Sarina Schrager, MD, MS

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.¹ Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.^2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 1^4-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.^4-9

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.⁵ For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.⁵ Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 2^10-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.^10-12

Continue to: CASE

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).⁷ Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.^5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.¹⁶

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.¹⁷

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.^5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.⁹ The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).^19-21PRS predicts an additional 18% of genetic risk in women of European descent.²¹

Continue to: CASE

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 4^8,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.⁸ For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.¹³BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.²² Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)²³ based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 5^7,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).²³ It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.^7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.²⁵ NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.²²

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.²⁶ There is a reduction in breast cancer incidence of 90%.²⁵ Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.²⁶

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.²⁷

Continue to: CASE

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; [email protected]

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.¹ Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.^2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 1^4-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.^4-9

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.⁵ For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.⁵ Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 2^10-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.^10-12

Continue to: CASE

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).⁷ Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.^5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.¹⁶

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.¹⁷

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.^5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.⁹ The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).^19-21PRS predicts an additional 18% of genetic risk in women of European descent.²¹

Continue to: CASE

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 4^8,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.⁸ For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.¹³BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.²² Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)²³ based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 5^7,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).²³ It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.^7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.²⁵ NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.²²

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.²⁶ There is a reduction in breast cancer incidence of 90%.²⁵ Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.²⁶

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.²⁷

Continue to: CASE

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; [email protected]

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.¹ Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.^2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 1^4-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.^4-9

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.⁵ For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.⁵ Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 2^10-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.^10-12

Continue to: CASE

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).⁷ Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.^5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.¹⁶

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.¹⁷

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.^5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.⁹ The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).^19-21PRS predicts an additional 18% of genetic risk in women of European descent.²¹

Continue to: CASE

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 4^8,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.⁸ For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.¹³BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.²² Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)²³ based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 5^7,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).²³ It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.^7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.²⁵ NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.²²

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.²⁶ There is a reduction in breast cancer incidence of 90%.²⁵ Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.²⁶

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.²⁷

Continue to: CASE

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; [email protected]

CASE

Sara T* recently moved back to the area to be closer to her family. The 34-year-old patient visited our office to discuss the benefits and potential risks of genetic counseling. She explained that her aunt had just died at age 64 of ovarian cancer. Also, her maternal cousin had been diagnosed at age 42 with breast cancer, and her maternal grandmother had died at age 45 of an unknown “female cancer.” She was scared to find out if she had high-risk genes because she felt it would change her life forever. However, if she ignored the issue, she thought she might worry too much.

We discussed the implications of a positive result, such as having to live with the knowledge and to make decisions about potential screening and risk-reducing surgery. On the other hand, not knowing could allow for the undetected growth of cancer that might otherwise be mitigated to some degree if she knew her risk status and pursued an aggressive screening program.

We worked with Ms. T to map out her next steps.

*The patient’s name has been changed to protect her identity.

Breast cancer is the most commonly diagnosed cancer in women worldwide, representing nearly one-quarter of all female cancer diagnoses in 2018.¹ It is the second-leading cause of cancer death in women in developed nations and the leading cause of cancer death in women in developing nations.¹ In the United States, 1 in 8 women will develop breast cancer in her lifetime.² By comparison, the rate of ovarian cancer is much lower, with a lifetime prevalence of 1 in 70 to 80 women.^3,4 Although ovarian cancer is less common than breast cancer, its associated mortality is high, and most cases are discovered at advanced stages.

The outsized threat of BRCA mutations. It is estimated that 5% to 10% of all breast cancers are hereditary, with 80% of these attributable to BRCA1 (45%) and BRCA2 (35%).⁵ These autosomal dominant mutations occur at the germline level, within the egg or sperm, and are therefore incorporated into the DNA of every cell and passed from one generation to the next. Families with BRCA mutations have much higher lifetime rates of cancer. The lifetime risk of breast cancer due to BRCA mutations is estimated at > 80% (BRCA1) and 45% (BRCA2).⁵BRCA mutations account for between 10% and 18% of all ovarian cancers⁶ and convey a lifetime risk of 40% (BRCA1) and 15% (BRCA2) to carriers.⁵

USPSTF now also recommends BRCA1/2 screening for any woman with a family history of tubal or peritoneal cancer.

Male BRCA carriers have a lifetime breast cancer risk of 1% to 5% with BRCA1 and 5% to 10% with BRCA2,^7,8 compared with about 1:1000 lifetime incidence in the unselected male population. Male carriers are also at risk for more aggressive prostate cancers.^7,8

Continue to: Certain populatiosn carry undue burden of BRCA-related disease

Certain populations carry undue burden of BRCA-related disease due to specific founder mutations. While the estimated global prevalence of BRCA mutations is 0.2% to 1%, for those of Ashkenazi Jewish descent the range is 2% to 3%, representing a relative risk up to 15 times that of the general population.⁹ Hispanic Americans also appear to have higher rates of BRCA-related cancers.¹⁰ Ongoing genetics research continues to identify founder mutations worldwide,¹⁰ which may inform future screening guidelines.

In addition to BRCA mutations, there are other, less common mutations (TABLE 1⁵) known to cause hereditary breast and ovarian cancer.

Identifying BRCA genes enables treatment planning. Compared with sporadic cancers, BRCA-related breast cancers are diagnosed at earlier ages,¹¹are more likely to have lymph node involvement at time of discovery,¹²are more likely to be triple negative (no expression of estrogen, progesterone, or HER2 receptors),^11,12 and are associated with worse overall and breast cancer–specific survival.¹³

Similarly, BRCA-related ovarian cancer is more likely to be high-grade and endometrioid or serous subtype.¹⁴Knowledge of BRCA carrier status allows for risk-reducing strategies that are effective in reducing the incidence of cancer and improving cancer-­specific survival.^15,16As such, it is crucial that the primary care provider understand guidelines to help identify this high-risk population and work with patients on risk-reducing strategies.

Shared decision-making helps give clarity to the way forward

Shared decision-making is a process of communication whereby the clinician and the patient identify a decision to be made, review data relevant to clinical options, discuss patient perspectives and preferences regarding each option, and arrive at the decision together.¹⁷ Shared decision-making is important when treating women with BRCA mutations because there is no single correct plan. Individual values and competing medical issues may strongly guide each woman’s decisions about screening and cancer prevention treatment decisions.

Continue to: Shared decision-making in this situation...

Shared decision-making in this situation is a strategy to use the evidence of risk along with patient preferences around fertility issues to help come to a decision that is the right one for the patient. Primary care clinicians aware of the general risks and benefits of each available option can refer women at high risk for breast or ovarian cancer to a specialist multidisciplinary clinic that can provide tailored risk assessment and risk reduction counseling as needed.^18-20

Genetic screening recommendations

Screening is recommended for women who have any 1 of several family risk factors (TABLE 2²¹). A number of risk assessment tools are available for primary care clinicians to determine which patients are at high enough risk for a hereditary breast or ovarian cancer to warrant referral to a genetic counselor.^22-25 If screening suggests high risk, the US Preventive Services Task Force (USPSTF) recommends (Grade B) referral for genetic counseling.²¹

Explain to patients who are candidates for further investigation that a genetic counselor will review their family history and recommend testing for the specific mutations that increase cancer risk. Discuss potential benefits and harms of genetic testing. A benefit of genetic testing is that aggressive screening may suggest preventive procedures to reduce the risk of future cancer. Most tests come back definitively positive or negative, but an indeterminate result may cause harm. A small minority of results may indicate a genetic variant of unknown significance. The ramifications of this variant may not be known. Some women will experience anxiety about nonspecific test results and will be afraid to share them with family members. There is also some concern about privacy issues, potential insurance bias, and coverage of any preventive strategies.²⁶

CASE

Based on Ms. T’s family history and her desire to know more, we referred her to a genetic counselor and she decided to undergo genetic testing. She screened positive for BRCA1. Ms. T was in a serious relationship and thought she would like to have children at some point. She returned to our office after receiving the positive genetic test results, wondering about screening for breast and ovarian cancer.

Breast cancer screening and risk-reduction strategies

Screening. Because the risk of breast cancer is high in women with BRCA mutations, and because cancer in these women is more likely to be advanced at diagnosis, starting a screening program at an early age is prudent. Observational studies suggest that breastfeeding reduces the risk of breast and ovarian cancer in women with BRCA mutations, as it does for women in the general population.²⁷ Women should return for a clinical breast exam every 6 to 12 months starting at age 25; they should start radiologic screening with magnetic resonance imaging at age 25 and mammography at age 30 (TABLE 3^27,28).

Continue to: Risk-reduction strategies

Risk-reduction strategies. There is weak evidence to support the use of tamoxifen or other synthetic estrogen reuptake modulators (SERMs) to reduce breast cancer risk in women with BRCA mutations. Many of these cancers do not express estrogen receptors, which may explain the lack of efficacy in certain cases. Several observational studies have shown that tamoxifen can reduce the risk of contralateral breast cancer in women with BRCA mutations who have already been diagnosed with cancer in the other breast.^29-31 However, tamoxifen does not reduce a patient’s risk of ovarian cancer, and it may increase her risk of uterine cancer.

Shared decisionmaking is important when treating women with BRCA mutations because there is no single correct plan.

Prophylactic bilateral mastectomy is the mainstay of breast cancer prevention in this population. Data from a systematic review suggest that this surgery may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.³² However, this review did not demonstrate a reduction in mortality from breast cancer, likely due to poor data quality.³² The National Comprehensive Cancer Network (NCCN) recommends discussing prophylactic mastectomy with all women who have BRCA mutations.²⁸ Further conversations are important to review the risk of tissue left behind and quality-of-life issues, including the inability to breastfeed if the woman wants more children and the cosmetic changes with reconstruction.

Ovarian cancer screening and risk-reduction strategies

Screening. No effective screening strategy has been endorsed for ovarian cancer, as most previous studies have shown screening to be ineffective.^26,33 Recently, studies both in the United Kingdom and the United States have investigated a screening strategy using the risk-of-ovarian-cancer algorithm (ROCA), which calculates an individual’s risk based on serum levels of cancer antigen 125 (CA-125).^34,35 These studies measured CA-125 levels every 3 to 4 months followed by transvaginal ultrasound if CA-125 increased substantially (as determined by ROCA). Absent an abnormal increase in CA-125, transvaginal ultrasound was performed annually. These screening strategies showed improved specificity over annual screening programs, and the cancers detected were more likely to be diagnosed at an early stage (stage II vs stage III) and had higher rates of zero residual disease after surgery compared with those detected 1 year after screening ended.^34,35 However, survival data are not yet available. More research is needed to determine if more frequent screening approaches could improve survival in high-risk women.

Prophylactic bilateral mastectomy may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.

NCCN and the American College of Obstetricians and Gynecologists (ACOG) do not endorse routine screening with transvaginal ultrasound and serum CA-125 for high-risk women, as the benefits are uncertain. However, they do advise that these screens may be considered as a short-term strategy for women ages 30 to 35 who defer risk-reducing surgery.^26,36 The USPSTF does not make a recommendation regarding ovarian cancer screening in high-risk women.³⁷

Risk-reduction strategies. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only recommended technique for reducing the risk of ovarian cancer in women at high risk.^26,33,36 Meta-analyses have shown an 80% reduction in ovarian cancer risk¹⁶ and 68% reduction in all-cause mortality with this approach.³⁸ The NCCN recommends RRSO for women with a known BRCA1 mutation between the ages of 35 and 40 who have completed childbearing.³⁶ Since the onset of ovarian cancer tends to be later in women with BRCA2 mutations, it is reasonable to delay RRSO until age 40 to 45 in this population if they have taken other steps to maximize breast cancer prevention (ie, bilateral mastectomy).³⁶

Continue to: Adverse effects of RRSO...

Adverse effects of RRSO include surgery complications (wound infection, small bowel obstruction, bladder perforation) and effects of early menopause (vasomotor symptoms, decreased sexual functioning, and increased risk of osteoporosis, cardiovascular disease, and all-cause mortality).^39-41 In the absence of contraindications, ACOG recommends using hormone therapy in women undergoing RRSO until the natural age of menopause,⁴² particularly if their breast tissue has been removed.

Salpingectomy as an alternative. In an attempt to reduce these adverse effects of early menopause, and because a large proportion of high-grade serous tumors originate in the fallopian tube,⁴³ interest has increased in the use of risk-reducing salpingectomy (removal of fallopian tubes) and delayed oophorectomy in women at high risk of ovarian cancer.⁴² Studies have shown this may be a cost-effective approach and an acceptable alternative in BRCA mutation carriers who are unwilling to undergo RRSO.^44,45 A clinical trial investigating this approach in women with BRCA mutations is currently underway in the United States.⁴⁶ Many centers offer salpingectomy to high-risk patients < 40 years old, understanding that ovary removal is an eventuality for these patients.

When oral contraceptive pills might be beneficial. In younger women with BRCA mutations, there may also be a role for oral contraceptive pills (OCPs) as a risk-reducing strategy. Meta-analyses have shown an approximately 50% reduction in the risk of ovarian cancer among women with BRCA mutations who use OCPs.^47-49

ACOG advises that it is appropriate for women with BRCA mutations to use oral contraceptives if indicated (for pregnancy prevention or menstrual cycle regulation), and that it is reasonable to use them for cancer prevention.²⁶ NCCN does not make a formal recommendation, although it does state OCPs may reduce the risk of ovarian cancer in women with a BRCA mutation.³⁶ Case-control studies have produced conflicting data on the association between OCP use and breast cancer risk in BRCA mutation carriers,^50-53 although 2 meta-analyses found no significant association in this population.^47,48

Decision aids for women with BRCA mutations

Decision aids are visual displays of risk that help patients work through complex decisions. Most decision aids are in print or digital format and include information about the decision to be made as well as pictorial examples of possible outcomes. Pictographs are especially helpful in communicating information. Some decision aids for women with BRCA mutations can be complicated with multiple outcomes (ie, breast cancer and ovarian cancer) and multiple potential interventions (risk-reducing surgery, enhanced screening options).⁵⁴

Continue to: A Cochrane review...

A Cochrane review found that decision aids increased patients’ knowledge, helped patients clarify their values, and may improve value-concordant decisions.⁵⁵ Two papers describing the use of decision aids for women with BRCA mutations^56,57 documented decreased decisional conflict and increased satisfaction.

CASE

Ms. T underwent the recommended mammogram and MRI screening for breast ­cancer, as well as testing with serum CA-125 and ultrasound examinations for ovarian cancer. Her initial mammogram and MRI revealed early stage, triple-negative right breast cancer. She chose to undergo bilateral mastectomy and reconstruction. She has now completed treatment and continues to work closely with her oncology team for appropriate breast ­follow-up.

Two papers describing the use of decision aids for women with BRCA mutations documented decreased decisional conflict and increased satisfaction.

One year after her initial diagnosis, at the age of 35, she returned to discuss fertility. She was recently married, and she and her husband wanted to start having children. She was concerned about a safe timeline for her to pursue pregnancy, saying she felt “like a ticking time-bomb” given her prior cancer and carrier status. She wanted to discuss the risks and benefits of pregnancy and when she should consider prophylactic oophorectomy. She had a few options. She could have a baby and then undergo an RRSO, or she could talk to her gynecologist about having a salpingectomy to reduce her risk now and use assisted reproductive technology to get pregnant. She could also freeze eggs or embryos, have an RRSO, and then use a surrogate to get pregnant. We informed her that pregnancy would not affect her risk of ovarian cancer and discussed the options for pre-implantation genetic testing to assure that her children would not carry the genetic mutation.⁵⁸

We provided Ms. T and her husband with a decision aid to help them navigate the decision. They are currently evaluating the options and said they would let us know when they made a decision.

CORRESPONDENCE
Sarina Schrager, MD, MS, Northeast Family Medicine Center, 3209 Dryden Drive, Madison, WI, 53704; [email protected].

CASE

Sara T* recently moved back to the area to be closer to her family. The 34-year-old patient visited our office to discuss the benefits and potential risks of genetic counseling. She explained that her aunt had just died at age 64 of ovarian cancer. Also, her maternal cousin had been diagnosed at age 42 with breast cancer, and her maternal grandmother had died at age 45 of an unknown “female cancer.” She was scared to find out if she had high-risk genes because she felt it would change her life forever. However, if she ignored the issue, she thought she might worry too much.

We discussed the implications of a positive result, such as having to live with the knowledge and to make decisions about potential screening and risk-reducing surgery. On the other hand, not knowing could allow for the undetected growth of cancer that might otherwise be mitigated to some degree if she knew her risk status and pursued an aggressive screening program.

We worked with Ms. T to map out her next steps.

*The patient’s name has been changed to protect her identity.

Breast cancer is the most commonly diagnosed cancer in women worldwide, representing nearly one-quarter of all female cancer diagnoses in 2018.¹ It is the second-leading cause of cancer death in women in developed nations and the leading cause of cancer death in women in developing nations.¹ In the United States, 1 in 8 women will develop breast cancer in her lifetime.² By comparison, the rate of ovarian cancer is much lower, with a lifetime prevalence of 1 in 70 to 80 women.^3,4 Although ovarian cancer is less common than breast cancer, its associated mortality is high, and most cases are discovered at advanced stages.

The outsized threat of BRCA mutations. It is estimated that 5% to 10% of all breast cancers are hereditary, with 80% of these attributable to BRCA1 (45%) and BRCA2 (35%).⁵ These autosomal dominant mutations occur at the germline level, within the egg or sperm, and are therefore incorporated into the DNA of every cell and passed from one generation to the next. Families with BRCA mutations have much higher lifetime rates of cancer. The lifetime risk of breast cancer due to BRCA mutations is estimated at > 80% (BRCA1) and 45% (BRCA2).⁵BRCA mutations account for between 10% and 18% of all ovarian cancers⁶ and convey a lifetime risk of 40% (BRCA1) and 15% (BRCA2) to carriers.⁵

USPSTF now also recommends BRCA1/2 screening for any woman with a family history of tubal or peritoneal cancer.

Male BRCA carriers have a lifetime breast cancer risk of 1% to 5% with BRCA1 and 5% to 10% with BRCA2,^7,8 compared with about 1:1000 lifetime incidence in the unselected male population. Male carriers are also at risk for more aggressive prostate cancers.^7,8

Continue to: Certain populatiosn carry undue burden of BRCA-related disease

Certain populations carry undue burden of BRCA-related disease due to specific founder mutations. While the estimated global prevalence of BRCA mutations is 0.2% to 1%, for those of Ashkenazi Jewish descent the range is 2% to 3%, representing a relative risk up to 15 times that of the general population.⁹ Hispanic Americans also appear to have higher rates of BRCA-related cancers.¹⁰ Ongoing genetics research continues to identify founder mutations worldwide,¹⁰ which may inform future screening guidelines.

In addition to BRCA mutations, there are other, less common mutations (TABLE 1⁵) known to cause hereditary breast and ovarian cancer.

Identifying BRCA genes enables treatment planning. Compared with sporadic cancers, BRCA-related breast cancers are diagnosed at earlier ages,¹¹are more likely to have lymph node involvement at time of discovery,¹²are more likely to be triple negative (no expression of estrogen, progesterone, or HER2 receptors),^11,12 and are associated with worse overall and breast cancer–specific survival.¹³

Similarly, BRCA-related ovarian cancer is more likely to be high-grade and endometrioid or serous subtype.¹⁴Knowledge of BRCA carrier status allows for risk-reducing strategies that are effective in reducing the incidence of cancer and improving cancer-­specific survival.^15,16As such, it is crucial that the primary care provider understand guidelines to help identify this high-risk population and work with patients on risk-reducing strategies.

Shared decision-making helps give clarity to the way forward

Shared decision-making is a process of communication whereby the clinician and the patient identify a decision to be made, review data relevant to clinical options, discuss patient perspectives and preferences regarding each option, and arrive at the decision together.¹⁷ Shared decision-making is important when treating women with BRCA mutations because there is no single correct plan. Individual values and competing medical issues may strongly guide each woman’s decisions about screening and cancer prevention treatment decisions.

Continue to: Shared decision-making in this situation...

Shared decision-making in this situation is a strategy to use the evidence of risk along with patient preferences around fertility issues to help come to a decision that is the right one for the patient. Primary care clinicians aware of the general risks and benefits of each available option can refer women at high risk for breast or ovarian cancer to a specialist multidisciplinary clinic that can provide tailored risk assessment and risk reduction counseling as needed.^18-20

Genetic screening recommendations

Screening is recommended for women who have any 1 of several family risk factors (TABLE 2²¹). A number of risk assessment tools are available for primary care clinicians to determine which patients are at high enough risk for a hereditary breast or ovarian cancer to warrant referral to a genetic counselor.^22-25 If screening suggests high risk, the US Preventive Services Task Force (USPSTF) recommends (Grade B) referral for genetic counseling.²¹

Explain to patients who are candidates for further investigation that a genetic counselor will review their family history and recommend testing for the specific mutations that increase cancer risk. Discuss potential benefits and harms of genetic testing. A benefit of genetic testing is that aggressive screening may suggest preventive procedures to reduce the risk of future cancer. Most tests come back definitively positive or negative, but an indeterminate result may cause harm. A small minority of results may indicate a genetic variant of unknown significance. The ramifications of this variant may not be known. Some women will experience anxiety about nonspecific test results and will be afraid to share them with family members. There is also some concern about privacy issues, potential insurance bias, and coverage of any preventive strategies.²⁶

CASE

Based on Ms. T’s family history and her desire to know more, we referred her to a genetic counselor and she decided to undergo genetic testing. She screened positive for BRCA1. Ms. T was in a serious relationship and thought she would like to have children at some point. She returned to our office after receiving the positive genetic test results, wondering about screening for breast and ovarian cancer.

Breast cancer screening and risk-reduction strategies

Screening. Because the risk of breast cancer is high in women with BRCA mutations, and because cancer in these women is more likely to be advanced at diagnosis, starting a screening program at an early age is prudent. Observational studies suggest that breastfeeding reduces the risk of breast and ovarian cancer in women with BRCA mutations, as it does for women in the general population.²⁷ Women should return for a clinical breast exam every 6 to 12 months starting at age 25; they should start radiologic screening with magnetic resonance imaging at age 25 and mammography at age 30 (TABLE 3^27,28).

Continue to: Risk-reduction strategies

Risk-reduction strategies. There is weak evidence to support the use of tamoxifen or other synthetic estrogen reuptake modulators (SERMs) to reduce breast cancer risk in women with BRCA mutations. Many of these cancers do not express estrogen receptors, which may explain the lack of efficacy in certain cases. Several observational studies have shown that tamoxifen can reduce the risk of contralateral breast cancer in women with BRCA mutations who have already been diagnosed with cancer in the other breast.^29-31 However, tamoxifen does not reduce a patient’s risk of ovarian cancer, and it may increase her risk of uterine cancer.

Shared decisionmaking is important when treating women with BRCA mutations because there is no single correct plan.

Prophylactic bilateral mastectomy is the mainstay of breast cancer prevention in this population. Data from a systematic review suggest that this surgery may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.³² However, this review did not demonstrate a reduction in mortality from breast cancer, likely due to poor data quality.³² The National Comprehensive Cancer Network (NCCN) recommends discussing prophylactic mastectomy with all women who have BRCA mutations.²⁸ Further conversations are important to review the risk of tissue left behind and quality-of-life issues, including the inability to breastfeed if the woman wants more children and the cosmetic changes with reconstruction.

Ovarian cancer screening and risk-reduction strategies

Screening. No effective screening strategy has been endorsed for ovarian cancer, as most previous studies have shown screening to be ineffective.^26,33 Recently, studies both in the United Kingdom and the United States have investigated a screening strategy using the risk-of-ovarian-cancer algorithm (ROCA), which calculates an individual’s risk based on serum levels of cancer antigen 125 (CA-125).^34,35 These studies measured CA-125 levels every 3 to 4 months followed by transvaginal ultrasound if CA-125 increased substantially (as determined by ROCA). Absent an abnormal increase in CA-125, transvaginal ultrasound was performed annually. These screening strategies showed improved specificity over annual screening programs, and the cancers detected were more likely to be diagnosed at an early stage (stage II vs stage III) and had higher rates of zero residual disease after surgery compared with those detected 1 year after screening ended.^34,35 However, survival data are not yet available. More research is needed to determine if more frequent screening approaches could improve survival in high-risk women.

Prophylactic bilateral mastectomy may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.

NCCN and the American College of Obstetricians and Gynecologists (ACOG) do not endorse routine screening with transvaginal ultrasound and serum CA-125 for high-risk women, as the benefits are uncertain. However, they do advise that these screens may be considered as a short-term strategy for women ages 30 to 35 who defer risk-reducing surgery.^26,36 The USPSTF does not make a recommendation regarding ovarian cancer screening in high-risk women.³⁷

Risk-reduction strategies. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only recommended technique for reducing the risk of ovarian cancer in women at high risk.^26,33,36 Meta-analyses have shown an 80% reduction in ovarian cancer risk¹⁶ and 68% reduction in all-cause mortality with this approach.³⁸ The NCCN recommends RRSO for women with a known BRCA1 mutation between the ages of 35 and 40 who have completed childbearing.³⁶ Since the onset of ovarian cancer tends to be later in women with BRCA2 mutations, it is reasonable to delay RRSO until age 40 to 45 in this population if they have taken other steps to maximize breast cancer prevention (ie, bilateral mastectomy).³⁶

Continue to: Adverse effects of RRSO...

Adverse effects of RRSO include surgery complications (wound infection, small bowel obstruction, bladder perforation) and effects of early menopause (vasomotor symptoms, decreased sexual functioning, and increased risk of osteoporosis, cardiovascular disease, and all-cause mortality).^39-41 In the absence of contraindications, ACOG recommends using hormone therapy in women undergoing RRSO until the natural age of menopause,⁴² particularly if their breast tissue has been removed.

Salpingectomy as an alternative. In an attempt to reduce these adverse effects of early menopause, and because a large proportion of high-grade serous tumors originate in the fallopian tube,⁴³ interest has increased in the use of risk-reducing salpingectomy (removal of fallopian tubes) and delayed oophorectomy in women at high risk of ovarian cancer.⁴² Studies have shown this may be a cost-effective approach and an acceptable alternative in BRCA mutation carriers who are unwilling to undergo RRSO.^44,45 A clinical trial investigating this approach in women with BRCA mutations is currently underway in the United States.⁴⁶ Many centers offer salpingectomy to high-risk patients < 40 years old, understanding that ovary removal is an eventuality for these patients.

When oral contraceptive pills might be beneficial. In younger women with BRCA mutations, there may also be a role for oral contraceptive pills (OCPs) as a risk-reducing strategy. Meta-analyses have shown an approximately 50% reduction in the risk of ovarian cancer among women with BRCA mutations who use OCPs.^47-49

ACOG advises that it is appropriate for women with BRCA mutations to use oral contraceptives if indicated (for pregnancy prevention or menstrual cycle regulation), and that it is reasonable to use them for cancer prevention.²⁶ NCCN does not make a formal recommendation, although it does state OCPs may reduce the risk of ovarian cancer in women with a BRCA mutation.³⁶ Case-control studies have produced conflicting data on the association between OCP use and breast cancer risk in BRCA mutation carriers,^50-53 although 2 meta-analyses found no significant association in this population.^47,48

Decision aids for women with BRCA mutations

Decision aids are visual displays of risk that help patients work through complex decisions. Most decision aids are in print or digital format and include information about the decision to be made as well as pictorial examples of possible outcomes. Pictographs are especially helpful in communicating information. Some decision aids for women with BRCA mutations can be complicated with multiple outcomes (ie, breast cancer and ovarian cancer) and multiple potential interventions (risk-reducing surgery, enhanced screening options).⁵⁴

Continue to: A Cochrane review...

A Cochrane review found that decision aids increased patients’ knowledge, helped patients clarify their values, and may improve value-concordant decisions.⁵⁵ Two papers describing the use of decision aids for women with BRCA mutations^56,57 documented decreased decisional conflict and increased satisfaction.

CASE

Ms. T underwent the recommended mammogram and MRI screening for breast ­cancer, as well as testing with serum CA-125 and ultrasound examinations for ovarian cancer. Her initial mammogram and MRI revealed early stage, triple-negative right breast cancer. She chose to undergo bilateral mastectomy and reconstruction. She has now completed treatment and continues to work closely with her oncology team for appropriate breast ­follow-up.

Two papers describing the use of decision aids for women with BRCA mutations documented decreased decisional conflict and increased satisfaction.

One year after her initial diagnosis, at the age of 35, she returned to discuss fertility. She was recently married, and she and her husband wanted to start having children. She was concerned about a safe timeline for her to pursue pregnancy, saying she felt “like a ticking time-bomb” given her prior cancer and carrier status. She wanted to discuss the risks and benefits of pregnancy and when she should consider prophylactic oophorectomy. She had a few options. She could have a baby and then undergo an RRSO, or she could talk to her gynecologist about having a salpingectomy to reduce her risk now and use assisted reproductive technology to get pregnant. She could also freeze eggs or embryos, have an RRSO, and then use a surrogate to get pregnant. We informed her that pregnancy would not affect her risk of ovarian cancer and discussed the options for pre-implantation genetic testing to assure that her children would not carry the genetic mutation.⁵⁸

We provided Ms. T and her husband with a decision aid to help them navigate the decision. They are currently evaluating the options and said they would let us know when they made a decision.

CORRESPONDENCE
Sarina Schrager, MD, MS, Northeast Family Medicine Center, 3209 Dryden Drive, Madison, WI, 53704; [email protected].

CASE

Sara T* recently moved back to the area to be closer to her family. The 34-year-old patient visited our office to discuss the benefits and potential risks of genetic counseling. She explained that her aunt had just died at age 64 of ovarian cancer. Also, her maternal cousin had been diagnosed at age 42 with breast cancer, and her maternal grandmother had died at age 45 of an unknown “female cancer.” She was scared to find out if she had high-risk genes because she felt it would change her life forever. However, if she ignored the issue, she thought she might worry too much.

We discussed the implications of a positive result, such as having to live with the knowledge and to make decisions about potential screening and risk-reducing surgery. On the other hand, not knowing could allow for the undetected growth of cancer that might otherwise be mitigated to some degree if she knew her risk status and pursued an aggressive screening program.

We worked with Ms. T to map out her next steps.

*The patient’s name has been changed to protect her identity.

Breast cancer is the most commonly diagnosed cancer in women worldwide, representing nearly one-quarter of all female cancer diagnoses in 2018.¹ It is the second-leading cause of cancer death in women in developed nations and the leading cause of cancer death in women in developing nations.¹ In the United States, 1 in 8 women will develop breast cancer in her lifetime.² By comparison, the rate of ovarian cancer is much lower, with a lifetime prevalence of 1 in 70 to 80 women.^3,4 Although ovarian cancer is less common than breast cancer, its associated mortality is high, and most cases are discovered at advanced stages.

The outsized threat of BRCA mutations. It is estimated that 5% to 10% of all breast cancers are hereditary, with 80% of these attributable to BRCA1 (45%) and BRCA2 (35%).⁵ These autosomal dominant mutations occur at the germline level, within the egg or sperm, and are therefore incorporated into the DNA of every cell and passed from one generation to the next. Families with BRCA mutations have much higher lifetime rates of cancer. The lifetime risk of breast cancer due to BRCA mutations is estimated at > 80% (BRCA1) and 45% (BRCA2).⁵BRCA mutations account for between 10% and 18% of all ovarian cancers⁶ and convey a lifetime risk of 40% (BRCA1) and 15% (BRCA2) to carriers.⁵

USPSTF now also recommends BRCA1/2 screening for any woman with a family history of tubal or peritoneal cancer.

Male BRCA carriers have a lifetime breast cancer risk of 1% to 5% with BRCA1 and 5% to 10% with BRCA2,^7,8 compared with about 1:1000 lifetime incidence in the unselected male population. Male carriers are also at risk for more aggressive prostate cancers.^7,8

Continue to: Certain populatiosn carry undue burden of BRCA-related disease

Certain populations carry undue burden of BRCA-related disease due to specific founder mutations. While the estimated global prevalence of BRCA mutations is 0.2% to 1%, for those of Ashkenazi Jewish descent the range is 2% to 3%, representing a relative risk up to 15 times that of the general population.⁹ Hispanic Americans also appear to have higher rates of BRCA-related cancers.¹⁰ Ongoing genetics research continues to identify founder mutations worldwide,¹⁰ which may inform future screening guidelines.

In addition to BRCA mutations, there are other, less common mutations (TABLE 1⁵) known to cause hereditary breast and ovarian cancer.

Identifying BRCA genes enables treatment planning. Compared with sporadic cancers, BRCA-related breast cancers are diagnosed at earlier ages,¹¹are more likely to have lymph node involvement at time of discovery,¹²are more likely to be triple negative (no expression of estrogen, progesterone, or HER2 receptors),^11,12 and are associated with worse overall and breast cancer–specific survival.¹³

Similarly, BRCA-related ovarian cancer is more likely to be high-grade and endometrioid or serous subtype.¹⁴Knowledge of BRCA carrier status allows for risk-reducing strategies that are effective in reducing the incidence of cancer and improving cancer-­specific survival.^15,16As such, it is crucial that the primary care provider understand guidelines to help identify this high-risk population and work with patients on risk-reducing strategies.

Shared decision-making helps give clarity to the way forward

Shared decision-making is a process of communication whereby the clinician and the patient identify a decision to be made, review data relevant to clinical options, discuss patient perspectives and preferences regarding each option, and arrive at the decision together.¹⁷ Shared decision-making is important when treating women with BRCA mutations because there is no single correct plan. Individual values and competing medical issues may strongly guide each woman’s decisions about screening and cancer prevention treatment decisions.

Continue to: Shared decision-making in this situation...

Shared decision-making in this situation is a strategy to use the evidence of risk along with patient preferences around fertility issues to help come to a decision that is the right one for the patient. Primary care clinicians aware of the general risks and benefits of each available option can refer women at high risk for breast or ovarian cancer to a specialist multidisciplinary clinic that can provide tailored risk assessment and risk reduction counseling as needed.^18-20

Genetic screening recommendations

Screening is recommended for women who have any 1 of several family risk factors (TABLE 2²¹). A number of risk assessment tools are available for primary care clinicians to determine which patients are at high enough risk for a hereditary breast or ovarian cancer to warrant referral to a genetic counselor.^22-25 If screening suggests high risk, the US Preventive Services Task Force (USPSTF) recommends (Grade B) referral for genetic counseling.²¹

Explain to patients who are candidates for further investigation that a genetic counselor will review their family history and recommend testing for the specific mutations that increase cancer risk. Discuss potential benefits and harms of genetic testing. A benefit of genetic testing is that aggressive screening may suggest preventive procedures to reduce the risk of future cancer. Most tests come back definitively positive or negative, but an indeterminate result may cause harm. A small minority of results may indicate a genetic variant of unknown significance. The ramifications of this variant may not be known. Some women will experience anxiety about nonspecific test results and will be afraid to share them with family members. There is also some concern about privacy issues, potential insurance bias, and coverage of any preventive strategies.²⁶

CASE

Based on Ms. T’s family history and her desire to know more, we referred her to a genetic counselor and she decided to undergo genetic testing. She screened positive for BRCA1. Ms. T was in a serious relationship and thought she would like to have children at some point. She returned to our office after receiving the positive genetic test results, wondering about screening for breast and ovarian cancer.

Breast cancer screening and risk-reduction strategies

Screening. Because the risk of breast cancer is high in women with BRCA mutations, and because cancer in these women is more likely to be advanced at diagnosis, starting a screening program at an early age is prudent. Observational studies suggest that breastfeeding reduces the risk of breast and ovarian cancer in women with BRCA mutations, as it does for women in the general population.²⁷ Women should return for a clinical breast exam every 6 to 12 months starting at age 25; they should start radiologic screening with magnetic resonance imaging at age 25 and mammography at age 30 (TABLE 3^27,28).

Continue to: Risk-reduction strategies

Risk-reduction strategies. There is weak evidence to support the use of tamoxifen or other synthetic estrogen reuptake modulators (SERMs) to reduce breast cancer risk in women with BRCA mutations. Many of these cancers do not express estrogen receptors, which may explain the lack of efficacy in certain cases. Several observational studies have shown that tamoxifen can reduce the risk of contralateral breast cancer in women with BRCA mutations who have already been diagnosed with cancer in the other breast.^29-31 However, tamoxifen does not reduce a patient’s risk of ovarian cancer, and it may increase her risk of uterine cancer.

Shared decisionmaking is important when treating women with BRCA mutations because there is no single correct plan.

Prophylactic bilateral mastectomy is the mainstay of breast cancer prevention in this population. Data from a systematic review suggest that this surgery may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.³² However, this review did not demonstrate a reduction in mortality from breast cancer, likely due to poor data quality.³² The National Comprehensive Cancer Network (NCCN) recommends discussing prophylactic mastectomy with all women who have BRCA mutations.²⁸ Further conversations are important to review the risk of tissue left behind and quality-of-life issues, including the inability to breastfeed if the woman wants more children and the cosmetic changes with reconstruction.

Ovarian cancer screening and risk-reduction strategies

Screening. No effective screening strategy has been endorsed for ovarian cancer, as most previous studies have shown screening to be ineffective.^26,33 Recently, studies both in the United Kingdom and the United States have investigated a screening strategy using the risk-of-ovarian-cancer algorithm (ROCA), which calculates an individual’s risk based on serum levels of cancer antigen 125 (CA-125).^34,35 These studies measured CA-125 levels every 3 to 4 months followed by transvaginal ultrasound if CA-125 increased substantially (as determined by ROCA). Absent an abnormal increase in CA-125, transvaginal ultrasound was performed annually. These screening strategies showed improved specificity over annual screening programs, and the cancers detected were more likely to be diagnosed at an early stage (stage II vs stage III) and had higher rates of zero residual disease after surgery compared with those detected 1 year after screening ended.^34,35 However, survival data are not yet available. More research is needed to determine if more frequent screening approaches could improve survival in high-risk women.

Prophylactic bilateral mastectomy may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.

NCCN and the American College of Obstetricians and Gynecologists (ACOG) do not endorse routine screening with transvaginal ultrasound and serum CA-125 for high-risk women, as the benefits are uncertain. However, they do advise that these screens may be considered as a short-term strategy for women ages 30 to 35 who defer risk-reducing surgery.^26,36 The USPSTF does not make a recommendation regarding ovarian cancer screening in high-risk women.³⁷

Risk-reduction strategies. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only recommended technique for reducing the risk of ovarian cancer in women at high risk.^26,33,36 Meta-analyses have shown an 80% reduction in ovarian cancer risk¹⁶ and 68% reduction in all-cause mortality with this approach.³⁸ The NCCN recommends RRSO for women with a known BRCA1 mutation between the ages of 35 and 40 who have completed childbearing.³⁶ Since the onset of ovarian cancer tends to be later in women with BRCA2 mutations, it is reasonable to delay RRSO until age 40 to 45 in this population if they have taken other steps to maximize breast cancer prevention (ie, bilateral mastectomy).³⁶

Continue to: Adverse effects of RRSO...

Adverse effects of RRSO include surgery complications (wound infection, small bowel obstruction, bladder perforation) and effects of early menopause (vasomotor symptoms, decreased sexual functioning, and increased risk of osteoporosis, cardiovascular disease, and all-cause mortality).^39-41 In the absence of contraindications, ACOG recommends using hormone therapy in women undergoing RRSO until the natural age of menopause,⁴² particularly if their breast tissue has been removed.

Salpingectomy as an alternative. In an attempt to reduce these adverse effects of early menopause, and because a large proportion of high-grade serous tumors originate in the fallopian tube,⁴³ interest has increased in the use of risk-reducing salpingectomy (removal of fallopian tubes) and delayed oophorectomy in women at high risk of ovarian cancer.⁴² Studies have shown this may be a cost-effective approach and an acceptable alternative in BRCA mutation carriers who are unwilling to undergo RRSO.^44,45 A clinical trial investigating this approach in women with BRCA mutations is currently underway in the United States.⁴⁶ Many centers offer salpingectomy to high-risk patients < 40 years old, understanding that ovary removal is an eventuality for these patients.

When oral contraceptive pills might be beneficial. In younger women with BRCA mutations, there may also be a role for oral contraceptive pills (OCPs) as a risk-reducing strategy. Meta-analyses have shown an approximately 50% reduction in the risk of ovarian cancer among women with BRCA mutations who use OCPs.^47-49

ACOG advises that it is appropriate for women with BRCA mutations to use oral contraceptives if indicated (for pregnancy prevention or menstrual cycle regulation), and that it is reasonable to use them for cancer prevention.²⁶ NCCN does not make a formal recommendation, although it does state OCPs may reduce the risk of ovarian cancer in women with a BRCA mutation.³⁶ Case-control studies have produced conflicting data on the association between OCP use and breast cancer risk in BRCA mutation carriers,^50-53 although 2 meta-analyses found no significant association in this population.^47,48

Decision aids for women with BRCA mutations

Decision aids are visual displays of risk that help patients work through complex decisions. Most decision aids are in print or digital format and include information about the decision to be made as well as pictorial examples of possible outcomes. Pictographs are especially helpful in communicating information. Some decision aids for women with BRCA mutations can be complicated with multiple outcomes (ie, breast cancer and ovarian cancer) and multiple potential interventions (risk-reducing surgery, enhanced screening options).⁵⁴

Continue to: A Cochrane review...

A Cochrane review found that decision aids increased patients’ knowledge, helped patients clarify their values, and may improve value-concordant decisions.⁵⁵ Two papers describing the use of decision aids for women with BRCA mutations^56,57 documented decreased decisional conflict and increased satisfaction.

CASE

Ms. T underwent the recommended mammogram and MRI screening for breast ­cancer, as well as testing with serum CA-125 and ultrasound examinations for ovarian cancer. Her initial mammogram and MRI revealed early stage, triple-negative right breast cancer. She chose to undergo bilateral mastectomy and reconstruction. She has now completed treatment and continues to work closely with her oncology team for appropriate breast ­follow-up.

Two papers describing the use of decision aids for women with BRCA mutations documented decreased decisional conflict and increased satisfaction.

One year after her initial diagnosis, at the age of 35, she returned to discuss fertility. She was recently married, and she and her husband wanted to start having children. She was concerned about a safe timeline for her to pursue pregnancy, saying she felt “like a ticking time-bomb” given her prior cancer and carrier status. She wanted to discuss the risks and benefits of pregnancy and when she should consider prophylactic oophorectomy. She had a few options. She could have a baby and then undergo an RRSO, or she could talk to her gynecologist about having a salpingectomy to reduce her risk now and use assisted reproductive technology to get pregnant. She could also freeze eggs or embryos, have an RRSO, and then use a surrogate to get pregnant. We informed her that pregnancy would not affect her risk of ovarian cancer and discussed the options for pre-implantation genetic testing to assure that her children would not carry the genetic mutation.⁵⁸

We provided Ms. T and her husband with a decision aid to help them navigate the decision. They are currently evaluating the options and said they would let us know when they made a decision.

CORRESPONDENCE
Sarina Schrager, MD, MS, Northeast Family Medicine Center, 3209 Dryden Drive, Madison, WI, 53704; [email protected].

CASE › Mary, a 34-year-old woman, is a new patient to your practice after moving to the area for a job. She has a history of migraine headaches triggered by her menstrual periods. She has been taking combined oral contraceptives (COCs) since she was 17, with a few years off when she had 2 children. Her migraines improved when she was pregnant, but worsened postpartum with each of her daughters to a point where she had to stop breastfeeding at 4 months to go back on the pills.

On the COCs, she gets one or 2 mild-to-moderate headaches a month. She uses sumatriptan for abortive treatment with good relief. She has not missed work in the past 4 years because of her migraines. During the 6 months she was off COCs when trying to get pregnant, she routinely missed 2 to 3 workdays per month due to migraines. She knows when she is going to get a headache because she sees flashing lights in her left visual field. She has no other neurologic symptoms with the headaches, and the character of the headaches has not changed. She is a non-smoker, has normal blood pressure and lipid levels, and no other vascular risk factors.

You review her history and talk to her about the risk of stroke with migraines and with COCs. She is almost 35 years of age and you recommend stopping the COCs due to the risk. She feels strongly that she wants to continue taking the COCs, saying her quality of life is poor when she is off the pills. What should you do?

Migraine headaches are 2 to 3 times more prevalent in women than in men,¹ with a lifetime risk of 43% vs 18%, respectively.² Women account for about 80% of the $1 billion spent each year in the United States in medical expenses and lost work productivity related to migraines.^1,2

Clinical patterns suggestive of menstrual migraine. About half of women affected by migraine have menstrually-related migraines (MRM); 3% to 12% have pure menstrual migraines (PMM).³ MRM and PMM are both characterized by the presence of symptoms in at least 2 to 3 consecutive cycles, with symptoms occurring from between 2 days before to 3 days after the onset of menstruation. However, in PMM, symptoms do not occur at any other time of the menstrual cycle; in MRM, symptoms can occur at other times of the cycle. PMM is more likely to respond to hormone therapy than is MRM.

Multiple studies in the United States, Europe, and Asia have noted that migraines related to menses typically last longer, are more severe, less likely to be associated with aura, and more likely to be recurrent and recalcitrant to treatment than non-menstrual migraines.¹ TABLE 1³ describes diagnostic criteria for migraine without aura.

Prevalence patterns point to the role of estrogen. The prevalence of migraines in women increases around puberty, peaks between ages 30 and 40, and decreases after natural menopause.⁶ Migraine prevalence increases during the first week postpartum, when levels of estrogen and progesterone decrease suddenly and significantly.¹ Migraine frequency and intensity decrease in the second and third trimesters of pregnancy and after menopause, when estrogen levels fluctuate significantly less.¹ In the Women’s Health Initiative study, women who used hormone replacement therapy (HRT) had a 42% increased risk of migraines compared with women in the study who had never used HRT.⁸

Migraines related to menses typically last longer, are more severe, less likely to be associated with aura, and more likely to be recalcitrant to treatment than non-menstrual migraines.The association of migraine with female hormones was further supported by a Dutch study of male-to-female transgender patients on estrogen therapy, who had a 26% incidence of migraine, equivalent to the 25% prevalence in natal female controls in this study, compared with just 7.5% in male controls.⁹ The association between migraine and estrogen withdrawal was investigated in studies performed more than 40 years ago, when women experiencing migraines around the time of menses were given intramuscular estradiol and experienced a delay in symptom onset.¹⁰

Abortive and prophylactic treatments: Factors that guide selection

In considering probable menstrual migraine, take a detailed history, review headache diaries if available to determine association of headaches with menses, and perform a thorough neurologic examination. If a diagnosis of menstrual migraine is established, discuss the benefits of different treatment options, both abortive and prophylactic.

For the patient with MRM, take into account frequency of symptoms, predictability of menstruation, medication costs, and comorbidities. Both triptans and nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective treatments for MRM.¹¹ Abortive therapy may be appropriate if a patient prefers to take medication intermittently, if her menses are unpredictable, or if she does not get migraine headaches with every menses. Mefenamic acid, sumatriptan, and rizatriptan have category B recommendations for abortive treatment for menstrual migraines (TABLE 2^11-16). (For the patient who has regular MRM but unpredictable menses, ovulation predictor kits can be used to help predict the onset of menses, although this would involve additional cost.)

Triptans are contraindicated for women with a history of cardiac disease or uncontrolled hypertension. For the patient who has predictable menses and regularly occurring menstrual migraine, some data show that a short-term prophylactic regimen with triptans started 2 to 3 days before the onset of menses and continued for 5 to 7 days total can reduce the incidence of menstrual migraine (TABLE 2^11-16). At least one high-quality randomized controlled trial (RCT) showed a significant reduction in the incidence of MRM when women were treated prophylactically with frovatriptan, a long-acting triptan with a half-life of approximately 26 hours. Participants received frovatriptan 2.5 mg once a day or twice a day or placebo in the perimenstrual period (day -2 to +3). The incidence of MRM was 52%, 41%, and 67%, respectively (P<.0001).^11,17

Another RCT of fair quality examined the effect of naratriptan (half-life 6-8 hours) on the median number of menstrual migraines over 4 menstrual cycles. Women who received 1 mg of naratriptan BID for 2 to 3 days before menses had 2 MRM episodes over the 4 cycles compared with 4 MRM episodes in women who received placebo over the same time period (P<.05).^11,18 A third RCT, also of fair quality, compared 2 different regimens of zolmitriptan (half-life 3 hours) with placebo and found that women who received 2.5 mg of zolmitriptan either BID or TID 2 to 3 days prior to menses had a reduction both in frequency of menstrual migraines and in the mean number of breakthrough headaches per menstrual cycle, as well as a reduction in the need for rescue medications.^12,19 Triptans are contraindicated in women with a history of cardiac disease or uncontrolled hypertension. Also, triptans can be expensive, precluding their use for some patients.

Evidence is insufficient to recommend for or against the use of NSAIDs as prophylaxis for MRM.¹¹ NSAIDs may be contraindicated in women with a history of peptic ulcer disease or gastrointestinal bleeding. That said, if NSAIDs are not contraindicated, a trial may be reasonable given their low cost.

Data are sparse on the use of vitamins and supplements in treating and preventing PMM or MRM. In one very small double-blind, placebo-controlled study in 1991 (N=24, with efficacy data for 20), participants received a 2-week course of oral magnesium premenstrually. There was a statistically significant reduction in the number of days with headache per month (from 4.7±3.1 days to 2.4±2.2 days; P<.01) and in the total pain index (P<.03).²⁰ A number of studies have demonstrated a correlation between hypomagnesemia and migraine headaches.^5,21 The exact mechanism for this relationship is unclear.

Some recent evidence-based reviews have examined the efficacy of nutraceuticals such as magnesium, feverfew, butterbur, coenzyme Q10, and riboflavin on typical migraine, but it is not clear if these results are translatable to the treatment and prophylaxis of menstrual migraine.^11,22 A multicenter, single-blind, RCT is underway to examine the efficacy of acupuncture as prophylaxis for MRM.²³

The association between MRM and hormonal variation makes exogenous hormone therapy a tempting prophylactic treatment. A study by Somerville showed that using exogenous estrogen to mitigate the decrease in estrogen through the menstrual cycle can raise the headache threshold and thereby decrease the frequency and severity of MRM.¹⁰ Progesterone levels also vary throughout the menstrual cycle; however, this variation has not been shown to correlate with MRM. Some investigators have speculated that continuous exogenous progesterone may decrease the frequency of MRM through the blunting of estrogen cycles.^5,10,24

Most studies examining the role of exogenous estrogen in reducing menstrual migraines have used topical estrogen (either in patch or gel formulations) in the perimenstrual window (TABLE 2^11-16). The topical estrogen route has been examined, in particular, as it is presumed to confer less risk of hypercoagulability by avoiding first-pass metabolism. However, there is conflicting evidence on this issue, in particular regarding premenopausal women.^13,25 Additionally, many of the studies of estrogen supplementation show a trend toward increased headache once estrogen is discontinued, presumably due to estrogen withdrawal.^10,24

That said, one study by MacGregor, et al demonstrates that the use of estradiol gel in the perimenstrual window leads to a 22% reduction in migraine days as well as less severe migrainous symptoms.²⁶ This trend has been demonstrated in other studies examining estrogen supplementation. Of note, the estrogen studies generally are small, older, and of fair to poor quality.¹¹ These studies have used higher doses of estrogen than are commonly used for contraception today because lower doses of estrogen seem not to have the same impact on migraine.^5,24

As for COCs, with either normal or extended cycling, data are more mixed than for estrogen supplementation alone; equivalent numbers of women experience improvement, no change, or worsening of their headache pattern. Many women have continuing or worsening migraines in the hormone-free week, and thus most studies have examined the use of extended cycling COCs.⁵ Sulak, et al demonstrated a statistically significant reduction in headache frequency using extended-cycling COCs, though they did not examine MRM in particular.²⁷ The efficacy of extended-cycling COCs for reduction of MRM was confirmed by Coffee and colleagues with a small but statistically significant decrease in daily headache scores.²⁸

Evidence is insufficient to recommend for or against the use of NSAIDs as prophylaxis for menstrually-related migraines.

Adverse effects. All estrogen therapies pose the risk of adverse effects (deep vein thrombosis, hypertension, breast tenderness, nausea, etc). Additionally, estrogen supplementation may actually trigger migraines in some women if, when it is discontinued, the blood estrogen level does not remain above a threshold concentration.^5,10,24 Estrogen may also trigger migraine in previously headache-free women and may convert migraine without aura into migraine with aura. In either case, therapy should be stopped.^5,24

There is promising evidence from 2 small RCTs and one observational trial that progestin-only contraceptive pills (POP) may reduce the frequency and severity of menstrual migraines (TABLE 2^11-16). More prospective data are needed to confirm this reduction, as there have not been specific studies examining other progesterone-only preparations to prevent menstrual migraines.

Risk of ischemic stroke. Unfortunately, there are population data showing that second-generation and, to a smaller degree, third-generation progestins, which include the desogestrel used in the above studies, may increase the risk of ischemic stroke. This is a particular concern in women who experience migraine.²⁹ Second-generation progestins include levonorgestrel, which is in the levonorgestrel IUD; however, there is no direct evidence for increased ischemic stroke in this particular preparation, and the circulating plasma levels are low. Etonorgestrel, the active ingredient in the contraceptive implant, is a third-generation progestin, though there is no direct evidence of increased ischemic stroke with use of the etonorgestrel implant.

There is a 2- to 4-fold increased risk of ischemic stroke in women who experience migraine.^1,5,30 As stated above, this risk may be further increased by some progesterone formulations. But there is also a demonstrable increase in ischemic stroke risk with the use of estrogen, particularly at the higher concentrations that have been shown to prevent MRM.^31,32 The overall incidence of ischemic stroke in menstrual-age women is low, which has limited the number of studies with enough power to quantify the absolute increased risk of stroke in conjunction with estrogen use. Nevertheless, exogenous estrogen is thought to increase the risk of ischemic stroke an additional 2- to 4-fold.^{1,5,29,30,32-34}

A number of studies have demonstrated a correlation between hypomagnesemia and migraine headaches. The exact mechanism for this relationship is unclear.Women who experience aura. MRM, as it is defined, typically excludes women who experience aura; however, the number of women who experience aura with migraine either in proximity to their menses or throughout the month has not been well documented. The risk of ischemic stroke is higher for women who experience migraine with aura than those with migraine alone, possibly because aura is associated with reduced regional vascular flow leading to hypoperfusion, which sets the stage for a possible ischemic event.^4,5,35 The risk of ischemic stroke is amplified further for women who are over 35, who smoke, or who have additional vascular risk factors (eg, uncontrolled hypertension, diabetes, or known vascular or cardiac disease).^1,5,34 This array of evidence serves as the basis for the US Medical Eligibility Criteria (USMEC) recommendations³⁶ for hormonal contraceptive use, in particular the absolute contraindication for estrogen use in women who experience migraine with aura (TABLE 3^36-38).

CASE ›  Given Mary’s experience of aura with migraine, you talk with her at length about the risk of ischemic stroke and the USMEC recommendation that she absolutely should not be taking COCs. You suggest a progestin-only method of contraception such as depot medroxyprogesterone acetate, a progestin intrauterine device, or a hormonal implant, which may suppress ovulation and decrease her headaches. You discuss that while some women may have headaches with these progestin-only methods, stroke risk is significantly reduced. You also suggest a trial of prophylactic triptans as another possible option.

She says she understands the increased risk of stroke but is still unwilling to try anything else right now due to worries about her quality of life. You decide jointly to refill COCs for 3 months, and you document the shared decision process in the chart. After advising the patient that you will not continue to prescribe COCs for an extended period of time, you also schedule a follow-up appointment to further discuss risks and benefits of migraine treatment and means of reducing other risk factors for stroke.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin, Department of Family Medicine, 1100 Delaplaine Ct, Madison, WI 53715; [email protected].

CASE › Mary, a 34-year-old woman, is a new patient to your practice after moving to the area for a job. She has a history of migraine headaches triggered by her menstrual periods. She has been taking combined oral contraceptives (COCs) since she was 17, with a few years off when she had 2 children. Her migraines improved when she was pregnant, but worsened postpartum with each of her daughters to a point where she had to stop breastfeeding at 4 months to go back on the pills.

On the COCs, she gets one or 2 mild-to-moderate headaches a month. She uses sumatriptan for abortive treatment with good relief. She has not missed work in the past 4 years because of her migraines. During the 6 months she was off COCs when trying to get pregnant, she routinely missed 2 to 3 workdays per month due to migraines. She knows when she is going to get a headache because she sees flashing lights in her left visual field. She has no other neurologic symptoms with the headaches, and the character of the headaches has not changed. She is a non-smoker, has normal blood pressure and lipid levels, and no other vascular risk factors.

You review her history and talk to her about the risk of stroke with migraines and with COCs. She is almost 35 years of age and you recommend stopping the COCs due to the risk. She feels strongly that she wants to continue taking the COCs, saying her quality of life is poor when she is off the pills. What should you do?

Migraine headaches are 2 to 3 times more prevalent in women than in men,¹ with a lifetime risk of 43% vs 18%, respectively.² Women account for about 80% of the $1 billion spent each year in the United States in medical expenses and lost work productivity related to migraines.^1,2

Clinical patterns suggestive of menstrual migraine. About half of women affected by migraine have menstrually-related migraines (MRM); 3% to 12% have pure menstrual migraines (PMM).³ MRM and PMM are both characterized by the presence of symptoms in at least 2 to 3 consecutive cycles, with symptoms occurring from between 2 days before to 3 days after the onset of menstruation. However, in PMM, symptoms do not occur at any other time of the menstrual cycle; in MRM, symptoms can occur at other times of the cycle. PMM is more likely to respond to hormone therapy than is MRM.

Multiple studies in the United States, Europe, and Asia have noted that migraines related to menses typically last longer, are more severe, less likely to be associated with aura, and more likely to be recurrent and recalcitrant to treatment than non-menstrual migraines.¹ TABLE 1³ describes diagnostic criteria for migraine without aura.

Prevalence patterns point to the role of estrogen. The prevalence of migraines in women increases around puberty, peaks between ages 30 and 40, and decreases after natural menopause.⁶ Migraine prevalence increases during the first week postpartum, when levels of estrogen and progesterone decrease suddenly and significantly.¹ Migraine frequency and intensity decrease in the second and third trimesters of pregnancy and after menopause, when estrogen levels fluctuate significantly less.¹ In the Women’s Health Initiative study, women who used hormone replacement therapy (HRT) had a 42% increased risk of migraines compared with women in the study who had never used HRT.⁸

Migraines related to menses typically last longer, are more severe, less likely to be associated with aura, and more likely to be recalcitrant to treatment than non-menstrual migraines.The association of migraine with female hormones was further supported by a Dutch study of male-to-female transgender patients on estrogen therapy, who had a 26% incidence of migraine, equivalent to the 25% prevalence in natal female controls in this study, compared with just 7.5% in male controls.⁹ The association between migraine and estrogen withdrawal was investigated in studies performed more than 40 years ago, when women experiencing migraines around the time of menses were given intramuscular estradiol and experienced a delay in symptom onset.¹⁰

Abortive and prophylactic treatments: Factors that guide selection

In considering probable menstrual migraine, take a detailed history, review headache diaries if available to determine association of headaches with menses, and perform a thorough neurologic examination. If a diagnosis of menstrual migraine is established, discuss the benefits of different treatment options, both abortive and prophylactic.

For the patient with MRM, take into account frequency of symptoms, predictability of menstruation, medication costs, and comorbidities. Both triptans and nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective treatments for MRM.¹¹ Abortive therapy may be appropriate if a patient prefers to take medication intermittently, if her menses are unpredictable, or if she does not get migraine headaches with every menses. Mefenamic acid, sumatriptan, and rizatriptan have category B recommendations for abortive treatment for menstrual migraines (TABLE 2^11-16). (For the patient who has regular MRM but unpredictable menses, ovulation predictor kits can be used to help predict the onset of menses, although this would involve additional cost.)

Triptans are contraindicated for women with a history of cardiac disease or uncontrolled hypertension. For the patient who has predictable menses and regularly occurring menstrual migraine, some data show that a short-term prophylactic regimen with triptans started 2 to 3 days before the onset of menses and continued for 5 to 7 days total can reduce the incidence of menstrual migraine (TABLE 2^11-16). At least one high-quality randomized controlled trial (RCT) showed a significant reduction in the incidence of MRM when women were treated prophylactically with frovatriptan, a long-acting triptan with a half-life of approximately 26 hours. Participants received frovatriptan 2.5 mg once a day or twice a day or placebo in the perimenstrual period (day -2 to +3). The incidence of MRM was 52%, 41%, and 67%, respectively (P<.0001).^11,17

Another RCT of fair quality examined the effect of naratriptan (half-life 6-8 hours) on the median number of menstrual migraines over 4 menstrual cycles. Women who received 1 mg of naratriptan BID for 2 to 3 days before menses had 2 MRM episodes over the 4 cycles compared with 4 MRM episodes in women who received placebo over the same time period (P<.05).^11,18 A third RCT, also of fair quality, compared 2 different regimens of zolmitriptan (half-life 3 hours) with placebo and found that women who received 2.5 mg of zolmitriptan either BID or TID 2 to 3 days prior to menses had a reduction both in frequency of menstrual migraines and in the mean number of breakthrough headaches per menstrual cycle, as well as a reduction in the need for rescue medications.^12,19 Triptans are contraindicated in women with a history of cardiac disease or uncontrolled hypertension. Also, triptans can be expensive, precluding their use for some patients.

Evidence is insufficient to recommend for or against the use of NSAIDs as prophylaxis for MRM.¹¹ NSAIDs may be contraindicated in women with a history of peptic ulcer disease or gastrointestinal bleeding. That said, if NSAIDs are not contraindicated, a trial may be reasonable given their low cost.

Data are sparse on the use of vitamins and supplements in treating and preventing PMM or MRM. In one very small double-blind, placebo-controlled study in 1991 (N=24, with efficacy data for 20), participants received a 2-week course of oral magnesium premenstrually. There was a statistically significant reduction in the number of days with headache per month (from 4.7±3.1 days to 2.4±2.2 days; P<.01) and in the total pain index (P<.03).²⁰ A number of studies have demonstrated a correlation between hypomagnesemia and migraine headaches.^5,21 The exact mechanism for this relationship is unclear.

Some recent evidence-based reviews have examined the efficacy of nutraceuticals such as magnesium, feverfew, butterbur, coenzyme Q10, and riboflavin on typical migraine, but it is not clear if these results are translatable to the treatment and prophylaxis of menstrual migraine.^11,22 A multicenter, single-blind, RCT is underway to examine the efficacy of acupuncture as prophylaxis for MRM.²³

The association between MRM and hormonal variation makes exogenous hormone therapy a tempting prophylactic treatment. A study by Somerville showed that using exogenous estrogen to mitigate the decrease in estrogen through the menstrual cycle can raise the headache threshold and thereby decrease the frequency and severity of MRM.¹⁰ Progesterone levels also vary throughout the menstrual cycle; however, this variation has not been shown to correlate with MRM. Some investigators have speculated that continuous exogenous progesterone may decrease the frequency of MRM through the blunting of estrogen cycles.^5,10,24

Most studies examining the role of exogenous estrogen in reducing menstrual migraines have used topical estrogen (either in patch or gel formulations) in the perimenstrual window (TABLE 2^11-16). The topical estrogen route has been examined, in particular, as it is presumed to confer less risk of hypercoagulability by avoiding first-pass metabolism. However, there is conflicting evidence on this issue, in particular regarding premenopausal women.^13,25 Additionally, many of the studies of estrogen supplementation show a trend toward increased headache once estrogen is discontinued, presumably due to estrogen withdrawal.^10,24

That said, one study by MacGregor, et al demonstrates that the use of estradiol gel in the perimenstrual window leads to a 22% reduction in migraine days as well as less severe migrainous symptoms.²⁶ This trend has been demonstrated in other studies examining estrogen supplementation. Of note, the estrogen studies generally are small, older, and of fair to poor quality.¹¹ These studies have used higher doses of estrogen than are commonly used for contraception today because lower doses of estrogen seem not to have the same impact on migraine.^5,24

As for COCs, with either normal or extended cycling, data are more mixed than for estrogen supplementation alone; equivalent numbers of women experience improvement, no change, or worsening of their headache pattern. Many women have continuing or worsening migraines in the hormone-free week, and thus most studies have examined the use of extended cycling COCs.⁵ Sulak, et al demonstrated a statistically significant reduction in headache frequency using extended-cycling COCs, though they did not examine MRM in particular.²⁷ The efficacy of extended-cycling COCs for reduction of MRM was confirmed by Coffee and colleagues with a small but statistically significant decrease in daily headache scores.²⁸

Evidence is insufficient to recommend for or against the use of NSAIDs as prophylaxis for menstrually-related migraines.

Adverse effects. All estrogen therapies pose the risk of adverse effects (deep vein thrombosis, hypertension, breast tenderness, nausea, etc). Additionally, estrogen supplementation may actually trigger migraines in some women if, when it is discontinued, the blood estrogen level does not remain above a threshold concentration.^5,10,24 Estrogen may also trigger migraine in previously headache-free women and may convert migraine without aura into migraine with aura. In either case, therapy should be stopped.^5,24

There is promising evidence from 2 small RCTs and one observational trial that progestin-only contraceptive pills (POP) may reduce the frequency and severity of menstrual migraines (TABLE 2^11-16). More prospective data are needed to confirm this reduction, as there have not been specific studies examining other progesterone-only preparations to prevent menstrual migraines.

Risk of ischemic stroke. Unfortunately, there are population data showing that second-generation and, to a smaller degree, third-generation progestins, which include the desogestrel used in the above studies, may increase the risk of ischemic stroke. This is a particular concern in women who experience migraine.²⁹ Second-generation progestins include levonorgestrel, which is in the levonorgestrel IUD; however, there is no direct evidence for increased ischemic stroke in this particular preparation, and the circulating plasma levels are low. Etonorgestrel, the active ingredient in the contraceptive implant, is a third-generation progestin, though there is no direct evidence of increased ischemic stroke with use of the etonorgestrel implant.

There is a 2- to 4-fold increased risk of ischemic stroke in women who experience migraine.^1,5,30 As stated above, this risk may be further increased by some progesterone formulations. But there is also a demonstrable increase in ischemic stroke risk with the use of estrogen, particularly at the higher concentrations that have been shown to prevent MRM.^31,32 The overall incidence of ischemic stroke in menstrual-age women is low, which has limited the number of studies with enough power to quantify the absolute increased risk of stroke in conjunction with estrogen use. Nevertheless, exogenous estrogen is thought to increase the risk of ischemic stroke an additional 2- to 4-fold.^{1,5,29,30,32-34}

A number of studies have demonstrated a correlation between hypomagnesemia and migraine headaches. The exact mechanism for this relationship is unclear.Women who experience aura. MRM, as it is defined, typically excludes women who experience aura; however, the number of women who experience aura with migraine either in proximity to their menses or throughout the month has not been well documented. The risk of ischemic stroke is higher for women who experience migraine with aura than those with migraine alone, possibly because aura is associated with reduced regional vascular flow leading to hypoperfusion, which sets the stage for a possible ischemic event.^4,5,35 The risk of ischemic stroke is amplified further for women who are over 35, who smoke, or who have additional vascular risk factors (eg, uncontrolled hypertension, diabetes, or known vascular or cardiac disease).^1,5,34 This array of evidence serves as the basis for the US Medical Eligibility Criteria (USMEC) recommendations³⁶ for hormonal contraceptive use, in particular the absolute contraindication for estrogen use in women who experience migraine with aura (TABLE 3^36-38).

CASE ›  Given Mary’s experience of aura with migraine, you talk with her at length about the risk of ischemic stroke and the USMEC recommendation that she absolutely should not be taking COCs. You suggest a progestin-only method of contraception such as depot medroxyprogesterone acetate, a progestin intrauterine device, or a hormonal implant, which may suppress ovulation and decrease her headaches. You discuss that while some women may have headaches with these progestin-only methods, stroke risk is significantly reduced. You also suggest a trial of prophylactic triptans as another possible option.

She says she understands the increased risk of stroke but is still unwilling to try anything else right now due to worries about her quality of life. You decide jointly to refill COCs for 3 months, and you document the shared decision process in the chart. After advising the patient that you will not continue to prescribe COCs for an extended period of time, you also schedule a follow-up appointment to further discuss risks and benefits of migraine treatment and means of reducing other risk factors for stroke.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin, Department of Family Medicine, 1100 Delaplaine Ct, Madison, WI 53715; [email protected].

CASE › Mary, a 34-year-old woman, is a new patient to your practice after moving to the area for a job. She has a history of migraine headaches triggered by her menstrual periods. She has been taking combined oral contraceptives (COCs) since she was 17, with a few years off when she had 2 children. Her migraines improved when she was pregnant, but worsened postpartum with each of her daughters to a point where she had to stop breastfeeding at 4 months to go back on the pills.

On the COCs, she gets one or 2 mild-to-moderate headaches a month. She uses sumatriptan for abortive treatment with good relief. She has not missed work in the past 4 years because of her migraines. During the 6 months she was off COCs when trying to get pregnant, she routinely missed 2 to 3 workdays per month due to migraines. She knows when she is going to get a headache because she sees flashing lights in her left visual field. She has no other neurologic symptoms with the headaches, and the character of the headaches has not changed. She is a non-smoker, has normal blood pressure and lipid levels, and no other vascular risk factors.

You review her history and talk to her about the risk of stroke with migraines and with COCs. She is almost 35 years of age and you recommend stopping the COCs due to the risk. She feels strongly that she wants to continue taking the COCs, saying her quality of life is poor when she is off the pills. What should you do?

Migraine headaches are 2 to 3 times more prevalent in women than in men,¹ with a lifetime risk of 43% vs 18%, respectively.² Women account for about 80% of the $1 billion spent each year in the United States in medical expenses and lost work productivity related to migraines.^1,2

Clinical patterns suggestive of menstrual migraine. About half of women affected by migraine have menstrually-related migraines (MRM); 3% to 12% have pure menstrual migraines (PMM).³ MRM and PMM are both characterized by the presence of symptoms in at least 2 to 3 consecutive cycles, with symptoms occurring from between 2 days before to 3 days after the onset of menstruation. However, in PMM, symptoms do not occur at any other time of the menstrual cycle; in MRM, symptoms can occur at other times of the cycle. PMM is more likely to respond to hormone therapy than is MRM.

Multiple studies in the United States, Europe, and Asia have noted that migraines related to menses typically last longer, are more severe, less likely to be associated with aura, and more likely to be recurrent and recalcitrant to treatment than non-menstrual migraines.¹ TABLE 1³ describes diagnostic criteria for migraine without aura.

Prevalence patterns point to the role of estrogen. The prevalence of migraines in women increases around puberty, peaks between ages 30 and 40, and decreases after natural menopause.⁶ Migraine prevalence increases during the first week postpartum, when levels of estrogen and progesterone decrease suddenly and significantly.¹ Migraine frequency and intensity decrease in the second and third trimesters of pregnancy and after menopause, when estrogen levels fluctuate significantly less.¹ In the Women’s Health Initiative study, women who used hormone replacement therapy (HRT) had a 42% increased risk of migraines compared with women in the study who had never used HRT.⁸

Migraines related to menses typically last longer, are more severe, less likely to be associated with aura, and more likely to be recalcitrant to treatment than non-menstrual migraines.The association of migraine with female hormones was further supported by a Dutch study of male-to-female transgender patients on estrogen therapy, who had a 26% incidence of migraine, equivalent to the 25% prevalence in natal female controls in this study, compared with just 7.5% in male controls.⁹ The association between migraine and estrogen withdrawal was investigated in studies performed more than 40 years ago, when women experiencing migraines around the time of menses were given intramuscular estradiol and experienced a delay in symptom onset.¹⁰

Abortive and prophylactic treatments: Factors that guide selection

In considering probable menstrual migraine, take a detailed history, review headache diaries if available to determine association of headaches with menses, and perform a thorough neurologic examination. If a diagnosis of menstrual migraine is established, discuss the benefits of different treatment options, both abortive and prophylactic.

For the patient with MRM, take into account frequency of symptoms, predictability of menstruation, medication costs, and comorbidities. Both triptans and nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective treatments for MRM.¹¹ Abortive therapy may be appropriate if a patient prefers to take medication intermittently, if her menses are unpredictable, or if she does not get migraine headaches with every menses. Mefenamic acid, sumatriptan, and rizatriptan have category B recommendations for abortive treatment for menstrual migraines (TABLE 2^11-16). (For the patient who has regular MRM but unpredictable menses, ovulation predictor kits can be used to help predict the onset of menses, although this would involve additional cost.)

Triptans are contraindicated for women with a history of cardiac disease or uncontrolled hypertension. For the patient who has predictable menses and regularly occurring menstrual migraine, some data show that a short-term prophylactic regimen with triptans started 2 to 3 days before the onset of menses and continued for 5 to 7 days total can reduce the incidence of menstrual migraine (TABLE 2^11-16). At least one high-quality randomized controlled trial (RCT) showed a significant reduction in the incidence of MRM when women were treated prophylactically with frovatriptan, a long-acting triptan with a half-life of approximately 26 hours. Participants received frovatriptan 2.5 mg once a day or twice a day or placebo in the perimenstrual period (day -2 to +3). The incidence of MRM was 52%, 41%, and 67%, respectively (P<.0001).^11,17

Another RCT of fair quality examined the effect of naratriptan (half-life 6-8 hours) on the median number of menstrual migraines over 4 menstrual cycles. Women who received 1 mg of naratriptan BID for 2 to 3 days before menses had 2 MRM episodes over the 4 cycles compared with 4 MRM episodes in women who received placebo over the same time period (P<.05).^11,18 A third RCT, also of fair quality, compared 2 different regimens of zolmitriptan (half-life 3 hours) with placebo and found that women who received 2.5 mg of zolmitriptan either BID or TID 2 to 3 days prior to menses had a reduction both in frequency of menstrual migraines and in the mean number of breakthrough headaches per menstrual cycle, as well as a reduction in the need for rescue medications.^12,19 Triptans are contraindicated in women with a history of cardiac disease or uncontrolled hypertension. Also, triptans can be expensive, precluding their use for some patients.

Evidence is insufficient to recommend for or against the use of NSAIDs as prophylaxis for MRM.¹¹ NSAIDs may be contraindicated in women with a history of peptic ulcer disease or gastrointestinal bleeding. That said, if NSAIDs are not contraindicated, a trial may be reasonable given their low cost.

Data are sparse on the use of vitamins and supplements in treating and preventing PMM or MRM. In one very small double-blind, placebo-controlled study in 1991 (N=24, with efficacy data for 20), participants received a 2-week course of oral magnesium premenstrually. There was a statistically significant reduction in the number of days with headache per month (from 4.7±3.1 days to 2.4±2.2 days; P<.01) and in the total pain index (P<.03).²⁰ A number of studies have demonstrated a correlation between hypomagnesemia and migraine headaches.^5,21 The exact mechanism for this relationship is unclear.

Some recent evidence-based reviews have examined the efficacy of nutraceuticals such as magnesium, feverfew, butterbur, coenzyme Q10, and riboflavin on typical migraine, but it is not clear if these results are translatable to the treatment and prophylaxis of menstrual migraine.^11,22 A multicenter, single-blind, RCT is underway to examine the efficacy of acupuncture as prophylaxis for MRM.²³

The association between MRM and hormonal variation makes exogenous hormone therapy a tempting prophylactic treatment. A study by Somerville showed that using exogenous estrogen to mitigate the decrease in estrogen through the menstrual cycle can raise the headache threshold and thereby decrease the frequency and severity of MRM.¹⁰ Progesterone levels also vary throughout the menstrual cycle; however, this variation has not been shown to correlate with MRM. Some investigators have speculated that continuous exogenous progesterone may decrease the frequency of MRM through the blunting of estrogen cycles.^5,10,24

Most studies examining the role of exogenous estrogen in reducing menstrual migraines have used topical estrogen (either in patch or gel formulations) in the perimenstrual window (TABLE 2^11-16). The topical estrogen route has been examined, in particular, as it is presumed to confer less risk of hypercoagulability by avoiding first-pass metabolism. However, there is conflicting evidence on this issue, in particular regarding premenopausal women.^13,25 Additionally, many of the studies of estrogen supplementation show a trend toward increased headache once estrogen is discontinued, presumably due to estrogen withdrawal.^10,24

That said, one study by MacGregor, et al demonstrates that the use of estradiol gel in the perimenstrual window leads to a 22% reduction in migraine days as well as less severe migrainous symptoms.²⁶ This trend has been demonstrated in other studies examining estrogen supplementation. Of note, the estrogen studies generally are small, older, and of fair to poor quality.¹¹ These studies have used higher doses of estrogen than are commonly used for contraception today because lower doses of estrogen seem not to have the same impact on migraine.^5,24

As for COCs, with either normal or extended cycling, data are more mixed than for estrogen supplementation alone; equivalent numbers of women experience improvement, no change, or worsening of their headache pattern. Many women have continuing or worsening migraines in the hormone-free week, and thus most studies have examined the use of extended cycling COCs.⁵ Sulak, et al demonstrated a statistically significant reduction in headache frequency using extended-cycling COCs, though they did not examine MRM in particular.²⁷ The efficacy of extended-cycling COCs for reduction of MRM was confirmed by Coffee and colleagues with a small but statistically significant decrease in daily headache scores.²⁸

Evidence is insufficient to recommend for or against the use of NSAIDs as prophylaxis for menstrually-related migraines.

Adverse effects. All estrogen therapies pose the risk of adverse effects (deep vein thrombosis, hypertension, breast tenderness, nausea, etc). Additionally, estrogen supplementation may actually trigger migraines in some women if, when it is discontinued, the blood estrogen level does not remain above a threshold concentration.^5,10,24 Estrogen may also trigger migraine in previously headache-free women and may convert migraine without aura into migraine with aura. In either case, therapy should be stopped.^5,24

There is promising evidence from 2 small RCTs and one observational trial that progestin-only contraceptive pills (POP) may reduce the frequency and severity of menstrual migraines (TABLE 2^11-16). More prospective data are needed to confirm this reduction, as there have not been specific studies examining other progesterone-only preparations to prevent menstrual migraines.

Risk of ischemic stroke. Unfortunately, there are population data showing that second-generation and, to a smaller degree, third-generation progestins, which include the desogestrel used in the above studies, may increase the risk of ischemic stroke. This is a particular concern in women who experience migraine.²⁹ Second-generation progestins include levonorgestrel, which is in the levonorgestrel IUD; however, there is no direct evidence for increased ischemic stroke in this particular preparation, and the circulating plasma levels are low. Etonorgestrel, the active ingredient in the contraceptive implant, is a third-generation progestin, though there is no direct evidence of increased ischemic stroke with use of the etonorgestrel implant.

There is a 2- to 4-fold increased risk of ischemic stroke in women who experience migraine.^1,5,30 As stated above, this risk may be further increased by some progesterone formulations. But there is also a demonstrable increase in ischemic stroke risk with the use of estrogen, particularly at the higher concentrations that have been shown to prevent MRM.^31,32 The overall incidence of ischemic stroke in menstrual-age women is low, which has limited the number of studies with enough power to quantify the absolute increased risk of stroke in conjunction with estrogen use. Nevertheless, exogenous estrogen is thought to increase the risk of ischemic stroke an additional 2- to 4-fold.^{1,5,29,30,32-34}

A number of studies have demonstrated a correlation between hypomagnesemia and migraine headaches. The exact mechanism for this relationship is unclear.Women who experience aura. MRM, as it is defined, typically excludes women who experience aura; however, the number of women who experience aura with migraine either in proximity to their menses or throughout the month has not been well documented. The risk of ischemic stroke is higher for women who experience migraine with aura than those with migraine alone, possibly because aura is associated with reduced regional vascular flow leading to hypoperfusion, which sets the stage for a possible ischemic event.^4,5,35 The risk of ischemic stroke is amplified further for women who are over 35, who smoke, or who have additional vascular risk factors (eg, uncontrolled hypertension, diabetes, or known vascular or cardiac disease).^1,5,34 This array of evidence serves as the basis for the US Medical Eligibility Criteria (USMEC) recommendations³⁶ for hormonal contraceptive use, in particular the absolute contraindication for estrogen use in women who experience migraine with aura (TABLE 3^36-38).

CASE ›  Given Mary’s experience of aura with migraine, you talk with her at length about the risk of ischemic stroke and the USMEC recommendation that she absolutely should not be taking COCs. You suggest a progestin-only method of contraception such as depot medroxyprogesterone acetate, a progestin intrauterine device, or a hormonal implant, which may suppress ovulation and decrease her headaches. You discuss that while some women may have headaches with these progestin-only methods, stroke risk is significantly reduced. You also suggest a trial of prophylactic triptans as another possible option.

She says she understands the increased risk of stroke but is still unwilling to try anything else right now due to worries about her quality of life. You decide jointly to refill COCs for 3 months, and you document the shared decision process in the chart. After advising the patient that you will not continue to prescribe COCs for an extended period of time, you also schedule a follow-up appointment to further discuss risks and benefits of migraine treatment and means of reducing other risk factors for stroke.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin, Department of Family Medicine, 1100 Delaplaine Ct, Madison, WI 53715; [email protected].

From the University of Wisconsin School of Medicine and Public Health, Madison, WI.

Abstract

• Objective: To describe the contributing etiologies, common presentations, diagnosis, evaluation, and management of abnormal uterine bleeding (AUB).
• Methods: Review of the literature in the context of 3 cases.
• Results: AUB is one of the most common reasons that reproductive-aged women seek health care. The causes are varied, depending in large part on the age and life stage of the woman. Diagnosis requires a systematic approach that is driven by a thorough health history and review of presenting symptoms.  Determining whether the bleeding is ovulatory or anovulatory is a central part of the evaluation. A methodical history, physical examination, and laboratory evaluation may enable the physician to rule out causes such as pregnancy and pregnancy-related disorders, medications, iatrogenic causes, systemic conditions, and obvious genital tract pathology.
• Conclusion: Clinicians must be knowledgeable about AUB and partner with women to develop appropriate, individualized treatment plans.

Abnormal vaginal bleeding is a common complaint in primary care. The prevalence of some type of abnormal bleeding is up to 30% among women of reproductive age [1].Over 18% of all gynecology outpatient visits in the United States are for menorrhagia alone [2].A retrospective analysis of medical expenditures data compared 1.4 million women with abnormal uterine bleeding to over 50 million women without abnormal bleeding. This study found that women with abnormal bleeding were more likely to be younger, Caucasian, and obese and had poorer physical and mental health quality of life scores [3].

The estimated direct and indirect costs of abnormal bleeding are $1 billion and $12 billion annually, respectively [4]. Indirect costs of abnormal bleeding include time off from work and cost of products to protect clothing from bleeding (eg, tampons and pads). Abnormal bleeding is also a common reason for women to be referred to gynecologists and is an indication for up to 25% of all gynecologic surgeries [5].

History Taking

Taking a menstrual history is an important step in determining whether the current bleeding pattern is normal or abnormal. Regularity of menstrual bleeding is clarified by asking about the frequency of the menses and their duration. Other important questions include age at menarche, presence of premenstrual syndrome symptoms, breast tenderness, cervical mucus changes, and amount of bleeding. An ovulatory cycle will usually include premenstrual symptoms whereas an anovulatory cycle will be random in its symptomatology. Women’s estimates of the amount of menstrual bleeding are notoriously inaccurate. Traditionally, more than 80 cc of menstrual blood loss per cycle is considered menorrhagia. However, women and their health care providers do not measure menstrual blood volume outside of study settings, and one study found that only half of women who presented with menorrhagia actually had more than 80 cc of blood loss [6]. There is movement toward use of more patient-centered measures to diagnose men-orrhagia, such as bleeding interfering with a woman’s daily activities, needing to wake up at night to change tampons or pads, or inability to exercise during menses. Anemia in the setting of menorrhagia by history is a less subjective way to diagnose menorrhagia.

Nomenclature and Differential Diagnosis

Differential diagnosis will vary based on symptomatology as well as age. Pregnancy is a possible cause of any type of abnormal bleeding in any woman of reproductive age (ie, after menarche and before menopause). Many systemic illnesses and medications can affect menstrual bleeding and should be included in a broad differential diagnosis of a presenting woman.

Case 1—Heavy Menstrual Bleeding

Initial Presentation

A 42-year-old woman presents reporting increasingly heavy, somewhat painful periods over the last 6 to 8 months. She experienced menarche at age 12 and has had regular, moderately heavy periods throughout her adult life. She denies any inter-menstrual bleeding.

• What additional history should be obtained?

Heavy menstrual bleeding refers to abnormally heavy bleeding that occurs in an ovulatory, cyclical pattern. Women with anovulatory cycles can also have heavy bleeding as well, and distinguishing ovulatory vs anovulatory cycles is often the first step in the evaluation.

The initial evaluation of a woman presenting with heavy menstrual bleeding includes a detailed history and physical examination. The first goal of the history is to establish the severity of bleeding, including any symptoms of hemodynamically significant anemia such as dizziness or exertional dyspnea. Next, the clinician should determine whether the bleeding pattern is ovulatory or anovulatory. Ovulatory heavy menstrual bleeding is most often caused by structural lesions (leiomyomas, endometriosis, adenomyosis, cervical polyps, and endometrial polyps) or a coagulopathy (von Willebrand disease, anticoagulant use, etc). Less commonly, ovulatory heavy menstrual bleeding may be due to systemic illness (including thyroid disease, renal disease, and liver disease) or endometrial hyperplasia or carcinoma.

Once an ovulatory pattern is confirmed, a history of dysmenorrhea, pelvic pain, lower urinary tract symptoms, constipation, dyspareunia, or infertility should be elicited. 

Further history taking should seek to identify any symptoms suggestive of thyroid, kidney, or liver disease, 

• What are key elements of the physical examination?

The physical examination should include visual inspection and palpation of the thyroid gland as well as an abdominal exam to evaluate for hepatosplenomegaly or lower abdominal tenderness or masses. Signs of anemia such as pallor should also be noted. The gynecologic exam should include visual inspection of the external genitalia, a bimanual exam, and a speculum exam. Cervical and endometrial polyps may be visible as masses at the cervical os or extending into the vaginal canal. An enlarged mobile uterus with irregular contours is consistent with leiomyomas [8].Endometriosis may manifest as tenderness, thickening, or nodularity of the uterine corpus, the vaginal canal, the uterosacral ligaments, or the adnexa. Endometriosis may also cause an asymmetric, fixed position of the uterus, the cervix, or the adnexa [9].Adenomyosis may cause diffuse moderate uterine enlargement with or without tenderness [10].Endometrial carcinoma may also cause uterine enlargement and/or immobility.

• What laboratory testing should be performed?

• What additional testing would be useful in narrowing the differential diagnosis?

If the physical examination and initial laboratory testing is nondiagnostic, the decision to initiate a trial of symptom management or proceed with further testing (imaging and/or tissue sampling) is based on risk of endometrial cancer, severity of symptoms, and patient preference. In many women, body habitus makes a confirmatory pelvic examination difficult, which may lower the threshold for obtaining a pelvic ultrasound.

Women with risk factors for endometrial cancer should undergo office-based endometrial biopsy as the first step in evaluation of heavy menstrual bleeding [7].Risk factors include older age (45 years and older), obesity (BMI > 30), diabetes mellitus, nulliparity, and history of chronic anovulation (eg, polycystic ovary syndrome). Pelvic ultrasound is the first step in the evaluation of women with an abnormal physical exam suggesting a structural lesion [7].If the physical exam is abnormal and the pelvic ultrasound is nondiagnostic, a hysteroscopy or saline-infusion sonohysterogram should be performed, as these tests are more sensitive for the detection of intracavitary lesions and submucosal fibroids [13].Most endometrial polyps will appear as a thickened or irregular endometrium on pelvic ultrasound, but be clearly delineated on sonohysterogram. Women who have a negative initial evaluation but then go on to have persistent bleeding despite a trial of therapy also require further evaluation.

Case Continued

The patient reports that her periods are regular, with a cycle length of 30 to 31 days. She usually notes some bloating and breast tenderness in the days leading up to onset of menses. She experiences lower abdominal cramping during days 1–3 of her period. This has worsened somewhat over the last year, and sometimes radiates to her low back. Her reproductive history is significant for 3 uncomplicated vaginal deliveries and 1 first trimester spontaneous abortion. She did not experience postpartum hemorrhage, and has no history of significant oropharyngeal bleeding or unexplained bruising. Her BMI is 23.3. Her physical exam is unremarkable, including a normal thyroid, abdominal, bimanual and speculum exam. Laboratory evaluation demonstrates a low-normal hemoglobin, hematocrit, and MCV. The TSH is normal and a urine pregnancy test is negative. She had a normal pap smear and HPV assay 2 years ago.

• What is the most likely diagnosis?

• What treatment is recommended?

Oral tranexamic acid is an anti-fibrinolytic that was recently approved by the FDA for treatment of menorrhagia or heavy menstrual bleeding. It has been used for many years to prevent bleeding during surgery and to treat bleeding disorders. It has been used for over 30 years to treat menorrhagia in Europe. It has a different mechanism of action than NSAIDs and hormonal contraceptives, and is therefore an appropriate alternative for women who cannot tolerate other medication options [16,17].Tranexamic acid is contraindicated in women with an elevated risk of thromboembolic disease.

For women who have insufficient response to medical management or for women who present with more severe symptoms, anemia, or prominent bulk-related symptoms due to fibroids, gynecologic referral should be made for consideration of surgical intervention. The preferred interventional approach to the treatment of uterine fibroid tumors depends upon the type of fibroid (eg submucosal, intramural, subserosal), the number of fibroids, desire for future childbearing, risk for surgical complications, and patient preference. Effective options include myomectomy, uterine artery embolization, endometrial ablation, and hysterectomy [18].

By contrast, good evidence supports the use of medication as first-line therapy for heavy menstrual bleeding when it occurs in the setting of endometriosis. Estrogen-progestin oral contraceptive pills, oral progestins, and depot medroxyprogesterone have all been demonstrated to be effective in decreasing pain [19,20].The levonorgestrel-releasing intrauterine system is also effective in decreasing pain due to endometriosis [21].

Women who do not respond to first-line therapy should be referred to a gynecologist for consideration of other treatment options. Effective second-line treatment options include oral danazol, intramuscular GnRH agonists, and surgical approaches such as laparoscopic ablation and/or excision of endometriosis implants [22].

A similar range of treatment options appears to be effective in the management of heavy menstrual bleeding due to adenomyosis. First-line therapies include oral NSAIDs, oral tranexamic acid, estrogen-progestin oral contraceptive pills, and the levonorgestrel-releasing intrauterine system [23,24].Women with an inadequate response to first-line treatment should be referred to a gynecologist for consideration definitive treatment with hysterectomy versus uterine artery embolization or a trial of a GnRH agonist [24].

For some women with heavy menstrual bleeding, no specific underlying cause is identified. Current evidence suggests that such patients may have disorders of local endometrial hemostasis leading to increased blood loss during otherwise normal menstrual cycles [25].The levonorgestrel-releasing intrauterine system may be the most effective medical therapy for heavy menstrual bleeding in the absence of a specific target lesion [26].For women wishing to avoid hormonal treatment, scheduled oral NSAIDs or oral tranexamic acid are inexpensive and effective options for reducing blood loss [27–29].Other medical treatment options include estrogen-progestin contraceptive pills, cyclic oral progestin, and depot medroxy-progesterone.

For patients who experience treatment failure with pharmaceutical therapy or who desire definitive treatment, both endometrial ablation and hysterectomy have been shown to be effective and associated with high rates of patient satisfaction [30].

Follow-up

The patient reports that she would like to avoid invasive testing if possible. Given her relatively low risk for endometrial cancer, she elects a trial of scheduled NSAIDs. Unfortunately, after a couple of cycles she reports that her heavy bleeding has not been well-controlled. A pelvic ultrasound demonstrates an anterior submucosal fibroid measuring 2.4 cm and a posterior intramural fibroid measuring 1.5 cm. She agrees to insertion of a levonorgestrel IUD and calls 6 months later to report a significant decrease in her bleeding.

Case 2—Anovulation

Initial Presentation

A 27-year-old female presents for pregnancy testing. She is 2 weeks late for her period. She and her husband are attempting pregnancy and she seems disappointed that the pregnancy test is negative. She is having trouble tracking her periods. Her cycles range from 24 to 45 days apart and often she skips cycles altogether. Her flow is scant at times but some months are heavy with soaking tampons/pads.

• What are diagnostic considerations in evaluating this bleeding pattern?

Menstrual history can help differentiate between of ovulatory and anovulatory abnormal bleeding. Typically, anovulatory bleeding is marked by irregular or infrequent periods. Flow can be scant to excessive. Women experiencing anovulatory cycles may fail to notice common ovulation symptoms (thin watery cervical mucus) or pre-menstrual symptoms (breast tenderness) [31].

The International Federation of Gynecology and Obstetrics (FIGO) designates AUD-O as “abnormal uterine bleeding due to ovulatory dysfunction” or “anovulatory abnormal uterine bleeding” [7,31].In general, if women are having menses at regular cycles their bleeding is likely to be ovulatory.

Differential Diagnosis

Anovulatory bleeding may be physiologic. After menarche, the hypothalamic-pituitary-ovarian axis is immature. This may result in anovulatory cycles for 2 to 3 years. Women entering perimenopausal transition may also experience intermittent anovulation and subsequent abnormal uterine bleeding. Other physiologic examples include lactation and pregnancy [31].

Physical Examination

A thorough history will help to narrow the differential diagnosis. The physical exam can evaluate for other findings that indicate endocrine dysfunction such as low body weight, hirsutism, balding, acne, high blood pressure, obesity (especially centripetal fat distribution). Acanthosis nigricans is a sign of insulin resistance which is part of the pathophysiology of PCOS. The gynecologic exam is often unremarkable in AUB-O although a bimanual exam can reveal adnexal enlargement indicative of cystic ovaries. Of note, clitoromegally is not common in PCOS. This finding would increase the likelihood of other causes of hyperandrogenism [32].

• What is the pathophysiologic basis for this patient’s bleeding pattern?

Pathophysiology of Anovulatory Bleeding

Anovulatory bleeding presumes that there is a normal anatomic and genetic makeup. For example, a woman without ovaries will be, by definition, anovulatory. Using current terminology anovulatory bleeding implies a disruption in the hypothalamic-pituitary-ovarian axis and is therefore primarily an endocrine disorder [31,33].

At the level of the ovary and uterus, anovulation results in prolonged estrogen effect on the endometrium. After ovulation, the corpus luteum produces progesterone which stops endometrial thickening and stabilizes the endometrium. Without ovulation, estrogen continues endometrial stimulation and excess proliferation of endometrial lining. The endometrium becomes unstable, undifferentiated, and sheds unpredictably. The blood vessels become larger, more tortuous and have increased fragility. The result is light or heavy menstrual bleeding, decreased frequency of periods but overall unpredictable menstrual bleeding [33].

Effects of Chronic Anovulation

Irregular cycles can be more than a mere inconvenience. Women who have anovulatory cycles associated with heavy menstrual bleeding are at risk for anemia. Anovulation that is a result of hyperandrogen state or other endocrine disorder has other health ramifications. Infertility and its treatment are common sequelae. Finally, over time, unopposed estrogen in anovulation increases the risk of endometrial hyperplasia, or cancer [7,34].

Case Continued

The patient reports menarche at age 12. Her periods were irregular for the first 1–2 years but became more regular after that. She has been taking combination oral contraceptives since the age of 20 to prevent pregnancy. She stopped this 1 year ago and she and her husband began actively trying to conceive 6 months ago. Her family history is notable for diabetes and hypertension in her father. Her mother had heavy periods leading up to menopause and had a hysterectomy with no malignancy at the age of 47. She has a BMI of 33; blood pressure is mildly elevated at 134/84 mm Hg. She has oily skin and acne along her chin and neck. She has mild hirsutism of her face. Otherwise her skin is normal appearing. She has an elevated waist circumference of 35 inches. The remainder of her exam is normal.

• What is the likely diagnosis?

Women with PCOS are at increased risk for metabolic syndrome, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease, endometrial cancer, and infertility. Women with PCOS who become pregnant have increased risk of pregnancy complications such as hypertensive disorders and gestational diabetes.

• What tests are indicated in this patient?

Appropriate laboratory testing is often determined based on findings in the history and physical as well as the patient’s age. Anovulation in the first 18 months to 3 years after menarche is common and testing for pregnancy, infection, and anemia are often sufficient. Menorrhagia in adolescents warrants testing for bleeding disorders as well [7].Within 3 years of menarche, menstrual cycles should become more regular. Persistent anovulatory cycles increase the likelihood of pathologic causes and warrant additional evaluation. Pregnancy testing, thyroid stimulation hormone and prolactin levels are recommended first line evaluation [7,32,34].If PCOS is suspected an ultrasound can be performed but as noted above, polycystic ovaries are not required to make the diagnosis after adolescence.

Additional testing includes testosterone levels to look for androgen secreting tumors. Late onset congenital adrenal hyperplasia is an uncommon cause of hyperandrogenism but is more common in women of Ashkenazi Jewish descent and those with a family history [34].Morning hydroxyprogesterone can be performed to evaluate for this. If women exhibit abrupt change in menstrual pattern and other signs of cortisol excess (hypertension, abdominal striae) 24-hour urine cortisol can detect Cushing’s syndrome [34].

In patients with PCOS, additional testing to evaluate for medical comorbidities is recommended. This includes screening for diabetes, dyslipidemia, and liver dysfunction.

Case Continued

The patient’s prolactin and TSH are normal. Tests for diabetes are normal. Her LDL is elevated to 162, triglycerides are 200, and her HDL is 38. The physician informs her that she meets criteria for PCOS and also that she has obesity and metabolic syndrome.

• What factors should be considered when making treatment recommendations for this patient?

Treatment for anovulation is guided by the goals of therapy. Since anovulation is an endocrine abnormality, medical treatment is first line [31].If secondary causes are diagnosed, these should be treated first. Other goals of treatment can include reducing amount and irregularity of menstruation, provide contraception, increasing ovulation in women with desired fertility, and reducing androgenic sequelae such as acne and hirsutism.

When treating the irregular or heavy bleeding associated with anovulation, first-line treatment is exogenous hormone. This can be in the form of combined estrogen/progesterone formulations (pill, patch, and ring). Medroxyprogesterone (medroxyprogesterone acetate 5–10 mg daily) taken 10 to 14 days per month is another option. Standard consideration for medical eligibility in prescribing these agents should be considered (see U.S. medical eligibility criteria for contraceptive use available at www.cdc.gov/reproductivehealth/unintendedpregnancy/usmec.htm). Combined formulations offer contraception, while cyclic progesterone does not. Both offer cyclic withdrawal bleeding. A Cochrane review did not find any RCTs comparing one to the other and therefore either are reasonable options [36].The levonorgestrel IUD is effective at treating AUB as well [31].Women may still experience intermittent vaginal bleeding or amenorrhea so it is less likely to result in cyclic withdrawal bleeding.

All of the above treatments provide the additional benefit of thinning the endometrium and preventing unopposed estrogen effect. This provides further protection the endometrial hyperplasia with chronic anovulatory cycles and unopposed estrogen [31].

In women with PCOS and associated metabolic conditions, first-line treatment is weight loss and other lifestyle interventions to improve or prevent other sequelae of the condition. Weight loss has been shown to reduce circulating androgen levels and increase ovulation. It has been shown to reduce glucose and lipid levels and hirsutism. Pregnancy rates increase as well. Weight loss achieved through medications and gastric bypass has similar effects. There is no special diet that has been shown to be more effective than another [32]. As little as a 5% weight reduction from baseline can improve PCOS symptoms [34,35].

Metformin is also commonly added to lifestyle modifications in women with PCOS to reduce risks for developing diabetes. There is little high quality evidence of added benefit above lifestyle modifications [34].Statin therapy can be considered in women with hyperlipidemia and PCOS [32].

For women with PCOS who desire to conceive, treatment should target increased ovulation. Pre-conception counseling and lifestyle modifications are again first line [32].Ovulation induction interventions carry increased risk of multiple gestation. For ovulation induction, clomiphene citrate is first line therapy. Metformin is commonly used as noted above to improve comorbidities associated with PCOS and can increase ovulation compared to placebo [37].However, RCTs do not support its use as first-line treatment of infertility treatment in PCOS. Clomiphene is 3 times more effective than metformin alone [32].

Medications can improve but often do not resolve hirsutism in women with PCOS. Combined hormonal contraceptives are commonly used off-label and no one type of pill has been shown to be superior. Anti-androgens are also off-label but empirically used. They can also improve lipid and other metabolic variables. They are all teratogenic and therefore should not be used in women who desire conception, and be used with effective contraceptives. Spironolactone is an androgen receptor antagonist. It takes months for effect. Some women will have improved menstrual frequency with this medication as well. Often adjunctive therapy such as eflornithine facial cream or laser therapy or a combination is needed to further treat hirsutism [32,35,38].

Follow-up

After discussion, the patient decides to adopt therapeutic lifestyle changes. She desires to get pregnant and does not opt for hormonal contraceptives at this time. She sees a nutritionist and begins calorie restriction and exercise. Three months later she has lost 20 pounds and feels “healthier.” Her lipid panel shows LDL of 125 and HDL of 43. Her triglycerides are now 160. Her blood pressure in the office is 118/78 mm Hg. She has lost “inches” around her middle. She has had more regular periods as well. She is still not pregnant so the physician asks her to begin tracking ovulation with cervical mucus evaluation and basal body temperature prior to considering further infertility evaluations. Three months after that she misses a period but is pleased to report a positive home pregnancy test.

Case 3—Breakthough Bleeding On Combined Hormonal Contraceptives 

A 28-year-old G0P0 in a monogamous relationship presents to her physician. She has been on oral contraceptive pills for 8 years. For the last 3 years she has been taking the pills on an extended cycle schedule. She normally takes an active pill daily for 3 cycles of pills (9 weeks), and then takes a 7-day pill-free week when she gets a menstrual period. This had been working fine until the last 6 months. She has noticed breakthrough spotting up to 2 weeks at a time during the 2nd and 3rd pack of pills.

• What is the approach to evaluation and treatment in this patient?

Bleeding in Women on Combined Hormonal Contraception

Many women are now using combined hormonal contraceptives on different schedules. Extended-cycle contraception has been shown to be as effective as the traditional 21/7 schedule of active pills/pill-free week. The FDA has approved several packaged extended-cycle contraceptives. Extended-cycle contraception decreases overall number of bleeding days and improves many menstrual-related symptoms [39].Breakthrough bleeding is the most common side effect of extended cycle contraception. It is classified as AUB-I (abnormal uterine bleeding—iatrogenic). It is most common in the first few months of use, and decreases as use continues. Up to 86% of women will have unscheduled bleeding during the first 3 months of use of extended cycle contraception, but this bleedingdecreases as use continues [40].

There is no consensus as to the underlying mechanism causing this abnormal bleeding. Most clinicians believe that it is related to the balance of estrogen/progestin in each combined hormonal contraceptive. Each woman reacts differently to this combination, making it difficult to predict who will have abnormal bleeding. In women who are beginning an extended-cycle regimen, reassurance is sufficient. Most abnormal bleeding will normalize within the first 2 to 3 months. Missed pills and smoking are consistently related to breakthrough bleeding in women who take combined oral contraceptive pills [41].In women who have previously had stable bleeding patterns and who present with new breakthrough bleeding, evaluation for secondary causes of bleeding may be considered (ie, urine hCG, TSH, STI cultures, evaluation for cervical cancer screening). A pelvic examination may help determine a possible secondary cause of bleeding, but is not necessary.

Treatment of unscheduled bleeding in women on extended-cycle contraception includes shortening the hormone-free interval and adding medications for prevention/treatment of bleeding episodes. The 7-day hormone-free interval in the context of low-dose hormonal contraception may be too long. One study demonstrated that a 7-day hormone-free interval was associated with a lack of pituitary-ovarian suppression, follicular development, and possible ovulation [42].A systematic review found that shortened hormone-free intervals decreased the amount of unscheduled bleeding [39].A small RCT (65 women) of continuous contraceptive ring users found that the group that removed the ring for 4 days during an episode of unscheduled bleeding, and then reinserted it had overall reduction in unscheduled bleeding [43].Some clinicians will also recommend trying a different pill formlation or a different schedule. There is no evidence to support this recommendation, but it can be helpful in some women.

Low-dose doxycycline (40 mg daily) for prevention of unscheduled bleeding shows promise [44].This low- dose doxycycline is also helpful to prevent more unscheduled bleeding in extended-cycle oral contraceptive users [44].However, an RCT found that traditional-dose doxycline (100 mg BID) taken for 5 days at the onset of a bleeding episode, did not decrease the amount or length of unscheduled bleeding [40].Neither estrogen dose [45]nor progestin dose [45]affected bleeding patterns. There is some suggestion based on a small study that women on pills with norethindrone may have less unscheduled bleeding than those who are on pills with levonorgestrel, but more research needs to be done before clinicians change practice [46].A Cochrane review looked at one small study that suggested third-generation progestins had more favorable bleeding profiles than second-generation progestins [47].

Follow-up

The physician investigates for secondary causes of the bleeding. The patient’s urine hCG, TSH, and prolactin levels are all normal. No fibroids or polyps are seen on ultrasound. The physician and patient discuss treatment options, including a low-dose doxycycline pill to help minimize bleeding, trying a different pill formulation, or use of naproxen during the bleeding episodes, but the patient does not want to take 2 pills every day. After further discussion, the patient decides she would like to change to the contraceptive ring with the plan of removing the ring for 4 days at the onset of any unscheduled bleeding. In a phone call 6 months later, the patient states that her unscheduled bleeding has been controlled.

Corresponding author: Sarina Schrager, MD, MS, Dept. of Family Medicine, University of Wisconsin School of Medicine and Public Health, 1100 Delaplaine Ct., Madison, WI 53715, [email protected].

From the University of Wisconsin School of Medicine and Public Health, Madison, WI.

Abstract

• Objective: To describe the contributing etiologies, common presentations, diagnosis, evaluation, and management of abnormal uterine bleeding (AUB).
• Methods: Review of the literature in the context of 3 cases.
• Results: AUB is one of the most common reasons that reproductive-aged women seek health care. The causes are varied, depending in large part on the age and life stage of the woman. Diagnosis requires a systematic approach that is driven by a thorough health history and review of presenting symptoms.  Determining whether the bleeding is ovulatory or anovulatory is a central part of the evaluation. A methodical history, physical examination, and laboratory evaluation may enable the physician to rule out causes such as pregnancy and pregnancy-related disorders, medications, iatrogenic causes, systemic conditions, and obvious genital tract pathology.
• Conclusion: Clinicians must be knowledgeable about AUB and partner with women to develop appropriate, individualized treatment plans.

Abnormal vaginal bleeding is a common complaint in primary care. The prevalence of some type of abnormal bleeding is up to 30% among women of reproductive age [1].Over 18% of all gynecology outpatient visits in the United States are for menorrhagia alone [2].A retrospective analysis of medical expenditures data compared 1.4 million women with abnormal uterine bleeding to over 50 million women without abnormal bleeding. This study found that women with abnormal bleeding were more likely to be younger, Caucasian, and obese and had poorer physical and mental health quality of life scores [3].

The estimated direct and indirect costs of abnormal bleeding are $1 billion and $12 billion annually, respectively [4]. Indirect costs of abnormal bleeding include time off from work and cost of products to protect clothing from bleeding (eg, tampons and pads). Abnormal bleeding is also a common reason for women to be referred to gynecologists and is an indication for up to 25% of all gynecologic surgeries [5].

History Taking

Taking a menstrual history is an important step in determining whether the current bleeding pattern is normal or abnormal. Regularity of menstrual bleeding is clarified by asking about the frequency of the menses and their duration. Other important questions include age at menarche, presence of premenstrual syndrome symptoms, breast tenderness, cervical mucus changes, and amount of bleeding. An ovulatory cycle will usually include premenstrual symptoms whereas an anovulatory cycle will be random in its symptomatology. Women’s estimates of the amount of menstrual bleeding are notoriously inaccurate. Traditionally, more than 80 cc of menstrual blood loss per cycle is considered menorrhagia. However, women and their health care providers do not measure menstrual blood volume outside of study settings, and one study found that only half of women who presented with menorrhagia actually had more than 80 cc of blood loss [6]. There is movement toward use of more patient-centered measures to diagnose men-orrhagia, such as bleeding interfering with a woman’s daily activities, needing to wake up at night to change tampons or pads, or inability to exercise during menses. Anemia in the setting of menorrhagia by history is a less subjective way to diagnose menorrhagia.

Nomenclature and Differential Diagnosis

Differential diagnosis will vary based on symptomatology as well as age. Pregnancy is a possible cause of any type of abnormal bleeding in any woman of reproductive age (ie, after menarche and before menopause). Many systemic illnesses and medications can affect menstrual bleeding and should be included in a broad differential diagnosis of a presenting woman.

Case 1—Heavy Menstrual Bleeding

Initial Presentation

A 42-year-old woman presents reporting increasingly heavy, somewhat painful periods over the last 6 to 8 months. She experienced menarche at age 12 and has had regular, moderately heavy periods throughout her adult life. She denies any inter-menstrual bleeding.

• What additional history should be obtained?

Heavy menstrual bleeding refers to abnormally heavy bleeding that occurs in an ovulatory, cyclical pattern. Women with anovulatory cycles can also have heavy bleeding as well, and distinguishing ovulatory vs anovulatory cycles is often the first step in the evaluation.

The initial evaluation of a woman presenting with heavy menstrual bleeding includes a detailed history and physical examination. The first goal of the history is to establish the severity of bleeding, including any symptoms of hemodynamically significant anemia such as dizziness or exertional dyspnea. Next, the clinician should determine whether the bleeding pattern is ovulatory or anovulatory. Ovulatory heavy menstrual bleeding is most often caused by structural lesions (leiomyomas, endometriosis, adenomyosis, cervical polyps, and endometrial polyps) or a coagulopathy (von Willebrand disease, anticoagulant use, etc). Less commonly, ovulatory heavy menstrual bleeding may be due to systemic illness (including thyroid disease, renal disease, and liver disease) or endometrial hyperplasia or carcinoma.

Once an ovulatory pattern is confirmed, a history of dysmenorrhea, pelvic pain, lower urinary tract symptoms, constipation, dyspareunia, or infertility should be elicited. 

Further history taking should seek to identify any symptoms suggestive of thyroid, kidney, or liver disease, 

• What are key elements of the physical examination?

The physical examination should include visual inspection and palpation of the thyroid gland as well as an abdominal exam to evaluate for hepatosplenomegaly or lower abdominal tenderness or masses. Signs of anemia such as pallor should also be noted. The gynecologic exam should include visual inspection of the external genitalia, a bimanual exam, and a speculum exam. Cervical and endometrial polyps may be visible as masses at the cervical os or extending into the vaginal canal. An enlarged mobile uterus with irregular contours is consistent with leiomyomas [8].Endometriosis may manifest as tenderness, thickening, or nodularity of the uterine corpus, the vaginal canal, the uterosacral ligaments, or the adnexa. Endometriosis may also cause an asymmetric, fixed position of the uterus, the cervix, or the adnexa [9].Adenomyosis may cause diffuse moderate uterine enlargement with or without tenderness [10].Endometrial carcinoma may also cause uterine enlargement and/or immobility.

• What laboratory testing should be performed?

• What additional testing would be useful in narrowing the differential diagnosis?

If the physical examination and initial laboratory testing is nondiagnostic, the decision to initiate a trial of symptom management or proceed with further testing (imaging and/or tissue sampling) is based on risk of endometrial cancer, severity of symptoms, and patient preference. In many women, body habitus makes a confirmatory pelvic examination difficult, which may lower the threshold for obtaining a pelvic ultrasound.

Women with risk factors for endometrial cancer should undergo office-based endometrial biopsy as the first step in evaluation of heavy menstrual bleeding [7].Risk factors include older age (45 years and older), obesity (BMI > 30), diabetes mellitus, nulliparity, and history of chronic anovulation (eg, polycystic ovary syndrome). Pelvic ultrasound is the first step in the evaluation of women with an abnormal physical exam suggesting a structural lesion [7].If the physical exam is abnormal and the pelvic ultrasound is nondiagnostic, a hysteroscopy or saline-infusion sonohysterogram should be performed, as these tests are more sensitive for the detection of intracavitary lesions and submucosal fibroids [13].Most endometrial polyps will appear as a thickened or irregular endometrium on pelvic ultrasound, but be clearly delineated on sonohysterogram. Women who have a negative initial evaluation but then go on to have persistent bleeding despite a trial of therapy also require further evaluation.

Case Continued

The patient reports that her periods are regular, with a cycle length of 30 to 31 days. She usually notes some bloating and breast tenderness in the days leading up to onset of menses. She experiences lower abdominal cramping during days 1–3 of her period. This has worsened somewhat over the last year, and sometimes radiates to her low back. Her reproductive history is significant for 3 uncomplicated vaginal deliveries and 1 first trimester spontaneous abortion. She did not experience postpartum hemorrhage, and has no history of significant oropharyngeal bleeding or unexplained bruising. Her BMI is 23.3. Her physical exam is unremarkable, including a normal thyroid, abdominal, bimanual and speculum exam. Laboratory evaluation demonstrates a low-normal hemoglobin, hematocrit, and MCV. The TSH is normal and a urine pregnancy test is negative. She had a normal pap smear and HPV assay 2 years ago.

• What is the most likely diagnosis?

• What treatment is recommended?

Oral tranexamic acid is an anti-fibrinolytic that was recently approved by the FDA for treatment of menorrhagia or heavy menstrual bleeding. It has been used for many years to prevent bleeding during surgery and to treat bleeding disorders. It has been used for over 30 years to treat menorrhagia in Europe. It has a different mechanism of action than NSAIDs and hormonal contraceptives, and is therefore an appropriate alternative for women who cannot tolerate other medication options [16,17].Tranexamic acid is contraindicated in women with an elevated risk of thromboembolic disease.

For women who have insufficient response to medical management or for women who present with more severe symptoms, anemia, or prominent bulk-related symptoms due to fibroids, gynecologic referral should be made for consideration of surgical intervention. The preferred interventional approach to the treatment of uterine fibroid tumors depends upon the type of fibroid (eg submucosal, intramural, subserosal), the number of fibroids, desire for future childbearing, risk for surgical complications, and patient preference. Effective options include myomectomy, uterine artery embolization, endometrial ablation, and hysterectomy [18].

By contrast, good evidence supports the use of medication as first-line therapy for heavy menstrual bleeding when it occurs in the setting of endometriosis. Estrogen-progestin oral contraceptive pills, oral progestins, and depot medroxyprogesterone have all been demonstrated to be effective in decreasing pain [19,20].The levonorgestrel-releasing intrauterine system is also effective in decreasing pain due to endometriosis [21].

Women who do not respond to first-line therapy should be referred to a gynecologist for consideration of other treatment options. Effective second-line treatment options include oral danazol, intramuscular GnRH agonists, and surgical approaches such as laparoscopic ablation and/or excision of endometriosis implants [22].

A similar range of treatment options appears to be effective in the management of heavy menstrual bleeding due to adenomyosis. First-line therapies include oral NSAIDs, oral tranexamic acid, estrogen-progestin oral contraceptive pills, and the levonorgestrel-releasing intrauterine system [23,24].Women with an inadequate response to first-line treatment should be referred to a gynecologist for consideration definitive treatment with hysterectomy versus uterine artery embolization or a trial of a GnRH agonist [24].

For some women with heavy menstrual bleeding, no specific underlying cause is identified. Current evidence suggests that such patients may have disorders of local endometrial hemostasis leading to increased blood loss during otherwise normal menstrual cycles [25].The levonorgestrel-releasing intrauterine system may be the most effective medical therapy for heavy menstrual bleeding in the absence of a specific target lesion [26].For women wishing to avoid hormonal treatment, scheduled oral NSAIDs or oral tranexamic acid are inexpensive and effective options for reducing blood loss [27–29].Other medical treatment options include estrogen-progestin contraceptive pills, cyclic oral progestin, and depot medroxy-progesterone.

For patients who experience treatment failure with pharmaceutical therapy or who desire definitive treatment, both endometrial ablation and hysterectomy have been shown to be effective and associated with high rates of patient satisfaction [30].

Follow-up

The patient reports that she would like to avoid invasive testing if possible. Given her relatively low risk for endometrial cancer, she elects a trial of scheduled NSAIDs. Unfortunately, after a couple of cycles she reports that her heavy bleeding has not been well-controlled. A pelvic ultrasound demonstrates an anterior submucosal fibroid measuring 2.4 cm and a posterior intramural fibroid measuring 1.5 cm. She agrees to insertion of a levonorgestrel IUD and calls 6 months later to report a significant decrease in her bleeding.

Case 2—Anovulation

Initial Presentation

A 27-year-old female presents for pregnancy testing. She is 2 weeks late for her period. She and her husband are attempting pregnancy and she seems disappointed that the pregnancy test is negative. She is having trouble tracking her periods. Her cycles range from 24 to 45 days apart and often she skips cycles altogether. Her flow is scant at times but some months are heavy with soaking tampons/pads.

• What are diagnostic considerations in evaluating this bleeding pattern?

Menstrual history can help differentiate between of ovulatory and anovulatory abnormal bleeding. Typically, anovulatory bleeding is marked by irregular or infrequent periods. Flow can be scant to excessive. Women experiencing anovulatory cycles may fail to notice common ovulation symptoms (thin watery cervical mucus) or pre-menstrual symptoms (breast tenderness) [31].

The International Federation of Gynecology and Obstetrics (FIGO) designates AUD-O as “abnormal uterine bleeding due to ovulatory dysfunction” or “anovulatory abnormal uterine bleeding” [7,31].In general, if women are having menses at regular cycles their bleeding is likely to be ovulatory.

Differential Diagnosis

Anovulatory bleeding may be physiologic. After menarche, the hypothalamic-pituitary-ovarian axis is immature. This may result in anovulatory cycles for 2 to 3 years. Women entering perimenopausal transition may also experience intermittent anovulation and subsequent abnormal uterine bleeding. Other physiologic examples include lactation and pregnancy [31].

Physical Examination

A thorough history will help to narrow the differential diagnosis. The physical exam can evaluate for other findings that indicate endocrine dysfunction such as low body weight, hirsutism, balding, acne, high blood pressure, obesity (especially centripetal fat distribution). Acanthosis nigricans is a sign of insulin resistance which is part of the pathophysiology of PCOS. The gynecologic exam is often unremarkable in AUB-O although a bimanual exam can reveal adnexal enlargement indicative of cystic ovaries. Of note, clitoromegally is not common in PCOS. This finding would increase the likelihood of other causes of hyperandrogenism [32].

• What is the pathophysiologic basis for this patient’s bleeding pattern?

Pathophysiology of Anovulatory Bleeding

Anovulatory bleeding presumes that there is a normal anatomic and genetic makeup. For example, a woman without ovaries will be, by definition, anovulatory. Using current terminology anovulatory bleeding implies a disruption in the hypothalamic-pituitary-ovarian axis and is therefore primarily an endocrine disorder [31,33].

At the level of the ovary and uterus, anovulation results in prolonged estrogen effect on the endometrium. After ovulation, the corpus luteum produces progesterone which stops endometrial thickening and stabilizes the endometrium. Without ovulation, estrogen continues endometrial stimulation and excess proliferation of endometrial lining. The endometrium becomes unstable, undifferentiated, and sheds unpredictably. The blood vessels become larger, more tortuous and have increased fragility. The result is light or heavy menstrual bleeding, decreased frequency of periods but overall unpredictable menstrual bleeding [33].

Effects of Chronic Anovulation

Irregular cycles can be more than a mere inconvenience. Women who have anovulatory cycles associated with heavy menstrual bleeding are at risk for anemia. Anovulation that is a result of hyperandrogen state or other endocrine disorder has other health ramifications. Infertility and its treatment are common sequelae. Finally, over time, unopposed estrogen in anovulation increases the risk of endometrial hyperplasia, or cancer [7,34].

Case Continued

The patient reports menarche at age 12. Her periods were irregular for the first 1–2 years but became more regular after that. She has been taking combination oral contraceptives since the age of 20 to prevent pregnancy. She stopped this 1 year ago and she and her husband began actively trying to conceive 6 months ago. Her family history is notable for diabetes and hypertension in her father. Her mother had heavy periods leading up to menopause and had a hysterectomy with no malignancy at the age of 47. She has a BMI of 33; blood pressure is mildly elevated at 134/84 mm Hg. She has oily skin and acne along her chin and neck. She has mild hirsutism of her face. Otherwise her skin is normal appearing. She has an elevated waist circumference of 35 inches. The remainder of her exam is normal.

• What is the likely diagnosis?

Women with PCOS are at increased risk for metabolic syndrome, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease, endometrial cancer, and infertility. Women with PCOS who become pregnant have increased risk of pregnancy complications such as hypertensive disorders and gestational diabetes.

• What tests are indicated in this patient?

Appropriate laboratory testing is often determined based on findings in the history and physical as well as the patient’s age. Anovulation in the first 18 months to 3 years after menarche is common and testing for pregnancy, infection, and anemia are often sufficient. Menorrhagia in adolescents warrants testing for bleeding disorders as well [7].Within 3 years of menarche, menstrual cycles should become more regular. Persistent anovulatory cycles increase the likelihood of pathologic causes and warrant additional evaluation. Pregnancy testing, thyroid stimulation hormone and prolactin levels are recommended first line evaluation [7,32,34].If PCOS is suspected an ultrasound can be performed but as noted above, polycystic ovaries are not required to make the diagnosis after adolescence.

Additional testing includes testosterone levels to look for androgen secreting tumors. Late onset congenital adrenal hyperplasia is an uncommon cause of hyperandrogenism but is more common in women of Ashkenazi Jewish descent and those with a family history [34].Morning hydroxyprogesterone can be performed to evaluate for this. If women exhibit abrupt change in menstrual pattern and other signs of cortisol excess (hypertension, abdominal striae) 24-hour urine cortisol can detect Cushing’s syndrome [34].

In patients with PCOS, additional testing to evaluate for medical comorbidities is recommended. This includes screening for diabetes, dyslipidemia, and liver dysfunction.

Case Continued

The patient’s prolactin and TSH are normal. Tests for diabetes are normal. Her LDL is elevated to 162, triglycerides are 200, and her HDL is 38. The physician informs her that she meets criteria for PCOS and also that she has obesity and metabolic syndrome.

• What factors should be considered when making treatment recommendations for this patient?

Treatment for anovulation is guided by the goals of therapy. Since anovulation is an endocrine abnormality, medical treatment is first line [31].If secondary causes are diagnosed, these should be treated first. Other goals of treatment can include reducing amount and irregularity of menstruation, provide contraception, increasing ovulation in women with desired fertility, and reducing androgenic sequelae such as acne and hirsutism.

When treating the irregular or heavy bleeding associated with anovulation, first-line treatment is exogenous hormone. This can be in the form of combined estrogen/progesterone formulations (pill, patch, and ring). Medroxyprogesterone (medroxyprogesterone acetate 5–10 mg daily) taken 10 to 14 days per month is another option. Standard consideration for medical eligibility in prescribing these agents should be considered (see U.S. medical eligibility criteria for contraceptive use available at www.cdc.gov/reproductivehealth/unintendedpregnancy/usmec.htm). Combined formulations offer contraception, while cyclic progesterone does not. Both offer cyclic withdrawal bleeding. A Cochrane review did not find any RCTs comparing one to the other and therefore either are reasonable options [36].The levonorgestrel IUD is effective at treating AUB as well [31].Women may still experience intermittent vaginal bleeding or amenorrhea so it is less likely to result in cyclic withdrawal bleeding.

All of the above treatments provide the additional benefit of thinning the endometrium and preventing unopposed estrogen effect. This provides further protection the endometrial hyperplasia with chronic anovulatory cycles and unopposed estrogen [31].

In women with PCOS and associated metabolic conditions, first-line treatment is weight loss and other lifestyle interventions to improve or prevent other sequelae of the condition. Weight loss has been shown to reduce circulating androgen levels and increase ovulation. It has been shown to reduce glucose and lipid levels and hirsutism. Pregnancy rates increase as well. Weight loss achieved through medications and gastric bypass has similar effects. There is no special diet that has been shown to be more effective than another [32]. As little as a 5% weight reduction from baseline can improve PCOS symptoms [34,35].

Metformin is also commonly added to lifestyle modifications in women with PCOS to reduce risks for developing diabetes. There is little high quality evidence of added benefit above lifestyle modifications [34].Statin therapy can be considered in women with hyperlipidemia and PCOS [32].

For women with PCOS who desire to conceive, treatment should target increased ovulation. Pre-conception counseling and lifestyle modifications are again first line [32].Ovulation induction interventions carry increased risk of multiple gestation. For ovulation induction, clomiphene citrate is first line therapy. Metformin is commonly used as noted above to improve comorbidities associated with PCOS and can increase ovulation compared to placebo [37].However, RCTs do not support its use as first-line treatment of infertility treatment in PCOS. Clomiphene is 3 times more effective than metformin alone [32].

Medications can improve but often do not resolve hirsutism in women with PCOS. Combined hormonal contraceptives are commonly used off-label and no one type of pill has been shown to be superior. Anti-androgens are also off-label but empirically used. They can also improve lipid and other metabolic variables. They are all teratogenic and therefore should not be used in women who desire conception, and be used with effective contraceptives. Spironolactone is an androgen receptor antagonist. It takes months for effect. Some women will have improved menstrual frequency with this medication as well. Often adjunctive therapy such as eflornithine facial cream or laser therapy or a combination is needed to further treat hirsutism [32,35,38].

Follow-up

After discussion, the patient decides to adopt therapeutic lifestyle changes. She desires to get pregnant and does not opt for hormonal contraceptives at this time. She sees a nutritionist and begins calorie restriction and exercise. Three months later she has lost 20 pounds and feels “healthier.” Her lipid panel shows LDL of 125 and HDL of 43. Her triglycerides are now 160. Her blood pressure in the office is 118/78 mm Hg. She has lost “inches” around her middle. She has had more regular periods as well. She is still not pregnant so the physician asks her to begin tracking ovulation with cervical mucus evaluation and basal body temperature prior to considering further infertility evaluations. Three months after that she misses a period but is pleased to report a positive home pregnancy test.

Case 3—Breakthough Bleeding On Combined Hormonal Contraceptives 

A 28-year-old G0P0 in a monogamous relationship presents to her physician. She has been on oral contraceptive pills for 8 years. For the last 3 years she has been taking the pills on an extended cycle schedule. She normally takes an active pill daily for 3 cycles of pills (9 weeks), and then takes a 7-day pill-free week when she gets a menstrual period. This had been working fine until the last 6 months. She has noticed breakthrough spotting up to 2 weeks at a time during the 2nd and 3rd pack of pills.

• What is the approach to evaluation and treatment in this patient?

Bleeding in Women on Combined Hormonal Contraception

Many women are now using combined hormonal contraceptives on different schedules. Extended-cycle contraception has been shown to be as effective as the traditional 21/7 schedule of active pills/pill-free week. The FDA has approved several packaged extended-cycle contraceptives. Extended-cycle contraception decreases overall number of bleeding days and improves many menstrual-related symptoms [39].Breakthrough bleeding is the most common side effect of extended cycle contraception. It is classified as AUB-I (abnormal uterine bleeding—iatrogenic). It is most common in the first few months of use, and decreases as use continues. Up to 86% of women will have unscheduled bleeding during the first 3 months of use of extended cycle contraception, but this bleedingdecreases as use continues [40].

There is no consensus as to the underlying mechanism causing this abnormal bleeding. Most clinicians believe that it is related to the balance of estrogen/progestin in each combined hormonal contraceptive. Each woman reacts differently to this combination, making it difficult to predict who will have abnormal bleeding. In women who are beginning an extended-cycle regimen, reassurance is sufficient. Most abnormal bleeding will normalize within the first 2 to 3 months. Missed pills and smoking are consistently related to breakthrough bleeding in women who take combined oral contraceptive pills [41].In women who have previously had stable bleeding patterns and who present with new breakthrough bleeding, evaluation for secondary causes of bleeding may be considered (ie, urine hCG, TSH, STI cultures, evaluation for cervical cancer screening). A pelvic examination may help determine a possible secondary cause of bleeding, but is not necessary.

Treatment of unscheduled bleeding in women on extended-cycle contraception includes shortening the hormone-free interval and adding medications for prevention/treatment of bleeding episodes. The 7-day hormone-free interval in the context of low-dose hormonal contraception may be too long. One study demonstrated that a 7-day hormone-free interval was associated with a lack of pituitary-ovarian suppression, follicular development, and possible ovulation [42].A systematic review found that shortened hormone-free intervals decreased the amount of unscheduled bleeding [39].A small RCT (65 women) of continuous contraceptive ring users found that the group that removed the ring for 4 days during an episode of unscheduled bleeding, and then reinserted it had overall reduction in unscheduled bleeding [43].Some clinicians will also recommend trying a different pill formlation or a different schedule. There is no evidence to support this recommendation, but it can be helpful in some women.

Low-dose doxycycline (40 mg daily) for prevention of unscheduled bleeding shows promise [44].This low- dose doxycycline is also helpful to prevent more unscheduled bleeding in extended-cycle oral contraceptive users [44].However, an RCT found that traditional-dose doxycline (100 mg BID) taken for 5 days at the onset of a bleeding episode, did not decrease the amount or length of unscheduled bleeding [40].Neither estrogen dose [45]nor progestin dose [45]affected bleeding patterns. There is some suggestion based on a small study that women on pills with norethindrone may have less unscheduled bleeding than those who are on pills with levonorgestrel, but more research needs to be done before clinicians change practice [46].A Cochrane review looked at one small study that suggested third-generation progestins had more favorable bleeding profiles than second-generation progestins [47].

Follow-up

The physician investigates for secondary causes of the bleeding. The patient’s urine hCG, TSH, and prolactin levels are all normal. No fibroids or polyps are seen on ultrasound. The physician and patient discuss treatment options, including a low-dose doxycycline pill to help minimize bleeding, trying a different pill formulation, or use of naproxen during the bleeding episodes, but the patient does not want to take 2 pills every day. After further discussion, the patient decides she would like to change to the contraceptive ring with the plan of removing the ring for 4 days at the onset of any unscheduled bleeding. In a phone call 6 months later, the patient states that her unscheduled bleeding has been controlled.

Corresponding author: Sarina Schrager, MD, MS, Dept. of Family Medicine, University of Wisconsin School of Medicine and Public Health, 1100 Delaplaine Ct., Madison, WI 53715, [email protected].

From the University of Wisconsin School of Medicine and Public Health, Madison, WI.

Abstract

• Objective: To describe the contributing etiologies, common presentations, diagnosis, evaluation, and management of abnormal uterine bleeding (AUB).
• Methods: Review of the literature in the context of 3 cases.
• Results: AUB is one of the most common reasons that reproductive-aged women seek health care. The causes are varied, depending in large part on the age and life stage of the woman. Diagnosis requires a systematic approach that is driven by a thorough health history and review of presenting symptoms.  Determining whether the bleeding is ovulatory or anovulatory is a central part of the evaluation. A methodical history, physical examination, and laboratory evaluation may enable the physician to rule out causes such as pregnancy and pregnancy-related disorders, medications, iatrogenic causes, systemic conditions, and obvious genital tract pathology.
• Conclusion: Clinicians must be knowledgeable about AUB and partner with women to develop appropriate, individualized treatment plans.

Abnormal vaginal bleeding is a common complaint in primary care. The prevalence of some type of abnormal bleeding is up to 30% among women of reproductive age [1].Over 18% of all gynecology outpatient visits in the United States are for menorrhagia alone [2].A retrospective analysis of medical expenditures data compared 1.4 million women with abnormal uterine bleeding to over 50 million women without abnormal bleeding. This study found that women with abnormal bleeding were more likely to be younger, Caucasian, and obese and had poorer physical and mental health quality of life scores [3].

The estimated direct and indirect costs of abnormal bleeding are $1 billion and $12 billion annually, respectively [4]. Indirect costs of abnormal bleeding include time off from work and cost of products to protect clothing from bleeding (eg, tampons and pads). Abnormal bleeding is also a common reason for women to be referred to gynecologists and is an indication for up to 25% of all gynecologic surgeries [5].

History Taking

Taking a menstrual history is an important step in determining whether the current bleeding pattern is normal or abnormal. Regularity of menstrual bleeding is clarified by asking about the frequency of the menses and their duration. Other important questions include age at menarche, presence of premenstrual syndrome symptoms, breast tenderness, cervical mucus changes, and amount of bleeding. An ovulatory cycle will usually include premenstrual symptoms whereas an anovulatory cycle will be random in its symptomatology. Women’s estimates of the amount of menstrual bleeding are notoriously inaccurate. Traditionally, more than 80 cc of menstrual blood loss per cycle is considered menorrhagia. However, women and their health care providers do not measure menstrual blood volume outside of study settings, and one study found that only half of women who presented with menorrhagia actually had more than 80 cc of blood loss [6]. There is movement toward use of more patient-centered measures to diagnose men-orrhagia, such as bleeding interfering with a woman’s daily activities, needing to wake up at night to change tampons or pads, or inability to exercise during menses. Anemia in the setting of menorrhagia by history is a less subjective way to diagnose menorrhagia.

Nomenclature and Differential Diagnosis

Differential diagnosis will vary based on symptomatology as well as age. Pregnancy is a possible cause of any type of abnormal bleeding in any woman of reproductive age (ie, after menarche and before menopause). Many systemic illnesses and medications can affect menstrual bleeding and should be included in a broad differential diagnosis of a presenting woman.

Case 1—Heavy Menstrual Bleeding

Initial Presentation

A 42-year-old woman presents reporting increasingly heavy, somewhat painful periods over the last 6 to 8 months. She experienced menarche at age 12 and has had regular, moderately heavy periods throughout her adult life. She denies any inter-menstrual bleeding.

• What additional history should be obtained?

Heavy menstrual bleeding refers to abnormally heavy bleeding that occurs in an ovulatory, cyclical pattern. Women with anovulatory cycles can also have heavy bleeding as well, and distinguishing ovulatory vs anovulatory cycles is often the first step in the evaluation.

The initial evaluation of a woman presenting with heavy menstrual bleeding includes a detailed history and physical examination. The first goal of the history is to establish the severity of bleeding, including any symptoms of hemodynamically significant anemia such as dizziness or exertional dyspnea. Next, the clinician should determine whether the bleeding pattern is ovulatory or anovulatory. Ovulatory heavy menstrual bleeding is most often caused by structural lesions (leiomyomas, endometriosis, adenomyosis, cervical polyps, and endometrial polyps) or a coagulopathy (von Willebrand disease, anticoagulant use, etc). Less commonly, ovulatory heavy menstrual bleeding may be due to systemic illness (including thyroid disease, renal disease, and liver disease) or endometrial hyperplasia or carcinoma.

Once an ovulatory pattern is confirmed, a history of dysmenorrhea, pelvic pain, lower urinary tract symptoms, constipation, dyspareunia, or infertility should be elicited. 

Further history taking should seek to identify any symptoms suggestive of thyroid, kidney, or liver disease, 

• What are key elements of the physical examination?

The physical examination should include visual inspection and palpation of the thyroid gland as well as an abdominal exam to evaluate for hepatosplenomegaly or lower abdominal tenderness or masses. Signs of anemia such as pallor should also be noted. The gynecologic exam should include visual inspection of the external genitalia, a bimanual exam, and a speculum exam. Cervical and endometrial polyps may be visible as masses at the cervical os or extending into the vaginal canal. An enlarged mobile uterus with irregular contours is consistent with leiomyomas [8].Endometriosis may manifest as tenderness, thickening, or nodularity of the uterine corpus, the vaginal canal, the uterosacral ligaments, or the adnexa. Endometriosis may also cause an asymmetric, fixed position of the uterus, the cervix, or the adnexa [9].Adenomyosis may cause diffuse moderate uterine enlargement with or without tenderness [10].Endometrial carcinoma may also cause uterine enlargement and/or immobility.

• What laboratory testing should be performed?

• What additional testing would be useful in narrowing the differential diagnosis?

If the physical examination and initial laboratory testing is nondiagnostic, the decision to initiate a trial of symptom management or proceed with further testing (imaging and/or tissue sampling) is based on risk of endometrial cancer, severity of symptoms, and patient preference. In many women, body habitus makes a confirmatory pelvic examination difficult, which may lower the threshold for obtaining a pelvic ultrasound.

Women with risk factors for endometrial cancer should undergo office-based endometrial biopsy as the first step in evaluation of heavy menstrual bleeding [7].Risk factors include older age (45 years and older), obesity (BMI > 30), diabetes mellitus, nulliparity, and history of chronic anovulation (eg, polycystic ovary syndrome). Pelvic ultrasound is the first step in the evaluation of women with an abnormal physical exam suggesting a structural lesion [7].If the physical exam is abnormal and the pelvic ultrasound is nondiagnostic, a hysteroscopy or saline-infusion sonohysterogram should be performed, as these tests are more sensitive for the detection of intracavitary lesions and submucosal fibroids [13].Most endometrial polyps will appear as a thickened or irregular endometrium on pelvic ultrasound, but be clearly delineated on sonohysterogram. Women who have a negative initial evaluation but then go on to have persistent bleeding despite a trial of therapy also require further evaluation.

Case Continued

The patient reports that her periods are regular, with a cycle length of 30 to 31 days. She usually notes some bloating and breast tenderness in the days leading up to onset of menses. She experiences lower abdominal cramping during days 1–3 of her period. This has worsened somewhat over the last year, and sometimes radiates to her low back. Her reproductive history is significant for 3 uncomplicated vaginal deliveries and 1 first trimester spontaneous abortion. She did not experience postpartum hemorrhage, and has no history of significant oropharyngeal bleeding or unexplained bruising. Her BMI is 23.3. Her physical exam is unremarkable, including a normal thyroid, abdominal, bimanual and speculum exam. Laboratory evaluation demonstrates a low-normal hemoglobin, hematocrit, and MCV. The TSH is normal and a urine pregnancy test is negative. She had a normal pap smear and HPV assay 2 years ago.

• What is the most likely diagnosis?

• What treatment is recommended?

Oral tranexamic acid is an anti-fibrinolytic that was recently approved by the FDA for treatment of menorrhagia or heavy menstrual bleeding. It has been used for many years to prevent bleeding during surgery and to treat bleeding disorders. It has been used for over 30 years to treat menorrhagia in Europe. It has a different mechanism of action than NSAIDs and hormonal contraceptives, and is therefore an appropriate alternative for women who cannot tolerate other medication options [16,17].Tranexamic acid is contraindicated in women with an elevated risk of thromboembolic disease.

For women who have insufficient response to medical management or for women who present with more severe symptoms, anemia, or prominent bulk-related symptoms due to fibroids, gynecologic referral should be made for consideration of surgical intervention. The preferred interventional approach to the treatment of uterine fibroid tumors depends upon the type of fibroid (eg submucosal, intramural, subserosal), the number of fibroids, desire for future childbearing, risk for surgical complications, and patient preference. Effective options include myomectomy, uterine artery embolization, endometrial ablation, and hysterectomy [18].

By contrast, good evidence supports the use of medication as first-line therapy for heavy menstrual bleeding when it occurs in the setting of endometriosis. Estrogen-progestin oral contraceptive pills, oral progestins, and depot medroxyprogesterone have all been demonstrated to be effective in decreasing pain [19,20].The levonorgestrel-releasing intrauterine system is also effective in decreasing pain due to endometriosis [21].

Women who do not respond to first-line therapy should be referred to a gynecologist for consideration of other treatment options. Effective second-line treatment options include oral danazol, intramuscular GnRH agonists, and surgical approaches such as laparoscopic ablation and/or excision of endometriosis implants [22].

A similar range of treatment options appears to be effective in the management of heavy menstrual bleeding due to adenomyosis. First-line therapies include oral NSAIDs, oral tranexamic acid, estrogen-progestin oral contraceptive pills, and the levonorgestrel-releasing intrauterine system [23,24].Women with an inadequate response to first-line treatment should be referred to a gynecologist for consideration definitive treatment with hysterectomy versus uterine artery embolization or a trial of a GnRH agonist [24].

For some women with heavy menstrual bleeding, no specific underlying cause is identified. Current evidence suggests that such patients may have disorders of local endometrial hemostasis leading to increased blood loss during otherwise normal menstrual cycles [25].The levonorgestrel-releasing intrauterine system may be the most effective medical therapy for heavy menstrual bleeding in the absence of a specific target lesion [26].For women wishing to avoid hormonal treatment, scheduled oral NSAIDs or oral tranexamic acid are inexpensive and effective options for reducing blood loss [27–29].Other medical treatment options include estrogen-progestin contraceptive pills, cyclic oral progestin, and depot medroxy-progesterone.

For patients who experience treatment failure with pharmaceutical therapy or who desire definitive treatment, both endometrial ablation and hysterectomy have been shown to be effective and associated with high rates of patient satisfaction [30].

Follow-up

The patient reports that she would like to avoid invasive testing if possible. Given her relatively low risk for endometrial cancer, she elects a trial of scheduled NSAIDs. Unfortunately, after a couple of cycles she reports that her heavy bleeding has not been well-controlled. A pelvic ultrasound demonstrates an anterior submucosal fibroid measuring 2.4 cm and a posterior intramural fibroid measuring 1.5 cm. She agrees to insertion of a levonorgestrel IUD and calls 6 months later to report a significant decrease in her bleeding.

Case 2—Anovulation

Initial Presentation

A 27-year-old female presents for pregnancy testing. She is 2 weeks late for her period. She and her husband are attempting pregnancy and she seems disappointed that the pregnancy test is negative. She is having trouble tracking her periods. Her cycles range from 24 to 45 days apart and often she skips cycles altogether. Her flow is scant at times but some months are heavy with soaking tampons/pads.

• What are diagnostic considerations in evaluating this bleeding pattern?

Menstrual history can help differentiate between of ovulatory and anovulatory abnormal bleeding. Typically, anovulatory bleeding is marked by irregular or infrequent periods. Flow can be scant to excessive. Women experiencing anovulatory cycles may fail to notice common ovulation symptoms (thin watery cervical mucus) or pre-menstrual symptoms (breast tenderness) [31].

The International Federation of Gynecology and Obstetrics (FIGO) designates AUD-O as “abnormal uterine bleeding due to ovulatory dysfunction” or “anovulatory abnormal uterine bleeding” [7,31].In general, if women are having menses at regular cycles their bleeding is likely to be ovulatory.

Differential Diagnosis

Anovulatory bleeding may be physiologic. After menarche, the hypothalamic-pituitary-ovarian axis is immature. This may result in anovulatory cycles for 2 to 3 years. Women entering perimenopausal transition may also experience intermittent anovulation and subsequent abnormal uterine bleeding. Other physiologic examples include lactation and pregnancy [31].

Physical Examination

A thorough history will help to narrow the differential diagnosis. The physical exam can evaluate for other findings that indicate endocrine dysfunction such as low body weight, hirsutism, balding, acne, high blood pressure, obesity (especially centripetal fat distribution). Acanthosis nigricans is a sign of insulin resistance which is part of the pathophysiology of PCOS. The gynecologic exam is often unremarkable in AUB-O although a bimanual exam can reveal adnexal enlargement indicative of cystic ovaries. Of note, clitoromegally is not common in PCOS. This finding would increase the likelihood of other causes of hyperandrogenism [32].

• What is the pathophysiologic basis for this patient’s bleeding pattern?

Pathophysiology of Anovulatory Bleeding

Anovulatory bleeding presumes that there is a normal anatomic and genetic makeup. For example, a woman without ovaries will be, by definition, anovulatory. Using current terminology anovulatory bleeding implies a disruption in the hypothalamic-pituitary-ovarian axis and is therefore primarily an endocrine disorder [31,33].

At the level of the ovary and uterus, anovulation results in prolonged estrogen effect on the endometrium. After ovulation, the corpus luteum produces progesterone which stops endometrial thickening and stabilizes the endometrium. Without ovulation, estrogen continues endometrial stimulation and excess proliferation of endometrial lining. The endometrium becomes unstable, undifferentiated, and sheds unpredictably. The blood vessels become larger, more tortuous and have increased fragility. The result is light or heavy menstrual bleeding, decreased frequency of periods but overall unpredictable menstrual bleeding [33].

Effects of Chronic Anovulation

Irregular cycles can be more than a mere inconvenience. Women who have anovulatory cycles associated with heavy menstrual bleeding are at risk for anemia. Anovulation that is a result of hyperandrogen state or other endocrine disorder has other health ramifications. Infertility and its treatment are common sequelae. Finally, over time, unopposed estrogen in anovulation increases the risk of endometrial hyperplasia, or cancer [7,34].

Case Continued

The patient reports menarche at age 12. Her periods were irregular for the first 1–2 years but became more regular after that. She has been taking combination oral contraceptives since the age of 20 to prevent pregnancy. She stopped this 1 year ago and she and her husband began actively trying to conceive 6 months ago. Her family history is notable for diabetes and hypertension in her father. Her mother had heavy periods leading up to menopause and had a hysterectomy with no malignancy at the age of 47. She has a BMI of 33; blood pressure is mildly elevated at 134/84 mm Hg. She has oily skin and acne along her chin and neck. She has mild hirsutism of her face. Otherwise her skin is normal appearing. She has an elevated waist circumference of 35 inches. The remainder of her exam is normal.

• What is the likely diagnosis?

Women with PCOS are at increased risk for metabolic syndrome, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease, endometrial cancer, and infertility. Women with PCOS who become pregnant have increased risk of pregnancy complications such as hypertensive disorders and gestational diabetes.

• What tests are indicated in this patient?

Appropriate laboratory testing is often determined based on findings in the history and physical as well as the patient’s age. Anovulation in the first 18 months to 3 years after menarche is common and testing for pregnancy, infection, and anemia are often sufficient. Menorrhagia in adolescents warrants testing for bleeding disorders as well [7].Within 3 years of menarche, menstrual cycles should become more regular. Persistent anovulatory cycles increase the likelihood of pathologic causes and warrant additional evaluation. Pregnancy testing, thyroid stimulation hormone and prolactin levels are recommended first line evaluation [7,32,34].If PCOS is suspected an ultrasound can be performed but as noted above, polycystic ovaries are not required to make the diagnosis after adolescence.

Additional testing includes testosterone levels to look for androgen secreting tumors. Late onset congenital adrenal hyperplasia is an uncommon cause of hyperandrogenism but is more common in women of Ashkenazi Jewish descent and those with a family history [34].Morning hydroxyprogesterone can be performed to evaluate for this. If women exhibit abrupt change in menstrual pattern and other signs of cortisol excess (hypertension, abdominal striae) 24-hour urine cortisol can detect Cushing’s syndrome [34].

In patients with PCOS, additional testing to evaluate for medical comorbidities is recommended. This includes screening for diabetes, dyslipidemia, and liver dysfunction.

Case Continued

The patient’s prolactin and TSH are normal. Tests for diabetes are normal. Her LDL is elevated to 162, triglycerides are 200, and her HDL is 38. The physician informs her that she meets criteria for PCOS and also that she has obesity and metabolic syndrome.

• What factors should be considered when making treatment recommendations for this patient?

Treatment for anovulation is guided by the goals of therapy. Since anovulation is an endocrine abnormality, medical treatment is first line [31].If secondary causes are diagnosed, these should be treated first. Other goals of treatment can include reducing amount and irregularity of menstruation, provide contraception, increasing ovulation in women with desired fertility, and reducing androgenic sequelae such as acne and hirsutism.

When treating the irregular or heavy bleeding associated with anovulation, first-line treatment is exogenous hormone. This can be in the form of combined estrogen/progesterone formulations (pill, patch, and ring). Medroxyprogesterone (medroxyprogesterone acetate 5–10 mg daily) taken 10 to 14 days per month is another option. Standard consideration for medical eligibility in prescribing these agents should be considered (see U.S. medical eligibility criteria for contraceptive use available at www.cdc.gov/reproductivehealth/unintendedpregnancy/usmec.htm). Combined formulations offer contraception, while cyclic progesterone does not. Both offer cyclic withdrawal bleeding. A Cochrane review did not find any RCTs comparing one to the other and therefore either are reasonable options [36].The levonorgestrel IUD is effective at treating AUB as well [31].Women may still experience intermittent vaginal bleeding or amenorrhea so it is less likely to result in cyclic withdrawal bleeding.

All of the above treatments provide the additional benefit of thinning the endometrium and preventing unopposed estrogen effect. This provides further protection the endometrial hyperplasia with chronic anovulatory cycles and unopposed estrogen [31].

In women with PCOS and associated metabolic conditions, first-line treatment is weight loss and other lifestyle interventions to improve or prevent other sequelae of the condition. Weight loss has been shown to reduce circulating androgen levels and increase ovulation. It has been shown to reduce glucose and lipid levels and hirsutism. Pregnancy rates increase as well. Weight loss achieved through medications and gastric bypass has similar effects. There is no special diet that has been shown to be more effective than another [32]. As little as a 5% weight reduction from baseline can improve PCOS symptoms [34,35].

Metformin is also commonly added to lifestyle modifications in women with PCOS to reduce risks for developing diabetes. There is little high quality evidence of added benefit above lifestyle modifications [34].Statin therapy can be considered in women with hyperlipidemia and PCOS [32].

For women with PCOS who desire to conceive, treatment should target increased ovulation. Pre-conception counseling and lifestyle modifications are again first line [32].Ovulation induction interventions carry increased risk of multiple gestation. For ovulation induction, clomiphene citrate is first line therapy. Metformin is commonly used as noted above to improve comorbidities associated with PCOS and can increase ovulation compared to placebo [37].However, RCTs do not support its use as first-line treatment of infertility treatment in PCOS. Clomiphene is 3 times more effective than metformin alone [32].

Medications can improve but often do not resolve hirsutism in women with PCOS. Combined hormonal contraceptives are commonly used off-label and no one type of pill has been shown to be superior. Anti-androgens are also off-label but empirically used. They can also improve lipid and other metabolic variables. They are all teratogenic and therefore should not be used in women who desire conception, and be used with effective contraceptives. Spironolactone is an androgen receptor antagonist. It takes months for effect. Some women will have improved menstrual frequency with this medication as well. Often adjunctive therapy such as eflornithine facial cream or laser therapy or a combination is needed to further treat hirsutism [32,35,38].

Follow-up

After discussion, the patient decides to adopt therapeutic lifestyle changes. She desires to get pregnant and does not opt for hormonal contraceptives at this time. She sees a nutritionist and begins calorie restriction and exercise. Three months later she has lost 20 pounds and feels “healthier.” Her lipid panel shows LDL of 125 and HDL of 43. Her triglycerides are now 160. Her blood pressure in the office is 118/78 mm Hg. She has lost “inches” around her middle. She has had more regular periods as well. She is still not pregnant so the physician asks her to begin tracking ovulation with cervical mucus evaluation and basal body temperature prior to considering further infertility evaluations. Three months after that she misses a period but is pleased to report a positive home pregnancy test.

Case 3—Breakthough Bleeding On Combined Hormonal Contraceptives 

A 28-year-old G0P0 in a monogamous relationship presents to her physician. She has been on oral contraceptive pills for 8 years. For the last 3 years she has been taking the pills on an extended cycle schedule. She normally takes an active pill daily for 3 cycles of pills (9 weeks), and then takes a 7-day pill-free week when she gets a menstrual period. This had been working fine until the last 6 months. She has noticed breakthrough spotting up to 2 weeks at a time during the 2nd and 3rd pack of pills.

• What is the approach to evaluation and treatment in this patient?

Bleeding in Women on Combined Hormonal Contraception

Many women are now using combined hormonal contraceptives on different schedules. Extended-cycle contraception has been shown to be as effective as the traditional 21/7 schedule of active pills/pill-free week. The FDA has approved several packaged extended-cycle contraceptives. Extended-cycle contraception decreases overall number of bleeding days and improves many menstrual-related symptoms [39].Breakthrough bleeding is the most common side effect of extended cycle contraception. It is classified as AUB-I (abnormal uterine bleeding—iatrogenic). It is most common in the first few months of use, and decreases as use continues. Up to 86% of women will have unscheduled bleeding during the first 3 months of use of extended cycle contraception, but this bleedingdecreases as use continues [40].

There is no consensus as to the underlying mechanism causing this abnormal bleeding. Most clinicians believe that it is related to the balance of estrogen/progestin in each combined hormonal contraceptive. Each woman reacts differently to this combination, making it difficult to predict who will have abnormal bleeding. In women who are beginning an extended-cycle regimen, reassurance is sufficient. Most abnormal bleeding will normalize within the first 2 to 3 months. Missed pills and smoking are consistently related to breakthrough bleeding in women who take combined oral contraceptive pills [41].In women who have previously had stable bleeding patterns and who present with new breakthrough bleeding, evaluation for secondary causes of bleeding may be considered (ie, urine hCG, TSH, STI cultures, evaluation for cervical cancer screening). A pelvic examination may help determine a possible secondary cause of bleeding, but is not necessary.

Treatment of unscheduled bleeding in women on extended-cycle contraception includes shortening the hormone-free interval and adding medications for prevention/treatment of bleeding episodes. The 7-day hormone-free interval in the context of low-dose hormonal contraception may be too long. One study demonstrated that a 7-day hormone-free interval was associated with a lack of pituitary-ovarian suppression, follicular development, and possible ovulation [42].A systematic review found that shortened hormone-free intervals decreased the amount of unscheduled bleeding [39].A small RCT (65 women) of continuous contraceptive ring users found that the group that removed the ring for 4 days during an episode of unscheduled bleeding, and then reinserted it had overall reduction in unscheduled bleeding [43].Some clinicians will also recommend trying a different pill formlation or a different schedule. There is no evidence to support this recommendation, but it can be helpful in some women.

Low-dose doxycycline (40 mg daily) for prevention of unscheduled bleeding shows promise [44].This low- dose doxycycline is also helpful to prevent more unscheduled bleeding in extended-cycle oral contraceptive users [44].However, an RCT found that traditional-dose doxycline (100 mg BID) taken for 5 days at the onset of a bleeding episode, did not decrease the amount or length of unscheduled bleeding [40].Neither estrogen dose [45]nor progestin dose [45]affected bleeding patterns. There is some suggestion based on a small study that women on pills with norethindrone may have less unscheduled bleeding than those who are on pills with levonorgestrel, but more research needs to be done before clinicians change practice [46].A Cochrane review looked at one small study that suggested third-generation progestins had more favorable bleeding profiles than second-generation progestins [47].

Follow-up

The physician investigates for secondary causes of the bleeding. The patient’s urine hCG, TSH, and prolactin levels are all normal. No fibroids or polyps are seen on ultrasound. The physician and patient discuss treatment options, including a low-dose doxycycline pill to help minimize bleeding, trying a different pill formulation, or use of naproxen during the bleeding episodes, but the patient does not want to take 2 pills every day. After further discussion, the patient decides she would like to change to the contraceptive ring with the plan of removing the ring for 4 days at the onset of any unscheduled bleeding. In a phone call 6 months later, the patient states that her unscheduled bleeding has been controlled.

Corresponding author: Sarina Schrager, MD, MS, Dept. of Family Medicine, University of Wisconsin School of Medicine and Public Health, 1100 Delaplaine Ct., Madison, WI 53715, [email protected].