for patients who experience the potentially life-altering effects of endometriosis.

IN THIS ARTICLE

• Staging endometriosis
• Medications for treating endometriosis
• Complications

Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity (ie, endometrial implants), most commonly found on the ovaries. Although its pathophysiology is not completely understood, the disease is associated with dysmenorrhea, dyspareunia, and infertility.^1,2 Endometriosis is an estrogen-dependent disorder, predominantly affecting women of childbearing age. It occurs in 10% to 15% of the general female population, but prevalence is even higher (35% to 50%) among women who experience pelvic pain and/or infertility.^1-4 Although endometriosis mainly affects women in their mid-to-late 20s, it can also manifest in adolescence.^3,5 Nearly half of all adolescents with intractable dysmenorrhea are diagnosed with endometriosis.⁵

ETIOLOGY

The etiology of endometriosis, while not completely understood, is likely multifactorial. Factors that may influence its development include gene expression, tissue response to hormones, neuronal tissue involvement, lack of protective factors, inflammation, and cellular oxidative stress.^6,7

Several theories regarding the etiology of endometriosis have been proposed; the most widely accepted is the transplantation theory, which suggests that endometriosis results from retrograde flow of menstrual tissue through the fallopian tubes. During menstruation, fragments of the endometrium are driven through the fallopian tubes and into the pelvic cavity, where they can implant onto the pelvic structures, leading to further growth and invasion.^2,6,8 Women who have polymenorrhea, prolonged menses, and early menarche therefore have an increased risk for endometriosis.⁸ This theory does not account for the fact that although nearly 90% of women have some elements of retrograde menstrual flow, only a fraction of them develop endometriosis.⁶

Two other plausible explanations are the coelomic metaplasia and embryonic rest theories. In the coelomic metaplasia theory, the mesothelium (coelomic epithelium)—which encases the ovaries—invaginates into the ovaries and undergoes a metaplastic change to endometrial tissue. This could explain the development of endometriosis in patients with the congenital malformation Müllerian agenesis. In the embryonic rest theory, Müllerian remnants in the rectovaginal area, left behind by the Müllerian duct system, have the potential to differentiate into endometrial tissue.^2,5,6,8

Another theory involving lymphatic or hematologic spread has been proposed, which would explain the presence of endometrial implants at sites distant from the uterus (eg, the pleural cavity and brain). However, this theory is not widely understood.⁶

The two most recent hypotheses on endometriosis are associated with an abnormal immune system and a possible genetic predisposition. The peritoneal fluid of women with endometriosis has different levels of prostanoids, cytokines, growth factors, and interleukins than that of women who do not have the condition. It is uncertain whether the relationship between peritoneal fluid changes and endometriosis is causal.⁶ A genetic correlation has been suggested, based on an increased prevalence of endometriosis in women with an affected first-degree relative; in a case-control study on family incidence of endometriosis, 5.9% to 9.6% of first-degree relatives and 1.3% of second-degree relatives were affected.⁹ The Oxford Endometriosis Gene (OXEGENE) study is currently investigating susceptible loci for endometriosis genes, which could provide a better understanding of the disease process.⁶

CLINICAL PRESENTATION

The most common symptoms of endometriosis are dysmenorrhea, deep dyspareunia, chronic pelvic pain, and infertility, but 20% to 25% of affected women are asymptomatic.^4,10,11 Pelvic pain in women most often heralds onset of menses and worsens during menstruation.¹ Other symptoms include back pain, dyschezia, dysuria, nausea, lethargy, and chronic fatigue.^4,8,10

Endometriosis is concomitant with infertility; endometrial adhesions that attach to pelvic organs cause distortion of pelvic structures and impaired ovum release and pick-up, and are believed to reduce fecundity. Additionally, women with endometriosis have low ovarian reserve and low-quality oocytes.^6,8 Altered chemical elements (ie, prostanoids, cytokines, growth factors, and interleukins) may also contribute to endometrial-related infertility; intrapelvic growth factors could affect the fallopian tubes or pelvic environment, and thus the oocytes in a similar fashion.⁶

In adolescents, endometriosis can present as cyclic or acyclic pain; severe dysmenorrhea; dysmenorrhea that responds poorly to medications (eg, oral contraceptive pills [OCPs] or NSAIDs); and prolonged menstruation with premenstrual spotting.¹

The physical exam may reveal tender nodules in the posterior vaginal fornix; cervical motion tenderness; a fixed uterus, cervix, or adnexa; uterine motion tenderness; thickening, pain, tenderness, or nodularity of the uterosacral ligament; or tender adnexal masses due to endometriomas.^8,10

PATHOLOGIC CHARACTERISTICS AND STAGING

Gross pathology of endometriosis varies based on duration of disease and depth of implants or lesions. Implants range from punctate foci to small stellate patches that vary in color but typically measure less than 2 cm. They manifest most commonly in the ovaries, followed by the anterior and posterior cul-de-sac, posterior broad ligament, and uterosacral ligament. Implants can also be located on the uterus, fallopian tubes, sigmoid colon, ureter, small intestine, lungs, and brain (see Figure).³

Due to recurrent cyclic hemorrhage within a deep implant, endometriomas typically appear in the ovaries, entirely replacing normal ovarian tissue. Endometriomas are composed of dark, thick, degenerated blood products that result in a brown cyst—hence their designation as chocolate cysts. Microscopically, they are comprised of endometrial glands, stroma, and sometimes smooth muscle.³

Staging of endometriosis is determined by the volume, depth, location, and size of the implants (see Table 1). It is important to note that staging does not necessarily reflect symptom severity.¹²

DIAGNOSIS

There are several approaches to the diagnostic evaluation of endometriosis, all of which should be guided by the clinical presentation and physical examination. Clinical characteristics can be nonspecific and highly variable, warranting more reliable diagnostic methods.

Laparoscopy is the diagnostic gold standard for endometriosis, and biopsy of implants revealing endometrial tissue is confirmatory. Less invasive diagnostic methods include ultrasound and MRI—but without confirmatory histologic sampling, these only yield a presumptive diagnosis.

With ultrasonography, a transvaginal approach should be taken. While endometriomas have a variety of presentations on ultrasound, most appear as a homogenous, hypoechoic, focal lesion within the ovary. MRI has greater specificity than ultrasound for diagnosis of endometriomas. However, “shading,” or loss of signal, within an endometrioma is a feature commonly found on MRI.³

Other tests that aid in the diagnosis, but are not definitive, include sedimentation rate and tumor marker CA-125. These are both commonly elevated in patients with endometriosis. Measurement of CA-125 is helpful for identifying patients with infertility and severe endometriosis, who would therefore benefit from early surgical intervention.⁸

TREATMENT

There is no permanent cure for endometriosis; treatment entails nonsurgical and surgical approaches to symptom resolution. Treatment is directed by the patient’s desire to maintain fertility.

Conservative treatment of pelvic pain with NSAIDs is a common approach. Progestins are also used to treat pelvic pain; they create an acyclic, hypo-estrogenic environment by blocking ovarian estrogen secretion and subsequent endometrial cell proliferation. In addition to alleviating pain, progestins also prevent disease recurrence after surgery.^2,13 Options include combination OCPs, levonorgestrel intrauterine devices, medroxyprogesterone acetate, and etonogestrel implants. Combination OCPs and medroxyprogesterone acetate are considered to be firstline treatment.⁸

Gonadotropin-releasing hormone agonists (GnRH-a), such as leuprolide acetate, and androgenic agents, such as danocrine, are also indicated for relief of pain resulting from biopsy-confirmed endometriosis. Danocrine has been shown to ameliorate pain in up to 92% of patients.^3,8 Other unconventional treatment modalities include aromatase inhibitors, selective estrogen receptor modulators, anti-inflammatory agents, and immunomodulators.² For an outline of the medication choices and their mechanisms of action, see Table 2.

Surgery, or ablation of the implants, is another viable treatment option; it can be performed via laparoscopy or laparotomy. Although the success rate is high, implants recur in 28% of patients 18 months after surgery and in 40% of patients after nine years; 40% to 50% of patients have adhesion recurrence.³

Patients who have concomitant infertility can be treated with advanced reproductive techniques, including intrauterine insemination and ovarian hyperstimulation. The monthly fecundity rate with such techniques is 9% to 18%.³ Laparoscopic surgery with ablation of endometrial implants may increase fertility in patients with endometriosis.⁸

Hysterectomy and bilateral salpingo-oophorectomy are definitive treatment options reserved for patients with intractable pain and those who do not wish to maintain fertility.^3,8 Recurrent symptoms occur in 10% of patients 10 years after hysterectomy with bilateral salpingectomy, compared with 62% of those who have hysterectomy alone.⁸ Complete surgical removal of endometriomas, and ovary if affected, can reduce risk for epithelial ovarian cancer in the future.²

COMPLICATIONS

Adhesions are a common complication of endometriosis. Ultrasound can be used for diagnosis and to determine whether pelvic organs are fixed (ie, fixed retroverted uterus). MRI may also be used; adhesions appear as “speculated low-signal-intensity stranding that obscures organ interfaces.”³ Other suggestive findings on MRI include posterior displacement of the pelvic organs, elevation of the posterior vaginal fornix, hydrosalpinx, loculated fluid collections, and angulated bowel loops.³

Malignant transformation is rare, affecting fewer than 1% of patients with endometriosis. Most malignancies arise from ovarian endometriosis and can be related to unopposed estrogen therapy; they are typically large and have a solid component. The most common endometriosis-related malignant neoplasm is endometrioid carcinoma, followed by clear-cell carcinoma.³

CONCLUSION

Patients with endometriosis often present with complaints such as dysmenorrhea, deep dyspareunia, and chronic pelvic pain, but surgical and histologic findings indicate that symptom severity does not necessarily equate to disease severity. Definitive diagnosis requires an invasive surgical procedure.

In the absence of a cure, endometriosis treatment focuses on symptom control and improvement in quality of life. Familiarity with the disease process and knowledge of treatment options will help health care providers achieve this goal for patients who experience the potentially life-altering effects of endometriosis.

IN THIS ARTICLE

• Staging endometriosis
• Medications for treating endometriosis
• Complications

Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity (ie, endometrial implants), most commonly found on the ovaries. Although its pathophysiology is not completely understood, the disease is associated with dysmenorrhea, dyspareunia, and infertility.^1,2 Endometriosis is an estrogen-dependent disorder, predominantly affecting women of childbearing age. It occurs in 10% to 15% of the general female population, but prevalence is even higher (35% to 50%) among women who experience pelvic pain and/or infertility.^1-4 Although endometriosis mainly affects women in their mid-to-late 20s, it can also manifest in adolescence.^3,5 Nearly half of all adolescents with intractable dysmenorrhea are diagnosed with endometriosis.⁵

ETIOLOGY

The etiology of endometriosis, while not completely understood, is likely multifactorial. Factors that may influence its development include gene expression, tissue response to hormones, neuronal tissue involvement, lack of protective factors, inflammation, and cellular oxidative stress.^6,7

Several theories regarding the etiology of endometriosis have been proposed; the most widely accepted is the transplantation theory, which suggests that endometriosis results from retrograde flow of menstrual tissue through the fallopian tubes. During menstruation, fragments of the endometrium are driven through the fallopian tubes and into the pelvic cavity, where they can implant onto the pelvic structures, leading to further growth and invasion.^2,6,8 Women who have polymenorrhea, prolonged menses, and early menarche therefore have an increased risk for endometriosis.⁸ This theory does not account for the fact that although nearly 90% of women have some elements of retrograde menstrual flow, only a fraction of them develop endometriosis.⁶

Two other plausible explanations are the coelomic metaplasia and embryonic rest theories. In the coelomic metaplasia theory, the mesothelium (coelomic epithelium)—which encases the ovaries—invaginates into the ovaries and undergoes a metaplastic change to endometrial tissue. This could explain the development of endometriosis in patients with the congenital malformation Müllerian agenesis. In the embryonic rest theory, Müllerian remnants in the rectovaginal area, left behind by the Müllerian duct system, have the potential to differentiate into endometrial tissue.^2,5,6,8

Another theory involving lymphatic or hematologic spread has been proposed, which would explain the presence of endometrial implants at sites distant from the uterus (eg, the pleural cavity and brain). However, this theory is not widely understood.⁶

The two most recent hypotheses on endometriosis are associated with an abnormal immune system and a possible genetic predisposition. The peritoneal fluid of women with endometriosis has different levels of prostanoids, cytokines, growth factors, and interleukins than that of women who do not have the condition. It is uncertain whether the relationship between peritoneal fluid changes and endometriosis is causal.⁶ A genetic correlation has been suggested, based on an increased prevalence of endometriosis in women with an affected first-degree relative; in a case-control study on family incidence of endometriosis, 5.9% to 9.6% of first-degree relatives and 1.3% of second-degree relatives were affected.⁹ The Oxford Endometriosis Gene (OXEGENE) study is currently investigating susceptible loci for endometriosis genes, which could provide a better understanding of the disease process.⁶

CLINICAL PRESENTATION

The most common symptoms of endometriosis are dysmenorrhea, deep dyspareunia, chronic pelvic pain, and infertility, but 20% to 25% of affected women are asymptomatic.^4,10,11 Pelvic pain in women most often heralds onset of menses and worsens during menstruation.¹ Other symptoms include back pain, dyschezia, dysuria, nausea, lethargy, and chronic fatigue.^4,8,10

Endometriosis is concomitant with infertility; endometrial adhesions that attach to pelvic organs cause distortion of pelvic structures and impaired ovum release and pick-up, and are believed to reduce fecundity. Additionally, women with endometriosis have low ovarian reserve and low-quality oocytes.^6,8 Altered chemical elements (ie, prostanoids, cytokines, growth factors, and interleukins) may also contribute to endometrial-related infertility; intrapelvic growth factors could affect the fallopian tubes or pelvic environment, and thus the oocytes in a similar fashion.⁶

In adolescents, endometriosis can present as cyclic or acyclic pain; severe dysmenorrhea; dysmenorrhea that responds poorly to medications (eg, oral contraceptive pills [OCPs] or NSAIDs); and prolonged menstruation with premenstrual spotting.¹

The physical exam may reveal tender nodules in the posterior vaginal fornix; cervical motion tenderness; a fixed uterus, cervix, or adnexa; uterine motion tenderness; thickening, pain, tenderness, or nodularity of the uterosacral ligament; or tender adnexal masses due to endometriomas.^8,10

PATHOLOGIC CHARACTERISTICS AND STAGING

Gross pathology of endometriosis varies based on duration of disease and depth of implants or lesions. Implants range from punctate foci to small stellate patches that vary in color but typically measure less than 2 cm. They manifest most commonly in the ovaries, followed by the anterior and posterior cul-de-sac, posterior broad ligament, and uterosacral ligament. Implants can also be located on the uterus, fallopian tubes, sigmoid colon, ureter, small intestine, lungs, and brain (see Figure).³

Due to recurrent cyclic hemorrhage within a deep implant, endometriomas typically appear in the ovaries, entirely replacing normal ovarian tissue. Endometriomas are composed of dark, thick, degenerated blood products that result in a brown cyst—hence their designation as chocolate cysts. Microscopically, they are comprised of endometrial glands, stroma, and sometimes smooth muscle.³

Staging of endometriosis is determined by the volume, depth, location, and size of the implants (see Table 1). It is important to note that staging does not necessarily reflect symptom severity.¹²

DIAGNOSIS

There are several approaches to the diagnostic evaluation of endometriosis, all of which should be guided by the clinical presentation and physical examination. Clinical characteristics can be nonspecific and highly variable, warranting more reliable diagnostic methods.

Laparoscopy is the diagnostic gold standard for endometriosis, and biopsy of implants revealing endometrial tissue is confirmatory. Less invasive diagnostic methods include ultrasound and MRI—but without confirmatory histologic sampling, these only yield a presumptive diagnosis.

With ultrasonography, a transvaginal approach should be taken. While endometriomas have a variety of presentations on ultrasound, most appear as a homogenous, hypoechoic, focal lesion within the ovary. MRI has greater specificity than ultrasound for diagnosis of endometriomas. However, “shading,” or loss of signal, within an endometrioma is a feature commonly found on MRI.³

Other tests that aid in the diagnosis, but are not definitive, include sedimentation rate and tumor marker CA-125. These are both commonly elevated in patients with endometriosis. Measurement of CA-125 is helpful for identifying patients with infertility and severe endometriosis, who would therefore benefit from early surgical intervention.⁸

TREATMENT

There is no permanent cure for endometriosis; treatment entails nonsurgical and surgical approaches to symptom resolution. Treatment is directed by the patient’s desire to maintain fertility.

Conservative treatment of pelvic pain with NSAIDs is a common approach. Progestins are also used to treat pelvic pain; they create an acyclic, hypo-estrogenic environment by blocking ovarian estrogen secretion and subsequent endometrial cell proliferation. In addition to alleviating pain, progestins also prevent disease recurrence after surgery.^2,13 Options include combination OCPs, levonorgestrel intrauterine devices, medroxyprogesterone acetate, and etonogestrel implants. Combination OCPs and medroxyprogesterone acetate are considered to be firstline treatment.⁸

Gonadotropin-releasing hormone agonists (GnRH-a), such as leuprolide acetate, and androgenic agents, such as danocrine, are also indicated for relief of pain resulting from biopsy-confirmed endometriosis. Danocrine has been shown to ameliorate pain in up to 92% of patients.^3,8 Other unconventional treatment modalities include aromatase inhibitors, selective estrogen receptor modulators, anti-inflammatory agents, and immunomodulators.² For an outline of the medication choices and their mechanisms of action, see Table 2.

Surgery, or ablation of the implants, is another viable treatment option; it can be performed via laparoscopy or laparotomy. Although the success rate is high, implants recur in 28% of patients 18 months after surgery and in 40% of patients after nine years; 40% to 50% of patients have adhesion recurrence.³

Patients who have concomitant infertility can be treated with advanced reproductive techniques, including intrauterine insemination and ovarian hyperstimulation. The monthly fecundity rate with such techniques is 9% to 18%.³ Laparoscopic surgery with ablation of endometrial implants may increase fertility in patients with endometriosis.⁸

Hysterectomy and bilateral salpingo-oophorectomy are definitive treatment options reserved for patients with intractable pain and those who do not wish to maintain fertility.^3,8 Recurrent symptoms occur in 10% of patients 10 years after hysterectomy with bilateral salpingectomy, compared with 62% of those who have hysterectomy alone.⁸ Complete surgical removal of endometriomas, and ovary if affected, can reduce risk for epithelial ovarian cancer in the future.²

COMPLICATIONS

Adhesions are a common complication of endometriosis. Ultrasound can be used for diagnosis and to determine whether pelvic organs are fixed (ie, fixed retroverted uterus). MRI may also be used; adhesions appear as “speculated low-signal-intensity stranding that obscures organ interfaces.”³ Other suggestive findings on MRI include posterior displacement of the pelvic organs, elevation of the posterior vaginal fornix, hydrosalpinx, loculated fluid collections, and angulated bowel loops.³

Malignant transformation is rare, affecting fewer than 1% of patients with endometriosis. Most malignancies arise from ovarian endometriosis and can be related to unopposed estrogen therapy; they are typically large and have a solid component. The most common endometriosis-related malignant neoplasm is endometrioid carcinoma, followed by clear-cell carcinoma.³

CONCLUSION

Patients with endometriosis often present with complaints such as dysmenorrhea, deep dyspareunia, and chronic pelvic pain, but surgical and histologic findings indicate that symptom severity does not necessarily equate to disease severity. Definitive diagnosis requires an invasive surgical procedure.

In the absence of a cure, endometriosis treatment focuses on symptom control and improvement in quality of life. Familiarity with the disease process and knowledge of treatment options will help health care providers achieve this goal for patients who experience the potentially life-altering effects of endometriosis.