Expert Commentary

Vaccines have been a lifesaving public health measure since 1000 CE, when the Chinese first used smallpox inoculations to induce immunity.¹ Work by pioneers such as Edward Jenner, Louis Pasteur, and Maurice Hilleman has averted countless millions of vaccine-preventable illnesses and deaths, and vaccines have become a routine part of health maintenance throughout the human life cycle.

Pregnant patients who receive vaccines often have an added benefit of protection provided to their infants through passive transfer of antibodies. Several vaccine platforms have been utilized in pregnancy with well-documented improvements in maternal and obstetric outcomes as well as improved neonatal outcomes in the first several months of life. 

Risks of COVID-19 in pregnancy

The COVID-19 pandemic placed a spotlight on medically at-risk groups. Pregnant women  are 3 times more likely to require admission to the intensive care unit, have increased requirement for extracorporeal membrane oxygenation treatment, and are up to 70% more likely to die than nonpregnant peers—and this risk increases with the presence of additional comorbidities.

In the case of COVID-19, vaccination trials that have shaped worldwide clinical practice unfortunately followed the historical trend of excluding pregnant patients from participation. This has required clinicians to guide their patients through the decision of whether or not to accept vaccination without having the same reassurances regarding safety and effectiveness afforded to their nonpregnant counterparts. With more than 86,000 pregnant women infected with COVID-19 through April 19, 2021, this lack of information regarding vaccine safety in pregnancy is a significant public health gap.²

COVID-19 vaccines

The current COVID-19 vaccines approved for use in the United States under an Emergency Use Authorization issued by the US Food and Drug Administration are nonreplicating and thus cannot cause infection in the mother or fetus. These are the Pfizer-BioNTech mRNA vaccine, the Moderna mRNA-1273 vaccine, and the Janssen Biotech Inc. monovalent vaccine. Furthermore, in animal studies that included the Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccines, no fetal, embryonal, female reproductive, or postnatal development safety concerns were demonstrated.

As of April 19, 2021, 94,335 pregnant women had received a COVID-19 vaccination, and 4,622 of these enrolled in the Centers for Disease Control and Prevention’s (CDC) V-safe Vaccine Pregnancy Registry.³ The data reported noted no unexpected pregnancy or infant outcomes related to COVID-19 vaccination in pregnancy. Adverse effects of the vaccine were similar to those in nonpregnant cohorts. Additionally, emerging data suggest passage of immunity to neonates, with maternal antibodies demonstrated in cord blood at time of delivery as well as in breast milk.⁴ To date, these data mainly have come from women immunized with the Moderna and Pfizer-BioNTech mRNA vaccines.

Counseling pregnant patients

Our counseling aligns with that of the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC’s Advisory Committee on Immunization Practices in that COVID-19 vaccination should not be withheld from pregnant patients or patients who want to become pregnant. In pregnant patients with comorbidities that place them at higher risk for severe COVID-19 infection, all available formulations of the COVID-19 vaccination should be strongly considered.

As evidence for vaccination safety continues to emerge, patients should continue to discuss their individual needs for vaccination in a shared decision-making format with their obstetric providers.

Vaccines have been a lifesaving public health measure since 1000 CE, when the Chinese first used smallpox inoculations to induce immunity.¹ Work by pioneers such as Edward Jenner, Louis Pasteur, and Maurice Hilleman has averted countless millions of vaccine-preventable illnesses and deaths, and vaccines have become a routine part of health maintenance throughout the human life cycle.

Pregnant patients who receive vaccines often have an added benefit of protection provided to their infants through passive transfer of antibodies. Several vaccine platforms have been utilized in pregnancy with well-documented improvements in maternal and obstetric outcomes as well as improved neonatal outcomes in the first several months of life. 

Risks of COVID-19 in pregnancy

The COVID-19 pandemic placed a spotlight on medically at-risk groups. Pregnant women  are 3 times more likely to require admission to the intensive care unit, have increased requirement for extracorporeal membrane oxygenation treatment, and are up to 70% more likely to die than nonpregnant peers—and this risk increases with the presence of additional comorbidities.

In the case of COVID-19, vaccination trials that have shaped worldwide clinical practice unfortunately followed the historical trend of excluding pregnant patients from participation. This has required clinicians to guide their patients through the decision of whether or not to accept vaccination without having the same reassurances regarding safety and effectiveness afforded to their nonpregnant counterparts. With more than 86,000 pregnant women infected with COVID-19 through April 19, 2021, this lack of information regarding vaccine safety in pregnancy is a significant public health gap.²

COVID-19 vaccines

The current COVID-19 vaccines approved for use in the United States under an Emergency Use Authorization issued by the US Food and Drug Administration are nonreplicating and thus cannot cause infection in the mother or fetus. These are the Pfizer-BioNTech mRNA vaccine, the Moderna mRNA-1273 vaccine, and the Janssen Biotech Inc. monovalent vaccine. Furthermore, in animal studies that included the Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccines, no fetal, embryonal, female reproductive, or postnatal development safety concerns were demonstrated.

As of April 19, 2021, 94,335 pregnant women had received a COVID-19 vaccination, and 4,622 of these enrolled in the Centers for Disease Control and Prevention’s (CDC) V-safe Vaccine Pregnancy Registry.³ The data reported noted no unexpected pregnancy or infant outcomes related to COVID-19 vaccination in pregnancy. Adverse effects of the vaccine were similar to those in nonpregnant cohorts. Additionally, emerging data suggest passage of immunity to neonates, with maternal antibodies demonstrated in cord blood at time of delivery as well as in breast milk.⁴ To date, these data mainly have come from women immunized with the Moderna and Pfizer-BioNTech mRNA vaccines.

Counseling pregnant patients

Our counseling aligns with that of the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC’s Advisory Committee on Immunization Practices in that COVID-19 vaccination should not be withheld from pregnant patients or patients who want to become pregnant. In pregnant patients with comorbidities that place them at higher risk for severe COVID-19 infection, all available formulations of the COVID-19 vaccination should be strongly considered.

As evidence for vaccination safety continues to emerge, patients should continue to discuss their individual needs for vaccination in a shared decision-making format with their obstetric providers.

Vaccines have been a lifesaving public health measure since 1000 CE, when the Chinese first used smallpox inoculations to induce immunity.¹ Work by pioneers such as Edward Jenner, Louis Pasteur, and Maurice Hilleman has averted countless millions of vaccine-preventable illnesses and deaths, and vaccines have become a routine part of health maintenance throughout the human life cycle.

Pregnant patients who receive vaccines often have an added benefit of protection provided to their infants through passive transfer of antibodies. Several vaccine platforms have been utilized in pregnancy with well-documented improvements in maternal and obstetric outcomes as well as improved neonatal outcomes in the first several months of life. 

Risks of COVID-19 in pregnancy

The COVID-19 pandemic placed a spotlight on medically at-risk groups. Pregnant women  are 3 times more likely to require admission to the intensive care unit, have increased requirement for extracorporeal membrane oxygenation treatment, and are up to 70% more likely to die than nonpregnant peers—and this risk increases with the presence of additional comorbidities.

In the case of COVID-19, vaccination trials that have shaped worldwide clinical practice unfortunately followed the historical trend of excluding pregnant patients from participation. This has required clinicians to guide their patients through the decision of whether or not to accept vaccination without having the same reassurances regarding safety and effectiveness afforded to their nonpregnant counterparts. With more than 86,000 pregnant women infected with COVID-19 through April 19, 2021, this lack of information regarding vaccine safety in pregnancy is a significant public health gap.²

COVID-19 vaccines

The current COVID-19 vaccines approved for use in the United States under an Emergency Use Authorization issued by the US Food and Drug Administration are nonreplicating and thus cannot cause infection in the mother or fetus. These are the Pfizer-BioNTech mRNA vaccine, the Moderna mRNA-1273 vaccine, and the Janssen Biotech Inc. monovalent vaccine. Furthermore, in animal studies that included the Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccines, no fetal, embryonal, female reproductive, or postnatal development safety concerns were demonstrated.

As of April 19, 2021, 94,335 pregnant women had received a COVID-19 vaccination, and 4,622 of these enrolled in the Centers for Disease Control and Prevention’s (CDC) V-safe Vaccine Pregnancy Registry.³ The data reported noted no unexpected pregnancy or infant outcomes related to COVID-19 vaccination in pregnancy. Adverse effects of the vaccine were similar to those in nonpregnant cohorts. Additionally, emerging data suggest passage of immunity to neonates, with maternal antibodies demonstrated in cord blood at time of delivery as well as in breast milk.⁴ To date, these data mainly have come from women immunized with the Moderna and Pfizer-BioNTech mRNA vaccines.

Counseling pregnant patients

Our counseling aligns with that of the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC’s Advisory Committee on Immunization Practices in that COVID-19 vaccination should not be withheld from pregnant patients or patients who want to become pregnant. In pregnant patients with comorbidities that place them at higher risk for severe COVID-19 infection, all available formulations of the COVID-19 vaccination should be strongly considered.

As evidence for vaccination safety continues to emerge, patients should continue to discuss their individual needs for vaccination in a shared decision-making format with their obstetric providers.

In December 2020, the US Food and Drug Administration’s Emergency Use Authorization of the first COVID-19 vaccine presented us with a new tactic in the war against SARS-COV-2—and a new dilemma for obstetricians. What we had learned about COVID-19 infection in pregnancy by that point was alarming. While the vast majority (>90%) of pregnant women who contract COVID-19 recover without requiring hospitalization, pregnant women are at increased risk for severe illness and mechanical ventilation when compared with their nonpregnant counterparts.¹ Vertical transmission to the fetus is a rare event, but the increased risk of preterm birth, miscarriage, and preeclampsia makes the fetus a second victim in many cases.² Moreover, much is still unknown about the long-term impact of severe illness on maternal and fetal health.

Gaining vaccine approval

The COVID-19 vaccine, with its high efficacy rates in the nonpregnant adult population, presents an opportunity to reduce maternal morbidity related to this devastating illness. But unlike other vaccines, such as the flu shot and TDAP, results from prospective studies on COVID-19 vaccination of expectant women are pending. Under the best of circumstances, gaining acceptance of any vaccine during pregnancy faces barriers such as vaccine hesitancy and a general concern from pregnant women about the effect of medical interventions on the fetus. There is no reason to expect that either the mRNA vaccines or the replication-incompetent adenovirus recombinant vector vaccine could cause harm to the developing fetus, but the fact that currently available COVID-19 vaccines use newer technologies complicates the decision for many women.

Nevertheless, what we do know now is much more than we did in December, particularly when it comes to the mRNA vaccines. To date, observational studies of women who received the mRNA vaccine in pregnancy have shown no increased risk of adverse maternal, fetal, or obstetric outcomes.³ Emerging data also indicate that antibodies to the SARS-CoV-2 spike protein—the target of all 3 vaccines—is present in cord blood, potentially protecting the infant in the first months of life from contracting COVID-19 if the mother receives the vaccine during pregnancy.^4,5

Our approach to counseling

How can we best help our patients navigate the risks and benefits of the COVID-19 vaccine? First, by acknowledging the obvious: We are in the midst of a pandemic with high rates of community spread, which makes COVID-19 different from any other vaccine-preventable disease at this time. Providing patients with a structure for making an educated decision is essential, taking into account (1) what we know about COVID-19 infection during pregnancy, (2) what we know about vaccine efficacy and safety to date, and (3) individual factors such as:

• The presence of comorbidities such as obesity, heart disease, respiratory disease, and diabetes.
• Potential exposures—“Do you have children in school or daycare? Do childcare providers or other workers come to your home? What is your occupation?”
• The ability to take precautions (social distancing, wearing a mask, etc)

All things considered, the decision to accept the COVID-19 vaccine or not ultimately belongs to the patient. Given disease prevalence and the latest information on vaccine safety in pregnancy, I have been advising my patients in the second trimester or beyond to receive the vaccine with the caveat that delaying the vaccine until the postpartum period is a completely valid alternative. The most important gift we can offer our patients is to arm them with the necessary information so that they can make the choice best for them and their family as we continue to fight this war on COVID-19.

In December 2020, the US Food and Drug Administration’s Emergency Use Authorization of the first COVID-19 vaccine presented us with a new tactic in the war against SARS-COV-2—and a new dilemma for obstetricians. What we had learned about COVID-19 infection in pregnancy by that point was alarming. While the vast majority (>90%) of pregnant women who contract COVID-19 recover without requiring hospitalization, pregnant women are at increased risk for severe illness and mechanical ventilation when compared with their nonpregnant counterparts.¹ Vertical transmission to the fetus is a rare event, but the increased risk of preterm birth, miscarriage, and preeclampsia makes the fetus a second victim in many cases.² Moreover, much is still unknown about the long-term impact of severe illness on maternal and fetal health.

Gaining vaccine approval

The COVID-19 vaccine, with its high efficacy rates in the nonpregnant adult population, presents an opportunity to reduce maternal morbidity related to this devastating illness. But unlike other vaccines, such as the flu shot and TDAP, results from prospective studies on COVID-19 vaccination of expectant women are pending. Under the best of circumstances, gaining acceptance of any vaccine during pregnancy faces barriers such as vaccine hesitancy and a general concern from pregnant women about the effect of medical interventions on the fetus. There is no reason to expect that either the mRNA vaccines or the replication-incompetent adenovirus recombinant vector vaccine could cause harm to the developing fetus, but the fact that currently available COVID-19 vaccines use newer technologies complicates the decision for many women.

Nevertheless, what we do know now is much more than we did in December, particularly when it comes to the mRNA vaccines. To date, observational studies of women who received the mRNA vaccine in pregnancy have shown no increased risk of adverse maternal, fetal, or obstetric outcomes.³ Emerging data also indicate that antibodies to the SARS-CoV-2 spike protein—the target of all 3 vaccines—is present in cord blood, potentially protecting the infant in the first months of life from contracting COVID-19 if the mother receives the vaccine during pregnancy.^4,5

Our approach to counseling

How can we best help our patients navigate the risks and benefits of the COVID-19 vaccine? First, by acknowledging the obvious: We are in the midst of a pandemic with high rates of community spread, which makes COVID-19 different from any other vaccine-preventable disease at this time. Providing patients with a structure for making an educated decision is essential, taking into account (1) what we know about COVID-19 infection during pregnancy, (2) what we know about vaccine efficacy and safety to date, and (3) individual factors such as:

• The presence of comorbidities such as obesity, heart disease, respiratory disease, and diabetes.
• Potential exposures—“Do you have children in school or daycare? Do childcare providers or other workers come to your home? What is your occupation?”
• The ability to take precautions (social distancing, wearing a mask, etc)

All things considered, the decision to accept the COVID-19 vaccine or not ultimately belongs to the patient. Given disease prevalence and the latest information on vaccine safety in pregnancy, I have been advising my patients in the second trimester or beyond to receive the vaccine with the caveat that delaying the vaccine until the postpartum period is a completely valid alternative. The most important gift we can offer our patients is to arm them with the necessary information so that they can make the choice best for them and their family as we continue to fight this war on COVID-19.

In December 2020, the US Food and Drug Administration’s Emergency Use Authorization of the first COVID-19 vaccine presented us with a new tactic in the war against SARS-COV-2—and a new dilemma for obstetricians. What we had learned about COVID-19 infection in pregnancy by that point was alarming. While the vast majority (>90%) of pregnant women who contract COVID-19 recover without requiring hospitalization, pregnant women are at increased risk for severe illness and mechanical ventilation when compared with their nonpregnant counterparts.¹ Vertical transmission to the fetus is a rare event, but the increased risk of preterm birth, miscarriage, and preeclampsia makes the fetus a second victim in many cases.² Moreover, much is still unknown about the long-term impact of severe illness on maternal and fetal health.

Gaining vaccine approval

The COVID-19 vaccine, with its high efficacy rates in the nonpregnant adult population, presents an opportunity to reduce maternal morbidity related to this devastating illness. But unlike other vaccines, such as the flu shot and TDAP, results from prospective studies on COVID-19 vaccination of expectant women are pending. Under the best of circumstances, gaining acceptance of any vaccine during pregnancy faces barriers such as vaccine hesitancy and a general concern from pregnant women about the effect of medical interventions on the fetus. There is no reason to expect that either the mRNA vaccines or the replication-incompetent adenovirus recombinant vector vaccine could cause harm to the developing fetus, but the fact that currently available COVID-19 vaccines use newer technologies complicates the decision for many women.

Nevertheless, what we do know now is much more than we did in December, particularly when it comes to the mRNA vaccines. To date, observational studies of women who received the mRNA vaccine in pregnancy have shown no increased risk of adverse maternal, fetal, or obstetric outcomes.³ Emerging data also indicate that antibodies to the SARS-CoV-2 spike protein—the target of all 3 vaccines—is present in cord blood, potentially protecting the infant in the first months of life from contracting COVID-19 if the mother receives the vaccine during pregnancy.^4,5

Our approach to counseling

How can we best help our patients navigate the risks and benefits of the COVID-19 vaccine? First, by acknowledging the obvious: We are in the midst of a pandemic with high rates of community spread, which makes COVID-19 different from any other vaccine-preventable disease at this time. Providing patients with a structure for making an educated decision is essential, taking into account (1) what we know about COVID-19 infection during pregnancy, (2) what we know about vaccine efficacy and safety to date, and (3) individual factors such as:

• The presence of comorbidities such as obesity, heart disease, respiratory disease, and diabetes.
• Potential exposures—“Do you have children in school or daycare? Do childcare providers or other workers come to your home? What is your occupation?”
• The ability to take precautions (social distancing, wearing a mask, etc)

All things considered, the decision to accept the COVID-19 vaccine or not ultimately belongs to the patient. Given disease prevalence and the latest information on vaccine safety in pregnancy, I have been advising my patients in the second trimester or beyond to receive the vaccine with the caveat that delaying the vaccine until the postpartum period is a completely valid alternative. The most important gift we can offer our patients is to arm them with the necessary information so that they can make the choice best for them and their family as we continue to fight this war on COVID-19.

CASE 34-year-old woman with lipid panel results from 1 year ago

A woman with no chronic medical conditions was seen by her gynecologist for a routine well-woman examination. She does not see another primary care provider. She is age 34 years and has a levonorgestrel intrauterine device that was placed after the birth of her second child 2 years prior. She does not take any other medications. She has never smoked and drinks a glass of wine with dinner a couple of times each week. She finds it challenging with her full-time job and her parental responsibilities with 2 young children to get regular exercise but otherwise is active. She does not have a family history of premature cardiovascular disease. Last year, during her prior well-woman examination, she had a fasting lipid panel: her low-density lipoprotein (LDL) was 102 mg/dL (reference range, ≤160 mg/dL), high-density lipoprotein (HDL) 52 mg/dL (reference range, ≥40 mg/dL), triglycerides 140 mg/dL (reference range, <160 mg/dL), and total cholesterol 182 mg/dL (reference range, <200 mg/dL).

During this visit, the patient’s vitals are normal (blood pressure 116/58) and her physical examination is unremarkable. Her physician orders routine labs to be checked, including a fasting lipid panel. She has to figure out when she will be able to get these labs drawn, as she needs to coordinate with her work and childcare schedules. A week later, she leaves work at 4:00 PM and picks up her young children (aged 2 and 4 years) from childcare, bringing them to the laboratory to have her blood drawn. Not only are her children cranky in the waiting room, but she is feeling tired as she hasn’t eaten all day because her physician told her she is supposed to be fasting. She has to pay for parking at the lot for the laboratory since it is connected to the medical center.

Was this lipid panel high value?

When and how often should we be checking lipid panels?

Do patients need to fast for these tests?
 

The potential benefits and costs of routine lipid panel screening

Hyperlipidemia is relatively prevalent, usually asymptomatic, and has been linked to cardiovascular outcomes. Thus, screening for lipid abnormalities is recommended to identify patients that would benefit from various interventions aimed at reducing cardiovascular disease risk, including lipid-lowering therapy.¹ High levels of LDL cholesterol and low levels of HDL cholesterol are important risk factors for coronary heart disease.

Lipid panels are widely available blood tests with modest monetary costs, generally ranging from about $10 to $100 in the outpatient setting. Of note, a 2014 study examining inpatient charges for this common laboratory test found that hospital charges in California ranged from about $10 to $10,000 for a lipid panel.² Despite the relatively low cost of each individual lipid panel, the aggregate costs to the health system of these frequently and widely performed tests are large. In fact, low-cost, high-volume health services, such as repeat cholesterol testing, account for the majority of unnecessary health spending in the United States, contributing nearly twice as much unnecessary cost as high-priced low-value services.³

To the patient, the cost is not only monetary. Some patients will need to take an additional hour or two off work as well as consider childcare, transportation, parking, and other mundane logistics to sit in a laboratory waiting room—a cost that may not be considered modest at all by the patient.^4,5

Therefore, like most services in health care, the answer to whether or not a lipid panel is high-value care is: it depends.⁵ In the correct circumstances, the test generally is regarded as high value due to well-documented potential benefits and low monetary costs. However, when performed unnecessarily—either in patient groups that are unlikely to benefit or at intervals that are too soon to add helpful information—then all that is left are the financial and psychosocial costs, which make this a low-value test in these scenarios. For this patient, this test contributed to inconvenience and mild hardships with essentially no benefit, thus would be considered low-value care.

Continue to: When should we perform lipid screening in low-risk women?

When should we perform lipid screening in low-risk women?

There are conflicting guidelines and opinions about at what age lipid screening should be routinely performed in adults. The United States Preventive Services Task Force (USPSTF) 2016 guidelines found “insufficient evidence that screening for dyslipidemia before age 40 years has an effect on either short- or longer-term cardiovascular outcomes.”⁶ Therefore, the USPSTF “recommends neither for nor against screening for dyslipidemia in this age group,” and instead encourages “clinicians to use their clinical judgment for [these] patients.”⁶

A common practice is to obtain a baseline lipid profile at the time of initiation of care with an adult primary care practitioner, if the patient was not previously screened, and to then determine subsequent testing based on these results and the patient’s risk factors for cardiovascular disease. For patients with normal lipid screening results and lower cardiovascular risk factors (no hypertension, diabetes mellitus, cigarette smoking, family history of premature coronary heart disease), experts suggest follow-up lipid screening be performed in men at age 35 and in women at age 45.⁷ Therefore, for this patient who had essentially a normal lipid panel a year prior, she should not have required repeat lipid testing until she is age 45.

As for how frequently subsequent lipid testing should be performed, the Centers for Disease Control and Prevention states, “most healthy adults should have their cholesterol checked every 4 to 6 years.”⁸ Those taking lipid-lowering medications or those with risk factors such as heart disease, diabetes, or concerning family history should have their cholesterol checked more frequently. If patients are near a threshold for treatment, some experts suggest repeating measurements every 3 years, but even in these settings, annual testing would be considered excessive.⁷

A standard lipid panel screen includes total cholesterol, LDL, HDL, and triglycerides. While a variety of assays have been developed that subfractionate lipoprotein particles based on size, density, or charge, these tests do not add value for low-risk patient screening and should only be used on an individualized basis for selected intermediate to high-risk patients. The American Society for Clinical Pathology released a Choosing Wisely recommendation that advises, “Do not routinely order expanded lipid panels (particle sizing, nuclear magnetic resonance) as screening tests for cardiovascular disease.”⁹

Do lipid panels need to be fasting?

For adults who are not taking lipid-lowering therapy, measurement of either a fasting or a nonfasting plasma lipid profile is effective for documenting baseline LDL and estimating cardiovascular risk.¹ In other words, nonfasting lipid testing is appropriate for most low-risk screening. Nonfasting testing generally is more convenient for patients; however, nonfasting lipid panels could result in elevated triglyceride levels. If an initial nonfasting lipid profile reveals a triglyceride level of 400 mg/dL or higher, then a repeat lipid profile in the fasting state should be performed for assessment of fasting triglyceride levels and baseline LDL.¹ Some patients may prefer to simply get a fasting lipid panel initially so that they do not run the risk of having to return for a second test, especially if they are at increased risk for high triglyceride levels (ie, if they are obese, have diabetes, or are taking medications such as steroids, which can increase triglyceride levels).

The bottom line

Some patients receive primary care directly from their gynecologist, and thus it is important for women’s health clinicians to be aware of appropriate cholesterol screening practices. While lipid panels may commonly be ordered routinely as part of annual health check-ups, the evidence suggests that this is an unnecessary practice that contributes to wasteful health spending at both individual and system levels; it also is an avoidable inconvenience for patients. It is unclear when lipid screening should be initiated for adult patients, but it seems reasonable to check baseline levels for a new patient who has not previously been screened. In low-risk patients with normal lipid panel levels, experts recommend initiating retesting at age 45 for women and obtaining repeat lipid levels no more than every 4 to 6 years. For most patients, nonfasting lipid levels will suffice for screening. Avoiding common unnecessary testing is an effective way to improve value for patients. ●

CASE 34-year-old woman with lipid panel results from 1 year ago

A woman with no chronic medical conditions was seen by her gynecologist for a routine well-woman examination. She does not see another primary care provider. She is age 34 years and has a levonorgestrel intrauterine device that was placed after the birth of her second child 2 years prior. She does not take any other medications. She has never smoked and drinks a glass of wine with dinner a couple of times each week. She finds it challenging with her full-time job and her parental responsibilities with 2 young children to get regular exercise but otherwise is active. She does not have a family history of premature cardiovascular disease. Last year, during her prior well-woman examination, she had a fasting lipid panel: her low-density lipoprotein (LDL) was 102 mg/dL (reference range, ≤160 mg/dL), high-density lipoprotein (HDL) 52 mg/dL (reference range, ≥40 mg/dL), triglycerides 140 mg/dL (reference range, <160 mg/dL), and total cholesterol 182 mg/dL (reference range, <200 mg/dL).

During this visit, the patient’s vitals are normal (blood pressure 116/58) and her physical examination is unremarkable. Her physician orders routine labs to be checked, including a fasting lipid panel. She has to figure out when she will be able to get these labs drawn, as she needs to coordinate with her work and childcare schedules. A week later, she leaves work at 4:00 PM and picks up her young children (aged 2 and 4 years) from childcare, bringing them to the laboratory to have her blood drawn. Not only are her children cranky in the waiting room, but she is feeling tired as she hasn’t eaten all day because her physician told her she is supposed to be fasting. She has to pay for parking at the lot for the laboratory since it is connected to the medical center.

Was this lipid panel high value?

When and how often should we be checking lipid panels?

Do patients need to fast for these tests?
 

The potential benefits and costs of routine lipid panel screening

Hyperlipidemia is relatively prevalent, usually asymptomatic, and has been linked to cardiovascular outcomes. Thus, screening for lipid abnormalities is recommended to identify patients that would benefit from various interventions aimed at reducing cardiovascular disease risk, including lipid-lowering therapy.¹ High levels of LDL cholesterol and low levels of HDL cholesterol are important risk factors for coronary heart disease.

Lipid panels are widely available blood tests with modest monetary costs, generally ranging from about $10 to $100 in the outpatient setting. Of note, a 2014 study examining inpatient charges for this common laboratory test found that hospital charges in California ranged from about $10 to $10,000 for a lipid panel.² Despite the relatively low cost of each individual lipid panel, the aggregate costs to the health system of these frequently and widely performed tests are large. In fact, low-cost, high-volume health services, such as repeat cholesterol testing, account for the majority of unnecessary health spending in the United States, contributing nearly twice as much unnecessary cost as high-priced low-value services.³

To the patient, the cost is not only monetary. Some patients will need to take an additional hour or two off work as well as consider childcare, transportation, parking, and other mundane logistics to sit in a laboratory waiting room—a cost that may not be considered modest at all by the patient.^4,5

Therefore, like most services in health care, the answer to whether or not a lipid panel is high-value care is: it depends.⁵ In the correct circumstances, the test generally is regarded as high value due to well-documented potential benefits and low monetary costs. However, when performed unnecessarily—either in patient groups that are unlikely to benefit or at intervals that are too soon to add helpful information—then all that is left are the financial and psychosocial costs, which make this a low-value test in these scenarios. For this patient, this test contributed to inconvenience and mild hardships with essentially no benefit, thus would be considered low-value care.

Continue to: When should we perform lipid screening in low-risk women?

When should we perform lipid screening in low-risk women?

There are conflicting guidelines and opinions about at what age lipid screening should be routinely performed in adults. The United States Preventive Services Task Force (USPSTF) 2016 guidelines found “insufficient evidence that screening for dyslipidemia before age 40 years has an effect on either short- or longer-term cardiovascular outcomes.”⁶ Therefore, the USPSTF “recommends neither for nor against screening for dyslipidemia in this age group,” and instead encourages “clinicians to use their clinical judgment for [these] patients.”⁶

A common practice is to obtain a baseline lipid profile at the time of initiation of care with an adult primary care practitioner, if the patient was not previously screened, and to then determine subsequent testing based on these results and the patient’s risk factors for cardiovascular disease. For patients with normal lipid screening results and lower cardiovascular risk factors (no hypertension, diabetes mellitus, cigarette smoking, family history of premature coronary heart disease), experts suggest follow-up lipid screening be performed in men at age 35 and in women at age 45.⁷ Therefore, for this patient who had essentially a normal lipid panel a year prior, she should not have required repeat lipid testing until she is age 45.

As for how frequently subsequent lipid testing should be performed, the Centers for Disease Control and Prevention states, “most healthy adults should have their cholesterol checked every 4 to 6 years.”⁸ Those taking lipid-lowering medications or those with risk factors such as heart disease, diabetes, or concerning family history should have their cholesterol checked more frequently. If patients are near a threshold for treatment, some experts suggest repeating measurements every 3 years, but even in these settings, annual testing would be considered excessive.⁷

A standard lipid panel screen includes total cholesterol, LDL, HDL, and triglycerides. While a variety of assays have been developed that subfractionate lipoprotein particles based on size, density, or charge, these tests do not add value for low-risk patient screening and should only be used on an individualized basis for selected intermediate to high-risk patients. The American Society for Clinical Pathology released a Choosing Wisely recommendation that advises, “Do not routinely order expanded lipid panels (particle sizing, nuclear magnetic resonance) as screening tests for cardiovascular disease.”⁹

Do lipid panels need to be fasting?

For adults who are not taking lipid-lowering therapy, measurement of either a fasting or a nonfasting plasma lipid profile is effective for documenting baseline LDL and estimating cardiovascular risk.¹ In other words, nonfasting lipid testing is appropriate for most low-risk screening. Nonfasting testing generally is more convenient for patients; however, nonfasting lipid panels could result in elevated triglyceride levels. If an initial nonfasting lipid profile reveals a triglyceride level of 400 mg/dL or higher, then a repeat lipid profile in the fasting state should be performed for assessment of fasting triglyceride levels and baseline LDL.¹ Some patients may prefer to simply get a fasting lipid panel initially so that they do not run the risk of having to return for a second test, especially if they are at increased risk for high triglyceride levels (ie, if they are obese, have diabetes, or are taking medications such as steroids, which can increase triglyceride levels).

The bottom line

Some patients receive primary care directly from their gynecologist, and thus it is important for women’s health clinicians to be aware of appropriate cholesterol screening practices. While lipid panels may commonly be ordered routinely as part of annual health check-ups, the evidence suggests that this is an unnecessary practice that contributes to wasteful health spending at both individual and system levels; it also is an avoidable inconvenience for patients. It is unclear when lipid screening should be initiated for adult patients, but it seems reasonable to check baseline levels for a new patient who has not previously been screened. In low-risk patients with normal lipid panel levels, experts recommend initiating retesting at age 45 for women and obtaining repeat lipid levels no more than every 4 to 6 years. For most patients, nonfasting lipid levels will suffice for screening. Avoiding common unnecessary testing is an effective way to improve value for patients. ●

CASE 34-year-old woman with lipid panel results from 1 year ago

A woman with no chronic medical conditions was seen by her gynecologist for a routine well-woman examination. She does not see another primary care provider. She is age 34 years and has a levonorgestrel intrauterine device that was placed after the birth of her second child 2 years prior. She does not take any other medications. She has never smoked and drinks a glass of wine with dinner a couple of times each week. She finds it challenging with her full-time job and her parental responsibilities with 2 young children to get regular exercise but otherwise is active. She does not have a family history of premature cardiovascular disease. Last year, during her prior well-woman examination, she had a fasting lipid panel: her low-density lipoprotein (LDL) was 102 mg/dL (reference range, ≤160 mg/dL), high-density lipoprotein (HDL) 52 mg/dL (reference range, ≥40 mg/dL), triglycerides 140 mg/dL (reference range, <160 mg/dL), and total cholesterol 182 mg/dL (reference range, <200 mg/dL).

During this visit, the patient’s vitals are normal (blood pressure 116/58) and her physical examination is unremarkable. Her physician orders routine labs to be checked, including a fasting lipid panel. She has to figure out when she will be able to get these labs drawn, as she needs to coordinate with her work and childcare schedules. A week later, she leaves work at 4:00 PM and picks up her young children (aged 2 and 4 years) from childcare, bringing them to the laboratory to have her blood drawn. Not only are her children cranky in the waiting room, but she is feeling tired as she hasn’t eaten all day because her physician told her she is supposed to be fasting. She has to pay for parking at the lot for the laboratory since it is connected to the medical center.

Was this lipid panel high value?

When and how often should we be checking lipid panels?

Do patients need to fast for these tests?
 

The potential benefits and costs of routine lipid panel screening

Hyperlipidemia is relatively prevalent, usually asymptomatic, and has been linked to cardiovascular outcomes. Thus, screening for lipid abnormalities is recommended to identify patients that would benefit from various interventions aimed at reducing cardiovascular disease risk, including lipid-lowering therapy.¹ High levels of LDL cholesterol and low levels of HDL cholesterol are important risk factors for coronary heart disease.

Lipid panels are widely available blood tests with modest monetary costs, generally ranging from about $10 to $100 in the outpatient setting. Of note, a 2014 study examining inpatient charges for this common laboratory test found that hospital charges in California ranged from about $10 to $10,000 for a lipid panel.² Despite the relatively low cost of each individual lipid panel, the aggregate costs to the health system of these frequently and widely performed tests are large. In fact, low-cost, high-volume health services, such as repeat cholesterol testing, account for the majority of unnecessary health spending in the United States, contributing nearly twice as much unnecessary cost as high-priced low-value services.³

To the patient, the cost is not only monetary. Some patients will need to take an additional hour or two off work as well as consider childcare, transportation, parking, and other mundane logistics to sit in a laboratory waiting room—a cost that may not be considered modest at all by the patient.^4,5

Therefore, like most services in health care, the answer to whether or not a lipid panel is high-value care is: it depends.⁵ In the correct circumstances, the test generally is regarded as high value due to well-documented potential benefits and low monetary costs. However, when performed unnecessarily—either in patient groups that are unlikely to benefit or at intervals that are too soon to add helpful information—then all that is left are the financial and psychosocial costs, which make this a low-value test in these scenarios. For this patient, this test contributed to inconvenience and mild hardships with essentially no benefit, thus would be considered low-value care.

Continue to: When should we perform lipid screening in low-risk women?

When should we perform lipid screening in low-risk women?

There are conflicting guidelines and opinions about at what age lipid screening should be routinely performed in adults. The United States Preventive Services Task Force (USPSTF) 2016 guidelines found “insufficient evidence that screening for dyslipidemia before age 40 years has an effect on either short- or longer-term cardiovascular outcomes.”⁶ Therefore, the USPSTF “recommends neither for nor against screening for dyslipidemia in this age group,” and instead encourages “clinicians to use their clinical judgment for [these] patients.”⁶

A common practice is to obtain a baseline lipid profile at the time of initiation of care with an adult primary care practitioner, if the patient was not previously screened, and to then determine subsequent testing based on these results and the patient’s risk factors for cardiovascular disease. For patients with normal lipid screening results and lower cardiovascular risk factors (no hypertension, diabetes mellitus, cigarette smoking, family history of premature coronary heart disease), experts suggest follow-up lipid screening be performed in men at age 35 and in women at age 45.⁷ Therefore, for this patient who had essentially a normal lipid panel a year prior, she should not have required repeat lipid testing until she is age 45.

As for how frequently subsequent lipid testing should be performed, the Centers for Disease Control and Prevention states, “most healthy adults should have their cholesterol checked every 4 to 6 years.”⁸ Those taking lipid-lowering medications or those with risk factors such as heart disease, diabetes, or concerning family history should have their cholesterol checked more frequently. If patients are near a threshold for treatment, some experts suggest repeating measurements every 3 years, but even in these settings, annual testing would be considered excessive.⁷

A standard lipid panel screen includes total cholesterol, LDL, HDL, and triglycerides. While a variety of assays have been developed that subfractionate lipoprotein particles based on size, density, or charge, these tests do not add value for low-risk patient screening and should only be used on an individualized basis for selected intermediate to high-risk patients. The American Society for Clinical Pathology released a Choosing Wisely recommendation that advises, “Do not routinely order expanded lipid panels (particle sizing, nuclear magnetic resonance) as screening tests for cardiovascular disease.”⁹

Do lipid panels need to be fasting?

For adults who are not taking lipid-lowering therapy, measurement of either a fasting or a nonfasting plasma lipid profile is effective for documenting baseline LDL and estimating cardiovascular risk.¹ In other words, nonfasting lipid testing is appropriate for most low-risk screening. Nonfasting testing generally is more convenient for patients; however, nonfasting lipid panels could result in elevated triglyceride levels. If an initial nonfasting lipid profile reveals a triglyceride level of 400 mg/dL or higher, then a repeat lipid profile in the fasting state should be performed for assessment of fasting triglyceride levels and baseline LDL.¹ Some patients may prefer to simply get a fasting lipid panel initially so that they do not run the risk of having to return for a second test, especially if they are at increased risk for high triglyceride levels (ie, if they are obese, have diabetes, or are taking medications such as steroids, which can increase triglyceride levels).

The bottom line

Some patients receive primary care directly from their gynecologist, and thus it is important for women’s health clinicians to be aware of appropriate cholesterol screening practices. While lipid panels may commonly be ordered routinely as part of annual health check-ups, the evidence suggests that this is an unnecessary practice that contributes to wasteful health spending at both individual and system levels; it also is an avoidable inconvenience for patients. It is unclear when lipid screening should be initiated for adult patients, but it seems reasonable to check baseline levels for a new patient who has not previously been screened. In low-risk patients with normal lipid panel levels, experts recommend initiating retesting at age 45 for women and obtaining repeat lipid levels no more than every 4 to 6 years. For most patients, nonfasting lipid levels will suffice for screening. Avoiding common unnecessary testing is an effective way to improve value for patients. ●

Gray KJ, Bordt EA, Atyeo C, et al. COVID-19 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol. 2021;S0002-9378(21)00187-3. doi: 10.1016/j.ajog.2021.03.023

EXPERT COMMENTARY

Pregnant women are among those at highest risk for severe disease and death from SARS-CoV-2 infection. However, exclusion of pregnant and lactating women from the initial COVID-19 vaccine trials has made counseling these patients challenging due to both the novelty of the vaccines themselves and the general lack of data in this vulnerable population. Data for the efficacy and risks of vaccination are needed to inform shared decision making between clinician and patient.

Details of the study

Gray and colleagues conducted a prospective cohort study of 84 pregnant, 31 lactating, and 16 nonpregnant women who received 1 of the 2 COVID-19 mRNA vaccines approved by the US Food and Drug Administration for emergency use authorization (BNT162b2 Pfizer/BioNTech or mRNA-1273 Moderna). The study’s primary objective was to evaluate the humoral immune response (antibody quantification) and adverse effects of these vaccines in the pregnant and lactating women compared with both nonpregnant women and a cohort of 37 women who had natural COVID-19 infection during pregnancy.

Antibody quantification from blood and breast milk was performed at 4 time points: V0, the first vaccine dose; V1, the second vaccine dose; V2, 2 to 6 weeks after the second vaccine dose; and at delivery. Umbilical cord blood also was collected from the subset of delivered patients (n = 13).

Results. The ultimately IgG-dominated antibody response to the vaccine in pregnant and lactating women was comparable to that in nonpregnant women, and all vaccine antibody responses were significantly higher than that in response to natural SARS-CoV-2 infection. IgG antibodies also were found in umbilical cord blood and breast milk, supporting the transfer of immunity to both the fetus and infant. There were no significant differences in adverse effects between pregnant and nonpregnant women.

Study strengths and limitations

This study’s main strength is that it demonstrated a similar increase in humoral immune response to the COVID-19 mRNA vaccines in a previously unstudied population of pregnant and lactating women, supporting the potential efficacy of the vaccines in this group at high risk for complications from SARS-CoV-2. Other data to support this include the increased vaccine antibody response compared with the antibody response after SARS-CoV-2 infection in pregnant women as well as the presence of maternal-infant transfer of antibodies via cord blood and breast milk. All of these are important data to inform patients and practitioners who are trying to make shared, informed decisions about a novel vaccine during a global pandemic.

The main limitation of this study is a limited patient population of mostly White, non-Hispanic, health care workers with few comorbidities and only 13 delivered vaccinated patients within the study period. Long-term immunity, immune responses other than antibody titers, and potential fetal effects also were not explored in this study. ●

Gray KJ, Bordt EA, Atyeo C, et al. COVID-19 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol. 2021;S0002-9378(21)00187-3. doi: 10.1016/j.ajog.2021.03.023

EXPERT COMMENTARY

Pregnant women are among those at highest risk for severe disease and death from SARS-CoV-2 infection. However, exclusion of pregnant and lactating women from the initial COVID-19 vaccine trials has made counseling these patients challenging due to both the novelty of the vaccines themselves and the general lack of data in this vulnerable population. Data for the efficacy and risks of vaccination are needed to inform shared decision making between clinician and patient.

Details of the study

Gray and colleagues conducted a prospective cohort study of 84 pregnant, 31 lactating, and 16 nonpregnant women who received 1 of the 2 COVID-19 mRNA vaccines approved by the US Food and Drug Administration for emergency use authorization (BNT162b2 Pfizer/BioNTech or mRNA-1273 Moderna). The study’s primary objective was to evaluate the humoral immune response (antibody quantification) and adverse effects of these vaccines in the pregnant and lactating women compared with both nonpregnant women and a cohort of 37 women who had natural COVID-19 infection during pregnancy.

Antibody quantification from blood and breast milk was performed at 4 time points: V0, the first vaccine dose; V1, the second vaccine dose; V2, 2 to 6 weeks after the second vaccine dose; and at delivery. Umbilical cord blood also was collected from the subset of delivered patients (n = 13).

Results. The ultimately IgG-dominated antibody response to the vaccine in pregnant and lactating women was comparable to that in nonpregnant women, and all vaccine antibody responses were significantly higher than that in response to natural SARS-CoV-2 infection. IgG antibodies also were found in umbilical cord blood and breast milk, supporting the transfer of immunity to both the fetus and infant. There were no significant differences in adverse effects between pregnant and nonpregnant women.

Study strengths and limitations

This study’s main strength is that it demonstrated a similar increase in humoral immune response to the COVID-19 mRNA vaccines in a previously unstudied population of pregnant and lactating women, supporting the potential efficacy of the vaccines in this group at high risk for complications from SARS-CoV-2. Other data to support this include the increased vaccine antibody response compared with the antibody response after SARS-CoV-2 infection in pregnant women as well as the presence of maternal-infant transfer of antibodies via cord blood and breast milk. All of these are important data to inform patients and practitioners who are trying to make shared, informed decisions about a novel vaccine during a global pandemic.

The main limitation of this study is a limited patient population of mostly White, non-Hispanic, health care workers with few comorbidities and only 13 delivered vaccinated patients within the study period. Long-term immunity, immune responses other than antibody titers, and potential fetal effects also were not explored in this study. ●

Gray KJ, Bordt EA, Atyeo C, et al. COVID-19 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol. 2021;S0002-9378(21)00187-3. doi: 10.1016/j.ajog.2021.03.023

EXPERT COMMENTARY

Pregnant women are among those at highest risk for severe disease and death from SARS-CoV-2 infection. However, exclusion of pregnant and lactating women from the initial COVID-19 vaccine trials has made counseling these patients challenging due to both the novelty of the vaccines themselves and the general lack of data in this vulnerable population. Data for the efficacy and risks of vaccination are needed to inform shared decision making between clinician and patient.

Details of the study

Gray and colleagues conducted a prospective cohort study of 84 pregnant, 31 lactating, and 16 nonpregnant women who received 1 of the 2 COVID-19 mRNA vaccines approved by the US Food and Drug Administration for emergency use authorization (BNT162b2 Pfizer/BioNTech or mRNA-1273 Moderna). The study’s primary objective was to evaluate the humoral immune response (antibody quantification) and adverse effects of these vaccines in the pregnant and lactating women compared with both nonpregnant women and a cohort of 37 women who had natural COVID-19 infection during pregnancy.

Antibody quantification from blood and breast milk was performed at 4 time points: V0, the first vaccine dose; V1, the second vaccine dose; V2, 2 to 6 weeks after the second vaccine dose; and at delivery. Umbilical cord blood also was collected from the subset of delivered patients (n = 13).

Results. The ultimately IgG-dominated antibody response to the vaccine in pregnant and lactating women was comparable to that in nonpregnant women, and all vaccine antibody responses were significantly higher than that in response to natural SARS-CoV-2 infection. IgG antibodies also were found in umbilical cord blood and breast milk, supporting the transfer of immunity to both the fetus and infant. There were no significant differences in adverse effects between pregnant and nonpregnant women.

Study strengths and limitations

This study’s main strength is that it demonstrated a similar increase in humoral immune response to the COVID-19 mRNA vaccines in a previously unstudied population of pregnant and lactating women, supporting the potential efficacy of the vaccines in this group at high risk for complications from SARS-CoV-2. Other data to support this include the increased vaccine antibody response compared with the antibody response after SARS-CoV-2 infection in pregnant women as well as the presence of maternal-infant transfer of antibodies via cord blood and breast milk. All of these are important data to inform patients and practitioners who are trying to make shared, informed decisions about a novel vaccine during a global pandemic.

The main limitation of this study is a limited patient population of mostly White, non-Hispanic, health care workers with few comorbidities and only 13 delivered vaccinated patients within the study period. Long-term immunity, immune responses other than antibody titers, and potential fetal effects also were not explored in this study. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384:630-642. doi: 10.1056/NEJMoa2008283

Expert Commentary

By age 50, approximately 70% of White women and 80% of Black women will have uterine fibroids.¹ Of these, about 25% will have symptoms—most often including heavy menstrual bleeding,² and associated pain the second most common symptom.³ First-line treatment has traditionally been hormonal contraceptives. Injectable gonadotropin-releasing hormone (GnRH) antagonist like leuprolide acetate have been commonly employed, although their actual approved indication is “for concomitant use with iron therapy for preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (fibroids).”⁴ Recently, an oral GnRH antagonist, elagolix, combined with estrogen and progestogen, was approved for treatment of uterine fibroids for up to 24 months. However, it is dosed twice per day because of its short half-life and results in a loss of bone mineral density at 1 year.^5,6

Details of the studies

Al-Hendy and colleagues report on two double-blind 24-week phase 3 trials involving women with heavy menstrual bleeding associated with fibroids. There were just under 400 women in each trial. There was a 1:1:1 randomization to: placebo, once-daily oral relugolix 40 mg with 1 mg estradiol and 0.5 mg norethindrone acetate, or oral relugolix by itself for 12 weeks followed by the combination for 12 weeks (referred to as the “delayed relugolix combination therapy” arm).

Results. The primary end point was the percentage of patients who had a volume of menstrual blood loss less than 80 mL and a ≥50% reduction in blood loss volume as measured by the alkaline hematin method. The baseline blood loss in these studies ranged from approximately 210–250 mL. Secondary end points included amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, uterine volume, and the largest fibroid volume.

In trials one and two, 73% and 71% of patients in the relugolix combination groups, respectively, achieved the primary endpoint, compared with 19% and 15% in the placebo groups (P <.001). In addition, all secondary endpoints except largest fibroid volume were significantly improved versus placebo. Adverse events, including any change in bone mineral density, were no different between the combination and placebo groups. The delayed combination groups did have more hot flashes and diminished bone density compared with both the placebo and combination groups.

Strengths and weaknesses

The studies appropriately enrolled women with a mean age of 41–42 years and a mean BMI >30 kg/m², and more than 50% were African American. Thus, the samples are adequately representative of the type of population most likely to have fibroids and associated symptoms. The results showed the advantages of built-in “add back therapy” with estrogen plus progestogen, as the vasomotor symptoms and bone loss that treatment with a GnRH antagonist alone produces were reduced.

Although the trials were only conducted for 24 weeks, efficacy was seen as early as 4 weeks, and was clearly maintained throughout the full trials—and there is no scientific reason to assume it would not be maintained indefinitely. However, one cannot make a similar assumption about long-term safety. As another GnRH antagonist, with a shorter half-life requiring twice-daily-dosing with add back therapy, has been approved for use for 2 years, it is likely that the once-daily formulation of combination relugolix will be approved for this timeframe as well. Still, with patients’ mean age of 41–42 years, what will clinicians do after 2-year treatment? Clearly, study of long-term safety would be valuable. ●

Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384:630-642. doi: 10.1056/NEJMoa2008283

Expert Commentary

By age 50, approximately 70% of White women and 80% of Black women will have uterine fibroids.¹ Of these, about 25% will have symptoms—most often including heavy menstrual bleeding,² and associated pain the second most common symptom.³ First-line treatment has traditionally been hormonal contraceptives. Injectable gonadotropin-releasing hormone (GnRH) antagonist like leuprolide acetate have been commonly employed, although their actual approved indication is “for concomitant use with iron therapy for preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (fibroids).”⁴ Recently, an oral GnRH antagonist, elagolix, combined with estrogen and progestogen, was approved for treatment of uterine fibroids for up to 24 months. However, it is dosed twice per day because of its short half-life and results in a loss of bone mineral density at 1 year.^5,6

Details of the studies

Al-Hendy and colleagues report on two double-blind 24-week phase 3 trials involving women with heavy menstrual bleeding associated with fibroids. There were just under 400 women in each trial. There was a 1:1:1 randomization to: placebo, once-daily oral relugolix 40 mg with 1 mg estradiol and 0.5 mg norethindrone acetate, or oral relugolix by itself for 12 weeks followed by the combination for 12 weeks (referred to as the “delayed relugolix combination therapy” arm).

Results. The primary end point was the percentage of patients who had a volume of menstrual blood loss less than 80 mL and a ≥50% reduction in blood loss volume as measured by the alkaline hematin method. The baseline blood loss in these studies ranged from approximately 210–250 mL. Secondary end points included amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, uterine volume, and the largest fibroid volume.

In trials one and two, 73% and 71% of patients in the relugolix combination groups, respectively, achieved the primary endpoint, compared with 19% and 15% in the placebo groups (P <.001). In addition, all secondary endpoints except largest fibroid volume were significantly improved versus placebo. Adverse events, including any change in bone mineral density, were no different between the combination and placebo groups. The delayed combination groups did have more hot flashes and diminished bone density compared with both the placebo and combination groups.

Strengths and weaknesses

The studies appropriately enrolled women with a mean age of 41–42 years and a mean BMI >30 kg/m², and more than 50% were African American. Thus, the samples are adequately representative of the type of population most likely to have fibroids and associated symptoms. The results showed the advantages of built-in “add back therapy” with estrogen plus progestogen, as the vasomotor symptoms and bone loss that treatment with a GnRH antagonist alone produces were reduced.

Although the trials were only conducted for 24 weeks, efficacy was seen as early as 4 weeks, and was clearly maintained throughout the full trials—and there is no scientific reason to assume it would not be maintained indefinitely. However, one cannot make a similar assumption about long-term safety. As another GnRH antagonist, with a shorter half-life requiring twice-daily-dosing with add back therapy, has been approved for use for 2 years, it is likely that the once-daily formulation of combination relugolix will be approved for this timeframe as well. Still, with patients’ mean age of 41–42 years, what will clinicians do after 2-year treatment? Clearly, study of long-term safety would be valuable. ●

Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384:630-642. doi: 10.1056/NEJMoa2008283

Expert Commentary

By age 50, approximately 70% of White women and 80% of Black women will have uterine fibroids.¹ Of these, about 25% will have symptoms—most often including heavy menstrual bleeding,² and associated pain the second most common symptom.³ First-line treatment has traditionally been hormonal contraceptives. Injectable gonadotropin-releasing hormone (GnRH) antagonist like leuprolide acetate have been commonly employed, although their actual approved indication is “for concomitant use with iron therapy for preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (fibroids).”⁴ Recently, an oral GnRH antagonist, elagolix, combined with estrogen and progestogen, was approved for treatment of uterine fibroids for up to 24 months. However, it is dosed twice per day because of its short half-life and results in a loss of bone mineral density at 1 year.^5,6

Details of the studies

Al-Hendy and colleagues report on two double-blind 24-week phase 3 trials involving women with heavy menstrual bleeding associated with fibroids. There were just under 400 women in each trial. There was a 1:1:1 randomization to: placebo, once-daily oral relugolix 40 mg with 1 mg estradiol and 0.5 mg norethindrone acetate, or oral relugolix by itself for 12 weeks followed by the combination for 12 weeks (referred to as the “delayed relugolix combination therapy” arm).

Results. The primary end point was the percentage of patients who had a volume of menstrual blood loss less than 80 mL and a ≥50% reduction in blood loss volume as measured by the alkaline hematin method. The baseline blood loss in these studies ranged from approximately 210–250 mL. Secondary end points included amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, uterine volume, and the largest fibroid volume.

In trials one and two, 73% and 71% of patients in the relugolix combination groups, respectively, achieved the primary endpoint, compared with 19% and 15% in the placebo groups (P <.001). In addition, all secondary endpoints except largest fibroid volume were significantly improved versus placebo. Adverse events, including any change in bone mineral density, were no different between the combination and placebo groups. The delayed combination groups did have more hot flashes and diminished bone density compared with both the placebo and combination groups.

Strengths and weaknesses

The studies appropriately enrolled women with a mean age of 41–42 years and a mean BMI >30 kg/m², and more than 50% were African American. Thus, the samples are adequately representative of the type of population most likely to have fibroids and associated symptoms. The results showed the advantages of built-in “add back therapy” with estrogen plus progestogen, as the vasomotor symptoms and bone loss that treatment with a GnRH antagonist alone produces were reduced.

Although the trials were only conducted for 24 weeks, efficacy was seen as early as 4 weeks, and was clearly maintained throughout the full trials—and there is no scientific reason to assume it would not be maintained indefinitely. However, one cannot make a similar assumption about long-term safety. As another GnRH antagonist, with a shorter half-life requiring twice-daily-dosing with add back therapy, has been approved for use for 2 years, it is likely that the once-daily formulation of combination relugolix will be approved for this timeframe as well. Still, with patients’ mean age of 41–42 years, what will clinicians do after 2-year treatment? Clearly, study of long-term safety would be valuable. ●

Women with endometriosis often present for medical care for one or more of the following health issues: pelvic pain, infertility, and/or an adnexal cyst (endometrioma). For women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis, hormone therapy is often necessary to achieve maximal long-term reduction in pain and optimize health. I focus on opportunities to optimize hormonal treatment of endometriosis in this editorial.

When plan A is not working, move expeditiously to plan B

Cyclic or continuous combination estrogen-progestin contraceptives are commonly prescribed to treat pelvic pain caused by endometriosis. Although endometriosis pain may initially improve with estrogen-progestin contraceptives, many women on this medication will eventually report that they have worsening pelvic pain that adversely impacts their daily activities. Surprisingly, clinicians often continue to prescribe estrogen-progestin contraceptives even after the patient reports that the treatment is not effective, and their pain continues to be bothersome.

Patients benefit when they have access to the full range of hormone treatments that have been approved by the FDA for the treatment of moderate to severe pelvic pain caused by endometriosis (TABLE). In the situation where an estrogen-progestin contraceptive is no longer effective at reducing the pelvic pain, I will often offer the patient the option of norethindrone acetate (NEA) or elagolix treatment. My experience is that stopping the estrogen-progestin contraceptive and starting NEA or elagolix will result in a significant decrease in pain symptoms and improvement in the patient’s quality of life.

Continue to: Norethindrone acetate...

NEA 5 mg daily is approved by the FDA to treat endometriosis.¹ NEA was approved at a time when large controlled clinical trials were not routinely required for a medicine to be approved. The data to support NEA treatment of pelvic pain caused by endometriosis is based on cohort studies. In a study of 194 women, median age 21 years with moderate to severe pelvic pain and surgically proven endometriosis, the effect of NEA on pelvic pain was explored.² The initial dose of NEA was 5 mg daily. If the patient did not achieve a reduction in pelvic pain and amenorrhea on the NEA dose of 5 mg daily, the dose was increased by 2.5 mg every 2 weeks, up to a maximum of 15 mg, until amenorrhea and/or a decrease in pelvic pain was achieved. Ninety-five percent of the women in this cohort had previously been treated with an estrogen-progestin contraceptive or a GnRH antagonist and had discontinued those medications because of inadequate control of pelvic pain or because of side effects of the medication.

In this large cohort, 65% of women reported significant improvement in pelvic pain, with a median pain score of 5 before treatment and 0 following NEA treatment. About 55% of the women reported no side effects. The most commonly reported side effects were weight gain (16%; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%). (In this study women could report more than one side effect.)

In another cohort study of 52 women with pelvic pain and surgically confirmed endometriosis, NEA treatment resulted in pain relief in 94% of the women.³ Breakthrough bleeding was a common side effect, reported by 58% of participants. The investigators concluded that NEA treatment was a “cost-effective alternative with relatively mild side effects in the treatment of symptomatic endometriosis.” A conclusion which I endorse.

NEA has been reported to effectively treat ovarian endometriomas and rectovaginal endometriosis.^4,5 In a cohort of 18 women who had previously had the surgical resection of an ovarian endometriosis cyst and had postoperative recurrence of pelvic pain and ovarian endometriosis, treatment was initiated with an escalating NEA regimen.⁴ Treatment was initiated with NEA 5 mg daily, with the dosage increased every 2 weeks by 2.5 mg until amenorrhea was established. Most women achieved amenorrhea with NEA 5 mg daily, and 89% had reduced pelvic pain. The investigators reported complete regression of the endometriosis cyst(s) in 74% of the women. In my experience, NEA does not result in complete regression of endometriosis cysts, but it does cause a reduction in cyst diameter and total volume.

In a retrospective cohort study, 61 women with pelvic pain and rectovaginal endometriosis had 5 years of treatment with NEA 2.5 mg or 5.0 mg daily.⁵ NEA treatment resulted in a decrease in dysmenorrhea, deep dyspareunia, and dyschezia. The most common side effects attributed to NEA treatment were weight gain (30%), vaginal bleeding (23%), decreased libido (11%), headache (9%), bloating or swelling (8%), depression (7%), and acne (5%). In women who had sequential imaging studies, NEA treatment resulted in a decrease in rectovaginal lesion volume, stable disease volume, or an increase in lesion volume in 56%, 32%, and 12% of the women, respectively. The investigators concluded that for women with rectovaginal endometriosis, NEA treatment is a low-cost option for long-term treatment.

In my practice, I do not prescribe NEA at doses greater than 5 mg daily. There are case reports that NEA at a dose of ≥10 mg daily is associated with the development of a hepatic adenoma,⁶ elevated liver transaminase concentration,⁷ and jaundice.⁸ If NEA 5 mg daily is not effective in controlling pelvic pain caused by endometriosis, I stop the NEA and start a GnRH analogue, most often elagolix.

NEA 5 mg is not FDA approved as a contraceptive. However, norethindrone 0.35 mg daily, also known as the “mini-pill”, is approved as a progestin-only contraceptive.⁹ NEA is rapidly and completely deacetylated to norethindrone, and the disposition of oral NEA is indistinguishable from that of norethindrone.¹ Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg has contraceptive properties if taken daily.

Continue to: Elagolix...

Elagolix

Elagolix is FDA approved for the treatment of pelvic pain caused by endometriosis. I reviewed the key studies resulting in FDA approval in the November 2018 issue of OBG Management.¹⁰

In the Elaris Endometriosis-I study, 872 women with endometriosis and pelvic pain were randomly assigned to treatment with 1 of 2 doses of elagolix (high-dose [200 mg twice daily] and low-dose [150 mg once daily]) or placebo.¹¹ After 3 months of therapy, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). After 3 months of therapy, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.01 low-dose elagolix vs placebo and P<.001 high-dose elagolix vs placebo).

Hot flashes that were severe enough to be reported as an adverse event by the study participants were reported by 42%, 24%, and 7% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups. Bone density was measured at baseline and after 6 months of treatment. Lumbar bone density changes were -2.61%, -0.32%, and +0.47% and hip femoral neck bone density changes were -1.89%, -0.39%, and +0.02% in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively.

Another large clinical trial of elagolix for the treatment of pelvic pain caused by endometriosis, Elaris EM-II, involving 817 women, produced results very similar to those reported in Elaris EM-I. The elagolix continuation studies, Elaris EM-III and -IV, demonstrated efficacy and safety of elagolix through 12 months of treatment.¹²

In my 2018 review,¹⁰ I noted that elagolix dose adjustment can be utilized to attempt to achieve maximal pain relief with minimal vasomotor symptoms. Elagolix at 200 mg twice daily produces a mean estradiol concentration of 12 pg/mL, whereas elagolix at 150 mg daily resulted in a mean estradiol concentration of 41 pg/mL.¹³ The estrogen threshold hypothesis posits that in women with endometriosis a stable estradiol concentration of 20 to 30 pg/mL is often associated with decreased pain and fewer vasomotor events.¹⁴ To achieve the target estradiol range of 20 to 30 pg/mL, I often initiate elagolix treatment with 200 mg twice daily. This enables a rapid onset of amenorrhea and a reduction in pelvic pain. Once amenorrhea has been achieved and a decrease in pelvic pain has occurred, I adjust the dose downward to 200 mg twice daily on even calendar days of each month and 200 mg once daily on odd calendar days each month. Some women will have continued pain relief and amenorrhea when the dose is further decreased to 200 mg once daily. If bothersome bleeding recurs and/or pain symptoms increase in severity, the dose can be increased to 200 mg twice daily or an alternating regimen of 200 mg twice daily and 200 mg once daily, every 2 days. An alternative to dose adjustment is to combine elagolix with NEA, which can reduce the severity of hot flashes and reduce bone loss caused by hypoestrogenism.^15,16

Health insurers and pharmacy benefits managers may require a prior authorization before approving and dispensing elagolix. The prior authorization process can be burdensome for clinicians, consuming limited healthcare resources, contributing to burnout and frustrating patients.¹⁷ Elagolix is less expensive than depot-leuprolide acetate and nafarelin nasal spray and somewhat more expensive than a goserelin implant.^18,19

Elagolix is not approved as a contraceptive. In the Elaris EM-I and -II trials women were advised to use 2 forms of contraception, although pregnancies did occur. There were 6 pregnancies among 475 women taking elagolix 150 mg daily and 2 pregnancies among 477 women taking elagolix 200 mg twice daily.²⁰ Women taking elagolix should be advised to use a contraceptive, but not an estrogen-progestin contraceptive.

Continue to: Do not use opioids to treat chronic pelvic pain caused by endometriosis...

Do not use opioids to treat chronic pelvic pain caused by endometriosis

One of the greatest public health tragedies of our era is the opioid misuse epidemic. Hundreds of thousands of deaths have been caused by opioid misuse. The Centers for Disease Control and Prevention reported that for the 12-month period ending in May 2020, there were 81,000 opioid-related deaths, the greatest number ever reported in a 12-month period.²¹ Many authorities believe that in the United States opioid medications have been over-prescribed, contributing to the opioid misuse epidemic. There is little evidence that chronic pelvic pain is optimally managed by chronic treatment with an opioid.^22,23 Prescribing opioids to vulnerable individuals to treat chronic pelvic pain may result in opioid dependency and adversely affect the patient’s health. It is best to pledge not to prescribe an opioid medication for a woman with chronic pelvic pain caused by endometriosis. In situations when pelvic pain is difficult to control with hormonal therapy and nonopioid pain medications, referral to a specialty pain practice may be warranted.

Post–conservative surgery hormone treatment reduces pelvic pain recurrence

In a meta-analysis of 14 studies that reported on endometriosis recurrence rates following conservative surgery, recurrence (defined as recurrent pelvic pain or an imaging study showing recurrent endometriosis) was significantly reduced with the use of hormone treatment compared with expectant management or placebo treatment.²⁴ The postoperative relative risk of endometriosis recurrence was reduced by 83% with progestin treatment, 64% with estrogen-progestin contraceptive treatment, and 38% with GnRH analogue treatment. Overall, the number of patients that needed to be treated to prevent one endometriosis recurrence was 10, assuming a recurrence rate of 25% in the placebo treatment or expectant management groups.

For women with pelvic pain caused by endometriosis who develop a recurrence of pelvic pain while on postoperative hormone treatment, it is important for the prescribing clinician to be flexible and consider changing the hormone regimen. For example, if a postoperative patient is treated with a continuous estrogen-progestin contraceptive and develops recurrent pain, I will stop the contraceptive and initiate treatment with either NEA or elagolix.

Capitalize on opportunities to improve the medical care of women with endometriosis

Early diagnosis of endometriosis can be facilitated by recognizing that the condition is a common cause of moderate to severe dysmenorrhea. In 5 studies involving 1,187 women, the mean length of time from onset of pelvic pain symptoms to diagnosis of endometriosis was 8.6 years.²⁵ If a woman with pelvic pain caused by endometriosis has not had sufficient pain relief with one brand of continuous estrogen-progestin contraceptive, it is best not to prescribe an alternative brand but rather to switch to a progestin-only treatment or a GnRH antagonist. If plan A is not working, move expeditiously to plan B. ●

Women with endometriosis often present for medical care for one or more of the following health issues: pelvic pain, infertility, and/or an adnexal cyst (endometrioma). For women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis, hormone therapy is often necessary to achieve maximal long-term reduction in pain and optimize health. I focus on opportunities to optimize hormonal treatment of endometriosis in this editorial.

When plan A is not working, move expeditiously to plan B

Cyclic or continuous combination estrogen-progestin contraceptives are commonly prescribed to treat pelvic pain caused by endometriosis. Although endometriosis pain may initially improve with estrogen-progestin contraceptives, many women on this medication will eventually report that they have worsening pelvic pain that adversely impacts their daily activities. Surprisingly, clinicians often continue to prescribe estrogen-progestin contraceptives even after the patient reports that the treatment is not effective, and their pain continues to be bothersome.

Patients benefit when they have access to the full range of hormone treatments that have been approved by the FDA for the treatment of moderate to severe pelvic pain caused by endometriosis (TABLE). In the situation where an estrogen-progestin contraceptive is no longer effective at reducing the pelvic pain, I will often offer the patient the option of norethindrone acetate (NEA) or elagolix treatment. My experience is that stopping the estrogen-progestin contraceptive and starting NEA or elagolix will result in a significant decrease in pain symptoms and improvement in the patient’s quality of life.

Continue to: Norethindrone acetate...

NEA 5 mg daily is approved by the FDA to treat endometriosis.¹ NEA was approved at a time when large controlled clinical trials were not routinely required for a medicine to be approved. The data to support NEA treatment of pelvic pain caused by endometriosis is based on cohort studies. In a study of 194 women, median age 21 years with moderate to severe pelvic pain and surgically proven endometriosis, the effect of NEA on pelvic pain was explored.² The initial dose of NEA was 5 mg daily. If the patient did not achieve a reduction in pelvic pain and amenorrhea on the NEA dose of 5 mg daily, the dose was increased by 2.5 mg every 2 weeks, up to a maximum of 15 mg, until amenorrhea and/or a decrease in pelvic pain was achieved. Ninety-five percent of the women in this cohort had previously been treated with an estrogen-progestin contraceptive or a GnRH antagonist and had discontinued those medications because of inadequate control of pelvic pain or because of side effects of the medication.

In this large cohort, 65% of women reported significant improvement in pelvic pain, with a median pain score of 5 before treatment and 0 following NEA treatment. About 55% of the women reported no side effects. The most commonly reported side effects were weight gain (16%; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%). (In this study women could report more than one side effect.)

In another cohort study of 52 women with pelvic pain and surgically confirmed endometriosis, NEA treatment resulted in pain relief in 94% of the women.³ Breakthrough bleeding was a common side effect, reported by 58% of participants. The investigators concluded that NEA treatment was a “cost-effective alternative with relatively mild side effects in the treatment of symptomatic endometriosis.” A conclusion which I endorse.

NEA has been reported to effectively treat ovarian endometriomas and rectovaginal endometriosis.^4,5 In a cohort of 18 women who had previously had the surgical resection of an ovarian endometriosis cyst and had postoperative recurrence of pelvic pain and ovarian endometriosis, treatment was initiated with an escalating NEA regimen.⁴ Treatment was initiated with NEA 5 mg daily, with the dosage increased every 2 weeks by 2.5 mg until amenorrhea was established. Most women achieved amenorrhea with NEA 5 mg daily, and 89% had reduced pelvic pain. The investigators reported complete regression of the endometriosis cyst(s) in 74% of the women. In my experience, NEA does not result in complete regression of endometriosis cysts, but it does cause a reduction in cyst diameter and total volume.

In a retrospective cohort study, 61 women with pelvic pain and rectovaginal endometriosis had 5 years of treatment with NEA 2.5 mg or 5.0 mg daily.⁵ NEA treatment resulted in a decrease in dysmenorrhea, deep dyspareunia, and dyschezia. The most common side effects attributed to NEA treatment were weight gain (30%), vaginal bleeding (23%), decreased libido (11%), headache (9%), bloating or swelling (8%), depression (7%), and acne (5%). In women who had sequential imaging studies, NEA treatment resulted in a decrease in rectovaginal lesion volume, stable disease volume, or an increase in lesion volume in 56%, 32%, and 12% of the women, respectively. The investigators concluded that for women with rectovaginal endometriosis, NEA treatment is a low-cost option for long-term treatment.

In my practice, I do not prescribe NEA at doses greater than 5 mg daily. There are case reports that NEA at a dose of ≥10 mg daily is associated with the development of a hepatic adenoma,⁶ elevated liver transaminase concentration,⁷ and jaundice.⁸ If NEA 5 mg daily is not effective in controlling pelvic pain caused by endometriosis, I stop the NEA and start a GnRH analogue, most often elagolix.

NEA 5 mg is not FDA approved as a contraceptive. However, norethindrone 0.35 mg daily, also known as the “mini-pill”, is approved as a progestin-only contraceptive.⁹ NEA is rapidly and completely deacetylated to norethindrone, and the disposition of oral NEA is indistinguishable from that of norethindrone.¹ Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg has contraceptive properties if taken daily.

Continue to: Elagolix...

Elagolix

Elagolix is FDA approved for the treatment of pelvic pain caused by endometriosis. I reviewed the key studies resulting in FDA approval in the November 2018 issue of OBG Management.¹⁰

In the Elaris Endometriosis-I study, 872 women with endometriosis and pelvic pain were randomly assigned to treatment with 1 of 2 doses of elagolix (high-dose [200 mg twice daily] and low-dose [150 mg once daily]) or placebo.¹¹ After 3 months of therapy, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). After 3 months of therapy, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.01 low-dose elagolix vs placebo and P<.001 high-dose elagolix vs placebo).

Hot flashes that were severe enough to be reported as an adverse event by the study participants were reported by 42%, 24%, and 7% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups. Bone density was measured at baseline and after 6 months of treatment. Lumbar bone density changes were -2.61%, -0.32%, and +0.47% and hip femoral neck bone density changes were -1.89%, -0.39%, and +0.02% in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively.

Another large clinical trial of elagolix for the treatment of pelvic pain caused by endometriosis, Elaris EM-II, involving 817 women, produced results very similar to those reported in Elaris EM-I. The elagolix continuation studies, Elaris EM-III and -IV, demonstrated efficacy and safety of elagolix through 12 months of treatment.¹²

In my 2018 review,¹⁰ I noted that elagolix dose adjustment can be utilized to attempt to achieve maximal pain relief with minimal vasomotor symptoms. Elagolix at 200 mg twice daily produces a mean estradiol concentration of 12 pg/mL, whereas elagolix at 150 mg daily resulted in a mean estradiol concentration of 41 pg/mL.¹³ The estrogen threshold hypothesis posits that in women with endometriosis a stable estradiol concentration of 20 to 30 pg/mL is often associated with decreased pain and fewer vasomotor events.¹⁴ To achieve the target estradiol range of 20 to 30 pg/mL, I often initiate elagolix treatment with 200 mg twice daily. This enables a rapid onset of amenorrhea and a reduction in pelvic pain. Once amenorrhea has been achieved and a decrease in pelvic pain has occurred, I adjust the dose downward to 200 mg twice daily on even calendar days of each month and 200 mg once daily on odd calendar days each month. Some women will have continued pain relief and amenorrhea when the dose is further decreased to 200 mg once daily. If bothersome bleeding recurs and/or pain symptoms increase in severity, the dose can be increased to 200 mg twice daily or an alternating regimen of 200 mg twice daily and 200 mg once daily, every 2 days. An alternative to dose adjustment is to combine elagolix with NEA, which can reduce the severity of hot flashes and reduce bone loss caused by hypoestrogenism.^15,16

Health insurers and pharmacy benefits managers may require a prior authorization before approving and dispensing elagolix. The prior authorization process can be burdensome for clinicians, consuming limited healthcare resources, contributing to burnout and frustrating patients.¹⁷ Elagolix is less expensive than depot-leuprolide acetate and nafarelin nasal spray and somewhat more expensive than a goserelin implant.^18,19

Elagolix is not approved as a contraceptive. In the Elaris EM-I and -II trials women were advised to use 2 forms of contraception, although pregnancies did occur. There were 6 pregnancies among 475 women taking elagolix 150 mg daily and 2 pregnancies among 477 women taking elagolix 200 mg twice daily.²⁰ Women taking elagolix should be advised to use a contraceptive, but not an estrogen-progestin contraceptive.

Continue to: Do not use opioids to treat chronic pelvic pain caused by endometriosis...

Do not use opioids to treat chronic pelvic pain caused by endometriosis

One of the greatest public health tragedies of our era is the opioid misuse epidemic. Hundreds of thousands of deaths have been caused by opioid misuse. The Centers for Disease Control and Prevention reported that for the 12-month period ending in May 2020, there were 81,000 opioid-related deaths, the greatest number ever reported in a 12-month period.²¹ Many authorities believe that in the United States opioid medications have been over-prescribed, contributing to the opioid misuse epidemic. There is little evidence that chronic pelvic pain is optimally managed by chronic treatment with an opioid.^22,23 Prescribing opioids to vulnerable individuals to treat chronic pelvic pain may result in opioid dependency and adversely affect the patient’s health. It is best to pledge not to prescribe an opioid medication for a woman with chronic pelvic pain caused by endometriosis. In situations when pelvic pain is difficult to control with hormonal therapy and nonopioid pain medications, referral to a specialty pain practice may be warranted.

Post–conservative surgery hormone treatment reduces pelvic pain recurrence

In a meta-analysis of 14 studies that reported on endometriosis recurrence rates following conservative surgery, recurrence (defined as recurrent pelvic pain or an imaging study showing recurrent endometriosis) was significantly reduced with the use of hormone treatment compared with expectant management or placebo treatment.²⁴ The postoperative relative risk of endometriosis recurrence was reduced by 83% with progestin treatment, 64% with estrogen-progestin contraceptive treatment, and 38% with GnRH analogue treatment. Overall, the number of patients that needed to be treated to prevent one endometriosis recurrence was 10, assuming a recurrence rate of 25% in the placebo treatment or expectant management groups.

For women with pelvic pain caused by endometriosis who develop a recurrence of pelvic pain while on postoperative hormone treatment, it is important for the prescribing clinician to be flexible and consider changing the hormone regimen. For example, if a postoperative patient is treated with a continuous estrogen-progestin contraceptive and develops recurrent pain, I will stop the contraceptive and initiate treatment with either NEA or elagolix.

Capitalize on opportunities to improve the medical care of women with endometriosis

Early diagnosis of endometriosis can be facilitated by recognizing that the condition is a common cause of moderate to severe dysmenorrhea. In 5 studies involving 1,187 women, the mean length of time from onset of pelvic pain symptoms to diagnosis of endometriosis was 8.6 years.²⁵ If a woman with pelvic pain caused by endometriosis has not had sufficient pain relief with one brand of continuous estrogen-progestin contraceptive, it is best not to prescribe an alternative brand but rather to switch to a progestin-only treatment or a GnRH antagonist. If plan A is not working, move expeditiously to plan B. ●

Women with endometriosis often present for medical care for one or more of the following health issues: pelvic pain, infertility, and/or an adnexal cyst (endometrioma). For women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis, hormone therapy is often necessary to achieve maximal long-term reduction in pain and optimize health. I focus on opportunities to optimize hormonal treatment of endometriosis in this editorial.

When plan A is not working, move expeditiously to plan B

Cyclic or continuous combination estrogen-progestin contraceptives are commonly prescribed to treat pelvic pain caused by endometriosis. Although endometriosis pain may initially improve with estrogen-progestin contraceptives, many women on this medication will eventually report that they have worsening pelvic pain that adversely impacts their daily activities. Surprisingly, clinicians often continue to prescribe estrogen-progestin contraceptives even after the patient reports that the treatment is not effective, and their pain continues to be bothersome.

Patients benefit when they have access to the full range of hormone treatments that have been approved by the FDA for the treatment of moderate to severe pelvic pain caused by endometriosis (TABLE). In the situation where an estrogen-progestin contraceptive is no longer effective at reducing the pelvic pain, I will often offer the patient the option of norethindrone acetate (NEA) or elagolix treatment. My experience is that stopping the estrogen-progestin contraceptive and starting NEA or elagolix will result in a significant decrease in pain symptoms and improvement in the patient’s quality of life.

Continue to: Norethindrone acetate...

NEA 5 mg daily is approved by the FDA to treat endometriosis.¹ NEA was approved at a time when large controlled clinical trials were not routinely required for a medicine to be approved. The data to support NEA treatment of pelvic pain caused by endometriosis is based on cohort studies. In a study of 194 women, median age 21 years with moderate to severe pelvic pain and surgically proven endometriosis, the effect of NEA on pelvic pain was explored.² The initial dose of NEA was 5 mg daily. If the patient did not achieve a reduction in pelvic pain and amenorrhea on the NEA dose of 5 mg daily, the dose was increased by 2.5 mg every 2 weeks, up to a maximum of 15 mg, until amenorrhea and/or a decrease in pelvic pain was achieved. Ninety-five percent of the women in this cohort had previously been treated with an estrogen-progestin contraceptive or a GnRH antagonist and had discontinued those medications because of inadequate control of pelvic pain or because of side effects of the medication.

In this large cohort, 65% of women reported significant improvement in pelvic pain, with a median pain score of 5 before treatment and 0 following NEA treatment. About 55% of the women reported no side effects. The most commonly reported side effects were weight gain (16%; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%). (In this study women could report more than one side effect.)

In another cohort study of 52 women with pelvic pain and surgically confirmed endometriosis, NEA treatment resulted in pain relief in 94% of the women.³ Breakthrough bleeding was a common side effect, reported by 58% of participants. The investigators concluded that NEA treatment was a “cost-effective alternative with relatively mild side effects in the treatment of symptomatic endometriosis.” A conclusion which I endorse.

NEA has been reported to effectively treat ovarian endometriomas and rectovaginal endometriosis.^4,5 In a cohort of 18 women who had previously had the surgical resection of an ovarian endometriosis cyst and had postoperative recurrence of pelvic pain and ovarian endometriosis, treatment was initiated with an escalating NEA regimen.⁴ Treatment was initiated with NEA 5 mg daily, with the dosage increased every 2 weeks by 2.5 mg until amenorrhea was established. Most women achieved amenorrhea with NEA 5 mg daily, and 89% had reduced pelvic pain. The investigators reported complete regression of the endometriosis cyst(s) in 74% of the women. In my experience, NEA does not result in complete regression of endometriosis cysts, but it does cause a reduction in cyst diameter and total volume.

In a retrospective cohort study, 61 women with pelvic pain and rectovaginal endometriosis had 5 years of treatment with NEA 2.5 mg or 5.0 mg daily.⁵ NEA treatment resulted in a decrease in dysmenorrhea, deep dyspareunia, and dyschezia. The most common side effects attributed to NEA treatment were weight gain (30%), vaginal bleeding (23%), decreased libido (11%), headache (9%), bloating or swelling (8%), depression (7%), and acne (5%). In women who had sequential imaging studies, NEA treatment resulted in a decrease in rectovaginal lesion volume, stable disease volume, or an increase in lesion volume in 56%, 32%, and 12% of the women, respectively. The investigators concluded that for women with rectovaginal endometriosis, NEA treatment is a low-cost option for long-term treatment.

In my practice, I do not prescribe NEA at doses greater than 5 mg daily. There are case reports that NEA at a dose of ≥10 mg daily is associated with the development of a hepatic adenoma,⁶ elevated liver transaminase concentration,⁷ and jaundice.⁸ If NEA 5 mg daily is not effective in controlling pelvic pain caused by endometriosis, I stop the NEA and start a GnRH analogue, most often elagolix.

NEA 5 mg is not FDA approved as a contraceptive. However, norethindrone 0.35 mg daily, also known as the “mini-pill”, is approved as a progestin-only contraceptive.⁹ NEA is rapidly and completely deacetylated to norethindrone, and the disposition of oral NEA is indistinguishable from that of norethindrone.¹ Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg has contraceptive properties if taken daily.

Continue to: Elagolix...

Elagolix

Elagolix is FDA approved for the treatment of pelvic pain caused by endometriosis. I reviewed the key studies resulting in FDA approval in the November 2018 issue of OBG Management.¹⁰

In the Elaris Endometriosis-I study, 872 women with endometriosis and pelvic pain were randomly assigned to treatment with 1 of 2 doses of elagolix (high-dose [200 mg twice daily] and low-dose [150 mg once daily]) or placebo.¹¹ After 3 months of therapy, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). After 3 months of therapy, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.01 low-dose elagolix vs placebo and P<.001 high-dose elagolix vs placebo).

Hot flashes that were severe enough to be reported as an adverse event by the study participants were reported by 42%, 24%, and 7% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups. Bone density was measured at baseline and after 6 months of treatment. Lumbar bone density changes were -2.61%, -0.32%, and +0.47% and hip femoral neck bone density changes were -1.89%, -0.39%, and +0.02% in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively.

Another large clinical trial of elagolix for the treatment of pelvic pain caused by endometriosis, Elaris EM-II, involving 817 women, produced results very similar to those reported in Elaris EM-I. The elagolix continuation studies, Elaris EM-III and -IV, demonstrated efficacy and safety of elagolix through 12 months of treatment.¹²

In my 2018 review,¹⁰ I noted that elagolix dose adjustment can be utilized to attempt to achieve maximal pain relief with minimal vasomotor symptoms. Elagolix at 200 mg twice daily produces a mean estradiol concentration of 12 pg/mL, whereas elagolix at 150 mg daily resulted in a mean estradiol concentration of 41 pg/mL.¹³ The estrogen threshold hypothesis posits that in women with endometriosis a stable estradiol concentration of 20 to 30 pg/mL is often associated with decreased pain and fewer vasomotor events.¹⁴ To achieve the target estradiol range of 20 to 30 pg/mL, I often initiate elagolix treatment with 200 mg twice daily. This enables a rapid onset of amenorrhea and a reduction in pelvic pain. Once amenorrhea has been achieved and a decrease in pelvic pain has occurred, I adjust the dose downward to 200 mg twice daily on even calendar days of each month and 200 mg once daily on odd calendar days each month. Some women will have continued pain relief and amenorrhea when the dose is further decreased to 200 mg once daily. If bothersome bleeding recurs and/or pain symptoms increase in severity, the dose can be increased to 200 mg twice daily or an alternating regimen of 200 mg twice daily and 200 mg once daily, every 2 days. An alternative to dose adjustment is to combine elagolix with NEA, which can reduce the severity of hot flashes and reduce bone loss caused by hypoestrogenism.^15,16

Health insurers and pharmacy benefits managers may require a prior authorization before approving and dispensing elagolix. The prior authorization process can be burdensome for clinicians, consuming limited healthcare resources, contributing to burnout and frustrating patients.¹⁷ Elagolix is less expensive than depot-leuprolide acetate and nafarelin nasal spray and somewhat more expensive than a goserelin implant.^18,19

Elagolix is not approved as a contraceptive. In the Elaris EM-I and -II trials women were advised to use 2 forms of contraception, although pregnancies did occur. There were 6 pregnancies among 475 women taking elagolix 150 mg daily and 2 pregnancies among 477 women taking elagolix 200 mg twice daily.²⁰ Women taking elagolix should be advised to use a contraceptive, but not an estrogen-progestin contraceptive.

Continue to: Do not use opioids to treat chronic pelvic pain caused by endometriosis...

Do not use opioids to treat chronic pelvic pain caused by endometriosis

One of the greatest public health tragedies of our era is the opioid misuse epidemic. Hundreds of thousands of deaths have been caused by opioid misuse. The Centers for Disease Control and Prevention reported that for the 12-month period ending in May 2020, there were 81,000 opioid-related deaths, the greatest number ever reported in a 12-month period.²¹ Many authorities believe that in the United States opioid medications have been over-prescribed, contributing to the opioid misuse epidemic. There is little evidence that chronic pelvic pain is optimally managed by chronic treatment with an opioid.^22,23 Prescribing opioids to vulnerable individuals to treat chronic pelvic pain may result in opioid dependency and adversely affect the patient’s health. It is best to pledge not to prescribe an opioid medication for a woman with chronic pelvic pain caused by endometriosis. In situations when pelvic pain is difficult to control with hormonal therapy and nonopioid pain medications, referral to a specialty pain practice may be warranted.

Post–conservative surgery hormone treatment reduces pelvic pain recurrence

In a meta-analysis of 14 studies that reported on endometriosis recurrence rates following conservative surgery, recurrence (defined as recurrent pelvic pain or an imaging study showing recurrent endometriosis) was significantly reduced with the use of hormone treatment compared with expectant management or placebo treatment.²⁴ The postoperative relative risk of endometriosis recurrence was reduced by 83% with progestin treatment, 64% with estrogen-progestin contraceptive treatment, and 38% with GnRH analogue treatment. Overall, the number of patients that needed to be treated to prevent one endometriosis recurrence was 10, assuming a recurrence rate of 25% in the placebo treatment or expectant management groups.

For women with pelvic pain caused by endometriosis who develop a recurrence of pelvic pain while on postoperative hormone treatment, it is important for the prescribing clinician to be flexible and consider changing the hormone regimen. For example, if a postoperative patient is treated with a continuous estrogen-progestin contraceptive and develops recurrent pain, I will stop the contraceptive and initiate treatment with either NEA or elagolix.

Capitalize on opportunities to improve the medical care of women with endometriosis

Early diagnosis of endometriosis can be facilitated by recognizing that the condition is a common cause of moderate to severe dysmenorrhea. In 5 studies involving 1,187 women, the mean length of time from onset of pelvic pain symptoms to diagnosis of endometriosis was 8.6 years.²⁵ If a woman with pelvic pain caused by endometriosis has not had sufficient pain relief with one brand of continuous estrogen-progestin contraceptive, it is best not to prescribe an alternative brand but rather to switch to a progestin-only treatment or a GnRH antagonist. If plan A is not working, move expeditiously to plan B. ●

There are no currently US Food and Drug Administration (FDA)-approved therapies for testosterone use in women. Its use by clinicians is through dose modification of FDA-approved therapies for men, or preparations created by compounding pharmacies. Recently, several professional organizations, including the American College of Obstetricians and Gynecologists (ACOG), North American Menopause Society, International Society for the Study of Women’s Sexual Health, and the International Society for Sexual Medicine, convened an expert panel to develop a global position statement on testosterone therapy for women.¹ In this roundtable for OBG Management, moderated by Mickey Karram, MD, several experts discuss this position statement as well as the overall clinical advantages and drawbacks of using testosterone in women.

Testosterone indications

Mickey Karram, MD: For which indications do you prescribe testosterone supplementation in women?

Lauren Streicher, MD: I offer systemic testosterone therapy to postmenopausal women who have hypoactive sexual desire disorder (HSDD) and low serum testosterone levels, with one caveat—it is important that the patient’s reported distressing lack of libido is not explained by another condition or circumstance. Many women present reporting low libido but, on further questioning, it is typically revealed that dyspareunia precipitated their loss of interest in sex. It is normal to not want to do something that is painful. In addition, low libido can often be explained by chronic disease, such as diabetes, cancer, or clinical depression.

Some medications, including selective serotonin reuptake inhibitors (SSRIs), frequently cause a decline in sexual interest. Finally, psychosocial and partner issues may be the culprit.

James Simon, MD, CCP, NCMP, IF: Much of the beneficial data for testosterone’s use is for sexual function in postmenopausal women.² Female sexual dysfunction is highly prevalent among women during the postmenopause.³ Androgen levels progressively decrease throughout adult life in all women, so the postmenopausal additional lack of estrogen has a recognized effect on genitourinary health. There is evidence that the insufficiency of androgens as well as estrogens after menopause can lead to genitourinary symptoms of menopause (GSM).⁴

Testosterone also is used for increasing strength, lean muscle mass, bone mineral density, and sense of well-being.⁵

Rebecca Glaser, MD: I consider testosterone supplementation in my clinical practice in both premenopausal and postmenopausal women for symptoms of androgen/hormone deficiency, including diminished sense of well-being; dysphoric mood; anxiety; irritability; fatigue; decreased libido, sexual activity, or pleasure; vasomotor instability; bone loss; decreased muscle strength; insomnia; changes in cognition; memory loss; urinary symptoms; incontinence; vaginal atrophy and dryness; and joint and muscular pain. We also have shown through preliminary and short-term data and case studies that testosterone therapy has a potential beneficial effect on migraine headaches, as well as active breast cancers in both premenopausal and postmenopausal women.^6-10

Continue to: What is appropriate bloodwork?...

Dr. Karram: Do you obtain blood work before initiating testosterone treatment? If so, what tests do you order and what testosterone levels are considered to be normal for premenopausal and postmenopausal women?

Dr. Streicher: Unlike estrogen, which is predictably low in a postmenopausal woman, serum testosterone (T) levels are highly variable because of the adrenal component. Ovarian testosterone production does not cease at the same time as estrogen production. So I do obtain total and free T levels, prior to initiating treatment. Having said that, it has been well established that T levels correlate poorly with level of sexual interest, and there is no specific blood level that can be used to differentiate women with and without sexual dysfunction. We all have patients who have nonexistent T levels and have a very healthy libido, and other women with sky-high levels who have no libido. But it is useful to know levels prior to initiating therapy to be able to monitor levels throughout treatment. Also, if levels are in the premenopausal physiologic range, not only is she unlikely to respond but she is also at risk for developing androgenic adverse effects, such as acne and hair growth. In general, a low free T level (even if it is in the normal postmenopausal range) in a clinical setting of HSDD supports supplementation.

The assessment and interpretation of T levels can be challenging, particularly as the majority of testosterone is protein-bound and biologically inactive. Free T levels (the biologically active testosterone) in many labs are unreliable and need to be calculated.

In addition to total and free T, I check levels of sex hormone-binding globulin (SHBG), the protein that binds testosterone and renders it biologically inactive. If someone has high SHBG levels and is taking an oral estrogen, simply switching to a transdermal estrogen will result in decreased SHBG and increased free T.

Levels of total and free T vary from lab to lab, so it is best to be familiar with those ranges and then be consistent in which lab you choose.

Dr. Glaser: Although I personally do order blood work on most patients (T, free T, estradiol, complete blood count, thyroid-stimulating hormone, and follicle-stimulating hormone), after 15 years of research and publishing data on testosterone implants, I do not believe that T levels are absolutely necessary or even beneficial in most cases. It rarely changes management in my patients.

As Lauren said, it is well known that T levels do not correlate with androgen deficiency symptoms or clinical conditions caused by androgen deficiency. If a patient has symptoms of androgen deficiency, a trial of testosterone therapy should be given.

T levels are not a valid marker of tissue exposure in women, reflecting less than 20% of total androgen activity. The major source of testosterone in pre and postmenopausal women is the local intracrine production of testosterone from the adrenal precursor steroids dehydroepiandrosterone (DHEA) and androstenedione, which would not be reflected in T levels.

In our study involving 300 women, we found no relationship between baseline T levels, presenting symptoms, or response to therapy.⁶ Premenopausal and postmenopausal women had similar baseline T levels and similar response to therapy. Even women with baseline T levels in the mid-range responded to therapy.

Some of the most controversial topics in treating women with testosterone are related to dosing and T levels throughout therapy. Guideline authors often use the terms ‘physiologic dosing’ and ‘physiologic ranges’ when making recommendations for therapy. Although “physiologic” sounds appropriate/ scientific, these rigid opinions/recommendations are not evidence based. There are no data supporting the use of endogenous T ranges to guide dosing or monitor testosterone therapy.

The decision to initiate testosterone therapy is a clinical decision between the doctor and the patient based on the patient’s symptomatology, which is the therapeutic endpoint. Testosterone therapy must be done with adequate doses determined by clinical effect (benefits) versus side effects or adverse events (risks). T levels may be helpful, along with clinical evaluation when troubleshooting.

Utilizing data from thousands of patients, we have developed serum ranges for testosterone implants.¹¹ Even so, no two patients are the same, nor do they respond to therapy the same. It is always a clinical decision.

Continue to: Dr. Simon...

Dr. Simon: In the recent global consensus statement on testosterone use,¹ the experts were in agreement that “no cut-off blood level can be used for any measured circulating androgen to differentiate women with and without sexual dysfunction.” They give their recommendation a C, and I agree that testosterone supplementation, with specific dosage levels, are a clinical decision.

Before initiating testosterone therapy, it is recommended that liver function and fasting lipids are assessed, as liver disease and hyperlipidemia are contraindications to treatment. These levels should be monitored twice in the first year and annually thereafter while the patient is taking testosterone. Breast and pelvic examinations, mammography, and evaluation for abnormal bleeding should be performed as well as the blood tests.¹² These recommendations are focused on safety not efficacy.

Administration route

Dr. Karram: How do you administer testosterone, and why?

Dr. Streicher: As there are no FDA approved testosterone products for women, clinicians must determine the dosage and route of delivery based on published clinical trials.

Dr. Glaser: I treat patients with subcutaneous pellet implants. The implants provide consistent and continuous delivery of therapeutic amounts of testosterone. There is a reason testosterone pellets have been used for more than 80 years and are more popular now than ever—they work. The insertion procedure is simple and takes about 2 minutes. The treatment is cost-effective, avoids first pass, has no adverse effect on the liver or clotting factors, and there is no transference. Decades of data support both the efficacy and safety of testosterone implants.⁶ However, testosterone implants are not regulated by the FDA and all patients are required to sign a consent informing them of off-label use, benefits, and risks of testosterone implant therapy.

Dr. Simon: I think the consent is important, as there is no package labeling to warn of possible side effects.

Dr. Streicher: Oral testosterone therapy, because of its first pass through the liver and association with adverse lipid profiles with negative effects on high- and low-density lipoprotein cholesterol levels, is not recommended. I prefer a transdermal approach. Pellets, implants, and injections have the potential to result in supraphysiologic blood concentrations. It must be emphasized that the goal of treatment is to approximate premenopausal physiologic levels. More is not better; excessive levels do not demonstrate a greater sexual response and are in fact more likely to have a negative impact due to androgenic side effects.

In most clinical trials, a 300 mg/d testosterone patch was effective, but these patches are not commercially available so I rely on transdermal gel from a compounding pharmacy. The typical dose needed to raise levels into the high to normal range for most women is 2.5 mg up to 5 mg per day of testosterone 1%, which translates to roughly 1 mL. Many pharmacies provide a dispenser, which allots the appropriate dose. Alternatively, I instruct the patient to place a dollop on her thigh (roughly in size of a single M&M candy).

I always tell my patients that the response is not immediate, typically taking 8 to 12 weeks for the effect to become clinically significant. I generally see a patient back 8 weeks after initiation of treatment to check T levels and evaluate response.

Dr. Simon: There are some data demonstrating that intravaginal testosterone can be a potential treatment for GSM. Intravaginal testosterone coupled with aromatase inhibitor therapy used for breast cancer treatment resulted in supraphysiologic T levels and reportedly improved vaginal maturation index and reduced dyspareunia. More study is needed.¹³

Dr. Streicher: Agreed. The lower third of the vagina and the vestibule is rich in testosterone receptors. Like Dr. Simon, in some cases of vaginal atrophy I prescribe a compounded local vaginal testosterone.

Continue to: Testosterone and premenopausal women...

Testosterone and premenopausal women

Dr. Karram: Is there a role for testosterone supplementation in premenopausal women with normal estrogen production?

Dr. Glaser: Yes. In fact, in our study, more than one-third of the patients were premenopausal, which makes sense.⁶ There is a marked decline of T levels and the adrenal precursor steroids (DHEA and androstenedione) in women between the ages of 20–30 years and around age 50. As we said, symptoms of androgen deficiency often occur prior to menopause and are not related to estrogen levels. In our study, testosterone implant therapy relieved symptoms of hormone (androgen) deficiency, including vasomotor symptoms, sleep problems, depressive mood, irritability, anxiety, physical and mental exhaustion (fatigue, memory issues), sexual problems, bladder problems (incontinence, frequency), vaginal dryness, and joint and muscular pain. Premenopausal and postmenopausal patients reported similar hormone deficiency symptoms. Premenopausal women did report a higher incidence of psychological complaints (depressive mood, anxiety, and irritability), while postmenopausal women reported more hot flashes, vaginal dryness, and urologic symptoms. Both groups demonstrated similar improvement in symptoms.

In addition, we have seen relief of severe migraine headache in premenopausal (as well as postmenopausal) women treated with testosterone implant therapy.^6,7

Dr. Streicher: The goal of testosterone supplementation is to approximate physiological testosterone concentrations for premenopausal women. While testosterone may improve well-being and sexual function in premenopausal women, the data are limited and really inconclusive. More study is needed given that there is likely a wide therapeutic range with many variables. Having said that, there are some data that indicate that testosterone in premenopausal women may enhance general sense of well-being.¹⁴

Why is there no FDA-approved agent?

Dr. Karram: Why do you think the FDA has been reluctant to approve a testosterone agent for women?

Dr. Simon: Three potential testosterone drugs for use in women have been unsuccessfully brought to market after the FDA did not approve them. There are 31 approved products for men, each of which were approved because they safely restored normal testosterone concentrations in men with reduced levels and an associated medical condition. Unlike this scenario for men, for women, the FDA has required products to show clinical effectiveness in trials. For instance, Estratest, a combination estrogen-testosterone product, was in use in the 1960s—approved for women with estrogen-resistant hot flushes, and used in practice for sexual dysfunction. After the FDA implemented its Drug Efficacy Study and Implementation regulation system after 2000, which required safety and efficacy trial(s) before drug approval, the manufacturer removed the drug from market when presented efficacy study data for the added testosterone in the drug were deemed inadequate.¹⁵

Dr. Streicher: We have yet another example of the disparity between the FDA approval processes for sexual function drugs for men versus women. Take Intrinsia as another example. It was a 300-mg testosterone patch that underwent clinical trials in women who were post-oophorectomy with HSDD. The patch had demonstrated efficacy with minimal adverse effects and no statistically significant dangerous effects. However, the FDA declined approval, citing “safety considerations” and requested longer-term clinical trials to evaluate potential cardiovascular or breast problems. Given that Intrinsia supplementation simply restored normal physiologic testosterone levels, and there was no such requirement in men who received supplementation post-orchiectomy, this requirement was nonsensical and unjustified.

Compounded formulations

Dr. Karram: Are compounding pharmacies appropriately regulated, and how can you be assured that the source of your testosterone is appropriate?

Dr. Glaser: Compounding pharmacies are regulated by the State Boards of Pharmacy, Drug Enforcement Agency, Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, State Bureaus of Narcotics and Dangerous Drugs, and Departments of Health (in some states).

Compounding is a highly regulated profession that is constantly under scrutiny by agencies, patients, and physicians. Any additional regulations could adversely impact the accessibility of patients to individually compounded medications including intravenous and oncology medications. Over the past 20 years, I have treated hundreds of patients with breast cancer with compounded vaginal testosterone (with or without estriol) and subcutaneous testosterone (with or without anastrozole), greatly improving quality of life in women suffering from severe symptoms. Without the availability of compounded medications, there would have been no or limited alternatives for adequate and much needed therapy. Notably, there have been no adverse events or safety-related issues in more than 20 years.

Regarding whether or not “the source of your testosterone is appropriate,” pharmacists can only use United States Pharmacopeia (USP) grades of testosterone. Testosterone used in compounding is required by the FDA to be of USP grade from an FDA registered and compliant facility. In addition, compounding support companies run additional USP tests to confirm their products meet USP standards prior to being delivered to individual compounding pharmacies.

Dr. Streicher: However, there potentially can be substantial variability between formulations and batches. Product purity can also be an issue. It is reassuring if the compounding pharmacy is compliant with purity of Active Pharmaceutical Ingredients and Good Manufacturing Practice rules and guidelines that assure the minimum requirements to assure high quality and batch-to-batch consistency. I find it helpful to always work with the same pharmacy once you have established uniformity and reliability. If there is concern, it is appropriate to check a patient’s serum level 2 weeks after initiation of therapy.

Dr. Simon: I think the problem with some compounding pharmacies is that there may be incentives back and forth with the clinician to use a certain outlet, whereby the patient’s best interest may not be served. I do believe that there is a role for compounding pharmacies, however. We also use them because some women may have strange reactions or be allergic to the preservatives, formulating agents, or even lactose, in various pills and patches, gels, and creams.

Continue to: Testosterone for aging and cognition?...

Testosterone for aging and cognition?

Dr. Karram: Do you think that testosterone supplementation in the elderly can have a positive impact on aging, Alzheimer disease, and dementia?

Dr. Streicher: The jury is still out on the cognitive effects of postmenopausal androgen supplementation. There is currently insufficient evidence to support the use of testosterone to enhance cognitive performance, or to delay cognitive decline. I prescribe testosterone only to treat HSDD, but I do tell my patient that she may possibly also benefit in terms of cognitive function, musculoskeletal parameters, and well-being. Large RCTs are needed in those areas to justify prescribing for those benefits alone.

Dr. Simon: I would say this is the place for future development, but where there is very likely to be a benefit is on sarcopenia.

Dr. Glaser: There is some evidence that testosterone is neuroprotective.¹⁶ In my clinical practice I have seen “self-reported” memory issues improved on therapy, often returning toward the end of the testosterone implant cycle. Adequate amounts of bioavailable testosterone at the androgen receptor are critical for optimal health, immune function, and disease prevention.

Dr. Karram: In conclusion, this expert panel agrees that testosterone supplementation is beneficial for sexual dysfunction in postmenopausal women, with also many other potential benefits that require further investigation. Route of administration preferred by Dr. Simon and Dr. Streicher is transdermal or a transvaginal cream. Dr. Glaser uses a subcutaneous pellet approach. Thank you all for an engaging and informative discussion. ●

There are no currently US Food and Drug Administration (FDA)-approved therapies for testosterone use in women. Its use by clinicians is through dose modification of FDA-approved therapies for men, or preparations created by compounding pharmacies. Recently, several professional organizations, including the American College of Obstetricians and Gynecologists (ACOG), North American Menopause Society, International Society for the Study of Women’s Sexual Health, and the International Society for Sexual Medicine, convened an expert panel to develop a global position statement on testosterone therapy for women.¹ In this roundtable for OBG Management, moderated by Mickey Karram, MD, several experts discuss this position statement as well as the overall clinical advantages and drawbacks of using testosterone in women.

Testosterone indications

Mickey Karram, MD: For which indications do you prescribe testosterone supplementation in women?

Lauren Streicher, MD: I offer systemic testosterone therapy to postmenopausal women who have hypoactive sexual desire disorder (HSDD) and low serum testosterone levels, with one caveat—it is important that the patient’s reported distressing lack of libido is not explained by another condition or circumstance. Many women present reporting low libido but, on further questioning, it is typically revealed that dyspareunia precipitated their loss of interest in sex. It is normal to not want to do something that is painful. In addition, low libido can often be explained by chronic disease, such as diabetes, cancer, or clinical depression.

Some medications, including selective serotonin reuptake inhibitors (SSRIs), frequently cause a decline in sexual interest. Finally, psychosocial and partner issues may be the culprit.

James Simon, MD, CCP, NCMP, IF: Much of the beneficial data for testosterone’s use is for sexual function in postmenopausal women.² Female sexual dysfunction is highly prevalent among women during the postmenopause.³ Androgen levels progressively decrease throughout adult life in all women, so the postmenopausal additional lack of estrogen has a recognized effect on genitourinary health. There is evidence that the insufficiency of androgens as well as estrogens after menopause can lead to genitourinary symptoms of menopause (GSM).⁴

Testosterone also is used for increasing strength, lean muscle mass, bone mineral density, and sense of well-being.⁵

Rebecca Glaser, MD: I consider testosterone supplementation in my clinical practice in both premenopausal and postmenopausal women for symptoms of androgen/hormone deficiency, including diminished sense of well-being; dysphoric mood; anxiety; irritability; fatigue; decreased libido, sexual activity, or pleasure; vasomotor instability; bone loss; decreased muscle strength; insomnia; changes in cognition; memory loss; urinary symptoms; incontinence; vaginal atrophy and dryness; and joint and muscular pain. We also have shown through preliminary and short-term data and case studies that testosterone therapy has a potential beneficial effect on migraine headaches, as well as active breast cancers in both premenopausal and postmenopausal women.^6-10

Continue to: What is appropriate bloodwork?...

Dr. Karram: Do you obtain blood work before initiating testosterone treatment? If so, what tests do you order and what testosterone levels are considered to be normal for premenopausal and postmenopausal women?

Dr. Streicher: Unlike estrogen, which is predictably low in a postmenopausal woman, serum testosterone (T) levels are highly variable because of the adrenal component. Ovarian testosterone production does not cease at the same time as estrogen production. So I do obtain total and free T levels, prior to initiating treatment. Having said that, it has been well established that T levels correlate poorly with level of sexual interest, and there is no specific blood level that can be used to differentiate women with and without sexual dysfunction. We all have patients who have nonexistent T levels and have a very healthy libido, and other women with sky-high levels who have no libido. But it is useful to know levels prior to initiating therapy to be able to monitor levels throughout treatment. Also, if levels are in the premenopausal physiologic range, not only is she unlikely to respond but she is also at risk for developing androgenic adverse effects, such as acne and hair growth. In general, a low free T level (even if it is in the normal postmenopausal range) in a clinical setting of HSDD supports supplementation.

The assessment and interpretation of T levels can be challenging, particularly as the majority of testosterone is protein-bound and biologically inactive. Free T levels (the biologically active testosterone) in many labs are unreliable and need to be calculated.

In addition to total and free T, I check levels of sex hormone-binding globulin (SHBG), the protein that binds testosterone and renders it biologically inactive. If someone has high SHBG levels and is taking an oral estrogen, simply switching to a transdermal estrogen will result in decreased SHBG and increased free T.

Levels of total and free T vary from lab to lab, so it is best to be familiar with those ranges and then be consistent in which lab you choose.

Dr. Glaser: Although I personally do order blood work on most patients (T, free T, estradiol, complete blood count, thyroid-stimulating hormone, and follicle-stimulating hormone), after 15 years of research and publishing data on testosterone implants, I do not believe that T levels are absolutely necessary or even beneficial in most cases. It rarely changes management in my patients.

As Lauren said, it is well known that T levels do not correlate with androgen deficiency symptoms or clinical conditions caused by androgen deficiency. If a patient has symptoms of androgen deficiency, a trial of testosterone therapy should be given.

T levels are not a valid marker of tissue exposure in women, reflecting less than 20% of total androgen activity. The major source of testosterone in pre and postmenopausal women is the local intracrine production of testosterone from the adrenal precursor steroids dehydroepiandrosterone (DHEA) and androstenedione, which would not be reflected in T levels.

In our study involving 300 women, we found no relationship between baseline T levels, presenting symptoms, or response to therapy.⁶ Premenopausal and postmenopausal women had similar baseline T levels and similar response to therapy. Even women with baseline T levels in the mid-range responded to therapy.

Some of the most controversial topics in treating women with testosterone are related to dosing and T levels throughout therapy. Guideline authors often use the terms ‘physiologic dosing’ and ‘physiologic ranges’ when making recommendations for therapy. Although “physiologic” sounds appropriate/ scientific, these rigid opinions/recommendations are not evidence based. There are no data supporting the use of endogenous T ranges to guide dosing or monitor testosterone therapy.

The decision to initiate testosterone therapy is a clinical decision between the doctor and the patient based on the patient’s symptomatology, which is the therapeutic endpoint. Testosterone therapy must be done with adequate doses determined by clinical effect (benefits) versus side effects or adverse events (risks). T levels may be helpful, along with clinical evaluation when troubleshooting.

Utilizing data from thousands of patients, we have developed serum ranges for testosterone implants.¹¹ Even so, no two patients are the same, nor do they respond to therapy the same. It is always a clinical decision.

Continue to: Dr. Simon...

Dr. Simon: In the recent global consensus statement on testosterone use,¹ the experts were in agreement that “no cut-off blood level can be used for any measured circulating androgen to differentiate women with and without sexual dysfunction.” They give their recommendation a C, and I agree that testosterone supplementation, with specific dosage levels, are a clinical decision.

Before initiating testosterone therapy, it is recommended that liver function and fasting lipids are assessed, as liver disease and hyperlipidemia are contraindications to treatment. These levels should be monitored twice in the first year and annually thereafter while the patient is taking testosterone. Breast and pelvic examinations, mammography, and evaluation for abnormal bleeding should be performed as well as the blood tests.¹² These recommendations are focused on safety not efficacy.

Administration route

Dr. Karram: How do you administer testosterone, and why?

Dr. Streicher: As there are no FDA approved testosterone products for women, clinicians must determine the dosage and route of delivery based on published clinical trials.

Dr. Glaser: I treat patients with subcutaneous pellet implants. The implants provide consistent and continuous delivery of therapeutic amounts of testosterone. There is a reason testosterone pellets have been used for more than 80 years and are more popular now than ever—they work. The insertion procedure is simple and takes about 2 minutes. The treatment is cost-effective, avoids first pass, has no adverse effect on the liver or clotting factors, and there is no transference. Decades of data support both the efficacy and safety of testosterone implants.⁶ However, testosterone implants are not regulated by the FDA and all patients are required to sign a consent informing them of off-label use, benefits, and risks of testosterone implant therapy.

Dr. Simon: I think the consent is important, as there is no package labeling to warn of possible side effects.

Dr. Streicher: Oral testosterone therapy, because of its first pass through the liver and association with adverse lipid profiles with negative effects on high- and low-density lipoprotein cholesterol levels, is not recommended. I prefer a transdermal approach. Pellets, implants, and injections have the potential to result in supraphysiologic blood concentrations. It must be emphasized that the goal of treatment is to approximate premenopausal physiologic levels. More is not better; excessive levels do not demonstrate a greater sexual response and are in fact more likely to have a negative impact due to androgenic side effects.

In most clinical trials, a 300 mg/d testosterone patch was effective, but these patches are not commercially available so I rely on transdermal gel from a compounding pharmacy. The typical dose needed to raise levels into the high to normal range for most women is 2.5 mg up to 5 mg per day of testosterone 1%, which translates to roughly 1 mL. Many pharmacies provide a dispenser, which allots the appropriate dose. Alternatively, I instruct the patient to place a dollop on her thigh (roughly in size of a single M&M candy).

I always tell my patients that the response is not immediate, typically taking 8 to 12 weeks for the effect to become clinically significant. I generally see a patient back 8 weeks after initiation of treatment to check T levels and evaluate response.

Dr. Simon: There are some data demonstrating that intravaginal testosterone can be a potential treatment for GSM. Intravaginal testosterone coupled with aromatase inhibitor therapy used for breast cancer treatment resulted in supraphysiologic T levels and reportedly improved vaginal maturation index and reduced dyspareunia. More study is needed.¹³

Dr. Streicher: Agreed. The lower third of the vagina and the vestibule is rich in testosterone receptors. Like Dr. Simon, in some cases of vaginal atrophy I prescribe a compounded local vaginal testosterone.

Continue to: Testosterone and premenopausal women...

Testosterone and premenopausal women

Dr. Karram: Is there a role for testosterone supplementation in premenopausal women with normal estrogen production?

Dr. Glaser: Yes. In fact, in our study, more than one-third of the patients were premenopausal, which makes sense.⁶ There is a marked decline of T levels and the adrenal precursor steroids (DHEA and androstenedione) in women between the ages of 20–30 years and around age 50. As we said, symptoms of androgen deficiency often occur prior to menopause and are not related to estrogen levels. In our study, testosterone implant therapy relieved symptoms of hormone (androgen) deficiency, including vasomotor symptoms, sleep problems, depressive mood, irritability, anxiety, physical and mental exhaustion (fatigue, memory issues), sexual problems, bladder problems (incontinence, frequency), vaginal dryness, and joint and muscular pain. Premenopausal and postmenopausal patients reported similar hormone deficiency symptoms. Premenopausal women did report a higher incidence of psychological complaints (depressive mood, anxiety, and irritability), while postmenopausal women reported more hot flashes, vaginal dryness, and urologic symptoms. Both groups demonstrated similar improvement in symptoms.

In addition, we have seen relief of severe migraine headache in premenopausal (as well as postmenopausal) women treated with testosterone implant therapy.^6,7

Dr. Streicher: The goal of testosterone supplementation is to approximate physiological testosterone concentrations for premenopausal women. While testosterone may improve well-being and sexual function in premenopausal women, the data are limited and really inconclusive. More study is needed given that there is likely a wide therapeutic range with many variables. Having said that, there are some data that indicate that testosterone in premenopausal women may enhance general sense of well-being.¹⁴

Why is there no FDA-approved agent?

Dr. Karram: Why do you think the FDA has been reluctant to approve a testosterone agent for women?

Dr. Simon: Three potential testosterone drugs for use in women have been unsuccessfully brought to market after the FDA did not approve them. There are 31 approved products for men, each of which were approved because they safely restored normal testosterone concentrations in men with reduced levels and an associated medical condition. Unlike this scenario for men, for women, the FDA has required products to show clinical effectiveness in trials. For instance, Estratest, a combination estrogen-testosterone product, was in use in the 1960s—approved for women with estrogen-resistant hot flushes, and used in practice for sexual dysfunction. After the FDA implemented its Drug Efficacy Study and Implementation regulation system after 2000, which required safety and efficacy trial(s) before drug approval, the manufacturer removed the drug from market when presented efficacy study data for the added testosterone in the drug were deemed inadequate.¹⁵

Dr. Streicher: We have yet another example of the disparity between the FDA approval processes for sexual function drugs for men versus women. Take Intrinsia as another example. It was a 300-mg testosterone patch that underwent clinical trials in women who were post-oophorectomy with HSDD. The patch had demonstrated efficacy with minimal adverse effects and no statistically significant dangerous effects. However, the FDA declined approval, citing “safety considerations” and requested longer-term clinical trials to evaluate potential cardiovascular or breast problems. Given that Intrinsia supplementation simply restored normal physiologic testosterone levels, and there was no such requirement in men who received supplementation post-orchiectomy, this requirement was nonsensical and unjustified.

Compounded formulations

Dr. Karram: Are compounding pharmacies appropriately regulated, and how can you be assured that the source of your testosterone is appropriate?

Dr. Glaser: Compounding pharmacies are regulated by the State Boards of Pharmacy, Drug Enforcement Agency, Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, State Bureaus of Narcotics and Dangerous Drugs, and Departments of Health (in some states).

Compounding is a highly regulated profession that is constantly under scrutiny by agencies, patients, and physicians. Any additional regulations could adversely impact the accessibility of patients to individually compounded medications including intravenous and oncology medications. Over the past 20 years, I have treated hundreds of patients with breast cancer with compounded vaginal testosterone (with or without estriol) and subcutaneous testosterone (with or without anastrozole), greatly improving quality of life in women suffering from severe symptoms. Without the availability of compounded medications, there would have been no or limited alternatives for adequate and much needed therapy. Notably, there have been no adverse events or safety-related issues in more than 20 years.

Regarding whether or not “the source of your testosterone is appropriate,” pharmacists can only use United States Pharmacopeia (USP) grades of testosterone. Testosterone used in compounding is required by the FDA to be of USP grade from an FDA registered and compliant facility. In addition, compounding support companies run additional USP tests to confirm their products meet USP standards prior to being delivered to individual compounding pharmacies.

Dr. Streicher: However, there potentially can be substantial variability between formulations and batches. Product purity can also be an issue. It is reassuring if the compounding pharmacy is compliant with purity of Active Pharmaceutical Ingredients and Good Manufacturing Practice rules and guidelines that assure the minimum requirements to assure high quality and batch-to-batch consistency. I find it helpful to always work with the same pharmacy once you have established uniformity and reliability. If there is concern, it is appropriate to check a patient’s serum level 2 weeks after initiation of therapy.

Dr. Simon: I think the problem with some compounding pharmacies is that there may be incentives back and forth with the clinician to use a certain outlet, whereby the patient’s best interest may not be served. I do believe that there is a role for compounding pharmacies, however. We also use them because some women may have strange reactions or be allergic to the preservatives, formulating agents, or even lactose, in various pills and patches, gels, and creams.

Continue to: Testosterone for aging and cognition?...

Testosterone for aging and cognition?

Dr. Karram: Do you think that testosterone supplementation in the elderly can have a positive impact on aging, Alzheimer disease, and dementia?

Dr. Streicher: The jury is still out on the cognitive effects of postmenopausal androgen supplementation. There is currently insufficient evidence to support the use of testosterone to enhance cognitive performance, or to delay cognitive decline. I prescribe testosterone only to treat HSDD, but I do tell my patient that she may possibly also benefit in terms of cognitive function, musculoskeletal parameters, and well-being. Large RCTs are needed in those areas to justify prescribing for those benefits alone.

Dr. Simon: I would say this is the place for future development, but where there is very likely to be a benefit is on sarcopenia.

Dr. Glaser: There is some evidence that testosterone is neuroprotective.¹⁶ In my clinical practice I have seen “self-reported” memory issues improved on therapy, often returning toward the end of the testosterone implant cycle. Adequate amounts of bioavailable testosterone at the androgen receptor are critical for optimal health, immune function, and disease prevention.

Dr. Karram: In conclusion, this expert panel agrees that testosterone supplementation is beneficial for sexual dysfunction in postmenopausal women, with also many other potential benefits that require further investigation. Route of administration preferred by Dr. Simon and Dr. Streicher is transdermal or a transvaginal cream. Dr. Glaser uses a subcutaneous pellet approach. Thank you all for an engaging and informative discussion. ●

There are no currently US Food and Drug Administration (FDA)-approved therapies for testosterone use in women. Its use by clinicians is through dose modification of FDA-approved therapies for men, or preparations created by compounding pharmacies. Recently, several professional organizations, including the American College of Obstetricians and Gynecologists (ACOG), North American Menopause Society, International Society for the Study of Women’s Sexual Health, and the International Society for Sexual Medicine, convened an expert panel to develop a global position statement on testosterone therapy for women.¹ In this roundtable for OBG Management, moderated by Mickey Karram, MD, several experts discuss this position statement as well as the overall clinical advantages and drawbacks of using testosterone in women.

Testosterone indications

Mickey Karram, MD: For which indications do you prescribe testosterone supplementation in women?

Lauren Streicher, MD: I offer systemic testosterone therapy to postmenopausal women who have hypoactive sexual desire disorder (HSDD) and low serum testosterone levels, with one caveat—it is important that the patient’s reported distressing lack of libido is not explained by another condition or circumstance. Many women present reporting low libido but, on further questioning, it is typically revealed that dyspareunia precipitated their loss of interest in sex. It is normal to not want to do something that is painful. In addition, low libido can often be explained by chronic disease, such as diabetes, cancer, or clinical depression.

Some medications, including selective serotonin reuptake inhibitors (SSRIs), frequently cause a decline in sexual interest. Finally, psychosocial and partner issues may be the culprit.

James Simon, MD, CCP, NCMP, IF: Much of the beneficial data for testosterone’s use is for sexual function in postmenopausal women.² Female sexual dysfunction is highly prevalent among women during the postmenopause.³ Androgen levels progressively decrease throughout adult life in all women, so the postmenopausal additional lack of estrogen has a recognized effect on genitourinary health. There is evidence that the insufficiency of androgens as well as estrogens after menopause can lead to genitourinary symptoms of menopause (GSM).⁴

Testosterone also is used for increasing strength, lean muscle mass, bone mineral density, and sense of well-being.⁵

Rebecca Glaser, MD: I consider testosterone supplementation in my clinical practice in both premenopausal and postmenopausal women for symptoms of androgen/hormone deficiency, including diminished sense of well-being; dysphoric mood; anxiety; irritability; fatigue; decreased libido, sexual activity, or pleasure; vasomotor instability; bone loss; decreased muscle strength; insomnia; changes in cognition; memory loss; urinary symptoms; incontinence; vaginal atrophy and dryness; and joint and muscular pain. We also have shown through preliminary and short-term data and case studies that testosterone therapy has a potential beneficial effect on migraine headaches, as well as active breast cancers in both premenopausal and postmenopausal women.^6-10

Continue to: What is appropriate bloodwork?...

Dr. Karram: Do you obtain blood work before initiating testosterone treatment? If so, what tests do you order and what testosterone levels are considered to be normal for premenopausal and postmenopausal women?

Dr. Streicher: Unlike estrogen, which is predictably low in a postmenopausal woman, serum testosterone (T) levels are highly variable because of the adrenal component. Ovarian testosterone production does not cease at the same time as estrogen production. So I do obtain total and free T levels, prior to initiating treatment. Having said that, it has been well established that T levels correlate poorly with level of sexual interest, and there is no specific blood level that can be used to differentiate women with and without sexual dysfunction. We all have patients who have nonexistent T levels and have a very healthy libido, and other women with sky-high levels who have no libido. But it is useful to know levels prior to initiating therapy to be able to monitor levels throughout treatment. Also, if levels are in the premenopausal physiologic range, not only is she unlikely to respond but she is also at risk for developing androgenic adverse effects, such as acne and hair growth. In general, a low free T level (even if it is in the normal postmenopausal range) in a clinical setting of HSDD supports supplementation.

The assessment and interpretation of T levels can be challenging, particularly as the majority of testosterone is protein-bound and biologically inactive. Free T levels (the biologically active testosterone) in many labs are unreliable and need to be calculated.

In addition to total and free T, I check levels of sex hormone-binding globulin (SHBG), the protein that binds testosterone and renders it biologically inactive. If someone has high SHBG levels and is taking an oral estrogen, simply switching to a transdermal estrogen will result in decreased SHBG and increased free T.

Levels of total and free T vary from lab to lab, so it is best to be familiar with those ranges and then be consistent in which lab you choose.

Dr. Glaser: Although I personally do order blood work on most patients (T, free T, estradiol, complete blood count, thyroid-stimulating hormone, and follicle-stimulating hormone), after 15 years of research and publishing data on testosterone implants, I do not believe that T levels are absolutely necessary or even beneficial in most cases. It rarely changes management in my patients.

As Lauren said, it is well known that T levels do not correlate with androgen deficiency symptoms or clinical conditions caused by androgen deficiency. If a patient has symptoms of androgen deficiency, a trial of testosterone therapy should be given.

T levels are not a valid marker of tissue exposure in women, reflecting less than 20% of total androgen activity. The major source of testosterone in pre and postmenopausal women is the local intracrine production of testosterone from the adrenal precursor steroids dehydroepiandrosterone (DHEA) and androstenedione, which would not be reflected in T levels.

In our study involving 300 women, we found no relationship between baseline T levels, presenting symptoms, or response to therapy.⁶ Premenopausal and postmenopausal women had similar baseline T levels and similar response to therapy. Even women with baseline T levels in the mid-range responded to therapy.

Some of the most controversial topics in treating women with testosterone are related to dosing and T levels throughout therapy. Guideline authors often use the terms ‘physiologic dosing’ and ‘physiologic ranges’ when making recommendations for therapy. Although “physiologic” sounds appropriate/ scientific, these rigid opinions/recommendations are not evidence based. There are no data supporting the use of endogenous T ranges to guide dosing or monitor testosterone therapy.

The decision to initiate testosterone therapy is a clinical decision between the doctor and the patient based on the patient’s symptomatology, which is the therapeutic endpoint. Testosterone therapy must be done with adequate doses determined by clinical effect (benefits) versus side effects or adverse events (risks). T levels may be helpful, along with clinical evaluation when troubleshooting.

Utilizing data from thousands of patients, we have developed serum ranges for testosterone implants.¹¹ Even so, no two patients are the same, nor do they respond to therapy the same. It is always a clinical decision.

Continue to: Dr. Simon...

Dr. Simon: In the recent global consensus statement on testosterone use,¹ the experts were in agreement that “no cut-off blood level can be used for any measured circulating androgen to differentiate women with and without sexual dysfunction.” They give their recommendation a C, and I agree that testosterone supplementation, with specific dosage levels, are a clinical decision.

Before initiating testosterone therapy, it is recommended that liver function and fasting lipids are assessed, as liver disease and hyperlipidemia are contraindications to treatment. These levels should be monitored twice in the first year and annually thereafter while the patient is taking testosterone. Breast and pelvic examinations, mammography, and evaluation for abnormal bleeding should be performed as well as the blood tests.¹² These recommendations are focused on safety not efficacy.

Administration route

Dr. Karram: How do you administer testosterone, and why?

Dr. Streicher: As there are no FDA approved testosterone products for women, clinicians must determine the dosage and route of delivery based on published clinical trials.

Dr. Glaser: I treat patients with subcutaneous pellet implants. The implants provide consistent and continuous delivery of therapeutic amounts of testosterone. There is a reason testosterone pellets have been used for more than 80 years and are more popular now than ever—they work. The insertion procedure is simple and takes about 2 minutes. The treatment is cost-effective, avoids first pass, has no adverse effect on the liver or clotting factors, and there is no transference. Decades of data support both the efficacy and safety of testosterone implants.⁶ However, testosterone implants are not regulated by the FDA and all patients are required to sign a consent informing them of off-label use, benefits, and risks of testosterone implant therapy.

Dr. Simon: I think the consent is important, as there is no package labeling to warn of possible side effects.

Dr. Streicher: Oral testosterone therapy, because of its first pass through the liver and association with adverse lipid profiles with negative effects on high- and low-density lipoprotein cholesterol levels, is not recommended. I prefer a transdermal approach. Pellets, implants, and injections have the potential to result in supraphysiologic blood concentrations. It must be emphasized that the goal of treatment is to approximate premenopausal physiologic levels. More is not better; excessive levels do not demonstrate a greater sexual response and are in fact more likely to have a negative impact due to androgenic side effects.

In most clinical trials, a 300 mg/d testosterone patch was effective, but these patches are not commercially available so I rely on transdermal gel from a compounding pharmacy. The typical dose needed to raise levels into the high to normal range for most women is 2.5 mg up to 5 mg per day of testosterone 1%, which translates to roughly 1 mL. Many pharmacies provide a dispenser, which allots the appropriate dose. Alternatively, I instruct the patient to place a dollop on her thigh (roughly in size of a single M&M candy).

I always tell my patients that the response is not immediate, typically taking 8 to 12 weeks for the effect to become clinically significant. I generally see a patient back 8 weeks after initiation of treatment to check T levels and evaluate response.

Dr. Simon: There are some data demonstrating that intravaginal testosterone can be a potential treatment for GSM. Intravaginal testosterone coupled with aromatase inhibitor therapy used for breast cancer treatment resulted in supraphysiologic T levels and reportedly improved vaginal maturation index and reduced dyspareunia. More study is needed.¹³

Dr. Streicher: Agreed. The lower third of the vagina and the vestibule is rich in testosterone receptors. Like Dr. Simon, in some cases of vaginal atrophy I prescribe a compounded local vaginal testosterone.

Continue to: Testosterone and premenopausal women...

Testosterone and premenopausal women

Dr. Karram: Is there a role for testosterone supplementation in premenopausal women with normal estrogen production?

Dr. Glaser: Yes. In fact, in our study, more than one-third of the patients were premenopausal, which makes sense.⁶ There is a marked decline of T levels and the adrenal precursor steroids (DHEA and androstenedione) in women between the ages of 20–30 years and around age 50. As we said, symptoms of androgen deficiency often occur prior to menopause and are not related to estrogen levels. In our study, testosterone implant therapy relieved symptoms of hormone (androgen) deficiency, including vasomotor symptoms, sleep problems, depressive mood, irritability, anxiety, physical and mental exhaustion (fatigue, memory issues), sexual problems, bladder problems (incontinence, frequency), vaginal dryness, and joint and muscular pain. Premenopausal and postmenopausal patients reported similar hormone deficiency symptoms. Premenopausal women did report a higher incidence of psychological complaints (depressive mood, anxiety, and irritability), while postmenopausal women reported more hot flashes, vaginal dryness, and urologic symptoms. Both groups demonstrated similar improvement in symptoms.

In addition, we have seen relief of severe migraine headache in premenopausal (as well as postmenopausal) women treated with testosterone implant therapy.^6,7

Dr. Streicher: The goal of testosterone supplementation is to approximate physiological testosterone concentrations for premenopausal women. While testosterone may improve well-being and sexual function in premenopausal women, the data are limited and really inconclusive. More study is needed given that there is likely a wide therapeutic range with many variables. Having said that, there are some data that indicate that testosterone in premenopausal women may enhance general sense of well-being.¹⁴

Why is there no FDA-approved agent?

Dr. Karram: Why do you think the FDA has been reluctant to approve a testosterone agent for women?

Dr. Simon: Three potential testosterone drugs for use in women have been unsuccessfully brought to market after the FDA did not approve them. There are 31 approved products for men, each of which were approved because they safely restored normal testosterone concentrations in men with reduced levels and an associated medical condition. Unlike this scenario for men, for women, the FDA has required products to show clinical effectiveness in trials. For instance, Estratest, a combination estrogen-testosterone product, was in use in the 1960s—approved for women with estrogen-resistant hot flushes, and used in practice for sexual dysfunction. After the FDA implemented its Drug Efficacy Study and Implementation regulation system after 2000, which required safety and efficacy trial(s) before drug approval, the manufacturer removed the drug from market when presented efficacy study data for the added testosterone in the drug were deemed inadequate.¹⁵

Dr. Streicher: We have yet another example of the disparity between the FDA approval processes for sexual function drugs for men versus women. Take Intrinsia as another example. It was a 300-mg testosterone patch that underwent clinical trials in women who were post-oophorectomy with HSDD. The patch had demonstrated efficacy with minimal adverse effects and no statistically significant dangerous effects. However, the FDA declined approval, citing “safety considerations” and requested longer-term clinical trials to evaluate potential cardiovascular or breast problems. Given that Intrinsia supplementation simply restored normal physiologic testosterone levels, and there was no such requirement in men who received supplementation post-orchiectomy, this requirement was nonsensical and unjustified.

Compounded formulations

Dr. Karram: Are compounding pharmacies appropriately regulated, and how can you be assured that the source of your testosterone is appropriate?

Dr. Glaser: Compounding pharmacies are regulated by the State Boards of Pharmacy, Drug Enforcement Agency, Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, State Bureaus of Narcotics and Dangerous Drugs, and Departments of Health (in some states).

Compounding is a highly regulated profession that is constantly under scrutiny by agencies, patients, and physicians. Any additional regulations could adversely impact the accessibility of patients to individually compounded medications including intravenous and oncology medications. Over the past 20 years, I have treated hundreds of patients with breast cancer with compounded vaginal testosterone (with or without estriol) and subcutaneous testosterone (with or without anastrozole), greatly improving quality of life in women suffering from severe symptoms. Without the availability of compounded medications, there would have been no or limited alternatives for adequate and much needed therapy. Notably, there have been no adverse events or safety-related issues in more than 20 years.

Regarding whether or not “the source of your testosterone is appropriate,” pharmacists can only use United States Pharmacopeia (USP) grades of testosterone. Testosterone used in compounding is required by the FDA to be of USP grade from an FDA registered and compliant facility. In addition, compounding support companies run additional USP tests to confirm their products meet USP standards prior to being delivered to individual compounding pharmacies.

Dr. Streicher: However, there potentially can be substantial variability between formulations and batches. Product purity can also be an issue. It is reassuring if the compounding pharmacy is compliant with purity of Active Pharmaceutical Ingredients and Good Manufacturing Practice rules and guidelines that assure the minimum requirements to assure high quality and batch-to-batch consistency. I find it helpful to always work with the same pharmacy once you have established uniformity and reliability. If there is concern, it is appropriate to check a patient’s serum level 2 weeks after initiation of therapy.

Dr. Simon: I think the problem with some compounding pharmacies is that there may be incentives back and forth with the clinician to use a certain outlet, whereby the patient’s best interest may not be served. I do believe that there is a role for compounding pharmacies, however. We also use them because some women may have strange reactions or be allergic to the preservatives, formulating agents, or even lactose, in various pills and patches, gels, and creams.

Continue to: Testosterone for aging and cognition?...

Testosterone for aging and cognition?

Dr. Karram: Do you think that testosterone supplementation in the elderly can have a positive impact on aging, Alzheimer disease, and dementia?

Dr. Streicher: The jury is still out on the cognitive effects of postmenopausal androgen supplementation. There is currently insufficient evidence to support the use of testosterone to enhance cognitive performance, or to delay cognitive decline. I prescribe testosterone only to treat HSDD, but I do tell my patient that she may possibly also benefit in terms of cognitive function, musculoskeletal parameters, and well-being. Large RCTs are needed in those areas to justify prescribing for those benefits alone.

Dr. Simon: I would say this is the place for future development, but where there is very likely to be a benefit is on sarcopenia.

Dr. Glaser: There is some evidence that testosterone is neuroprotective.¹⁶ In my clinical practice I have seen “self-reported” memory issues improved on therapy, often returning toward the end of the testosterone implant cycle. Adequate amounts of bioavailable testosterone at the androgen receptor are critical for optimal health, immune function, and disease prevention.

Dr. Karram: In conclusion, this expert panel agrees that testosterone supplementation is beneficial for sexual dysfunction in postmenopausal women, with also many other potential benefits that require further investigation. Route of administration preferred by Dr. Simon and Dr. Streicher is transdermal or a transvaginal cream. Dr. Glaser uses a subcutaneous pellet approach. Thank you all for an engaging and informative discussion. ●