Menopause

Illustration: Kimberly Martens for OBG Management

Sexual function is a complex, multifaceted process mediated by neurologic functions, hormonal regulation, and psychological factors. What could possibly go wrong?

As it turns out, quite a lot. Female sexual dysfunction is a common, vastly undertreated sexual health problem that can have wide-reaching effects on a woman’s life. These effects may include impaired body image, self-confidence, and self-worth. Sexual dysfunction also can contribute to relationship dissatisfaction and leave one feeling less connected with her partner.^1,2 Studies have shown women with sexual dysfunction have higher health care expenditures³ and that depression and fatigue are common comorbidities, as is frequently seen in other chronic conditions such as diabetes and back pain.⁴

Understanding the pathogenesis of female sexual dysfunction helps to guide our approach to its management. Indeed, increased understanding of its pathology has helped to usher in new and emerging treatment options, as well as a personalized, biopsychosocial approach to its management.

Related article:
2016 Update on female sexual dysfunction

In this Update, I discuss the interplay of physiologic and psychological factors that affect female sexual function as well as the latest options for its management. I have also assembled a panel of experts to discuss 2 cases representative of sexual dysfunction that you may encounter in your clinical practice and how prescribing decisions are made for their management.

Read about factors that impact sexual function and agents to help manage dysfunction.

Multiple transmitters in the brain can increase or decrease sexual desire and function

Neurotransmitters involved in sexual excitation include brain dopamine, melanocortin, oxytocin, vasopressin, and norepinephrine, whereas brain opioids, serotonin, prolactin, and endocannabinoids function as sexual inhibitors. Inhibitory transmitters are activated normally during sexual refractoriness but also from primary aversion or secondary avoidance disorders.¹ Drugs or conditions that reduce brain dopamine levels, increase the action of brain serotonin, or enhance brain opioid pathways have been shown to inhibit sexual desire, while those that increase hypothalamic and mesolimbic dopamine or decrease serotonin release have been shown to stimulate sexual desire.¹ 

Estradiol and progesterone can impact sexual function and desire

In addition to the neurotransmitters, hormones are important modulators of female sexual function. Decreasing levels of circulating estrogen after menopause lead to physiologic, biologic, and clinical changes in the urogenital tissues, such as decreased elastin, thinning of the epithelium, reduced vaginal blood flow, diminished lubrication, and decreased flexibility and elasticity. These changes result in the symptoms of genitourinary syndrome of menopause (GSM), which affects as many as half of all menopausal women.^5,6 In clinical trials, dyspareunia and vaginal dryness are the most bothersome GSM symptoms reported.⁷

The role of hormonal regulation in sexual dysfunction among premenopausal women is not yet fully understood, but we do know that estradiol has been shown to improve sexual desire, progesterone tends to dampen sexual desire, and that testosterone at physiological levels has been shown in most studies to have a neutral effect on sexual desire in a well-estrogenized patient.⁸

Related article:
Focus on treating genital atrophy symptoms

Experience and behavior modulate or reinforce sexual dysfunction

The most common psychological factors that trigger or amplify female sexual dysfunction are depression, anxiety, distraction, negative body image, sexual abuse, and emotional neglect.⁹ Contextual or sociocultural factors, such as relationship discord, life-stage stressors (the empty nest syndrome or anxiety and sleep deprivation from a new baby), as well as cultural or religious values that suppress sexuality, also should be considered.⁹ Experience-based neuroplasticity (changes in brain pathways that become solidified by negative or positive experiences) may elucidate how a multimodal approach, utilizing medical and psychological treatment, can be beneficial for patients, particularly those with hypoactive sexual desire disorder (HSDD).¹

New and emerging approaches to managing female sexual dysfunction

Three agents, one of which has been available for prescription for some time, one that is newly available, and one in the pipeline, are or may soon be in the gynecologist's armamentarium.

Flibanserin

Medications that target excitatory pathways or blunt inhibitory pathways are in development, and one, flibanserin (Addyi), has been US Food and Drug Administration (FDA)-approved for the treatment of acquired, generalized HSDD in premenopausal women.^1,10 Flibanserin is a nonhormonal, centrally acting, postsynaptic serotonin 1A receptor agonist and a serotonin 2A receptor antagonist that is taken daily at bedtime (100 mg); several weeks are usually needed before any effects are noted.¹ It is not approved for postmenopausal women and has a boxed warning about the risks of hypotension and syncope; its use is contraindicated in women who drink alcohol, in those who have hepatic impairment, and with the use of moderate or strong CYP3A4 inhibitors.¹¹

Also keep in mind that flibanserin is only available through a Risk Evaluation and Mitigation Strategy program, so clinicians who wish to prescribe it must enroll in and complete training to become certified providers.⁹

Related article:
What you need to know (and do) to prescribe the new drug flibanserin

Prasterone

Prasterone (Intrarosa), a once-daily intravaginal dehydroepiandrosterone (DHEA) product, is a prohormone that increases local estrogen and testosterone and has the advantage of improved sexual function, desire, arousal, lubrication, orgasm, satisfaction, as well as pain at sexual activity.¹² It was approved by the FDA in November 2016 to treat moderate to severe dyspareunia and has been available for prescribing since July 2017. Its cost is comparable to topical estrogen products, with a $25 copay program.

Because prasterone is not an estrogen, it does not have the boxed warning that all estrogen products are mandated by the FDA to have. This may make it more acceptable to patients, who often decline to use an estrogen product after seeing the boxed warning on the package. The Centers for Medicare and Medicaid Services (CMS) does not have prasterone on its list of potentially hazardous drugs for the elderly. However, keep in mind that because its label is for dyspareunia and not specifically for GSM, CMS considers it a drug of choice--in other words, like sildenafil (Viagra), a lifestyle choice and not for treatment of a medical condition. As such, at the present time, Medicare does not cover it.

Bremelanotide

Late-stage trials of bremelanotide, a melanocortin receptor agonist, are underway. Its mechanism of action is somewhat like that of flibanserin in that both drugs increase dopamine and norepinephrine levels. The advantage of bremelanotide is that it is used as needed. It is dosed subcutaneously (1.75 mg) and it can be used as often as a woman would like to use it. The FDA is expected to consider it for approval in about a year. Unpublished data from poster sessions at recent meetings show that, in a phase 3 study of 1,247 premenopausal women with HSDD (who had already been screened for depression and were found to have a physiologic condition), improvements in desire, arousal, lubrication, and orgasm were shown with bremelanotide. About 18% of women stopped using the drug because of adverse effects (nausea, vomiting, flushing, or headache) versus 2% for placebo. Like flibanserin, it is expected to be approved for premenopausal women only. 

Read how 3 experts would manage differing GSM symptoms.

What would you prescribe for these patients? 

CASE Genitourinary syndrome of menopause (GSM) in a 55-year-old woman

A 55-year-old widow is beginning a new relationship. She has not had partnered sexual activity for several years, but she recently has begun a relationship. She describes pain with attempted penetration with her new partner. Her last menstrual period was 3 years ago and she has experienced very minor menopausal symptoms, which are not bothersome. On examination, the vulva and vagina are pale, with thin epithelium and absent rugae. The tissue lacks elasticity. A virginal speculum is needed to visualize the cervix.

How would you go about deciding which of the many options for management of GSM you will recommend for this patient? What do you weigh as you consider DHEA versus estrogen and topical versus oral therapy?
 
JoAnn V. Pinkerton, MD: Vulvovaginal atrophy (VVA), part of GSM, is associated with postmenopausal estrogen deficiency and includes the signs and symptoms seen on this patient's physical exam: vaginal narrowing, pallor, loss of elasticity, as well as pain with intercourse.⁶ Estrogen therapy is the most effective treatment for vaginal atrophy.¹³ Since she does not have significant menopausal symptoms, low-dose vaginal estrogen preparations are effective and generally safe treatments for VVA; these include creams, tablets containing estradiol or conjugated equine estrogen (CEE), and a low-dose vaginal estradiol ring--all available at doses that result in minimal systemic absorption.

Choice is usually made based on patient desire and likely adherence. If the patient prefers nonestrogen therapies that improve VVA and have been approved for relief of dyspareunia in postmenopausal women, I would discuss with the patient the oral selective estrogen receptor modulator ospemifene,¹⁴ and the new intravaginal DHEA suppositories, prasterone.¹⁵ Ospemifene is taken daily as an oral tablet, has a small risk of blood clots, and is my choice for women who do not need systemic hormone therapy and prefer to avoid vaginal therapy.

Andrew M. Kaunitz, MD: GSM is prevalent in menopausal women and, if not treated, causes progressive vaginal dryness and sexual discomfort. When the main indication for hormonal management in a menopausal woman is GSM (as opposed to treatment of vasomotor symptoms or prevention of osteoporosis), the treatment of choice is low-dose local vaginal estrogen, ospemifene, or prasterone (DHEA). Prasterone is a vaginally administered nonestrogen steroid that was approved by the FDA to treat dyspareunia associated with GSM. DHEA is an endogenous inactive steroid that is converted locally into androgens and estrogens; one vaginal insert is placed nightly.^16,17

This 55-year-old widow has not been sexually active for some time. The facts that attempted penetration was painful and only an ultrathin (virginal) speculum could be used for examination indicate that contraction of the pelvic floor muscles is likely present. Simply starting medical management may not lead to comfortable/successful penetrative sex for this woman. In addition to  medical management, she would likely benefit from referral for physical therapy. Using dilators and other strategies, along with the positive impact that medical management will have on the vaginal mucosa, a woman's physical therapist can work with this patient to help the pelvic floor muscles relax and facilitate comfortable penetrative sex.

James A. Simon, MD: With only minor vasomotor symptoms, I would assess the other potential benefits of a systemic therapy. These might include cardiovascular risk reduction (systemic estrogens or estrogens/progesterone in some), breast cancer risk reduction (some data suggesting ospemifene can accomplish this), osteoporosis prevention (systemic estrogens and estrogen/androgens), etc. If there is an option for a treatment to address more than one symptom, in this case GSM, assessing the risks/benefits of each of these therapies should be estimated for this specific patient.

If there are no systemic benefits to be had, then any of the local treatments should be helpful. As there are no head-to-head comparisons available, local estrogen cream, tablets, rings, local DHEA, or systemic ospemifene each should be considered possible treatments. I also feel this patient may benefit from supplementary self-dilation and/or physical therapy.

Related article:
2017 Update on menopause

 
CASE Dyspareunia and vasomotor symptoms in a 42-year-old breast cancer survivor

A 42-year-old woman with a BRCA1 mutation has undergone prophylactic mastectomies as well as hysterectomy with bilateral salpingo-oophorectomy. She reports mild to moderate hot flashes and bothersome vaginal dryness and dyspareunia. Examination confirms GSM.

Would you advise systemic hormone therapy for this patient? What would your recommendation be for management of her GSM symptoms?

Dr. Simon: While one's gut reaction would be to avoid systemic estrogen therapy in a patient with a BRCA1 mutation, the scientific information confirming this fear is lacking.¹⁸ Such patients may benefit significantly from systemic estrogen therapy (reduced risk of cardiovascular disease and cognitive decline, etc.), and with both breasts and both ovaries removed, estrogen's breast cancer risks, if any in this population, are largely avoided. The patient also may benefit from additional local therapy with either estrogens or DHEA.

Dr. Kaunitz: Due to her high lifetime risk of breast and ovarian cancer, this woman has proceeded with risk-reducing breast and gynecologic surgery. As more BRCA mutation carriers are being identified and undergo risk-reducing bilateral mastectomy (usually with reconstruction) and salpingo-oophorectomy, clinicians and mutation carriers more frequently face decisions regarding use of systemic hormone therapy.

Mutation carriers who have undergone bilateral risk-reducing mastectomy experience a very low baseline future risk for breast cancer; accordingly, concerns regarding this disease should not prevent use of systemic hormone therapy. Furthermore, without hormone replacement, induced menopause in women this age is associated with an elevated risk of osteoporosis, persistent vasomotor symptoms, cardiovascular disease, stroke, mood changes, dementia, Parkinson disease, and overall mortality. Recognizing the safety of estrogen therapy in this setting, this 42-year-old BRCA1 mutation carrier can initiate estrogen therapy. Standard dose estrogen therapy refers to oral estradiol 1.0 mg, conjugated equine estrogen 0.625 mg,or transdermal estradiol 0.05 mg. In younger women like this 42-year-old with surgically induced menopause, higher than standard replacement doses of estrogen are often appropriate.¹⁷

Due to concerns the hormone therapy might further increase future risk of breast cancer, some mutation carriers may delay or avoid risk-reducing bilateral salpingo-oophorectomy, a potentially lifesaving surgery which reduces not only future risk of ovarian cancer but also future risk for breast cancer.

Among mutation carriers with intact breasts, several studies address risk of breast cancer with use of systemic hormone therapy. Although limited in numbers of participants and years of follow-up, in aggregate, these studies provide reassurance that short-term use of systemic hormone therapy does not increase breast cancer risk in women with BRCA1 or BRCA2 mutations and intact breasts.¹⁹

Dr. Pinkerton: For this woman with early surgical menopause and hysterectomy, estrogen therapy could improve her vasomotor symptoms and decrease her risk of bone loss and GSM.¹⁷ In the Women's Health Initiative trial, there were 7 fewer breast cancers per 10,000 women-years in the estrogen-onlyarm.²⁰ Observational studies suggest that hormone therapy, when given to the average age of menopause, decreases the risks of heart disease, Parkinson disease, and dementia.²¹ Limited observational evidence suggests that hormone therapy use does not further increase risk of breast cancer in women following oophorectomy for BRCA1 or BRCA2 gene mutation.²²

The absolute risks observed with hormone therapy tended to be small, especially in younger, healthy women. Systemic hormone therapy could treat her hot flashes and her GSM symptoms and potentially decrease health risks associated with premature estrogen deficiency. Nonestrogen therapies for hot flashes include low-dose antidepressants, gabapentin, and mind-body options, such as cognitive behavioral therapy and hypnosis, but these would not decrease her health risks or treat her GSM.

If she only requests treatment of her GSM symptoms, she would be a candidate for low-dose vaginal estrogen therapy, given as a cream, tablet, or ring depending on her choice. I would not choose ospemifene as my first choice as she is having hot flashes, and there are no data yet on the drug's health benefits in early menopause. If she prefers nonestrogen vaginal therapy, the new intravaginal DHEA might be a good choice as both estrogen and testosterone are increased locally in the vagina while hormone levels remain in the postmenopausal range. There is no boxed warning on the patient insert, although safety in women with breast cancer or in those with elevated risk of breast cancer has not been tested.

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

Illustration: Kimberly Martens for OBG Management

Sexual function is a complex, multifaceted process mediated by neurologic functions, hormonal regulation, and psychological factors. What could possibly go wrong?

As it turns out, quite a lot. Female sexual dysfunction is a common, vastly undertreated sexual health problem that can have wide-reaching effects on a woman’s life. These effects may include impaired body image, self-confidence, and self-worth. Sexual dysfunction also can contribute to relationship dissatisfaction and leave one feeling less connected with her partner.^1,2 Studies have shown women with sexual dysfunction have higher health care expenditures³ and that depression and fatigue are common comorbidities, as is frequently seen in other chronic conditions such as diabetes and back pain.⁴

Understanding the pathogenesis of female sexual dysfunction helps to guide our approach to its management. Indeed, increased understanding of its pathology has helped to usher in new and emerging treatment options, as well as a personalized, biopsychosocial approach to its management.

Related article:
2016 Update on female sexual dysfunction

In this Update, I discuss the interplay of physiologic and psychological factors that affect female sexual function as well as the latest options for its management. I have also assembled a panel of experts to discuss 2 cases representative of sexual dysfunction that you may encounter in your clinical practice and how prescribing decisions are made for their management.

Read about factors that impact sexual function and agents to help manage dysfunction.

Multiple transmitters in the brain can increase or decrease sexual desire and function

Neurotransmitters involved in sexual excitation include brain dopamine, melanocortin, oxytocin, vasopressin, and norepinephrine, whereas brain opioids, serotonin, prolactin, and endocannabinoids function as sexual inhibitors. Inhibitory transmitters are activated normally during sexual refractoriness but also from primary aversion or secondary avoidance disorders.¹ Drugs or conditions that reduce brain dopamine levels, increase the action of brain serotonin, or enhance brain opioid pathways have been shown to inhibit sexual desire, while those that increase hypothalamic and mesolimbic dopamine or decrease serotonin release have been shown to stimulate sexual desire.¹ 

Estradiol and progesterone can impact sexual function and desire

In addition to the neurotransmitters, hormones are important modulators of female sexual function. Decreasing levels of circulating estrogen after menopause lead to physiologic, biologic, and clinical changes in the urogenital tissues, such as decreased elastin, thinning of the epithelium, reduced vaginal blood flow, diminished lubrication, and decreased flexibility and elasticity. These changes result in the symptoms of genitourinary syndrome of menopause (GSM), which affects as many as half of all menopausal women.^5,6 In clinical trials, dyspareunia and vaginal dryness are the most bothersome GSM symptoms reported.⁷

The role of hormonal regulation in sexual dysfunction among premenopausal women is not yet fully understood, but we do know that estradiol has been shown to improve sexual desire, progesterone tends to dampen sexual desire, and that testosterone at physiological levels has been shown in most studies to have a neutral effect on sexual desire in a well-estrogenized patient.⁸

Related article:
Focus on treating genital atrophy symptoms

Experience and behavior modulate or reinforce sexual dysfunction

The most common psychological factors that trigger or amplify female sexual dysfunction are depression, anxiety, distraction, negative body image, sexual abuse, and emotional neglect.⁹ Contextual or sociocultural factors, such as relationship discord, life-stage stressors (the empty nest syndrome or anxiety and sleep deprivation from a new baby), as well as cultural or religious values that suppress sexuality, also should be considered.⁹ Experience-based neuroplasticity (changes in brain pathways that become solidified by negative or positive experiences) may elucidate how a multimodal approach, utilizing medical and psychological treatment, can be beneficial for patients, particularly those with hypoactive sexual desire disorder (HSDD).¹

New and emerging approaches to managing female sexual dysfunction

Three agents, one of which has been available for prescription for some time, one that is newly available, and one in the pipeline, are or may soon be in the gynecologist's armamentarium.

Flibanserin

Medications that target excitatory pathways or blunt inhibitory pathways are in development, and one, flibanserin (Addyi), has been US Food and Drug Administration (FDA)-approved for the treatment of acquired, generalized HSDD in premenopausal women.^1,10 Flibanserin is a nonhormonal, centrally acting, postsynaptic serotonin 1A receptor agonist and a serotonin 2A receptor antagonist that is taken daily at bedtime (100 mg); several weeks are usually needed before any effects are noted.¹ It is not approved for postmenopausal women and has a boxed warning about the risks of hypotension and syncope; its use is contraindicated in women who drink alcohol, in those who have hepatic impairment, and with the use of moderate or strong CYP3A4 inhibitors.¹¹

Also keep in mind that flibanserin is only available through a Risk Evaluation and Mitigation Strategy program, so clinicians who wish to prescribe it must enroll in and complete training to become certified providers.⁹

Related article:
What you need to know (and do) to prescribe the new drug flibanserin

Prasterone

Prasterone (Intrarosa), a once-daily intravaginal dehydroepiandrosterone (DHEA) product, is a prohormone that increases local estrogen and testosterone and has the advantage of improved sexual function, desire, arousal, lubrication, orgasm, satisfaction, as well as pain at sexual activity.¹² It was approved by the FDA in November 2016 to treat moderate to severe dyspareunia and has been available for prescribing since July 2017. Its cost is comparable to topical estrogen products, with a $25 copay program.

Because prasterone is not an estrogen, it does not have the boxed warning that all estrogen products are mandated by the FDA to have. This may make it more acceptable to patients, who often decline to use an estrogen product after seeing the boxed warning on the package. The Centers for Medicare and Medicaid Services (CMS) does not have prasterone on its list of potentially hazardous drugs for the elderly. However, keep in mind that because its label is for dyspareunia and not specifically for GSM, CMS considers it a drug of choice--in other words, like sildenafil (Viagra), a lifestyle choice and not for treatment of a medical condition. As such, at the present time, Medicare does not cover it.

Bremelanotide

Late-stage trials of bremelanotide, a melanocortin receptor agonist, are underway. Its mechanism of action is somewhat like that of flibanserin in that both drugs increase dopamine and norepinephrine levels. The advantage of bremelanotide is that it is used as needed. It is dosed subcutaneously (1.75 mg) and it can be used as often as a woman would like to use it. The FDA is expected to consider it for approval in about a year. Unpublished data from poster sessions at recent meetings show that, in a phase 3 study of 1,247 premenopausal women with HSDD (who had already been screened for depression and were found to have a physiologic condition), improvements in desire, arousal, lubrication, and orgasm were shown with bremelanotide. About 18% of women stopped using the drug because of adverse effects (nausea, vomiting, flushing, or headache) versus 2% for placebo. Like flibanserin, it is expected to be approved for premenopausal women only. 

Read how 3 experts would manage differing GSM symptoms.

What would you prescribe for these patients? 

CASE Genitourinary syndrome of menopause (GSM) in a 55-year-old woman

A 55-year-old widow is beginning a new relationship. She has not had partnered sexual activity for several years, but she recently has begun a relationship. She describes pain with attempted penetration with her new partner. Her last menstrual period was 3 years ago and she has experienced very minor menopausal symptoms, which are not bothersome. On examination, the vulva and vagina are pale, with thin epithelium and absent rugae. The tissue lacks elasticity. A virginal speculum is needed to visualize the cervix.

How would you go about deciding which of the many options for management of GSM you will recommend for this patient? What do you weigh as you consider DHEA versus estrogen and topical versus oral therapy?
 
JoAnn V. Pinkerton, MD: Vulvovaginal atrophy (VVA), part of GSM, is associated with postmenopausal estrogen deficiency and includes the signs and symptoms seen on this patient's physical exam: vaginal narrowing, pallor, loss of elasticity, as well as pain with intercourse.⁶ Estrogen therapy is the most effective treatment for vaginal atrophy.¹³ Since she does not have significant menopausal symptoms, low-dose vaginal estrogen preparations are effective and generally safe treatments for VVA; these include creams, tablets containing estradiol or conjugated equine estrogen (CEE), and a low-dose vaginal estradiol ring--all available at doses that result in minimal systemic absorption.

Choice is usually made based on patient desire and likely adherence. If the patient prefers nonestrogen therapies that improve VVA and have been approved for relief of dyspareunia in postmenopausal women, I would discuss with the patient the oral selective estrogen receptor modulator ospemifene,¹⁴ and the new intravaginal DHEA suppositories, prasterone.¹⁵ Ospemifene is taken daily as an oral tablet, has a small risk of blood clots, and is my choice for women who do not need systemic hormone therapy and prefer to avoid vaginal therapy.

Andrew M. Kaunitz, MD: GSM is prevalent in menopausal women and, if not treated, causes progressive vaginal dryness and sexual discomfort. When the main indication for hormonal management in a menopausal woman is GSM (as opposed to treatment of vasomotor symptoms or prevention of osteoporosis), the treatment of choice is low-dose local vaginal estrogen, ospemifene, or prasterone (DHEA). Prasterone is a vaginally administered nonestrogen steroid that was approved by the FDA to treat dyspareunia associated with GSM. DHEA is an endogenous inactive steroid that is converted locally into androgens and estrogens; one vaginal insert is placed nightly.^16,17

This 55-year-old widow has not been sexually active for some time. The facts that attempted penetration was painful and only an ultrathin (virginal) speculum could be used for examination indicate that contraction of the pelvic floor muscles is likely present. Simply starting medical management may not lead to comfortable/successful penetrative sex for this woman. In addition to  medical management, she would likely benefit from referral for physical therapy. Using dilators and other strategies, along with the positive impact that medical management will have on the vaginal mucosa, a woman's physical therapist can work with this patient to help the pelvic floor muscles relax and facilitate comfortable penetrative sex.

James A. Simon, MD: With only minor vasomotor symptoms, I would assess the other potential benefits of a systemic therapy. These might include cardiovascular risk reduction (systemic estrogens or estrogens/progesterone in some), breast cancer risk reduction (some data suggesting ospemifene can accomplish this), osteoporosis prevention (systemic estrogens and estrogen/androgens), etc. If there is an option for a treatment to address more than one symptom, in this case GSM, assessing the risks/benefits of each of these therapies should be estimated for this specific patient.

If there are no systemic benefits to be had, then any of the local treatments should be helpful. As there are no head-to-head comparisons available, local estrogen cream, tablets, rings, local DHEA, or systemic ospemifene each should be considered possible treatments. I also feel this patient may benefit from supplementary self-dilation and/or physical therapy.

Related article:
2017 Update on menopause

 
CASE Dyspareunia and vasomotor symptoms in a 42-year-old breast cancer survivor

A 42-year-old woman with a BRCA1 mutation has undergone prophylactic mastectomies as well as hysterectomy with bilateral salpingo-oophorectomy. She reports mild to moderate hot flashes and bothersome vaginal dryness and dyspareunia. Examination confirms GSM.

Would you advise systemic hormone therapy for this patient? What would your recommendation be for management of her GSM symptoms?

Dr. Simon: While one's gut reaction would be to avoid systemic estrogen therapy in a patient with a BRCA1 mutation, the scientific information confirming this fear is lacking.¹⁸ Such patients may benefit significantly from systemic estrogen therapy (reduced risk of cardiovascular disease and cognitive decline, etc.), and with both breasts and both ovaries removed, estrogen's breast cancer risks, if any in this population, are largely avoided. The patient also may benefit from additional local therapy with either estrogens or DHEA.

Dr. Kaunitz: Due to her high lifetime risk of breast and ovarian cancer, this woman has proceeded with risk-reducing breast and gynecologic surgery. As more BRCA mutation carriers are being identified and undergo risk-reducing bilateral mastectomy (usually with reconstruction) and salpingo-oophorectomy, clinicians and mutation carriers more frequently face decisions regarding use of systemic hormone therapy.

Mutation carriers who have undergone bilateral risk-reducing mastectomy experience a very low baseline future risk for breast cancer; accordingly, concerns regarding this disease should not prevent use of systemic hormone therapy. Furthermore, without hormone replacement, induced menopause in women this age is associated with an elevated risk of osteoporosis, persistent vasomotor symptoms, cardiovascular disease, stroke, mood changes, dementia, Parkinson disease, and overall mortality. Recognizing the safety of estrogen therapy in this setting, this 42-year-old BRCA1 mutation carrier can initiate estrogen therapy. Standard dose estrogen therapy refers to oral estradiol 1.0 mg, conjugated equine estrogen 0.625 mg,or transdermal estradiol 0.05 mg. In younger women like this 42-year-old with surgically induced menopause, higher than standard replacement doses of estrogen are often appropriate.¹⁷

Due to concerns the hormone therapy might further increase future risk of breast cancer, some mutation carriers may delay or avoid risk-reducing bilateral salpingo-oophorectomy, a potentially lifesaving surgery which reduces not only future risk of ovarian cancer but also future risk for breast cancer.

Among mutation carriers with intact breasts, several studies address risk of breast cancer with use of systemic hormone therapy. Although limited in numbers of participants and years of follow-up, in aggregate, these studies provide reassurance that short-term use of systemic hormone therapy does not increase breast cancer risk in women with BRCA1 or BRCA2 mutations and intact breasts.¹⁹

Dr. Pinkerton: For this woman with early surgical menopause and hysterectomy, estrogen therapy could improve her vasomotor symptoms and decrease her risk of bone loss and GSM.¹⁷ In the Women's Health Initiative trial, there were 7 fewer breast cancers per 10,000 women-years in the estrogen-onlyarm.²⁰ Observational studies suggest that hormone therapy, when given to the average age of menopause, decreases the risks of heart disease, Parkinson disease, and dementia.²¹ Limited observational evidence suggests that hormone therapy use does not further increase risk of breast cancer in women following oophorectomy for BRCA1 or BRCA2 gene mutation.²²

The absolute risks observed with hormone therapy tended to be small, especially in younger, healthy women. Systemic hormone therapy could treat her hot flashes and her GSM symptoms and potentially decrease health risks associated with premature estrogen deficiency. Nonestrogen therapies for hot flashes include low-dose antidepressants, gabapentin, and mind-body options, such as cognitive behavioral therapy and hypnosis, but these would not decrease her health risks or treat her GSM.

If she only requests treatment of her GSM symptoms, she would be a candidate for low-dose vaginal estrogen therapy, given as a cream, tablet, or ring depending on her choice. I would not choose ospemifene as my first choice as she is having hot flashes, and there are no data yet on the drug's health benefits in early menopause. If she prefers nonestrogen vaginal therapy, the new intravaginal DHEA might be a good choice as both estrogen and testosterone are increased locally in the vagina while hormone levels remain in the postmenopausal range. There is no boxed warning on the patient insert, although safety in women with breast cancer or in those with elevated risk of breast cancer has not been tested.

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

Illustration: Kimberly Martens for OBG Management

Sexual function is a complex, multifaceted process mediated by neurologic functions, hormonal regulation, and psychological factors. What could possibly go wrong?

As it turns out, quite a lot. Female sexual dysfunction is a common, vastly undertreated sexual health problem that can have wide-reaching effects on a woman’s life. These effects may include impaired body image, self-confidence, and self-worth. Sexual dysfunction also can contribute to relationship dissatisfaction and leave one feeling less connected with her partner.^1,2 Studies have shown women with sexual dysfunction have higher health care expenditures³ and that depression and fatigue are common comorbidities, as is frequently seen in other chronic conditions such as diabetes and back pain.⁴

Understanding the pathogenesis of female sexual dysfunction helps to guide our approach to its management. Indeed, increased understanding of its pathology has helped to usher in new and emerging treatment options, as well as a personalized, biopsychosocial approach to its management.

Related article:
2016 Update on female sexual dysfunction

In this Update, I discuss the interplay of physiologic and psychological factors that affect female sexual function as well as the latest options for its management. I have also assembled a panel of experts to discuss 2 cases representative of sexual dysfunction that you may encounter in your clinical practice and how prescribing decisions are made for their management.

Read about factors that impact sexual function and agents to help manage dysfunction.

Multiple transmitters in the brain can increase or decrease sexual desire and function

Neurotransmitters involved in sexual excitation include brain dopamine, melanocortin, oxytocin, vasopressin, and norepinephrine, whereas brain opioids, serotonin, prolactin, and endocannabinoids function as sexual inhibitors. Inhibitory transmitters are activated normally during sexual refractoriness but also from primary aversion or secondary avoidance disorders.¹ Drugs or conditions that reduce brain dopamine levels, increase the action of brain serotonin, or enhance brain opioid pathways have been shown to inhibit sexual desire, while those that increase hypothalamic and mesolimbic dopamine or decrease serotonin release have been shown to stimulate sexual desire.¹ 

Estradiol and progesterone can impact sexual function and desire

In addition to the neurotransmitters, hormones are important modulators of female sexual function. Decreasing levels of circulating estrogen after menopause lead to physiologic, biologic, and clinical changes in the urogenital tissues, such as decreased elastin, thinning of the epithelium, reduced vaginal blood flow, diminished lubrication, and decreased flexibility and elasticity. These changes result in the symptoms of genitourinary syndrome of menopause (GSM), which affects as many as half of all menopausal women.^5,6 In clinical trials, dyspareunia and vaginal dryness are the most bothersome GSM symptoms reported.⁷

The role of hormonal regulation in sexual dysfunction among premenopausal women is not yet fully understood, but we do know that estradiol has been shown to improve sexual desire, progesterone tends to dampen sexual desire, and that testosterone at physiological levels has been shown in most studies to have a neutral effect on sexual desire in a well-estrogenized patient.⁸

Related article:
Focus on treating genital atrophy symptoms

Experience and behavior modulate or reinforce sexual dysfunction

The most common psychological factors that trigger or amplify female sexual dysfunction are depression, anxiety, distraction, negative body image, sexual abuse, and emotional neglect.⁹ Contextual or sociocultural factors, such as relationship discord, life-stage stressors (the empty nest syndrome or anxiety and sleep deprivation from a new baby), as well as cultural or religious values that suppress sexuality, also should be considered.⁹ Experience-based neuroplasticity (changes in brain pathways that become solidified by negative or positive experiences) may elucidate how a multimodal approach, utilizing medical and psychological treatment, can be beneficial for patients, particularly those with hypoactive sexual desire disorder (HSDD).¹

New and emerging approaches to managing female sexual dysfunction

Three agents, one of which has been available for prescription for some time, one that is newly available, and one in the pipeline, are or may soon be in the gynecologist's armamentarium.

Flibanserin

Medications that target excitatory pathways or blunt inhibitory pathways are in development, and one, flibanserin (Addyi), has been US Food and Drug Administration (FDA)-approved for the treatment of acquired, generalized HSDD in premenopausal women.^1,10 Flibanserin is a nonhormonal, centrally acting, postsynaptic serotonin 1A receptor agonist and a serotonin 2A receptor antagonist that is taken daily at bedtime (100 mg); several weeks are usually needed before any effects are noted.¹ It is not approved for postmenopausal women and has a boxed warning about the risks of hypotension and syncope; its use is contraindicated in women who drink alcohol, in those who have hepatic impairment, and with the use of moderate or strong CYP3A4 inhibitors.¹¹

Also keep in mind that flibanserin is only available through a Risk Evaluation and Mitigation Strategy program, so clinicians who wish to prescribe it must enroll in and complete training to become certified providers.⁹

Related article:
What you need to know (and do) to prescribe the new drug flibanserin

Prasterone

Prasterone (Intrarosa), a once-daily intravaginal dehydroepiandrosterone (DHEA) product, is a prohormone that increases local estrogen and testosterone and has the advantage of improved sexual function, desire, arousal, lubrication, orgasm, satisfaction, as well as pain at sexual activity.¹² It was approved by the FDA in November 2016 to treat moderate to severe dyspareunia and has been available for prescribing since July 2017. Its cost is comparable to topical estrogen products, with a $25 copay program.

Because prasterone is not an estrogen, it does not have the boxed warning that all estrogen products are mandated by the FDA to have. This may make it more acceptable to patients, who often decline to use an estrogen product after seeing the boxed warning on the package. The Centers for Medicare and Medicaid Services (CMS) does not have prasterone on its list of potentially hazardous drugs for the elderly. However, keep in mind that because its label is for dyspareunia and not specifically for GSM, CMS considers it a drug of choice--in other words, like sildenafil (Viagra), a lifestyle choice and not for treatment of a medical condition. As such, at the present time, Medicare does not cover it.

Bremelanotide

Late-stage trials of bremelanotide, a melanocortin receptor agonist, are underway. Its mechanism of action is somewhat like that of flibanserin in that both drugs increase dopamine and norepinephrine levels. The advantage of bremelanotide is that it is used as needed. It is dosed subcutaneously (1.75 mg) and it can be used as often as a woman would like to use it. The FDA is expected to consider it for approval in about a year. Unpublished data from poster sessions at recent meetings show that, in a phase 3 study of 1,247 premenopausal women with HSDD (who had already been screened for depression and were found to have a physiologic condition), improvements in desire, arousal, lubrication, and orgasm were shown with bremelanotide. About 18% of women stopped using the drug because of adverse effects (nausea, vomiting, flushing, or headache) versus 2% for placebo. Like flibanserin, it is expected to be approved for premenopausal women only. 

Read how 3 experts would manage differing GSM symptoms.

What would you prescribe for these patients? 

CASE Genitourinary syndrome of menopause (GSM) in a 55-year-old woman

A 55-year-old widow is beginning a new relationship. She has not had partnered sexual activity for several years, but she recently has begun a relationship. She describes pain with attempted penetration with her new partner. Her last menstrual period was 3 years ago and she has experienced very minor menopausal symptoms, which are not bothersome. On examination, the vulva and vagina are pale, with thin epithelium and absent rugae. The tissue lacks elasticity. A virginal speculum is needed to visualize the cervix.

How would you go about deciding which of the many options for management of GSM you will recommend for this patient? What do you weigh as you consider DHEA versus estrogen and topical versus oral therapy?
 
JoAnn V. Pinkerton, MD: Vulvovaginal atrophy (VVA), part of GSM, is associated with postmenopausal estrogen deficiency and includes the signs and symptoms seen on this patient's physical exam: vaginal narrowing, pallor, loss of elasticity, as well as pain with intercourse.⁶ Estrogen therapy is the most effective treatment for vaginal atrophy.¹³ Since she does not have significant menopausal symptoms, low-dose vaginal estrogen preparations are effective and generally safe treatments for VVA; these include creams, tablets containing estradiol or conjugated equine estrogen (CEE), and a low-dose vaginal estradiol ring--all available at doses that result in minimal systemic absorption.

Choice is usually made based on patient desire and likely adherence. If the patient prefers nonestrogen therapies that improve VVA and have been approved for relief of dyspareunia in postmenopausal women, I would discuss with the patient the oral selective estrogen receptor modulator ospemifene,¹⁴ and the new intravaginal DHEA suppositories, prasterone.¹⁵ Ospemifene is taken daily as an oral tablet, has a small risk of blood clots, and is my choice for women who do not need systemic hormone therapy and prefer to avoid vaginal therapy.

Andrew M. Kaunitz, MD: GSM is prevalent in menopausal women and, if not treated, causes progressive vaginal dryness and sexual discomfort. When the main indication for hormonal management in a menopausal woman is GSM (as opposed to treatment of vasomotor symptoms or prevention of osteoporosis), the treatment of choice is low-dose local vaginal estrogen, ospemifene, or prasterone (DHEA). Prasterone is a vaginally administered nonestrogen steroid that was approved by the FDA to treat dyspareunia associated with GSM. DHEA is an endogenous inactive steroid that is converted locally into androgens and estrogens; one vaginal insert is placed nightly.^16,17

This 55-year-old widow has not been sexually active for some time. The facts that attempted penetration was painful and only an ultrathin (virginal) speculum could be used for examination indicate that contraction of the pelvic floor muscles is likely present. Simply starting medical management may not lead to comfortable/successful penetrative sex for this woman. In addition to  medical management, she would likely benefit from referral for physical therapy. Using dilators and other strategies, along with the positive impact that medical management will have on the vaginal mucosa, a woman's physical therapist can work with this patient to help the pelvic floor muscles relax and facilitate comfortable penetrative sex.

James A. Simon, MD: With only minor vasomotor symptoms, I would assess the other potential benefits of a systemic therapy. These might include cardiovascular risk reduction (systemic estrogens or estrogens/progesterone in some), breast cancer risk reduction (some data suggesting ospemifene can accomplish this), osteoporosis prevention (systemic estrogens and estrogen/androgens), etc. If there is an option for a treatment to address more than one symptom, in this case GSM, assessing the risks/benefits of each of these therapies should be estimated for this specific patient.

If there are no systemic benefits to be had, then any of the local treatments should be helpful. As there are no head-to-head comparisons available, local estrogen cream, tablets, rings, local DHEA, or systemic ospemifene each should be considered possible treatments. I also feel this patient may benefit from supplementary self-dilation and/or physical therapy.

Related article:
2017 Update on menopause

 
CASE Dyspareunia and vasomotor symptoms in a 42-year-old breast cancer survivor

A 42-year-old woman with a BRCA1 mutation has undergone prophylactic mastectomies as well as hysterectomy with bilateral salpingo-oophorectomy. She reports mild to moderate hot flashes and bothersome vaginal dryness and dyspareunia. Examination confirms GSM.

Would you advise systemic hormone therapy for this patient? What would your recommendation be for management of her GSM symptoms?

Dr. Simon: While one's gut reaction would be to avoid systemic estrogen therapy in a patient with a BRCA1 mutation, the scientific information confirming this fear is lacking.¹⁸ Such patients may benefit significantly from systemic estrogen therapy (reduced risk of cardiovascular disease and cognitive decline, etc.), and with both breasts and both ovaries removed, estrogen's breast cancer risks, if any in this population, are largely avoided. The patient also may benefit from additional local therapy with either estrogens or DHEA.

Dr. Kaunitz: Due to her high lifetime risk of breast and ovarian cancer, this woman has proceeded with risk-reducing breast and gynecologic surgery. As more BRCA mutation carriers are being identified and undergo risk-reducing bilateral mastectomy (usually with reconstruction) and salpingo-oophorectomy, clinicians and mutation carriers more frequently face decisions regarding use of systemic hormone therapy.

Mutation carriers who have undergone bilateral risk-reducing mastectomy experience a very low baseline future risk for breast cancer; accordingly, concerns regarding this disease should not prevent use of systemic hormone therapy. Furthermore, without hormone replacement, induced menopause in women this age is associated with an elevated risk of osteoporosis, persistent vasomotor symptoms, cardiovascular disease, stroke, mood changes, dementia, Parkinson disease, and overall mortality. Recognizing the safety of estrogen therapy in this setting, this 42-year-old BRCA1 mutation carrier can initiate estrogen therapy. Standard dose estrogen therapy refers to oral estradiol 1.0 mg, conjugated equine estrogen 0.625 mg,or transdermal estradiol 0.05 mg. In younger women like this 42-year-old with surgically induced menopause, higher than standard replacement doses of estrogen are often appropriate.¹⁷

Due to concerns the hormone therapy might further increase future risk of breast cancer, some mutation carriers may delay or avoid risk-reducing bilateral salpingo-oophorectomy, a potentially lifesaving surgery which reduces not only future risk of ovarian cancer but also future risk for breast cancer.

Among mutation carriers with intact breasts, several studies address risk of breast cancer with use of systemic hormone therapy. Although limited in numbers of participants and years of follow-up, in aggregate, these studies provide reassurance that short-term use of systemic hormone therapy does not increase breast cancer risk in women with BRCA1 or BRCA2 mutations and intact breasts.¹⁹

Dr. Pinkerton: For this woman with early surgical menopause and hysterectomy, estrogen therapy could improve her vasomotor symptoms and decrease her risk of bone loss and GSM.¹⁷ In the Women's Health Initiative trial, there were 7 fewer breast cancers per 10,000 women-years in the estrogen-onlyarm.²⁰ Observational studies suggest that hormone therapy, when given to the average age of menopause, decreases the risks of heart disease, Parkinson disease, and dementia.²¹ Limited observational evidence suggests that hormone therapy use does not further increase risk of breast cancer in women following oophorectomy for BRCA1 or BRCA2 gene mutation.²²

The absolute risks observed with hormone therapy tended to be small, especially in younger, healthy women. Systemic hormone therapy could treat her hot flashes and her GSM symptoms and potentially decrease health risks associated with premature estrogen deficiency. Nonestrogen therapies for hot flashes include low-dose antidepressants, gabapentin, and mind-body options, such as cognitive behavioral therapy and hypnosis, but these would not decrease her health risks or treat her GSM.

If she only requests treatment of her GSM symptoms, she would be a candidate for low-dose vaginal estrogen therapy, given as a cream, tablet, or ring depending on her choice. I would not choose ospemifene as my first choice as she is having hot flashes, and there are no data yet on the drug's health benefits in early menopause. If she prefers nonestrogen vaginal therapy, the new intravaginal DHEA might be a good choice as both estrogen and testosterone are increased locally in the vagina while hormone levels remain in the postmenopausal range. There is no boxed warning on the patient insert, although safety in women with breast cancer or in those with elevated risk of breast cancer has not been tested.

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

Lifestyle modification, rather than hormone therapy, should form the basis for managing estrogen-depletion symptoms and associated clinical problems in breast cancer survivors, according to a review of available evidence.

The review, conducted by the writing group for the Endocrine Society’s guidelines on management of menopausal symptoms, was prompted by the paucity of both randomized controlled trials in breast cancer survivors with estrogen deficiency issues and guidelines that sufficiently focus on treatment of this subgroup of women.

[email protected]

Lifestyle modification, rather than hormone therapy, should form the basis for managing estrogen-depletion symptoms and associated clinical problems in breast cancer survivors, according to a review of available evidence.

The review, conducted by the writing group for the Endocrine Society’s guidelines on management of menopausal symptoms, was prompted by the paucity of both randomized controlled trials in breast cancer survivors with estrogen deficiency issues and guidelines that sufficiently focus on treatment of this subgroup of women.

[email protected]

Lifestyle modification, rather than hormone therapy, should form the basis for managing estrogen-depletion symptoms and associated clinical problems in breast cancer survivors, according to a review of available evidence.

The review, conducted by the writing group for the Endocrine Society’s guidelines on management of menopausal symptoms, was prompted by the paucity of both randomized controlled trials in breast cancer survivors with estrogen deficiency issues and guidelines that sufficiently focus on treatment of this subgroup of women.

[email protected]

SAN FRANCISCO – Parathyroid hormone and parathyroid hormone–related protein analogs show promise for treating osteoporosis, but, for now, they’re reserved for the most severe cases.

Teriparatide, a parathyroid hormone analog, is the first treatment that stimulates bone formation instead of inhibiting bone resorption, but studies to date are too small to evaluate its effect on hip fractures, Jeffrey A. Tice, MD, said at the UCSF Annual Advances in Internal Medicine meeting.

[email protected]

SAN FRANCISCO – Parathyroid hormone and parathyroid hormone–related protein analogs show promise for treating osteoporosis, but, for now, they’re reserved for the most severe cases.

Teriparatide, a parathyroid hormone analog, is the first treatment that stimulates bone formation instead of inhibiting bone resorption, but studies to date are too small to evaluate its effect on hip fractures, Jeffrey A. Tice, MD, said at the UCSF Annual Advances in Internal Medicine meeting.

[email protected]

SAN FRANCISCO – Parathyroid hormone and parathyroid hormone–related protein analogs show promise for treating osteoporosis, but, for now, they’re reserved for the most severe cases.

Teriparatide, a parathyroid hormone analog, is the first treatment that stimulates bone formation instead of inhibiting bone resorption, but studies to date are too small to evaluate its effect on hip fractures, Jeffrey A. Tice, MD, said at the UCSF Annual Advances in Internal Medicine meeting.

[email protected]

NONESTROGEN PRODUCT FOR DYSPAREUNIA

FOR MORE INFORMATION, VISIT: http://www.amagpharma.com

ORAL MAINTENANCE TX FOR RECURRENT CANCER

FOR MORE INFORMATION, VISIT: http://www.zejula.com

MIGS STAPLING SYSTEM WITH REAL-TIME FEEDBACK

FOR MORE INFORMATION, VISIT: http://www.medtronic.com

BONE BUILDING AGENT

FOR MORE INFORMATION, VISIT: http://www.radiuspharm.com

PROTEOMIC BREAST CANCER ASSAY

FOR MORE INFORMATION, VISIT: http://www.provistadx.com

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

NONESTROGEN PRODUCT FOR DYSPAREUNIA

FOR MORE INFORMATION, VISIT: http://www.amagpharma.com

ORAL MAINTENANCE TX FOR RECURRENT CANCER

FOR MORE INFORMATION, VISIT: http://www.zejula.com

MIGS STAPLING SYSTEM WITH REAL-TIME FEEDBACK

FOR MORE INFORMATION, VISIT: http://www.medtronic.com

BONE BUILDING AGENT

FOR MORE INFORMATION, VISIT: http://www.radiuspharm.com

PROTEOMIC BREAST CANCER ASSAY

FOR MORE INFORMATION, VISIT: http://www.provistadx.com

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

NONESTROGEN PRODUCT FOR DYSPAREUNIA

FOR MORE INFORMATION, VISIT: http://www.amagpharma.com

ORAL MAINTENANCE TX FOR RECURRENT CANCER

FOR MORE INFORMATION, VISIT: http://www.zejula.com

MIGS STAPLING SYSTEM WITH REAL-TIME FEEDBACK

FOR MORE INFORMATION, VISIT: http://www.medtronic.com

BONE BUILDING AGENT

FOR MORE INFORMATION, VISIT: http://www.radiuspharm.com

PROTEOMIC BREAST CANCER ASSAY

FOR MORE INFORMATION, VISIT: http://www.provistadx.com

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

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

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

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

Read about updated NAMS guidelines on HT

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

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

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

What are the major findings?

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

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

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

When to initiate HT and duration of use

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

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

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

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

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

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

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

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

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

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

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

Related Article:
Focus on treating genital atrophy symptoms
 

The importance of relaying the new guidelines to patients

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

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

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

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

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

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

Details of the study

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

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

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

Calls for the current boxed warning to be revised

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

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

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

Related Article:
2016 Update on menopause
 

Recommended label revisions

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

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

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

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

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

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

Read about updated NAMS guidelines on HT

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

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

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

What are the major findings?

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

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

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

When to initiate HT and duration of use

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

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

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

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

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

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

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

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

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

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

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

Related Article:
Focus on treating genital atrophy symptoms
 

The importance of relaying the new guidelines to patients

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

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

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

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

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

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

Details of the study

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

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

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

Calls for the current boxed warning to be revised

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

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

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

Related Article:
2016 Update on menopause
 

Recommended label revisions

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

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

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

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

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

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

Read about updated NAMS guidelines on HT

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

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

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

What are the major findings?

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

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

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

When to initiate HT and duration of use

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

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

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

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

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

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

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

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

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

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

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

Related Article:
Focus on treating genital atrophy symptoms
 

The importance of relaying the new guidelines to patients

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

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

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

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

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

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

Details of the study

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

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

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

Calls for the current boxed warning to be revised

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

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

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

Related Article:
2016 Update on menopause
 

Recommended label revisions

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

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

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

MADRID – Romosozumab, an investigational bone-building agent, reduced new vertebral fractures by 73% among postmenopausal women with osteoporosis.

Compared with placebo, the monoclonal antibody also reduced the risk of a clinical fracture by 36% after 12 months of treatment, Piet Geusens, MD, said at the European Congress of Rheumatology. The effect was maintained at 24 months, with a 50% reduction in fracture risk, said Dr. Geusens of Maastricht University, the Netherlands.

Romosozumab also significantly reduced clinical and nonvertebral fractures and increased bone mineral density at the total hip, femoral neck, and lumbar spine in the phase III FRAME study, cosponsored by Amgen and UCB Pharma.

But recently, the finding of increased cardiovascular events in another highly anticipated phase III study of romosozumab cast a cloud of doubt over its rising star. During an interview at EULAR, a UCB company spokesman said the company no longer anticipates a 2017 Food and Drug Administration approval.

[email protected]

On Twitter @Alz_gal

MADRID – Romosozumab, an investigational bone-building agent, reduced new vertebral fractures by 73% among postmenopausal women with osteoporosis.

Compared with placebo, the monoclonal antibody also reduced the risk of a clinical fracture by 36% after 12 months of treatment, Piet Geusens, MD, said at the European Congress of Rheumatology. The effect was maintained at 24 months, with a 50% reduction in fracture risk, said Dr. Geusens of Maastricht University, the Netherlands.

Romosozumab also significantly reduced clinical and nonvertebral fractures and increased bone mineral density at the total hip, femoral neck, and lumbar spine in the phase III FRAME study, cosponsored by Amgen and UCB Pharma.

But recently, the finding of increased cardiovascular events in another highly anticipated phase III study of romosozumab cast a cloud of doubt over its rising star. During an interview at EULAR, a UCB company spokesman said the company no longer anticipates a 2017 Food and Drug Administration approval.

[email protected]

On Twitter @Alz_gal

MADRID – Romosozumab, an investigational bone-building agent, reduced new vertebral fractures by 73% among postmenopausal women with osteoporosis.

Compared with placebo, the monoclonal antibody also reduced the risk of a clinical fracture by 36% after 12 months of treatment, Piet Geusens, MD, said at the European Congress of Rheumatology. The effect was maintained at 24 months, with a 50% reduction in fracture risk, said Dr. Geusens of Maastricht University, the Netherlands.

Romosozumab also significantly reduced clinical and nonvertebral fractures and increased bone mineral density at the total hip, femoral neck, and lumbar spine in the phase III FRAME study, cosponsored by Amgen and UCB Pharma.

But recently, the finding of increased cardiovascular events in another highly anticipated phase III study of romosozumab cast a cloud of doubt over its rising star. During an interview at EULAR, a UCB company spokesman said the company no longer anticipates a 2017 Food and Drug Administration approval.

[email protected]

On Twitter @Alz_gal

VANCOUVER – Endometriosis, while generally considered a premenopausal condition, can also occur in women following surgical or natural menopause, and can undergo malignant transformation, although this risk is likely very small.

That was the main message from a new meta-analysis presented at the World Congress on Endometriosis. “We wanted to synthesize the case reports out there to show some common factors so physicians can be aware of them,” said Laura Gemmell, a second-year medical student at Case Western Reserve University, Cleveland, who presented the research.

designer491/Thinkstock

VANCOUVER – Endometriosis, while generally considered a premenopausal condition, can also occur in women following surgical or natural menopause, and can undergo malignant transformation, although this risk is likely very small.

That was the main message from a new meta-analysis presented at the World Congress on Endometriosis. “We wanted to synthesize the case reports out there to show some common factors so physicians can be aware of them,” said Laura Gemmell, a second-year medical student at Case Western Reserve University, Cleveland, who presented the research.

designer491/Thinkstock

VANCOUVER – Endometriosis, while generally considered a premenopausal condition, can also occur in women following surgical or natural menopause, and can undergo malignant transformation, although this risk is likely very small.

That was the main message from a new meta-analysis presented at the World Congress on Endometriosis. “We wanted to synthesize the case reports out there to show some common factors so physicians can be aware of them,” said Laura Gemmell, a second-year medical student at Case Western Reserve University, Cleveland, who presented the research.

designer491/Thinkstock

Hormone therapy, in the form of estrogen combined with progestin, is not recommended to prevent chronic conditions such as heart disease and diabetes in postmenopausal women, according to updated draft recommendations from the U.S. Preventive Services Task Force. They also recommended against the use of estrogen alone in postmenopausal women who have had a hysterectomy.

The updated recommendations were published online May 16 on the U.S. Preventive Services Task Force website.

After considering new evidence in the last several years, the recommendations are essentially unchanged from the final recommendations published in 2012, according to a Task Force statement published with the recommendations. “The benefits of using menopausal hormone therapy to prevent chronic conditions like heart disease and diabetes do not outweigh the harms in women who have gone through menopause,” Maureen G. Phipps, MD, MPH, a task force member, said in the statement.

The draft recommendations were based on a review of 17 randomized clinical trials published through Aug. 1, 2016, that included data from the Women’s Health Initiative.

Women taking estrogen/progestin reported a significantly lower risk (per 10,000 women approximately 5 years) of colorectal cancer, diabetes, and fractures, compared with women on a placebo, wrote Gerald Gartlehner, MD, and his colleagues at the RTI International–University of North Carolina Evidence-Based Practice Center in Research Triangle Park, NC, in the evidence report accompanying the draft recommendations.

However, the risks for several other conditions were significantly higher among women on hormone therapy, compared with placebo, including invasive breast cancer (52 more cases), coronary heart disease (41 more cases) probable dementia (88 more cases), gallbladder disease (259 more cases), stroke (53 more cases), and venous thromboembolism (120 more cases). Additionally, urinary incontinence rates were higher after a 1-year follow up among women on hormone therapy (876 more cases/10,000 women).

Some evidence suggests that women who began hormone therapy closer to menopause might have a lower risk for developing cardiovascular complications, but the evidence is insufficient for firm conclusions, the researchers wrote.

The recommendations against hormone therapy do not apply to women younger than 50 years who have undergone oophorectomies or premature menopause, or to those considering hormone therapy to manage menopausal symptoms, according to the Task Force.

Public comments on the draft recommendations may be submitted on the Task Force website until June 12. The researchers had no financial conflicts to disclose.

View the recommendations online at uspreventiveservicestaskforce.org.

[email protected]

Hormone therapy, in the form of estrogen combined with progestin, is not recommended to prevent chronic conditions such as heart disease and diabetes in postmenopausal women, according to updated draft recommendations from the U.S. Preventive Services Task Force. They also recommended against the use of estrogen alone in postmenopausal women who have had a hysterectomy.

The updated recommendations were published online May 16 on the U.S. Preventive Services Task Force website.

After considering new evidence in the last several years, the recommendations are essentially unchanged from the final recommendations published in 2012, according to a Task Force statement published with the recommendations. “The benefits of using menopausal hormone therapy to prevent chronic conditions like heart disease and diabetes do not outweigh the harms in women who have gone through menopause,” Maureen G. Phipps, MD, MPH, a task force member, said in the statement.

The draft recommendations were based on a review of 17 randomized clinical trials published through Aug. 1, 2016, that included data from the Women’s Health Initiative.

Women taking estrogen/progestin reported a significantly lower risk (per 10,000 women approximately 5 years) of colorectal cancer, diabetes, and fractures, compared with women on a placebo, wrote Gerald Gartlehner, MD, and his colleagues at the RTI International–University of North Carolina Evidence-Based Practice Center in Research Triangle Park, NC, in the evidence report accompanying the draft recommendations.

However, the risks for several other conditions were significantly higher among women on hormone therapy, compared with placebo, including invasive breast cancer (52 more cases), coronary heart disease (41 more cases) probable dementia (88 more cases), gallbladder disease (259 more cases), stroke (53 more cases), and venous thromboembolism (120 more cases). Additionally, urinary incontinence rates were higher after a 1-year follow up among women on hormone therapy (876 more cases/10,000 women).

Some evidence suggests that women who began hormone therapy closer to menopause might have a lower risk for developing cardiovascular complications, but the evidence is insufficient for firm conclusions, the researchers wrote.

The recommendations against hormone therapy do not apply to women younger than 50 years who have undergone oophorectomies or premature menopause, or to those considering hormone therapy to manage menopausal symptoms, according to the Task Force.

Public comments on the draft recommendations may be submitted on the Task Force website until June 12. The researchers had no financial conflicts to disclose.

View the recommendations online at uspreventiveservicestaskforce.org.

[email protected]

Hormone therapy, in the form of estrogen combined with progestin, is not recommended to prevent chronic conditions such as heart disease and diabetes in postmenopausal women, according to updated draft recommendations from the U.S. Preventive Services Task Force. They also recommended against the use of estrogen alone in postmenopausal women who have had a hysterectomy.

The updated recommendations were published online May 16 on the U.S. Preventive Services Task Force website.

After considering new evidence in the last several years, the recommendations are essentially unchanged from the final recommendations published in 2012, according to a Task Force statement published with the recommendations. “The benefits of using menopausal hormone therapy to prevent chronic conditions like heart disease and diabetes do not outweigh the harms in women who have gone through menopause,” Maureen G. Phipps, MD, MPH, a task force member, said in the statement.

The draft recommendations were based on a review of 17 randomized clinical trials published through Aug. 1, 2016, that included data from the Women’s Health Initiative.

Women taking estrogen/progestin reported a significantly lower risk (per 10,000 women approximately 5 years) of colorectal cancer, diabetes, and fractures, compared with women on a placebo, wrote Gerald Gartlehner, MD, and his colleagues at the RTI International–University of North Carolina Evidence-Based Practice Center in Research Triangle Park, NC, in the evidence report accompanying the draft recommendations.

However, the risks for several other conditions were significantly higher among women on hormone therapy, compared with placebo, including invasive breast cancer (52 more cases), coronary heart disease (41 more cases) probable dementia (88 more cases), gallbladder disease (259 more cases), stroke (53 more cases), and venous thromboembolism (120 more cases). Additionally, urinary incontinence rates were higher after a 1-year follow up among women on hormone therapy (876 more cases/10,000 women).

Some evidence suggests that women who began hormone therapy closer to menopause might have a lower risk for developing cardiovascular complications, but the evidence is insufficient for firm conclusions, the researchers wrote.

The recommendations against hormone therapy do not apply to women younger than 50 years who have undergone oophorectomies or premature menopause, or to those considering hormone therapy to manage menopausal symptoms, according to the Task Force.

Public comments on the draft recommendations may be submitted on the Task Force website until June 12. The researchers had no financial conflicts to disclose.

View the recommendations online at uspreventiveservicestaskforce.org.

[email protected]

SAN DIEGO – Endometrial cancer (EC) rates increased after 2002, coinciding with the release of results from the Women’s Health Initiative and including a 10% spike between 2006 and 2014, according to a large analysis of national data.

“Be aware of an increase of endometrial cancer and, whenever possible, look to minimize possible inciting causes,” Ginger Constantine, MD, lead study author, said in an interview prior to the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. “Be certain that the hormonal products that patients are taking are delivering adequate progesterone to the endometrium in those patients at an increased risk of endometrial cancer, such as those with unopposed estrogen.”

[email protected]

SAN DIEGO – Endometrial cancer (EC) rates increased after 2002, coinciding with the release of results from the Women’s Health Initiative and including a 10% spike between 2006 and 2014, according to a large analysis of national data.

“Be aware of an increase of endometrial cancer and, whenever possible, look to minimize possible inciting causes,” Ginger Constantine, MD, lead study author, said in an interview prior to the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. “Be certain that the hormonal products that patients are taking are delivering adequate progesterone to the endometrium in those patients at an increased risk of endometrial cancer, such as those with unopposed estrogen.”

[email protected]

SAN DIEGO – Endometrial cancer (EC) rates increased after 2002, coinciding with the release of results from the Women’s Health Initiative and including a 10% spike between 2006 and 2014, according to a large analysis of national data.

“Be aware of an increase of endometrial cancer and, whenever possible, look to minimize possible inciting causes,” Ginger Constantine, MD, lead study author, said in an interview prior to the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. “Be certain that the hormonal products that patients are taking are delivering adequate progesterone to the endometrium in those patients at an increased risk of endometrial cancer, such as those with unopposed estrogen.”

[email protected]

The American College of Physicians’ updated clinical practice guideline for treating osteoporosis strongly advocates bisphosphonates and strongly advises against estrogens or raloxifene. It was presented online May 8 in the Annals of Internal Medicine.

The new guideline is based on a review of the evidence published since the previous (2008) ACP guideline for preventing fractures in women and men with osteoporosis or low bone density and is intended to replace that document. It offers six main recommendations and several additional pointers for both clinicians and the approximately 50% of Americans older than age 50 years who are at risk for osteoporotic fracture, said Amir Qaseem, MD, PhD, lead author and vice president of clinical policy at the ACP, Philadelphia, and his associates.

The strongest recommendation, based on extensive high-quality evidence, is that clinicians offer women known to have osteoporosis pharmacologic therapy with the bisphosphonates alendronate, risedronate, or zoledronic acid, or the biologic agent denosumab, to reduce their risk of hip and vertebral fracture. Counseling on the importance of adherence despite the relative inconvenience of taking the medications and their possible adverse effects is urged, as is prescribing generic formulations whenever possible.

Raloxifene, ibandronate, and teriparatide have not been shown to reduce the risks of all types of fractures, so they are not recommended as first-line therapy. The updated guideline no longer addresses the use of calcitonin, because it is no longer used widely for osteoporosis. Similarly, it no longer addresses the use of etidronate or pamidronate, which are not approved by the Food and Drug Administration for this indication. The updated guideline added denosumab, a new biologic agent recently approved by the FDA.

Estrogens or raloxifene are not advised for established osteoporosis because good evidence shows they do not reduce fracture risk, according to the guideline. Moreover, these agents can be associated with serious harms that outweigh any potential benefits, including stroke and venous thromboembolism. This recommendation directly refutes one in the previous guideline that favored estrogen therapy, based on newer evidence, Dr. Qaseem and his associates said (Ann. Intern. Med. 2017 May 8.doi: 10.7326/M15-1361).

Four additional recommendations in the updated guideline are weaker because they are based on low-quality evidence.

One advises that the duration of pharmacologic therapy should be 5 years, although there is considerable variation in response to treatment and many patients may benefit from longer treatment. Another recommendation advises against bone mineral density monitoring during this 5-year period because current evidence shows no benefit for it.

Another recommendation advises that men who have clinically recognized osteoporosis should be offered bisphosphonate therapy to reduce their risk of vertebral fracture. The final recommendation advises clinicians to decide whether to treat “osteopenic women 65 years of age or older who are at a high risk for fracture,” based on patient preferences and the “benefits, harms, and costs of medications.”

The guideline notes that, for women who have normal bone mineral density, frequent monitoring for osteoporosis is unnecessary, because current evidence shows those with normal dual-energy x-ray absorptiometry scores do not progress to osteoporosis within 15 years. And it cautions that even though the World Health Organization’s Fracture Risk Assessment Tool scores are widely used, there is no evidence that they accurately reflect treatment efficacy.

The American College of Physicians’ updated clinical practice guideline for treating osteoporosis strongly advocates bisphosphonates and strongly advises against estrogens or raloxifene. It was presented online May 8 in the Annals of Internal Medicine.

The new guideline is based on a review of the evidence published since the previous (2008) ACP guideline for preventing fractures in women and men with osteoporosis or low bone density and is intended to replace that document. It offers six main recommendations and several additional pointers for both clinicians and the approximately 50% of Americans older than age 50 years who are at risk for osteoporotic fracture, said Amir Qaseem, MD, PhD, lead author and vice president of clinical policy at the ACP, Philadelphia, and his associates.

The strongest recommendation, based on extensive high-quality evidence, is that clinicians offer women known to have osteoporosis pharmacologic therapy with the bisphosphonates alendronate, risedronate, or zoledronic acid, or the biologic agent denosumab, to reduce their risk of hip and vertebral fracture. Counseling on the importance of adherence despite the relative inconvenience of taking the medications and their possible adverse effects is urged, as is prescribing generic formulations whenever possible.

Raloxifene, ibandronate, and teriparatide have not been shown to reduce the risks of all types of fractures, so they are not recommended as first-line therapy. The updated guideline no longer addresses the use of calcitonin, because it is no longer used widely for osteoporosis. Similarly, it no longer addresses the use of etidronate or pamidronate, which are not approved by the Food and Drug Administration for this indication. The updated guideline added denosumab, a new biologic agent recently approved by the FDA.

Estrogens or raloxifene are not advised for established osteoporosis because good evidence shows they do not reduce fracture risk, according to the guideline. Moreover, these agents can be associated with serious harms that outweigh any potential benefits, including stroke and venous thromboembolism. This recommendation directly refutes one in the previous guideline that favored estrogen therapy, based on newer evidence, Dr. Qaseem and his associates said (Ann. Intern. Med. 2017 May 8.doi: 10.7326/M15-1361).

Four additional recommendations in the updated guideline are weaker because they are based on low-quality evidence.

One advises that the duration of pharmacologic therapy should be 5 years, although there is considerable variation in response to treatment and many patients may benefit from longer treatment. Another recommendation advises against bone mineral density monitoring during this 5-year period because current evidence shows no benefit for it.

Another recommendation advises that men who have clinically recognized osteoporosis should be offered bisphosphonate therapy to reduce their risk of vertebral fracture. The final recommendation advises clinicians to decide whether to treat “osteopenic women 65 years of age or older who are at a high risk for fracture,” based on patient preferences and the “benefits, harms, and costs of medications.”

The guideline notes that, for women who have normal bone mineral density, frequent monitoring for osteoporosis is unnecessary, because current evidence shows those with normal dual-energy x-ray absorptiometry scores do not progress to osteoporosis within 15 years. And it cautions that even though the World Health Organization’s Fracture Risk Assessment Tool scores are widely used, there is no evidence that they accurately reflect treatment efficacy.

The American College of Physicians’ updated clinical practice guideline for treating osteoporosis strongly advocates bisphosphonates and strongly advises against estrogens or raloxifene. It was presented online May 8 in the Annals of Internal Medicine.

The new guideline is based on a review of the evidence published since the previous (2008) ACP guideline for preventing fractures in women and men with osteoporosis or low bone density and is intended to replace that document. It offers six main recommendations and several additional pointers for both clinicians and the approximately 50% of Americans older than age 50 years who are at risk for osteoporotic fracture, said Amir Qaseem, MD, PhD, lead author and vice president of clinical policy at the ACP, Philadelphia, and his associates.

The strongest recommendation, based on extensive high-quality evidence, is that clinicians offer women known to have osteoporosis pharmacologic therapy with the bisphosphonates alendronate, risedronate, or zoledronic acid, or the biologic agent denosumab, to reduce their risk of hip and vertebral fracture. Counseling on the importance of adherence despite the relative inconvenience of taking the medications and their possible adverse effects is urged, as is prescribing generic formulations whenever possible.

Raloxifene, ibandronate, and teriparatide have not been shown to reduce the risks of all types of fractures, so they are not recommended as first-line therapy. The updated guideline no longer addresses the use of calcitonin, because it is no longer used widely for osteoporosis. Similarly, it no longer addresses the use of etidronate or pamidronate, which are not approved by the Food and Drug Administration for this indication. The updated guideline added denosumab, a new biologic agent recently approved by the FDA.

Estrogens or raloxifene are not advised for established osteoporosis because good evidence shows they do not reduce fracture risk, according to the guideline. Moreover, these agents can be associated with serious harms that outweigh any potential benefits, including stroke and venous thromboembolism. This recommendation directly refutes one in the previous guideline that favored estrogen therapy, based on newer evidence, Dr. Qaseem and his associates said (Ann. Intern. Med. 2017 May 8.doi: 10.7326/M15-1361).

Four additional recommendations in the updated guideline are weaker because they are based on low-quality evidence.

One advises that the duration of pharmacologic therapy should be 5 years, although there is considerable variation in response to treatment and many patients may benefit from longer treatment. Another recommendation advises against bone mineral density monitoring during this 5-year period because current evidence shows no benefit for it.

Another recommendation advises that men who have clinically recognized osteoporosis should be offered bisphosphonate therapy to reduce their risk of vertebral fracture. The final recommendation advises clinicians to decide whether to treat “osteopenic women 65 years of age or older who are at a high risk for fracture,” based on patient preferences and the “benefits, harms, and costs of medications.”

The guideline notes that, for women who have normal bone mineral density, frequent monitoring for osteoporosis is unnecessary, because current evidence shows those with normal dual-energy x-ray absorptiometry scores do not progress to osteoporosis within 15 years. And it cautions that even though the World Health Organization’s Fracture Risk Assessment Tool scores are widely used, there is no evidence that they accurately reflect treatment efficacy.