OBG Management

OSPHENA HAS NEW INDICATION

FOR MORE INFORMATION, VISIT: https://www.osphena.com/.

NEW 3-IN-1 HYSTEROSCOPE

FOR MORE INFORMATION, VISIT: https://gynsurgicalsolutions.com/product/omni-hysteroscope/.

SURGICAL RF TECHNOLOGY

FOR MORE INFORMATION, VISIT: https://www.cynosure.com/tempsure-platform. 

PROFESSIONAL FOOT SUPPORTS

FOR MORE INFORMATION, VISIT: https://www.comenitymed.com.

OSPHENA HAS NEW INDICATION

FOR MORE INFORMATION, VISIT: https://www.osphena.com/.

NEW 3-IN-1 HYSTEROSCOPE

FOR MORE INFORMATION, VISIT: https://gynsurgicalsolutions.com/product/omni-hysteroscope/.

SURGICAL RF TECHNOLOGY

FOR MORE INFORMATION, VISIT: https://www.cynosure.com/tempsure-platform. 

PROFESSIONAL FOOT SUPPORTS

FOR MORE INFORMATION, VISIT: https://www.comenitymed.com.

OSPHENA HAS NEW INDICATION

FOR MORE INFORMATION, VISIT: https://www.osphena.com/.

NEW 3-IN-1 HYSTEROSCOPE

FOR MORE INFORMATION, VISIT: https://gynsurgicalsolutions.com/product/omni-hysteroscope/.

SURGICAL RF TECHNOLOGY

FOR MORE INFORMATION, VISIT: https://www.cynosure.com/tempsure-platform. 

PROFESSIONAL FOOT SUPPORTS

FOR MORE INFORMATION, VISIT: https://www.comenitymed.com.

Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual health problem in women of all ages, with population-based studies showing that about 36% to 39% of women report low sexual desire, and 8% to 10% meet the diagnostic criteria of low sexual desire and associated distress.^1,2 An expanded definition of HSDD may include³:

• lack of motivation for sexual activity (reduced or absent spontaneous desire or responsive desire to erotic cues and stimulation; inability to maintain desire or interest through sexual activity)

• loss of desire to initiate or participate in sexual activity (including avoiding situations that could lead to sexual activity) combined with significant personal distress (frustration, loss, sadness, worry) (FIGURE).⁴

Despite the high prevalence of HSDD, patients often are uncomfortable and reluctant to voice concerns about low sexual desire to their ObGyn. Further, clinicians may feel ill equipped to diagnose and treat patients with HSDD. ObGyns, however, are well positioned to initiate a general discussion about sexual concerns with patients and use screening tools, such as the Decreased Sexual Desire Screener (DSDS), to facilitate a discussion and clarify a diagnosis of generalized acquired HSDD (TABLES 1 and 2).⁵ Helpful guidance on HSDD is available from the American College of Obstetricians and Gynecologists and the International Society for the Study of Women’s Sexual Health.^6-8

Importantly, clinicians have a new treatment option they can offer to patients with HSDD. Bremelanotide was approved by the US Food and Drug Administration (FDA) on June 21, 2019, to treat acquired, generalized HSDD in premenopausal women. Up until this approval, flibanserin (approved in 2015) was the only drug FDA approved for the treatment of HSDD.

Assessing and treating HSDD today can be likened to managing depression 30 years ago, before selective serotonin receptor inhibitors were available. ObGyns would refer patients with depression to other health care providers, or not even ask patients about depressive symptoms because we had so little to offer. Once safe and effective antidepressants became available, knowing we could provide pharmacologic options made inquiring about depressive symptoms and the use of screening tools more readily incorporated into standard clinical practice. Depression is now recognized as a medical condition with biologic underpinnings, just like HSDD, and treatment options are available for both disorders.

For this Update, I had the opportunity to discuss the clinical trial experience with bremelanotide for HSDD with Dr. Sheryl Kingsberg, including efficacy and safety, dosage and administration, contraindications, and adverse events. She also details an ideal patient for treatment with bremelanotide, and we review pertinent aspects of flibanserin for comparative purposes.

Bremelanotide: A new therapeutic option

According to the product labeling for bremelanotide, the drug is indicated for the treatment of premenopausal women with acquired, generalized HSDD (low sexual desire that causes marked distress or interpersonal difficulty).⁹ This means that the HSDD developed in a woman who previously did not have problems with sexual desire, and that it occurred regardless of the type of stimulation, situation, or partner. In addition, the HSDD should not result from a coexisting medical or psychiatric condition, problems with the relationship, or the effects of a medication or drug substance.

Flibanserin also is indicated for the treatment of premenopausal women with HSDD. While both bremelanotide and flibanserin have indications only for premenopausal women, 2 studies of flibanserin in postmenopausal women have been published.^10,11 Results from these studies in naturally menopausal women suggest that flibanserin may be efficacious in this population, with improvement in sexual desire, reduced distress associated with low desire, and improvement in the number of satisfying sexual events (SSEs).

No trials of bremelanotide in postmenopausal women have been published, but since this drug acts on central nervous system receptors, as does flibanserin, it may have similar effectiveness in postmenopausal women as well.

Continue to: Clinical trials show bremelanotide improves desire, reduces distress...

Clinical trials show bremelanotide improves desire, reduces distress 

Two phase 3 clinical trials, dubbed the Reconnect studies, demonstrated that, compared with placebo, bremelanotide was associated with statistically significant improvements in sexual desire and levels of distress regarding sexual desire. 

The 2 identical, randomized, placebo-controlled multicenter trials included 1,247 premenopausal women with HSDD of at least 6 months' duration.^9,12 Bremelanotide 1.75 mg (or placebo) was self-administered subcutaneously with an autoinjector on an as-desired basis. The 24-week double-blind treatment period was followed by a 52-week open-label extension study. 

The co-primary efficacy end points were the change from baseline to end-of-study (week 24 of the double-blind treatment period) in the 1) Female Sexual Function Index (FSFI) desire domain score and 2) feeling bothered by low sexual desire as measured by Question 13 on the Female Sexual Distress Scale (FSDS). An increase in the FSFI desire domain score over time denotes improvement in sexual desire, while a decrease in the FSDS Question 13 score over time indicates improvement in the level of distress associated with low sexual desire. 

In the 2 clinical studies, the mean change from baseline (SD) in the FSFI desire domain score, which ranged from 1.2 to 6.0 at study outset (higher scores indicate greater desire), was: 

• study 1: 0.5 (1.1) in the bremelanotide-treated women and 0.2 (1.0) in the placebo-treated women (P = .0002) 
• study 2: 0.6 (1.0) in the bremelanotide group versus 0.2 (0.9) in the placebo group (P<.0001). 

For FSDS Question 13, for which the score range was 0 to 4 (higher scores indicate greater bother), the mean change from baseline score was: 

• study 1: -0.7 (1.2) in the bremelanotide-treated group compared with -0.4 (1.1) in the placebo-treated group (P<.0001) 
• study 2: -0.7 (1.1) in the bremelanotide group and -0.4 (1.1) in the placebo group (P = .0053). 

It should be noted that, in the past, SSEs were used as a primary end point in clinical studies. However, we have shifted from SSEs to desire and distress as an end point because SSEs have little to do with desire. Women worry about and are distressed by the fact that they no longer have sexual appetite. They no longer "want to want" even though their body will be responsive and they can have an orgasm. That is exemplified by the woman in our case scenario (see box, page 18), who very much wants the experience of being able to anticipate with pleasure the idea of having an enjoyable connection with her partner. 

Continue to: Physiologic target: The melanocortin receptor...

Physiologic target: The melanocortin receptor 

Bremelanotide's theorized mechanism of action is that it works to rebalance neurotransmitters that are implicated in causing HSDD, acting as an agonist on the melanocortin receptor to promote dopamine release and allow women to perceive sexual cues as rewarding. They can then respond to those cues the way they used to and therefore experience desire. Flibanserin has affinity for serotonin (5-hydroxytryptamine [5-HT]) receptors, with agonist and antagonist activity, as well as moderate antagonist activity on some dopamine receptors. 

The bottom line is that we now have treatments to address the underlying biologic aspect of HSDD, which is a biopsychosocial disorder. Again, this has parallels to depression and its biologic mechanism, for which we have effective treatments. 

Dosing is an as-needed injection 

Unlike the daily nighttime oral dose required with flibanserin, bremelanotide is a 1.75-mg dose administered as a subcutaneous injection (in either the thigh or the abdomen) with a pen-like autoinjector, on an as-needed basis. It should be administered at least 45 minutes before anticipated sexual activity. That is a benefit for many women who do not want to take a daily pill when they know that their "desire to desire" may be once per week or once every other week. 

Regarding the drug delivery mode, nobody dropped out of the bremelanotide clinical trials because of having to take an injection with an autoinjector, which employs a very thin needle and is virtually painless. A small number of bremelanotide-treated women, about 13%, had injection site reactions (compared with 8% in the placebo group), which is common with subcutaneous injection. Even in the phase 2 clinical trial, in which a syringe was used to administer the drug, no participants discontinued the study because of the injection mode. 

There are no clear pharmacokinetic data on how long bremelanotide's effects last, but it may be anywhere from 8 to 16 hours. Patients should not take more than 1 dose within 24 hours--but since the effect may last up to 16 hours that should not be a problem--and use of more than 8 doses per month is not recommended. 

While bremelanotide improves desire, certainly better than placebo, there is also some peripheral improvement in arousal, although women in the trials had only HSDD. We do not know whether bremelanotide would treat arousal disorder, but it will help women with or without arousal difficulties associated with their HSDD, as shown in a subgroup analysis in the trials.¹³ 

Counsel patients on treatment potentialities 

Clinicians should be aware of several precautions with bremelanotide use. 
Blood pressure increases. After each dose of bremelanotide, transient increases in blood pressure (6 mm Hg in systolic and 3 mm Hg in diastolic blood pressure) and reductions in heart rate (up to 5 beats per minute) occur; these measurements return to baseline usually within 12 hours postdose.⁹ When you think about whether having sexual desire will increase blood pressure, this may be physiologic. It is similar to walking up a flight of stairs. 

The drug is not recommended, however, for use in patients at high risk for cardiovascular disease, and it is contraindicated in women with uncontrolled hypertension or known cardiovascular disease. Blood pressure should be well controlled before bremelanotide is initiated--use of antihypertensive agents is not contraindicated with bremelanotide as the drugs do not interact. 

Clinicians are not required to participate in a Risk Evaluation and Mitigation Strategy (REMS) program to prescribe bremelanotide as they are with flibanserin (because of the increased risk of severe hypotension and syncope due to flibanserin's interaction with alcohol). 

Drug interactions. Bremelanotide is a melanocortin receptor agonist--a unique compound. Antidepressants, other psychoactive medications, and oral contraceptives are not contraindicated with bremelanotide as there are no known interactions. Alcohol use also is not a contraindication or caution, in contrast to flibanserin. (In April, the FDA issued a labeling change order for flibanserin, specifying that alcohol does not have to be avoided completely when taking flibanserin, but that women should discontinue drinking alcohol at least 2 hours before taking the drug at bedtime, or skip the flibanserin dose that evening.¹⁴) Bremelanotide may slow gastric emptying, though, so when a patient is taking oral drugs that require threshold concentrations for efficacy, such as antibiotics, they should avoid bremelanotide. In addition, some drugs, such as indomethacin, may have a delayed onset of action with concomitant bremelanotide use.⁹ 

Importantly, patients should avoid using bremelanotide if they are taking an oral naltrexone product for treatment of alcohol or opioid addiction, because bremelanotide may decrease systemic exposure of oral naltrexone. That would potentially lead to naltrexone treatment failure and its consequences.⁹ 

Skin pigmentation changes. Hyperpigmentation occurred with bremelanotide use on the face, gingiva, and breasts, as reported in the clinical trials, in 1% of treated patients who received up to 8 doses per month, compared with no such occurrences in placebo-treated patients. In addition, 38% of patients who received bremelanotide daily for 8 days developed focal hyperpigmentation. It was not confirmed in all patients whether the hyperpigmentation resolved. Women with dark skin were more likely to develop hyperpigmentation.⁹ 

Common adverse reactions. The most common adverse reactions with bremelanotide treatment are nausea, flushing, injection site reactions, and headache, with most events being mild to moderate in intensity. In the clinical trials, 40% of the bremelanotide-treated women experienced nausea (compared with 1% of placebo-treated women), with most occurrences being mild; for most participants nausea improved with the second dose. Women had nausea that either went away or was intermittent, or it was mild enough that the drug benefits outweighed the tolerability costs--of women who experienced nausea, 92% continued in the trial, and 8% dropped out because of nausea.⁹ 

Final considerations 

Asking patients about sexual function and using sexual function screening tools can help clinicians identify patients with the decreased sexual desire and associated distress characteristic of HSDD. ObGyns are the appropriate clinicians to treat these women and soon will have 2 pharmacologic options--bremelanotide (anticipated to be available in Fall 2019) and flibanserin--to offer patients with this biopsychosocial disorder that can adversely impact well-being and quality of life. Clinicians should individualize treatment, which may include psychotherapeutic counseling, and counsel patients on appropriate drug use and potential adverse effects. 

AMAG Pharmaceuticals, Inc. has announced that they will have a copay assistance program for bremelanotide, where the first prescription of four autoinjectors will be a $0 copay, followed by a $99 copay or less for refills.¹⁵  

Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual health problem in women of all ages, with population-based studies showing that about 36% to 39% of women report low sexual desire, and 8% to 10% meet the diagnostic criteria of low sexual desire and associated distress.^1,2 An expanded definition of HSDD may include³:

• lack of motivation for sexual activity (reduced or absent spontaneous desire or responsive desire to erotic cues and stimulation; inability to maintain desire or interest through sexual activity)

• loss of desire to initiate or participate in sexual activity (including avoiding situations that could lead to sexual activity) combined with significant personal distress (frustration, loss, sadness, worry) (FIGURE).⁴

Despite the high prevalence of HSDD, patients often are uncomfortable and reluctant to voice concerns about low sexual desire to their ObGyn. Further, clinicians may feel ill equipped to diagnose and treat patients with HSDD. ObGyns, however, are well positioned to initiate a general discussion about sexual concerns with patients and use screening tools, such as the Decreased Sexual Desire Screener (DSDS), to facilitate a discussion and clarify a diagnosis of generalized acquired HSDD (TABLES 1 and 2).⁵ Helpful guidance on HSDD is available from the American College of Obstetricians and Gynecologists and the International Society for the Study of Women’s Sexual Health.^6-8

Importantly, clinicians have a new treatment option they can offer to patients with HSDD. Bremelanotide was approved by the US Food and Drug Administration (FDA) on June 21, 2019, to treat acquired, generalized HSDD in premenopausal women. Up until this approval, flibanserin (approved in 2015) was the only drug FDA approved for the treatment of HSDD.

Assessing and treating HSDD today can be likened to managing depression 30 years ago, before selective serotonin receptor inhibitors were available. ObGyns would refer patients with depression to other health care providers, or not even ask patients about depressive symptoms because we had so little to offer. Once safe and effective antidepressants became available, knowing we could provide pharmacologic options made inquiring about depressive symptoms and the use of screening tools more readily incorporated into standard clinical practice. Depression is now recognized as a medical condition with biologic underpinnings, just like HSDD, and treatment options are available for both disorders.

For this Update, I had the opportunity to discuss the clinical trial experience with bremelanotide for HSDD with Dr. Sheryl Kingsberg, including efficacy and safety, dosage and administration, contraindications, and adverse events. She also details an ideal patient for treatment with bremelanotide, and we review pertinent aspects of flibanserin for comparative purposes.

Bremelanotide: A new therapeutic option

According to the product labeling for bremelanotide, the drug is indicated for the treatment of premenopausal women with acquired, generalized HSDD (low sexual desire that causes marked distress or interpersonal difficulty).⁹ This means that the HSDD developed in a woman who previously did not have problems with sexual desire, and that it occurred regardless of the type of stimulation, situation, or partner. In addition, the HSDD should not result from a coexisting medical or psychiatric condition, problems with the relationship, or the effects of a medication or drug substance.

Flibanserin also is indicated for the treatment of premenopausal women with HSDD. While both bremelanotide and flibanserin have indications only for premenopausal women, 2 studies of flibanserin in postmenopausal women have been published.^10,11 Results from these studies in naturally menopausal women suggest that flibanserin may be efficacious in this population, with improvement in sexual desire, reduced distress associated with low desire, and improvement in the number of satisfying sexual events (SSEs).

No trials of bremelanotide in postmenopausal women have been published, but since this drug acts on central nervous system receptors, as does flibanserin, it may have similar effectiveness in postmenopausal women as well.

Continue to: Clinical trials show bremelanotide improves desire, reduces distress...

Clinical trials show bremelanotide improves desire, reduces distress 

Two phase 3 clinical trials, dubbed the Reconnect studies, demonstrated that, compared with placebo, bremelanotide was associated with statistically significant improvements in sexual desire and levels of distress regarding sexual desire. 

The 2 identical, randomized, placebo-controlled multicenter trials included 1,247 premenopausal women with HSDD of at least 6 months' duration.^9,12 Bremelanotide 1.75 mg (or placebo) was self-administered subcutaneously with an autoinjector on an as-desired basis. The 24-week double-blind treatment period was followed by a 52-week open-label extension study. 

The co-primary efficacy end points were the change from baseline to end-of-study (week 24 of the double-blind treatment period) in the 1) Female Sexual Function Index (FSFI) desire domain score and 2) feeling bothered by low sexual desire as measured by Question 13 on the Female Sexual Distress Scale (FSDS). An increase in the FSFI desire domain score over time denotes improvement in sexual desire, while a decrease in the FSDS Question 13 score over time indicates improvement in the level of distress associated with low sexual desire. 

In the 2 clinical studies, the mean change from baseline (SD) in the FSFI desire domain score, which ranged from 1.2 to 6.0 at study outset (higher scores indicate greater desire), was: 

• study 1: 0.5 (1.1) in the bremelanotide-treated women and 0.2 (1.0) in the placebo-treated women (P = .0002) 
• study 2: 0.6 (1.0) in the bremelanotide group versus 0.2 (0.9) in the placebo group (P<.0001). 

For FSDS Question 13, for which the score range was 0 to 4 (higher scores indicate greater bother), the mean change from baseline score was: 

• study 1: -0.7 (1.2) in the bremelanotide-treated group compared with -0.4 (1.1) in the placebo-treated group (P<.0001) 
• study 2: -0.7 (1.1) in the bremelanotide group and -0.4 (1.1) in the placebo group (P = .0053). 

It should be noted that, in the past, SSEs were used as a primary end point in clinical studies. However, we have shifted from SSEs to desire and distress as an end point because SSEs have little to do with desire. Women worry about and are distressed by the fact that they no longer have sexual appetite. They no longer "want to want" even though their body will be responsive and they can have an orgasm. That is exemplified by the woman in our case scenario (see box, page 18), who very much wants the experience of being able to anticipate with pleasure the idea of having an enjoyable connection with her partner. 

Continue to: Physiologic target: The melanocortin receptor...

Physiologic target: The melanocortin receptor 

Bremelanotide's theorized mechanism of action is that it works to rebalance neurotransmitters that are implicated in causing HSDD, acting as an agonist on the melanocortin receptor to promote dopamine release and allow women to perceive sexual cues as rewarding. They can then respond to those cues the way they used to and therefore experience desire. Flibanserin has affinity for serotonin (5-hydroxytryptamine [5-HT]) receptors, with agonist and antagonist activity, as well as moderate antagonist activity on some dopamine receptors. 

The bottom line is that we now have treatments to address the underlying biologic aspect of HSDD, which is a biopsychosocial disorder. Again, this has parallels to depression and its biologic mechanism, for which we have effective treatments. 

Dosing is an as-needed injection 

Unlike the daily nighttime oral dose required with flibanserin, bremelanotide is a 1.75-mg dose administered as a subcutaneous injection (in either the thigh or the abdomen) with a pen-like autoinjector, on an as-needed basis. It should be administered at least 45 minutes before anticipated sexual activity. That is a benefit for many women who do not want to take a daily pill when they know that their "desire to desire" may be once per week or once every other week. 

Regarding the drug delivery mode, nobody dropped out of the bremelanotide clinical trials because of having to take an injection with an autoinjector, which employs a very thin needle and is virtually painless. A small number of bremelanotide-treated women, about 13%, had injection site reactions (compared with 8% in the placebo group), which is common with subcutaneous injection. Even in the phase 2 clinical trial, in which a syringe was used to administer the drug, no participants discontinued the study because of the injection mode. 

There are no clear pharmacokinetic data on how long bremelanotide's effects last, but it may be anywhere from 8 to 16 hours. Patients should not take more than 1 dose within 24 hours--but since the effect may last up to 16 hours that should not be a problem--and use of more than 8 doses per month is not recommended. 

While bremelanotide improves desire, certainly better than placebo, there is also some peripheral improvement in arousal, although women in the trials had only HSDD. We do not know whether bremelanotide would treat arousal disorder, but it will help women with or without arousal difficulties associated with their HSDD, as shown in a subgroup analysis in the trials.¹³ 

Counsel patients on treatment potentialities 

Clinicians should be aware of several precautions with bremelanotide use. 
Blood pressure increases. After each dose of bremelanotide, transient increases in blood pressure (6 mm Hg in systolic and 3 mm Hg in diastolic blood pressure) and reductions in heart rate (up to 5 beats per minute) occur; these measurements return to baseline usually within 12 hours postdose.⁹ When you think about whether having sexual desire will increase blood pressure, this may be physiologic. It is similar to walking up a flight of stairs. 

The drug is not recommended, however, for use in patients at high risk for cardiovascular disease, and it is contraindicated in women with uncontrolled hypertension or known cardiovascular disease. Blood pressure should be well controlled before bremelanotide is initiated--use of antihypertensive agents is not contraindicated with bremelanotide as the drugs do not interact. 

Clinicians are not required to participate in a Risk Evaluation and Mitigation Strategy (REMS) program to prescribe bremelanotide as they are with flibanserin (because of the increased risk of severe hypotension and syncope due to flibanserin's interaction with alcohol). 

Drug interactions. Bremelanotide is a melanocortin receptor agonist--a unique compound. Antidepressants, other psychoactive medications, and oral contraceptives are not contraindicated with bremelanotide as there are no known interactions. Alcohol use also is not a contraindication or caution, in contrast to flibanserin. (In April, the FDA issued a labeling change order for flibanserin, specifying that alcohol does not have to be avoided completely when taking flibanserin, but that women should discontinue drinking alcohol at least 2 hours before taking the drug at bedtime, or skip the flibanserin dose that evening.¹⁴) Bremelanotide may slow gastric emptying, though, so when a patient is taking oral drugs that require threshold concentrations for efficacy, such as antibiotics, they should avoid bremelanotide. In addition, some drugs, such as indomethacin, may have a delayed onset of action with concomitant bremelanotide use.⁹ 

Importantly, patients should avoid using bremelanotide if they are taking an oral naltrexone product for treatment of alcohol or opioid addiction, because bremelanotide may decrease systemic exposure of oral naltrexone. That would potentially lead to naltrexone treatment failure and its consequences.⁹ 

Skin pigmentation changes. Hyperpigmentation occurred with bremelanotide use on the face, gingiva, and breasts, as reported in the clinical trials, in 1% of treated patients who received up to 8 doses per month, compared with no such occurrences in placebo-treated patients. In addition, 38% of patients who received bremelanotide daily for 8 days developed focal hyperpigmentation. It was not confirmed in all patients whether the hyperpigmentation resolved. Women with dark skin were more likely to develop hyperpigmentation.⁹ 

Common adverse reactions. The most common adverse reactions with bremelanotide treatment are nausea, flushing, injection site reactions, and headache, with most events being mild to moderate in intensity. In the clinical trials, 40% of the bremelanotide-treated women experienced nausea (compared with 1% of placebo-treated women), with most occurrences being mild; for most participants nausea improved with the second dose. Women had nausea that either went away or was intermittent, or it was mild enough that the drug benefits outweighed the tolerability costs--of women who experienced nausea, 92% continued in the trial, and 8% dropped out because of nausea.⁹ 

Final considerations 

Asking patients about sexual function and using sexual function screening tools can help clinicians identify patients with the decreased sexual desire and associated distress characteristic of HSDD. ObGyns are the appropriate clinicians to treat these women and soon will have 2 pharmacologic options--bremelanotide (anticipated to be available in Fall 2019) and flibanserin--to offer patients with this biopsychosocial disorder that can adversely impact well-being and quality of life. Clinicians should individualize treatment, which may include psychotherapeutic counseling, and counsel patients on appropriate drug use and potential adverse effects. 

AMAG Pharmaceuticals, Inc. has announced that they will have a copay assistance program for bremelanotide, where the first prescription of four autoinjectors will be a $0 copay, followed by a $99 copay or less for refills.¹⁵  

Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual health problem in women of all ages, with population-based studies showing that about 36% to 39% of women report low sexual desire, and 8% to 10% meet the diagnostic criteria of low sexual desire and associated distress.^1,2 An expanded definition of HSDD may include³:

• lack of motivation for sexual activity (reduced or absent spontaneous desire or responsive desire to erotic cues and stimulation; inability to maintain desire or interest through sexual activity)

• loss of desire to initiate or participate in sexual activity (including avoiding situations that could lead to sexual activity) combined with significant personal distress (frustration, loss, sadness, worry) (FIGURE).⁴

Despite the high prevalence of HSDD, patients often are uncomfortable and reluctant to voice concerns about low sexual desire to their ObGyn. Further, clinicians may feel ill equipped to diagnose and treat patients with HSDD. ObGyns, however, are well positioned to initiate a general discussion about sexual concerns with patients and use screening tools, such as the Decreased Sexual Desire Screener (DSDS), to facilitate a discussion and clarify a diagnosis of generalized acquired HSDD (TABLES 1 and 2).⁵ Helpful guidance on HSDD is available from the American College of Obstetricians and Gynecologists and the International Society for the Study of Women’s Sexual Health.^6-8

Importantly, clinicians have a new treatment option they can offer to patients with HSDD. Bremelanotide was approved by the US Food and Drug Administration (FDA) on June 21, 2019, to treat acquired, generalized HSDD in premenopausal women. Up until this approval, flibanserin (approved in 2015) was the only drug FDA approved for the treatment of HSDD.

Assessing and treating HSDD today can be likened to managing depression 30 years ago, before selective serotonin receptor inhibitors were available. ObGyns would refer patients with depression to other health care providers, or not even ask patients about depressive symptoms because we had so little to offer. Once safe and effective antidepressants became available, knowing we could provide pharmacologic options made inquiring about depressive symptoms and the use of screening tools more readily incorporated into standard clinical practice. Depression is now recognized as a medical condition with biologic underpinnings, just like HSDD, and treatment options are available for both disorders.

For this Update, I had the opportunity to discuss the clinical trial experience with bremelanotide for HSDD with Dr. Sheryl Kingsberg, including efficacy and safety, dosage and administration, contraindications, and adverse events. She also details an ideal patient for treatment with bremelanotide, and we review pertinent aspects of flibanserin for comparative purposes.

Bremelanotide: A new therapeutic option

According to the product labeling for bremelanotide, the drug is indicated for the treatment of premenopausal women with acquired, generalized HSDD (low sexual desire that causes marked distress or interpersonal difficulty).⁹ This means that the HSDD developed in a woman who previously did not have problems with sexual desire, and that it occurred regardless of the type of stimulation, situation, or partner. In addition, the HSDD should not result from a coexisting medical or psychiatric condition, problems with the relationship, or the effects of a medication or drug substance.

Flibanserin also is indicated for the treatment of premenopausal women with HSDD. While both bremelanotide and flibanserin have indications only for premenopausal women, 2 studies of flibanserin in postmenopausal women have been published.^10,11 Results from these studies in naturally menopausal women suggest that flibanserin may be efficacious in this population, with improvement in sexual desire, reduced distress associated with low desire, and improvement in the number of satisfying sexual events (SSEs).

No trials of bremelanotide in postmenopausal women have been published, but since this drug acts on central nervous system receptors, as does flibanserin, it may have similar effectiveness in postmenopausal women as well.

Continue to: Clinical trials show bremelanotide improves desire, reduces distress...

Clinical trials show bremelanotide improves desire, reduces distress 

Two phase 3 clinical trials, dubbed the Reconnect studies, demonstrated that, compared with placebo, bremelanotide was associated with statistically significant improvements in sexual desire and levels of distress regarding sexual desire. 

The 2 identical, randomized, placebo-controlled multicenter trials included 1,247 premenopausal women with HSDD of at least 6 months' duration.^9,12 Bremelanotide 1.75 mg (or placebo) was self-administered subcutaneously with an autoinjector on an as-desired basis. The 24-week double-blind treatment period was followed by a 52-week open-label extension study. 

The co-primary efficacy end points were the change from baseline to end-of-study (week 24 of the double-blind treatment period) in the 1) Female Sexual Function Index (FSFI) desire domain score and 2) feeling bothered by low sexual desire as measured by Question 13 on the Female Sexual Distress Scale (FSDS). An increase in the FSFI desire domain score over time denotes improvement in sexual desire, while a decrease in the FSDS Question 13 score over time indicates improvement in the level of distress associated with low sexual desire. 

In the 2 clinical studies, the mean change from baseline (SD) in the FSFI desire domain score, which ranged from 1.2 to 6.0 at study outset (higher scores indicate greater desire), was: 

• study 1: 0.5 (1.1) in the bremelanotide-treated women and 0.2 (1.0) in the placebo-treated women (P = .0002) 
• study 2: 0.6 (1.0) in the bremelanotide group versus 0.2 (0.9) in the placebo group (P<.0001). 

For FSDS Question 13, for which the score range was 0 to 4 (higher scores indicate greater bother), the mean change from baseline score was: 

• study 1: -0.7 (1.2) in the bremelanotide-treated group compared with -0.4 (1.1) in the placebo-treated group (P<.0001) 
• study 2: -0.7 (1.1) in the bremelanotide group and -0.4 (1.1) in the placebo group (P = .0053). 

It should be noted that, in the past, SSEs were used as a primary end point in clinical studies. However, we have shifted from SSEs to desire and distress as an end point because SSEs have little to do with desire. Women worry about and are distressed by the fact that they no longer have sexual appetite. They no longer "want to want" even though their body will be responsive and they can have an orgasm. That is exemplified by the woman in our case scenario (see box, page 18), who very much wants the experience of being able to anticipate with pleasure the idea of having an enjoyable connection with her partner. 

Continue to: Physiologic target: The melanocortin receptor...

Physiologic target: The melanocortin receptor 

Bremelanotide's theorized mechanism of action is that it works to rebalance neurotransmitters that are implicated in causing HSDD, acting as an agonist on the melanocortin receptor to promote dopamine release and allow women to perceive sexual cues as rewarding. They can then respond to those cues the way they used to and therefore experience desire. Flibanserin has affinity for serotonin (5-hydroxytryptamine [5-HT]) receptors, with agonist and antagonist activity, as well as moderate antagonist activity on some dopamine receptors. 

The bottom line is that we now have treatments to address the underlying biologic aspect of HSDD, which is a biopsychosocial disorder. Again, this has parallels to depression and its biologic mechanism, for which we have effective treatments. 

Dosing is an as-needed injection 

Unlike the daily nighttime oral dose required with flibanserin, bremelanotide is a 1.75-mg dose administered as a subcutaneous injection (in either the thigh or the abdomen) with a pen-like autoinjector, on an as-needed basis. It should be administered at least 45 minutes before anticipated sexual activity. That is a benefit for many women who do not want to take a daily pill when they know that their "desire to desire" may be once per week or once every other week. 

Regarding the drug delivery mode, nobody dropped out of the bremelanotide clinical trials because of having to take an injection with an autoinjector, which employs a very thin needle and is virtually painless. A small number of bremelanotide-treated women, about 13%, had injection site reactions (compared with 8% in the placebo group), which is common with subcutaneous injection. Even in the phase 2 clinical trial, in which a syringe was used to administer the drug, no participants discontinued the study because of the injection mode. 

There are no clear pharmacokinetic data on how long bremelanotide's effects last, but it may be anywhere from 8 to 16 hours. Patients should not take more than 1 dose within 24 hours--but since the effect may last up to 16 hours that should not be a problem--and use of more than 8 doses per month is not recommended. 

While bremelanotide improves desire, certainly better than placebo, there is also some peripheral improvement in arousal, although women in the trials had only HSDD. We do not know whether bremelanotide would treat arousal disorder, but it will help women with or without arousal difficulties associated with their HSDD, as shown in a subgroup analysis in the trials.¹³ 

Counsel patients on treatment potentialities 

Clinicians should be aware of several precautions with bremelanotide use. 
Blood pressure increases. After each dose of bremelanotide, transient increases in blood pressure (6 mm Hg in systolic and 3 mm Hg in diastolic blood pressure) and reductions in heart rate (up to 5 beats per minute) occur; these measurements return to baseline usually within 12 hours postdose.⁹ When you think about whether having sexual desire will increase blood pressure, this may be physiologic. It is similar to walking up a flight of stairs. 

The drug is not recommended, however, for use in patients at high risk for cardiovascular disease, and it is contraindicated in women with uncontrolled hypertension or known cardiovascular disease. Blood pressure should be well controlled before bremelanotide is initiated--use of antihypertensive agents is not contraindicated with bremelanotide as the drugs do not interact. 

Clinicians are not required to participate in a Risk Evaluation and Mitigation Strategy (REMS) program to prescribe bremelanotide as they are with flibanserin (because of the increased risk of severe hypotension and syncope due to flibanserin's interaction with alcohol). 

Drug interactions. Bremelanotide is a melanocortin receptor agonist--a unique compound. Antidepressants, other psychoactive medications, and oral contraceptives are not contraindicated with bremelanotide as there are no known interactions. Alcohol use also is not a contraindication or caution, in contrast to flibanserin. (In April, the FDA issued a labeling change order for flibanserin, specifying that alcohol does not have to be avoided completely when taking flibanserin, but that women should discontinue drinking alcohol at least 2 hours before taking the drug at bedtime, or skip the flibanserin dose that evening.¹⁴) Bremelanotide may slow gastric emptying, though, so when a patient is taking oral drugs that require threshold concentrations for efficacy, such as antibiotics, they should avoid bremelanotide. In addition, some drugs, such as indomethacin, may have a delayed onset of action with concomitant bremelanotide use.⁹ 

Importantly, patients should avoid using bremelanotide if they are taking an oral naltrexone product for treatment of alcohol or opioid addiction, because bremelanotide may decrease systemic exposure of oral naltrexone. That would potentially lead to naltrexone treatment failure and its consequences.⁹ 

Skin pigmentation changes. Hyperpigmentation occurred with bremelanotide use on the face, gingiva, and breasts, as reported in the clinical trials, in 1% of treated patients who received up to 8 doses per month, compared with no such occurrences in placebo-treated patients. In addition, 38% of patients who received bremelanotide daily for 8 days developed focal hyperpigmentation. It was not confirmed in all patients whether the hyperpigmentation resolved. Women with dark skin were more likely to develop hyperpigmentation.⁹ 

Common adverse reactions. The most common adverse reactions with bremelanotide treatment are nausea, flushing, injection site reactions, and headache, with most events being mild to moderate in intensity. In the clinical trials, 40% of the bremelanotide-treated women experienced nausea (compared with 1% of placebo-treated women), with most occurrences being mild; for most participants nausea improved with the second dose. Women had nausea that either went away or was intermittent, or it was mild enough that the drug benefits outweighed the tolerability costs--of women who experienced nausea, 92% continued in the trial, and 8% dropped out because of nausea.⁹ 

Final considerations 

Asking patients about sexual function and using sexual function screening tools can help clinicians identify patients with the decreased sexual desire and associated distress characteristic of HSDD. ObGyns are the appropriate clinicians to treat these women and soon will have 2 pharmacologic options--bremelanotide (anticipated to be available in Fall 2019) and flibanserin--to offer patients with this biopsychosocial disorder that can adversely impact well-being and quality of life. Clinicians should individualize treatment, which may include psychotherapeutic counseling, and counsel patients on appropriate drug use and potential adverse effects. 

AMAG Pharmaceuticals, Inc. has announced that they will have a copay assistance program for bremelanotide, where the first prescription of four autoinjectors will be a $0 copay, followed by a $99 copay or less for refills.¹⁵  

Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.¹ This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.

Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.²

In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.

Morcellation uses—and risks

Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.

In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.

Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.^3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.⁴ For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.³

With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.^5-7

Continue to: The challenge of leiomyosarcoma...

The challenge of leiomyosarcoma

The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.

Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.⁸ However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.^9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).

Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.^11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.¹ Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.¹³

Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.⁹ Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.^12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.

CASE Woman with enlarged, irregular uterus and heavy bleeding

A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.

The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.

What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?

Continue to: Perform a thorough preoperative evaluation to optimize outcomes...

Perform a thorough preoperative evaluation to optimize outcomes

Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.

According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they¹⁵:

• are older than 45 years with abnormal uterine bleeding
• are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
• have persistent bleeding, or
• failed medical management.

Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.²

Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.¹⁶ There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.

Employ shared decision making

Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.¹⁷ For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.

Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.¹⁸ Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.

The contained morcellation approach

Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.

Continue to: Currently, one containment bag has been...

Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.¹⁹ Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.²⁰ Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.

One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.^21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.²³ Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.

CASE Next steps and treatment outcome

The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.

You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.

The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.

The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.

You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.

Society guidance on clinical applications

In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.

ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.^2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.²⁵

With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.

Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.¹ This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.

Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.²

In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.

Morcellation uses—and risks

Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.

In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.

Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.^3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.⁴ For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.³

With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.^5-7

Continue to: The challenge of leiomyosarcoma...

The challenge of leiomyosarcoma

The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.

Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.⁸ However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.^9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).

Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.^11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.¹ Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.¹³

Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.⁹ Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.^12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.

CASE Woman with enlarged, irregular uterus and heavy bleeding

A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.

The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.

What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?

Continue to: Perform a thorough preoperative evaluation to optimize outcomes...

Perform a thorough preoperative evaluation to optimize outcomes

Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.

According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they¹⁵:

• are older than 45 years with abnormal uterine bleeding
• are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
• have persistent bleeding, or
• failed medical management.

Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.²

Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.¹⁶ There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.

Employ shared decision making

Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.¹⁷ For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.

Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.¹⁸ Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.

The contained morcellation approach

Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.

Continue to: Currently, one containment bag has been...

Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.¹⁹ Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.²⁰ Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.

One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.^21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.²³ Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.

CASE Next steps and treatment outcome

The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.

You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.

The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.

The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.

You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.

Society guidance on clinical applications

In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.

ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.^2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.²⁵

With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.

Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.¹ This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.

Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.²

In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.

Morcellation uses—and risks

Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.

In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.

Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.^3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.⁴ For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.³

With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.^5-7

Continue to: The challenge of leiomyosarcoma...

The challenge of leiomyosarcoma

The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.

Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.⁸ However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.^9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).

Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.^11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.¹ Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.¹³

Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.⁹ Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.^12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.

CASE Woman with enlarged, irregular uterus and heavy bleeding

A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.

The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.

What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?

Continue to: Perform a thorough preoperative evaluation to optimize outcomes...

Perform a thorough preoperative evaluation to optimize outcomes

Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.

According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they¹⁵:

• are older than 45 years with abnormal uterine bleeding
• are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
• have persistent bleeding, or
• failed medical management.

Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.²

Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.¹⁶ There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.

Employ shared decision making

Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.¹⁷ For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.

Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.¹⁸ Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.

The contained morcellation approach

Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.

Continue to: Currently, one containment bag has been...

Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.¹⁹ Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.²⁰ Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.

One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.^21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.²³ Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.

CASE Next steps and treatment outcome

The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.

You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.

The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.

The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.

You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.

Society guidance on clinical applications

In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.

ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.^2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.²⁵

With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.

CASE HT for vasomotor symptoms in perimenopausal woman with cognitive concerns

Jackie is a 49-year-old woman. Her body mass index is 33 kg/m², and she has mild hypertension that is effectively controlled with antihypertensive medications. Otherwise, she is in good health.During her annual gynecologic exam, she reports that for the past 9 months her menstrual cycles have not been as regular as they used to be and that 3 months ago she skipped a cycle. She is having bothersome vasomotor symptoms (VMS) and is concerned about her memory. She says she is forgetful at work and in social situations. During a recent presentation, she could not remember the name of one of her former clients. At a work happy hour, she forgot the name of her coworker’s husband, although she did remember it later after returning home.

Her mother has Alzheimer disease (AD), and Jackie worries about whether she, too, might be developing dementia and whether her memory will fail her in social situations.

She is concerned about using hormone therapy (HT) for her vasomotor symptoms because she has heard that it can lead to breast cancer and/or AD.

How would you advise her?

HT remains the most effective treatment for bothersome VMS, but concerns about its cognitive safety persist. Such concerns, and indeed a black-box warning about the risk of dementia with HT use, initially arose following the 2003 publication of the Women’s Health Initiative Memory Study (WHIMS), a randomized, placebo-controlled trial of HT for the primary prevention of dementia in women aged 65 years and older at baseline.¹ The study found that combination estrogen/progestin therapy was associated with a 2-fold increase in dementia when compared with placebo.

One of the critical questions arising even before WHIMS was whether the cognitive risks associated with HT that were seen in WHIMS apply to younger women. Attempting to answer the question and adding fuel to the fire are the results of a recent case-control study from Finland.² This study compared HT use in Finnish women with and without AD and found that HT use was higher among Finnish women with AD compared with those without AD, regardless of age. The authors concluded, “Our data must be implemented into information for the present and future users of HT, even though the absolute risk increase is small.”

However, given the limitations inherent to observational and registry studies, and the contrasting findings of 3 high-quality, randomized controlled trials (RCTs; more details below), providers actually can reassure younger peri- and postmenopausal women about the cognitive safety of HT.³ They also can explain to patients that cognitive symptoms like the ones described in the case example are normal and provide general guidance to midlife women on how to optimize brain health.

Continue to: Closer look at WHI and RCT research pinpoints cognitively neutral HT...

Closer look at WHI and RCT research pinpoints cognitively neutral HT

In WHIMS, the combination of conjugated equine estrogen (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) led to a doubling of the risk of all-cause dementia compared with placebo in a sample of 4,532 women aged 65 years and older at baseline.¹ CEE alone (0.625 mg) did not lead to an increased risk of all-cause dementia.⁴

Whether those formulations led to cognitive impairment in younger postmenopausal women was the focus of WHIMS-Younger (WHIMS-Y), which involved WHI participants aged 50 to 55 years at baseline.⁵ Results revealed neutral cognitive effects (ie, no differences in cognitive performance in women randomly assigned to HT or placebo) in women tested 7.2 years after the end of the WHI trial. WHIMS-Y findings indicated that there were no sustained cognitive risks of CEE or CEE/MPA therapy. Two randomized, placebo-controlled trials involving younger postmenopausal women yielded similar findings.^6,7 HT shown to produce cognitively neutral effects during active treatment included transdermal estradiol plus micronized progesterone,⁶ CEE plus progesterone,⁶ and oral estradiol plus vaginal progesterone gel.⁷ The findings of these randomized trials are critical for guiding decisions regarding the cognitive risks of HT in early postmenopausal women (TABLE 1).

What about women with VMS?

A key gap in knowledge about the cognitive effects of HT is whether HT confers cognitive advantages to women with bothersome VMS. This is a striking absence given that the key indication for HT is the treatment of VMS. While some symptomatic women were included in the trials of HT in younger postmenopausal women described above, no large trial to date has selectively enrolled women with moderate-to-severe VMS to determine if HT is cognitively neutral, beneficial, or detrimental in that group. Some studies involving midlife women have found associations between VMS (as measured with ambulatory skin conductance monitors) and multiple measures of brain health, including memory performance,⁸ small ischemic lesions on structural brain scans,⁹ and altered brain function.¹⁰ In a small trial of a nonhormonal intervention for VMS, improvement in VMS following the intervention was directly related to improvement in memory performance.¹¹ The reliability of these findings continues to be evaluated but raises the hypothesis that VMS treatments might improve memory in midlife women.

Memory complaints common among midlife women

About 60% of women report an undesirable change in memory performance at midlife as compared with earlier in their lives.^12,13 Complaints of forgetfulness are higher in perimenopausal and postmenopausal women compared with premenopausal women, even when those women are similar in age.¹⁴ Two large prospective studies found that memory performance decreases during the perimenopause and then rebounds, suggesting a transient decrease in memory.^15,16 Although cognitive complaints are common among women in their 40s and 50s, AD is rare in that age group. The risk is largely limited to those women with a parent who developed dementia before age 65, as such cases suggest a familial form of AD.

Continue to: What causes cognitive difficulties during midlife?

What causes cognitive difficulties during midlife?

First, some cognitive decline is expected at midlife based on increasing age. Second, above and beyond the role of chronologic aging (ie, getting one year older each year), ovarian aging plays a role. A role of estrogen was verified in clinical trials showing that memory decreased following oophorectomy in premenopausal women in their 40s but returned to presurgical levels following treatment with estrogen therapy (ET).¹⁷ Cohort studies indicate that women who undergo oophorectomy before the typical age of menopause are at increased risk for cognitive impairment or dementia, but those who take ET after oophorectomy until the typical age of menopause do not show that risk.¹⁸

Third, cognitive problems are linked not only to VMS but also to sleep disturbance, depressed mood, and increased anxiety—all of which are common in midlife women.^15,19 Lastly, health factors play a role. Hypertension, obesity, insulin resistance, diabetes, and smoking are associated with adverse brain changes at midlife.²⁰

Giving advice to your patients

First, normalize the cognitive complaints, noting that some cognitive changes are an expected part of aging for all people regardless of whether they are male or female. Advise that while the best studies indicate that these cognitive lapses are especially common in perimenopausal women, they appear to be temporary; women are likely to resume normal cognitive function once the hormonal changes associated with menopause subside.^15,16 Note that the one unknown is the role that VMS play in memory problems and that some studies indicate a link between VMS and cognitive problems. Women may experience some cognitive improvement if VMS are effectively treated.

Advise patients that the Endocrine Society, the North American Menopause Society (NAMS), and the International Menopause Society all have published guidelines saying that the benefits of HT outweigh the risks for most women aged 50 to 60 years.²¹ For concerns about the cognitive adverse effects of HT, discuss the best quality evidence—that which comes from randomized trials—which shows no harmful effects of HT in midlife women.^5-7 Especially reassuring is that one of these high-quality studies was conducted by the same researchers who found that HT can be risky in older women (ie, the WHI Investigators).⁵

Going one step further: Protecting brain health

As primary care providers to midlife women, ObGyns can go one step further and advise patients on how to proactively nurture their brain health. Great evidence-based resources for information on maintaining brain health include the Alzheimer’s Association (https://www.alz.org) and the Women’s Brain Health Initiative (https://womensbrainhealth.org). Primary prevention of AD begins decades before the typical age of an AD diagnosis, and many risk factors for AD are modifiable.²² Patients can keep their brains healthy through myriad approaches including treating hypertension, reducing body mass index, engaging in regular aerobic exercise (brisk walking is fine), eating a Mediterranean diet, maintaining an active social life, and engaging in novel challenging activities like learning a new language or a new skill like dancing.²⁰

Also important is the overlap between cognitive issues, mood, and alcohol use. In the opening case, Jackie mentions alcohol use and social withdrawal. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking for women is defined as no more than 3 drinks on any single day and no more than 7 drinks per week.²³ Heavy alcohol use not only affects brain function but also mood, and depressed mood can lead women to drink excessively.²⁴

In addition, Jackie’s mother has AD, and that stressor can contribute to depressed feelings, especially if Jackie is involved in caregiving. A quick screen for depression with an instrument like the Patient Health Questionnaire-2 (PHQ-2; TABLE 2)²⁵ can rule out a more serious mood disorder—an approach that is particularly important for patients with a history of major depression, as 58% of those patients experience a major depressive episode during the menopausal transition.²⁶ For this reason, it is important to ask patients like Jackie if they have a history of depression; if they do and were treated medically, consider prescribing the antidepressant that worked in the past. For information on menopause and mood-related issues, providers can access new guidelines from NAMS and the National Network of Depression Centers (NNDC).²⁷ There is also a handy patient information sheet to accompany those guidelines on the NAMS website (https://www.menopause.org/).

Continue to: CASE Resolved...

CASE Resolved

When approaching Jackie, most importantly, I would normalize her experience and tell her that memory problems are common in the menopausal transition, especially for women with bothersome VMS. Research suggests that the memory problems she is experiencing are related to hormonal changes and not to AD, and that her memory will likely improve once she has transitioned through the menopause. I would tell her that AD is rare at midlife unless there is a family history of early onset of AD (before age 65), and I would verify the age at which her mother was diagnosed to confirm that it was late-onset AD.

For now, I would recommend that she be prescribed HT for her bothersome hot flashes using one of the “safe” formulations in the Table on page 24. I also would tell her that there is much she can do to lower her risk of AD and that it is best to start now as she enters her 50s because that is when AD changes typically start in the brain, and she can start to prevent those changes now.

I would tell her that experts in the field of AD agree that these lifestyle interventions are currently the best way to prevent AD and that the more of them she engages in, the more her brain will benefit. I would advise her to continue to manage her hypertension and to consider ways of lowering her BMI to enhance her brain health. Engaging in regular brisk walking or other aerobic exercise, as well as incorporating more of the Mediterranean diet into her daily food intake would also benefit her brain. As a working woman, she is exercising her brain, and she should consider other cognitively challenging activities to keep her brain in good shape.

I would follow up with her in a few months to see if her memory functioning is better. If it is not, and if her VMS continue to be bothersome, I would increase her dose of HT. Only if her VMS are treated but her memory problems are getting worse would I screen her with a Mini-Mental State Exam and refer her to a neurologist for an evaluation.
 

CASE HT for vasomotor symptoms in perimenopausal woman with cognitive concerns

Jackie is a 49-year-old woman. Her body mass index is 33 kg/m², and she has mild hypertension that is effectively controlled with antihypertensive medications. Otherwise, she is in good health.During her annual gynecologic exam, she reports that for the past 9 months her menstrual cycles have not been as regular as they used to be and that 3 months ago she skipped a cycle. She is having bothersome vasomotor symptoms (VMS) and is concerned about her memory. She says she is forgetful at work and in social situations. During a recent presentation, she could not remember the name of one of her former clients. At a work happy hour, she forgot the name of her coworker’s husband, although she did remember it later after returning home.

Her mother has Alzheimer disease (AD), and Jackie worries about whether she, too, might be developing dementia and whether her memory will fail her in social situations.

She is concerned about using hormone therapy (HT) for her vasomotor symptoms because she has heard that it can lead to breast cancer and/or AD.

How would you advise her?

HT remains the most effective treatment for bothersome VMS, but concerns about its cognitive safety persist. Such concerns, and indeed a black-box warning about the risk of dementia with HT use, initially arose following the 2003 publication of the Women’s Health Initiative Memory Study (WHIMS), a randomized, placebo-controlled trial of HT for the primary prevention of dementia in women aged 65 years and older at baseline.¹ The study found that combination estrogen/progestin therapy was associated with a 2-fold increase in dementia when compared with placebo.

One of the critical questions arising even before WHIMS was whether the cognitive risks associated with HT that were seen in WHIMS apply to younger women. Attempting to answer the question and adding fuel to the fire are the results of a recent case-control study from Finland.² This study compared HT use in Finnish women with and without AD and found that HT use was higher among Finnish women with AD compared with those without AD, regardless of age. The authors concluded, “Our data must be implemented into information for the present and future users of HT, even though the absolute risk increase is small.”

However, given the limitations inherent to observational and registry studies, and the contrasting findings of 3 high-quality, randomized controlled trials (RCTs; more details below), providers actually can reassure younger peri- and postmenopausal women about the cognitive safety of HT.³ They also can explain to patients that cognitive symptoms like the ones described in the case example are normal and provide general guidance to midlife women on how to optimize brain health.

Continue to: Closer look at WHI and RCT research pinpoints cognitively neutral HT...

Closer look at WHI and RCT research pinpoints cognitively neutral HT

In WHIMS, the combination of conjugated equine estrogen (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) led to a doubling of the risk of all-cause dementia compared with placebo in a sample of 4,532 women aged 65 years and older at baseline.¹ CEE alone (0.625 mg) did not lead to an increased risk of all-cause dementia.⁴

Whether those formulations led to cognitive impairment in younger postmenopausal women was the focus of WHIMS-Younger (WHIMS-Y), which involved WHI participants aged 50 to 55 years at baseline.⁵ Results revealed neutral cognitive effects (ie, no differences in cognitive performance in women randomly assigned to HT or placebo) in women tested 7.2 years after the end of the WHI trial. WHIMS-Y findings indicated that there were no sustained cognitive risks of CEE or CEE/MPA therapy. Two randomized, placebo-controlled trials involving younger postmenopausal women yielded similar findings.^6,7 HT shown to produce cognitively neutral effects during active treatment included transdermal estradiol plus micronized progesterone,⁶ CEE plus progesterone,⁶ and oral estradiol plus vaginal progesterone gel.⁷ The findings of these randomized trials are critical for guiding decisions regarding the cognitive risks of HT in early postmenopausal women (TABLE 1).

What about women with VMS?

A key gap in knowledge about the cognitive effects of HT is whether HT confers cognitive advantages to women with bothersome VMS. This is a striking absence given that the key indication for HT is the treatment of VMS. While some symptomatic women were included in the trials of HT in younger postmenopausal women described above, no large trial to date has selectively enrolled women with moderate-to-severe VMS to determine if HT is cognitively neutral, beneficial, or detrimental in that group. Some studies involving midlife women have found associations between VMS (as measured with ambulatory skin conductance monitors) and multiple measures of brain health, including memory performance,⁸ small ischemic lesions on structural brain scans,⁹ and altered brain function.¹⁰ In a small trial of a nonhormonal intervention for VMS, improvement in VMS following the intervention was directly related to improvement in memory performance.¹¹ The reliability of these findings continues to be evaluated but raises the hypothesis that VMS treatments might improve memory in midlife women.

Memory complaints common among midlife women

About 60% of women report an undesirable change in memory performance at midlife as compared with earlier in their lives.^12,13 Complaints of forgetfulness are higher in perimenopausal and postmenopausal women compared with premenopausal women, even when those women are similar in age.¹⁴ Two large prospective studies found that memory performance decreases during the perimenopause and then rebounds, suggesting a transient decrease in memory.^15,16 Although cognitive complaints are common among women in their 40s and 50s, AD is rare in that age group. The risk is largely limited to those women with a parent who developed dementia before age 65, as such cases suggest a familial form of AD.

Continue to: What causes cognitive difficulties during midlife?

What causes cognitive difficulties during midlife?

First, some cognitive decline is expected at midlife based on increasing age. Second, above and beyond the role of chronologic aging (ie, getting one year older each year), ovarian aging plays a role. A role of estrogen was verified in clinical trials showing that memory decreased following oophorectomy in premenopausal women in their 40s but returned to presurgical levels following treatment with estrogen therapy (ET).¹⁷ Cohort studies indicate that women who undergo oophorectomy before the typical age of menopause are at increased risk for cognitive impairment or dementia, but those who take ET after oophorectomy until the typical age of menopause do not show that risk.¹⁸

Third, cognitive problems are linked not only to VMS but also to sleep disturbance, depressed mood, and increased anxiety—all of which are common in midlife women.^15,19 Lastly, health factors play a role. Hypertension, obesity, insulin resistance, diabetes, and smoking are associated with adverse brain changes at midlife.²⁰

Giving advice to your patients

First, normalize the cognitive complaints, noting that some cognitive changes are an expected part of aging for all people regardless of whether they are male or female. Advise that while the best studies indicate that these cognitive lapses are especially common in perimenopausal women, they appear to be temporary; women are likely to resume normal cognitive function once the hormonal changes associated with menopause subside.^15,16 Note that the one unknown is the role that VMS play in memory problems and that some studies indicate a link between VMS and cognitive problems. Women may experience some cognitive improvement if VMS are effectively treated.

Advise patients that the Endocrine Society, the North American Menopause Society (NAMS), and the International Menopause Society all have published guidelines saying that the benefits of HT outweigh the risks for most women aged 50 to 60 years.²¹ For concerns about the cognitive adverse effects of HT, discuss the best quality evidence—that which comes from randomized trials—which shows no harmful effects of HT in midlife women.^5-7 Especially reassuring is that one of these high-quality studies was conducted by the same researchers who found that HT can be risky in older women (ie, the WHI Investigators).⁵

Going one step further: Protecting brain health

As primary care providers to midlife women, ObGyns can go one step further and advise patients on how to proactively nurture their brain health. Great evidence-based resources for information on maintaining brain health include the Alzheimer’s Association (https://www.alz.org) and the Women’s Brain Health Initiative (https://womensbrainhealth.org). Primary prevention of AD begins decades before the typical age of an AD diagnosis, and many risk factors for AD are modifiable.²² Patients can keep their brains healthy through myriad approaches including treating hypertension, reducing body mass index, engaging in regular aerobic exercise (brisk walking is fine), eating a Mediterranean diet, maintaining an active social life, and engaging in novel challenging activities like learning a new language or a new skill like dancing.²⁰

Also important is the overlap between cognitive issues, mood, and alcohol use. In the opening case, Jackie mentions alcohol use and social withdrawal. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking for women is defined as no more than 3 drinks on any single day and no more than 7 drinks per week.²³ Heavy alcohol use not only affects brain function but also mood, and depressed mood can lead women to drink excessively.²⁴

In addition, Jackie’s mother has AD, and that stressor can contribute to depressed feelings, especially if Jackie is involved in caregiving. A quick screen for depression with an instrument like the Patient Health Questionnaire-2 (PHQ-2; TABLE 2)²⁵ can rule out a more serious mood disorder—an approach that is particularly important for patients with a history of major depression, as 58% of those patients experience a major depressive episode during the menopausal transition.²⁶ For this reason, it is important to ask patients like Jackie if they have a history of depression; if they do and were treated medically, consider prescribing the antidepressant that worked in the past. For information on menopause and mood-related issues, providers can access new guidelines from NAMS and the National Network of Depression Centers (NNDC).²⁷ There is also a handy patient information sheet to accompany those guidelines on the NAMS website (https://www.menopause.org/).

Continue to: CASE Resolved...

CASE Resolved

When approaching Jackie, most importantly, I would normalize her experience and tell her that memory problems are common in the menopausal transition, especially for women with bothersome VMS. Research suggests that the memory problems she is experiencing are related to hormonal changes and not to AD, and that her memory will likely improve once she has transitioned through the menopause. I would tell her that AD is rare at midlife unless there is a family history of early onset of AD (before age 65), and I would verify the age at which her mother was diagnosed to confirm that it was late-onset AD.

For now, I would recommend that she be prescribed HT for her bothersome hot flashes using one of the “safe” formulations in the Table on page 24. I also would tell her that there is much she can do to lower her risk of AD and that it is best to start now as she enters her 50s because that is when AD changes typically start in the brain, and she can start to prevent those changes now.

I would tell her that experts in the field of AD agree that these lifestyle interventions are currently the best way to prevent AD and that the more of them she engages in, the more her brain will benefit. I would advise her to continue to manage her hypertension and to consider ways of lowering her BMI to enhance her brain health. Engaging in regular brisk walking or other aerobic exercise, as well as incorporating more of the Mediterranean diet into her daily food intake would also benefit her brain. As a working woman, she is exercising her brain, and she should consider other cognitively challenging activities to keep her brain in good shape.

I would follow up with her in a few months to see if her memory functioning is better. If it is not, and if her VMS continue to be bothersome, I would increase her dose of HT. Only if her VMS are treated but her memory problems are getting worse would I screen her with a Mini-Mental State Exam and refer her to a neurologist for an evaluation.
 

CASE HT for vasomotor symptoms in perimenopausal woman with cognitive concerns

Jackie is a 49-year-old woman. Her body mass index is 33 kg/m², and she has mild hypertension that is effectively controlled with antihypertensive medications. Otherwise, she is in good health.During her annual gynecologic exam, she reports that for the past 9 months her menstrual cycles have not been as regular as they used to be and that 3 months ago she skipped a cycle. She is having bothersome vasomotor symptoms (VMS) and is concerned about her memory. She says she is forgetful at work and in social situations. During a recent presentation, she could not remember the name of one of her former clients. At a work happy hour, she forgot the name of her coworker’s husband, although she did remember it later after returning home.

Her mother has Alzheimer disease (AD), and Jackie worries about whether she, too, might be developing dementia and whether her memory will fail her in social situations.

She is concerned about using hormone therapy (HT) for her vasomotor symptoms because she has heard that it can lead to breast cancer and/or AD.

How would you advise her?

HT remains the most effective treatment for bothersome VMS, but concerns about its cognitive safety persist. Such concerns, and indeed a black-box warning about the risk of dementia with HT use, initially arose following the 2003 publication of the Women’s Health Initiative Memory Study (WHIMS), a randomized, placebo-controlled trial of HT for the primary prevention of dementia in women aged 65 years and older at baseline.¹ The study found that combination estrogen/progestin therapy was associated with a 2-fold increase in dementia when compared with placebo.

One of the critical questions arising even before WHIMS was whether the cognitive risks associated with HT that were seen in WHIMS apply to younger women. Attempting to answer the question and adding fuel to the fire are the results of a recent case-control study from Finland.² This study compared HT use in Finnish women with and without AD and found that HT use was higher among Finnish women with AD compared with those without AD, regardless of age. The authors concluded, “Our data must be implemented into information for the present and future users of HT, even though the absolute risk increase is small.”

However, given the limitations inherent to observational and registry studies, and the contrasting findings of 3 high-quality, randomized controlled trials (RCTs; more details below), providers actually can reassure younger peri- and postmenopausal women about the cognitive safety of HT.³ They also can explain to patients that cognitive symptoms like the ones described in the case example are normal and provide general guidance to midlife women on how to optimize brain health.

Continue to: Closer look at WHI and RCT research pinpoints cognitively neutral HT...

Closer look at WHI and RCT research pinpoints cognitively neutral HT

In WHIMS, the combination of conjugated equine estrogen (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) led to a doubling of the risk of all-cause dementia compared with placebo in a sample of 4,532 women aged 65 years and older at baseline.¹ CEE alone (0.625 mg) did not lead to an increased risk of all-cause dementia.⁴

Whether those formulations led to cognitive impairment in younger postmenopausal women was the focus of WHIMS-Younger (WHIMS-Y), which involved WHI participants aged 50 to 55 years at baseline.⁵ Results revealed neutral cognitive effects (ie, no differences in cognitive performance in women randomly assigned to HT or placebo) in women tested 7.2 years after the end of the WHI trial. WHIMS-Y findings indicated that there were no sustained cognitive risks of CEE or CEE/MPA therapy. Two randomized, placebo-controlled trials involving younger postmenopausal women yielded similar findings.^6,7 HT shown to produce cognitively neutral effects during active treatment included transdermal estradiol plus micronized progesterone,⁶ CEE plus progesterone,⁶ and oral estradiol plus vaginal progesterone gel.⁷ The findings of these randomized trials are critical for guiding decisions regarding the cognitive risks of HT in early postmenopausal women (TABLE 1).

What about women with VMS?

A key gap in knowledge about the cognitive effects of HT is whether HT confers cognitive advantages to women with bothersome VMS. This is a striking absence given that the key indication for HT is the treatment of VMS. While some symptomatic women were included in the trials of HT in younger postmenopausal women described above, no large trial to date has selectively enrolled women with moderate-to-severe VMS to determine if HT is cognitively neutral, beneficial, or detrimental in that group. Some studies involving midlife women have found associations between VMS (as measured with ambulatory skin conductance monitors) and multiple measures of brain health, including memory performance,⁸ small ischemic lesions on structural brain scans,⁹ and altered brain function.¹⁰ In a small trial of a nonhormonal intervention for VMS, improvement in VMS following the intervention was directly related to improvement in memory performance.¹¹ The reliability of these findings continues to be evaluated but raises the hypothesis that VMS treatments might improve memory in midlife women.

Memory complaints common among midlife women

About 60% of women report an undesirable change in memory performance at midlife as compared with earlier in their lives.^12,13 Complaints of forgetfulness are higher in perimenopausal and postmenopausal women compared with premenopausal women, even when those women are similar in age.¹⁴ Two large prospective studies found that memory performance decreases during the perimenopause and then rebounds, suggesting a transient decrease in memory.^15,16 Although cognitive complaints are common among women in their 40s and 50s, AD is rare in that age group. The risk is largely limited to those women with a parent who developed dementia before age 65, as such cases suggest a familial form of AD.

Continue to: What causes cognitive difficulties during midlife?

What causes cognitive difficulties during midlife?

First, some cognitive decline is expected at midlife based on increasing age. Second, above and beyond the role of chronologic aging (ie, getting one year older each year), ovarian aging plays a role. A role of estrogen was verified in clinical trials showing that memory decreased following oophorectomy in premenopausal women in their 40s but returned to presurgical levels following treatment with estrogen therapy (ET).¹⁷ Cohort studies indicate that women who undergo oophorectomy before the typical age of menopause are at increased risk for cognitive impairment or dementia, but those who take ET after oophorectomy until the typical age of menopause do not show that risk.¹⁸

Third, cognitive problems are linked not only to VMS but also to sleep disturbance, depressed mood, and increased anxiety—all of which are common in midlife women.^15,19 Lastly, health factors play a role. Hypertension, obesity, insulin resistance, diabetes, and smoking are associated with adverse brain changes at midlife.²⁰

Giving advice to your patients

First, normalize the cognitive complaints, noting that some cognitive changes are an expected part of aging for all people regardless of whether they are male or female. Advise that while the best studies indicate that these cognitive lapses are especially common in perimenopausal women, they appear to be temporary; women are likely to resume normal cognitive function once the hormonal changes associated with menopause subside.^15,16 Note that the one unknown is the role that VMS play in memory problems and that some studies indicate a link between VMS and cognitive problems. Women may experience some cognitive improvement if VMS are effectively treated.

Advise patients that the Endocrine Society, the North American Menopause Society (NAMS), and the International Menopause Society all have published guidelines saying that the benefits of HT outweigh the risks for most women aged 50 to 60 years.²¹ For concerns about the cognitive adverse effects of HT, discuss the best quality evidence—that which comes from randomized trials—which shows no harmful effects of HT in midlife women.^5-7 Especially reassuring is that one of these high-quality studies was conducted by the same researchers who found that HT can be risky in older women (ie, the WHI Investigators).⁵

Going one step further: Protecting brain health

As primary care providers to midlife women, ObGyns can go one step further and advise patients on how to proactively nurture their brain health. Great evidence-based resources for information on maintaining brain health include the Alzheimer’s Association (https://www.alz.org) and the Women’s Brain Health Initiative (https://womensbrainhealth.org). Primary prevention of AD begins decades before the typical age of an AD diagnosis, and many risk factors for AD are modifiable.²² Patients can keep their brains healthy through myriad approaches including treating hypertension, reducing body mass index, engaging in regular aerobic exercise (brisk walking is fine), eating a Mediterranean diet, maintaining an active social life, and engaging in novel challenging activities like learning a new language or a new skill like dancing.²⁰

Also important is the overlap between cognitive issues, mood, and alcohol use. In the opening case, Jackie mentions alcohol use and social withdrawal. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking for women is defined as no more than 3 drinks on any single day and no more than 7 drinks per week.²³ Heavy alcohol use not only affects brain function but also mood, and depressed mood can lead women to drink excessively.²⁴

In addition, Jackie’s mother has AD, and that stressor can contribute to depressed feelings, especially if Jackie is involved in caregiving. A quick screen for depression with an instrument like the Patient Health Questionnaire-2 (PHQ-2; TABLE 2)²⁵ can rule out a more serious mood disorder—an approach that is particularly important for patients with a history of major depression, as 58% of those patients experience a major depressive episode during the menopausal transition.²⁶ For this reason, it is important to ask patients like Jackie if they have a history of depression; if they do and were treated medically, consider prescribing the antidepressant that worked in the past. For information on menopause and mood-related issues, providers can access new guidelines from NAMS and the National Network of Depression Centers (NNDC).²⁷ There is also a handy patient information sheet to accompany those guidelines on the NAMS website (https://www.menopause.org/).

Continue to: CASE Resolved...

CASE Resolved

When approaching Jackie, most importantly, I would normalize her experience and tell her that memory problems are common in the menopausal transition, especially for women with bothersome VMS. Research suggests that the memory problems she is experiencing are related to hormonal changes and not to AD, and that her memory will likely improve once she has transitioned through the menopause. I would tell her that AD is rare at midlife unless there is a family history of early onset of AD (before age 65), and I would verify the age at which her mother was diagnosed to confirm that it was late-onset AD.

For now, I would recommend that she be prescribed HT for her bothersome hot flashes using one of the “safe” formulations in the Table on page 24. I also would tell her that there is much she can do to lower her risk of AD and that it is best to start now as she enters her 50s because that is when AD changes typically start in the brain, and she can start to prevent those changes now.

I would tell her that experts in the field of AD agree that these lifestyle interventions are currently the best way to prevent AD and that the more of them she engages in, the more her brain will benefit. I would advise her to continue to manage her hypertension and to consider ways of lowering her BMI to enhance her brain health. Engaging in regular brisk walking or other aerobic exercise, as well as incorporating more of the Mediterranean diet into her daily food intake would also benefit her brain. As a working woman, she is exercising her brain, and she should consider other cognitively challenging activities to keep her brain in good shape.

I would follow up with her in a few months to see if her memory functioning is better. If it is not, and if her VMS continue to be bothersome, I would increase her dose of HT. Only if her VMS are treated but her memory problems are getting worse would I screen her with a Mini-Mental State Exam and refer her to a neurologist for an evaluation.
 

Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.¹ Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.

Postmenopausal bleeding: Its risk for cancer

Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.² Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.

Video 1

Vidyard Video

The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.³

Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.

Evaluation of postmenopausal bleeding

Transvaginal ultrasound

As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.³ Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).

Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.

Endometrial biopsy

An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.⁴

Continue to: Endometrial biopsy has some...

 

 

Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).⁵ Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.

Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.

 

Hysteroscopy

Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”⁶ As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.

It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.⁷ Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).

Continue to: Hysteroscopy and endometrial carcinoma...

 

 

Hysteroscopy and endometrial carcinoma

The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.⁸

For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.⁹

Three clinical scenarios

---

A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.

Patient 1: Discordant TVUS and biopsy, with benign findings

The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.

At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).

Video 2

Vidyard Video

This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.

Patient 2: Discordant TVUS and biopsy, with premalignant findings

The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.

At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).

Video 3

Vidyard Video

This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.

Patient 3: Discordant TVUS and biopsy, with malignant findings

The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.

Video 4A

Vidyard Video

At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).

Video 4B

Vidyard Video

This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.

Video 4C

Vidyard Video

 

 

Conclusion

Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.

Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.¹ Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.

Postmenopausal bleeding: Its risk for cancer

Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.² Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.

Video 1

Vidyard Video

The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.³

Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.

Evaluation of postmenopausal bleeding

Transvaginal ultrasound

As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.³ Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).

Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.

Endometrial biopsy

An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.⁴

Continue to: Endometrial biopsy has some...

 

 

Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).⁵ Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.

Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.

 

Hysteroscopy

Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”⁶ As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.

It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.⁷ Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).

Continue to: Hysteroscopy and endometrial carcinoma...

 

 

Hysteroscopy and endometrial carcinoma

The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.⁸

For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.⁹

Three clinical scenarios

---

A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.

Patient 1: Discordant TVUS and biopsy, with benign findings

The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.

At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).

Video 2

Vidyard Video

This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.

Patient 2: Discordant TVUS and biopsy, with premalignant findings

The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.

At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).

Video 3

Vidyard Video

This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.

Patient 3: Discordant TVUS and biopsy, with malignant findings

The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.

Video 4A

Vidyard Video

At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).

Video 4B

Vidyard Video

This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.

Video 4C

Vidyard Video

 

 

Conclusion

Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.