Menopause

Estetrol (Donesta) relieved vasomotor menopausal symptoms without stimulating breast tenderness or raising triglyceride levels in a dose-finding study of the investigational drug presented at the annual meeting of the North American Menopause Society.

Estetrol (E4), an estrogen produced by the fetal liver, is the first native estrogen acting selectively in tissues. Since it crosses the placenta, estetrol is present in maternal urine at about 9 weeks’ gestation. In fetal plasma, it circulates at concentrations about 12 times higher than maternal estetrol levels. The hormone has a half-life of 28-32 hours, longer than the half-life of most other estrogens.

E4 “has been shown to have a remarkably safe profile and I like to describe it as the first natural oral estrogen with the safety profile of a transdermal estrogen,” said Wulf H. Utian, MD, the Arthur H. Bill Professor of Obstetrics & Gynecology at Case Western Reserve University, Cleveland. Estetrol uniquely activates nuclear estrogen receptor–alpha, while antagonizing membrane estrogen receptor-alpha. These properties give E4 selective tissue action, with low breast stimulation meaning less breast tenderness and “low carcinogenic impact.”

Additionally, triglyceride levels are minimally affected, and serum markers for venous thromboembolism generally remain unchanged with E4 exposure, he said.

In a phase 2b dose-finding study, a variety of estetrol doses were compared with placebo to treat vasomotor symptoms in postmenopausal women aged 40-65 years with at least 7 moderate to severe hot flashes daily, or at least 50 moderate to severe hot flashes in the week before randomization. The multicenter, double-blind randomized controlled trial took place in five European countries, with 200 women overall completing the study. The study design excluded women with personal histories of malignancy, thromboembolism, or coagulopathy, and women with diabetes and poor glycemic control. Women with a uterus who had current or past endometrial hyperplasia, polyps, or an abnormal cervical smear were also excluded.

Women who had an intact uterus were included if transvaginal ultrasound showed endometrial thickness of 5 mm or less. Participants were randomized 1:1:1:1 to receive four different E4 doses: 2.5 mg, 5 mg, 10 mg, or 15 mg.

At the highest dose of 15 mg, E4 significantly reduced the frequency of vasomotor symptoms compared with placebo by study week 4 and throughout the 12-week study period (P less than .05).

This high dose also resulted in a 28% reduction in vasomotor symptom severity, compared with placebo by study week 12, with a significant separation from placebo by week 12.

In terms of the number of women who experienced at least a 50% drop in severe vasomotor symptoms, the 15-mg E4 dose also bested placebo (P less than .01). Among the group taking the 15 mg dose, significantly more also saw at least a 75% drop in frequency of severe vasomotor symptom (P less than .001).

Vaginal cytology showed that by week 12 all doses of E4 significantly increased the vaginal maturation index from baseline, a finding that corresponds with less thinning of vaginal tissues (P less than .001, compared with placebo for all doses).

The safety profile of E4 was good, Dr. Utian said. Coagulation markers were unaffected, and most lipid and blood glucose markers were also unchanged. There were “small but potentially beneficial changes in HDL-C [HDL cholesterol levels] and HbA_1c values [hemoglobin A_1c]” in groups taking the two highest doses of E4.

Also, C-telopeptide of type 1 collagen and osteocalcin values were reduced, “suggesting reduction in bone resorption,” he said.

According to Dr. Utian, those taking the two highest doses also saw a “slight though significant increase” from baseline in sex hormone–binding globulin levels, “indicating that the E4 estrogenic effect was mild and dose dependent.”

Endometrial biopsies showed no hyperplasia. In those taking the 15-mg E4 dose, mean endometrial thickness did increase from a mean 2 mm at baseline to 6 mm at 12 weeks. However, endometrial thickness returned to baseline after progestin therapy, said Dr. Utian. There were no unexpected adverse events during the study.

Dr. Utian reported consultant relationships with Mithra, the maker of estetrol; AMAG; Pharmavite; and Endoceutics. The study was funded by Mithra.
 

[email protected]

SOURCE: Utian W. NAMS 2018, Friday concurrent session 1.

Estetrol (Donesta) relieved vasomotor menopausal symptoms without stimulating breast tenderness or raising triglyceride levels in a dose-finding study of the investigational drug presented at the annual meeting of the North American Menopause Society.

Estetrol (E4), an estrogen produced by the fetal liver, is the first native estrogen acting selectively in tissues. Since it crosses the placenta, estetrol is present in maternal urine at about 9 weeks’ gestation. In fetal plasma, it circulates at concentrations about 12 times higher than maternal estetrol levels. The hormone has a half-life of 28-32 hours, longer than the half-life of most other estrogens.

E4 “has been shown to have a remarkably safe profile and I like to describe it as the first natural oral estrogen with the safety profile of a transdermal estrogen,” said Wulf H. Utian, MD, the Arthur H. Bill Professor of Obstetrics & Gynecology at Case Western Reserve University, Cleveland. Estetrol uniquely activates nuclear estrogen receptor–alpha, while antagonizing membrane estrogen receptor-alpha. These properties give E4 selective tissue action, with low breast stimulation meaning less breast tenderness and “low carcinogenic impact.”

Additionally, triglyceride levels are minimally affected, and serum markers for venous thromboembolism generally remain unchanged with E4 exposure, he said.

In a phase 2b dose-finding study, a variety of estetrol doses were compared with placebo to treat vasomotor symptoms in postmenopausal women aged 40-65 years with at least 7 moderate to severe hot flashes daily, or at least 50 moderate to severe hot flashes in the week before randomization. The multicenter, double-blind randomized controlled trial took place in five European countries, with 200 women overall completing the study. The study design excluded women with personal histories of malignancy, thromboembolism, or coagulopathy, and women with diabetes and poor glycemic control. Women with a uterus who had current or past endometrial hyperplasia, polyps, or an abnormal cervical smear were also excluded.

Women who had an intact uterus were included if transvaginal ultrasound showed endometrial thickness of 5 mm or less. Participants were randomized 1:1:1:1 to receive four different E4 doses: 2.5 mg, 5 mg, 10 mg, or 15 mg.

At the highest dose of 15 mg, E4 significantly reduced the frequency of vasomotor symptoms compared with placebo by study week 4 and throughout the 12-week study period (P less than .05).

This high dose also resulted in a 28% reduction in vasomotor symptom severity, compared with placebo by study week 12, with a significant separation from placebo by week 12.

In terms of the number of women who experienced at least a 50% drop in severe vasomotor symptoms, the 15-mg E4 dose also bested placebo (P less than .01). Among the group taking the 15 mg dose, significantly more also saw at least a 75% drop in frequency of severe vasomotor symptom (P less than .001).

Vaginal cytology showed that by week 12 all doses of E4 significantly increased the vaginal maturation index from baseline, a finding that corresponds with less thinning of vaginal tissues (P less than .001, compared with placebo for all doses).

The safety profile of E4 was good, Dr. Utian said. Coagulation markers were unaffected, and most lipid and blood glucose markers were also unchanged. There were “small but potentially beneficial changes in HDL-C [HDL cholesterol levels] and HbA_1c values [hemoglobin A_1c]” in groups taking the two highest doses of E4.

Also, C-telopeptide of type 1 collagen and osteocalcin values were reduced, “suggesting reduction in bone resorption,” he said.

According to Dr. Utian, those taking the two highest doses also saw a “slight though significant increase” from baseline in sex hormone–binding globulin levels, “indicating that the E4 estrogenic effect was mild and dose dependent.”

Endometrial biopsies showed no hyperplasia. In those taking the 15-mg E4 dose, mean endometrial thickness did increase from a mean 2 mm at baseline to 6 mm at 12 weeks. However, endometrial thickness returned to baseline after progestin therapy, said Dr. Utian. There were no unexpected adverse events during the study.

Dr. Utian reported consultant relationships with Mithra, the maker of estetrol; AMAG; Pharmavite; and Endoceutics. The study was funded by Mithra.
 

[email protected]

SOURCE: Utian W. NAMS 2018, Friday concurrent session 1.

Estetrol (Donesta) relieved vasomotor menopausal symptoms without stimulating breast tenderness or raising triglyceride levels in a dose-finding study of the investigational drug presented at the annual meeting of the North American Menopause Society.

Estetrol (E4), an estrogen produced by the fetal liver, is the first native estrogen acting selectively in tissues. Since it crosses the placenta, estetrol is present in maternal urine at about 9 weeks’ gestation. In fetal plasma, it circulates at concentrations about 12 times higher than maternal estetrol levels. The hormone has a half-life of 28-32 hours, longer than the half-life of most other estrogens.

E4 “has been shown to have a remarkably safe profile and I like to describe it as the first natural oral estrogen with the safety profile of a transdermal estrogen,” said Wulf H. Utian, MD, the Arthur H. Bill Professor of Obstetrics & Gynecology at Case Western Reserve University, Cleveland. Estetrol uniquely activates nuclear estrogen receptor–alpha, while antagonizing membrane estrogen receptor-alpha. These properties give E4 selective tissue action, with low breast stimulation meaning less breast tenderness and “low carcinogenic impact.”

Additionally, triglyceride levels are minimally affected, and serum markers for venous thromboembolism generally remain unchanged with E4 exposure, he said.

In a phase 2b dose-finding study, a variety of estetrol doses were compared with placebo to treat vasomotor symptoms in postmenopausal women aged 40-65 years with at least 7 moderate to severe hot flashes daily, or at least 50 moderate to severe hot flashes in the week before randomization. The multicenter, double-blind randomized controlled trial took place in five European countries, with 200 women overall completing the study. The study design excluded women with personal histories of malignancy, thromboembolism, or coagulopathy, and women with diabetes and poor glycemic control. Women with a uterus who had current or past endometrial hyperplasia, polyps, or an abnormal cervical smear were also excluded.

Women who had an intact uterus were included if transvaginal ultrasound showed endometrial thickness of 5 mm or less. Participants were randomized 1:1:1:1 to receive four different E4 doses: 2.5 mg, 5 mg, 10 mg, or 15 mg.

At the highest dose of 15 mg, E4 significantly reduced the frequency of vasomotor symptoms compared with placebo by study week 4 and throughout the 12-week study period (P less than .05).

This high dose also resulted in a 28% reduction in vasomotor symptom severity, compared with placebo by study week 12, with a significant separation from placebo by week 12.

In terms of the number of women who experienced at least a 50% drop in severe vasomotor symptoms, the 15-mg E4 dose also bested placebo (P less than .01). Among the group taking the 15 mg dose, significantly more also saw at least a 75% drop in frequency of severe vasomotor symptom (P less than .001).

Vaginal cytology showed that by week 12 all doses of E4 significantly increased the vaginal maturation index from baseline, a finding that corresponds with less thinning of vaginal tissues (P less than .001, compared with placebo for all doses).

The safety profile of E4 was good, Dr. Utian said. Coagulation markers were unaffected, and most lipid and blood glucose markers were also unchanged. There were “small but potentially beneficial changes in HDL-C [HDL cholesterol levels] and HbA_1c values [hemoglobin A_1c]” in groups taking the two highest doses of E4.

Also, C-telopeptide of type 1 collagen and osteocalcin values were reduced, “suggesting reduction in bone resorption,” he said.

According to Dr. Utian, those taking the two highest doses also saw a “slight though significant increase” from baseline in sex hormone–binding globulin levels, “indicating that the E4 estrogenic effect was mild and dose dependent.”

Endometrial biopsies showed no hyperplasia. In those taking the 15-mg E4 dose, mean endometrial thickness did increase from a mean 2 mm at baseline to 6 mm at 12 weeks. However, endometrial thickness returned to baseline after progestin therapy, said Dr. Utian. There were no unexpected adverse events during the study.

Dr. Utian reported consultant relationships with Mithra, the maker of estetrol; AMAG; Pharmavite; and Endoceutics. The study was funded by Mithra.
 

[email protected]

SOURCE: Utian W. NAMS 2018, Friday concurrent session 1.

CASE Midlife woman with low libido causing distress

At her annual gynecologic visit, a 55-year-old woman notes that she has almost no interest in sex. In the past, her libido was good and relations were pleasurable. Since her mid-40s, she has noticed a gradual decline in libido and orgasmic response. Sexual frequency has declined from once or twice weekly to just a few times per month. She has been married for 25 years and describes the relationship as caring and strong. Her husband is healthy with a good libido; his intermittent erectile dysfunction is treated with a phosphodiesterase-5 inhibitor. The patient’s low libido is distressing, as the decline in sexual frequency is causing some conflict for the couple. She requests that her testosterone level be checked because she heard that treatment with testosterone cream will solve this problem.

Evaluating and treating low libido in menopausal women

Low libido is a very common sexual problem for women. When sexual problems are accompanied by distress, they are classified as sexual dysfunctions. Although ObGyns should discuss sexual concerns at every comprehensive visit, if the patient has no associated distress, treatment is not necessarily indicated. A woman with low libido or anorgasmia who is satisfied with her sex life and is not bothered by these issues does not require any intervention.

Currently, the only indication for testosterone therapy that is supported by clinical trial evidence is low sexual desire with associated distress, known as hypoactive sexual desire disorder (HSDD). Although other sexual problems also commonly occur in menopausal women, such as disorders of orgasm and pain, testosterone is not recommended for these problems. In addition, testosterone is not approved by the US Food and Drug Administration (FDA) for the treatment of female sexual dysfunction.

Routinely inquire about sexual functioning

Ask your patients about sexual concerns at every comprehensive visit. You can easily incorporate into the review of systems a general question, such as, “Do you have any sexual concerns?” If the patient does mention a sexual problem, schedule a separate visit (given appointment time constraints) to address it. History and physical examination information you gather during the comprehensive visit will be helpful in the subsequent problem-focused visit.

Taking a thorough history is key when addressing a patient’s sexual problems, since identifying possible etiologies guides treatment. Often, the cause of female sexual dysfunction is multifactorial and includes physiologic, psychologic, and relationship issues.

Explore potential causes, recommend standard therapies

Common causes of low libido in menopausal women include vasomotor symptoms, insomnia, urinary incontinence, cancer or another major medical problem, weight gain, poor body image, genitourinary syndrome of menopause (GSM) with dyspareunia, fatigue, stress, aging, relationship duration, lack of novelty, relationship conflict, and a partner’s sexual problems. Other common etiologies include depression, anxiety, and substance use disorders, as well as medications used to treat these disorders, including selective serotonin reuptake inhibitors (SSRIs).

Continue to: There are many effective therapies...

There are many effective therapies for low sexual desire to consider prior to initiating a trial of testosterone, which should be considered for HSDD only if the disorder persists after addressing all other possible contributing factors (TABLE 1).

Sex therapy, for example, provides information on sexual functioning and helps improve communication and mutual pleasure and satisfaction. Strongly encourage—if not require—a consultation with a sex therapist before prescribing testosterone for low libido. Any testosterone-derived improvement in sexual functioning will be enhanced by improved communication and additional strategies to achieve mutual pleasure.

Hormone therapy. Vasomotor symptoms, with their associated sleep disruption, fatigue, and reduced quality of life (QOL), often adversely impact sexual desire. Estrogen therapy does not appear to improve libido in otherwise asymptomatic women; however, in women with bothersome vasomotor symptoms treated with estrogen, sexual interest may increase as a result of improved sleep, fatigue, and overall QOL. The benefits of systemic hormone therapy generally outweigh its risks for most healthy women younger than age 60 who have bothersome hot flashes and night sweats.¹

Nonhormonal and other therapies. GSM with dyspareunia is a principal cause of sexual dysfunction in older women.² Many safe and effective treatments are available, including low-dose vaginal estrogen therapy, nonhormonal moisturizers and lubricants, ospemifene, vaginal dehydroepiandrosterone, and pelvic floor physical therapy.³ Urinary incontinence commonly occurs in midlife women and contributes to low libido.⁴

Lifestyle approaches. Address fatigue and stress by having the patient adjust her work and sleep schedules, obtain help with housework and meals, and engage in mind-body interventions, counseling, or yoga. Sexual function may benefit from yoga practice, likely as a result of the patient experiencing reduced stress and enhanced body image. Improving overall health and body image with regular exercise, optimal diet, and weight management may contribute to a more satisfying sex life after the onset of menopause.

Relationship refresh. Women’s sexual interest often declines with relationship duration, and both men and women who are in new relationships generally have increased libido, affirming the importance of novelty over the long term. Couples will benefit from “date nights,” weekends away from home, and trying novel positions, locations, and times for sex. Couple’s counseling may address relationship conflict.

Expert referral. Depression, anxiety, and substance use disorders are prevalent in menopausal women and contribute to sexual dysfunction. Effective therapy is available, although some pharmacologic treatments (including SSRIs) may be an additional cause of sexual dysfunction. In addition to recommending appropriate counseling and support, referring the patient to a psychopharmacologist with expertise in managing sexual adverse effects of medications may optimize care.

Continue to: Sexual function improves, but patient still wants to try testosterone

The patient returns for follow-up visits scheduled specifically to address her sexual concerns. Sex is more comfortable and pleasurable since initiating low-dose vaginal estrogen therapy. Having been on an SSRI since her mid-40s for mild depression, the patient switched to bupropion and notes improved libido and orgasmic response. She is exercising more regularly and working with a nutritionist to address a 15-lb weight gain after menopause. The couple saw a sex therapist and is communicating better about sex with more novelty in their repertoire. They are enjoying a regular date night. Although the patient’s sex life has improved with these interventions, she is still very interested in trying testosterone.

Testosterone’s effects on HSDD in menopausal women

After addressing the many factors that contribute to sexual disinterest, a trial of testosterone may be appropriate for a menopausal woman who continues to experience low libido with associated distress.

Testosterone levels decrease with aging in both men and women. Although testosterone levels decline by approximately 50% with bilateral oophorectomy, there is no decline in androgen levels with natural menopause.⁵ Testosterone circulates tightly bound to sex hormone–binding globulin (SHBG), so free or active testosterone will be reduced by oral estrogens, which increase SHBG levels.⁶ As most menopausal women will have a low testosterone level due to aging, measuring the testosterone level does not provide information about the etiology of the sexual problem.

Although some studies have identified an association between endogenous androgen levels and sexual function, the associations are modest and are of uncertain clinical significance.^7-9 Not surprisingly, other factors, such as physical and psychologic health and the quality of the relationship, often are reported as more important predictors of sexual satisfaction than androgen levels.¹⁰

While endogenous testosterone levels may not correlate with sexual function, clinical trials of carefully selected menopausal women with HSDD have shown that androgen treatment generally results in improved sexual function.¹¹ Studies demonstrate substantial improvements in sexual desire, orgasmic response, and frequency in menopausal women treated with high doses of intramuscular testosterone, which result in supraphysiologic androgen levels.^12,13 While it is interesting that women with testosterone levels in the male low range have sizeable increases in sexual desire and response, long-term use of high-dose testosterone would result in unacceptable androgenic adverse effects and risks.

Continue to: Testosterone in low doses...

Testosterone in low doses. It is more relevant to consider the impact on female sexual function of low doses of testosterone, which raise the reduced testosterone levels seen in older women to the higher levels seen in reproductive-aged women.

A series of double-blind, multicenter, randomized, placebo-controlled trials in menopausal women with HSDD examined the impact on sexual function of a transdermal testosterone patch (300 μg) that increased blood testosterone levels to the upper limit of normal for young women.^14-17 In these studies, compared with placebo, women using testosterone reported significant improvements in sexual desire, arousal, orgasmic response, frequency, and sexually related distress. Findings were consistent in surgically and naturally menopausal women, with and without the use of concurrent estrogen therapy. Improvements were clinically limited, however. On average, testosterone-treated women experienced 1 to 1.5 additional satisfying sexual events in a 4-week period compared with those treated with placebo. The percentage of women reporting a clinically meaningful benefit from treatment was significantly greater in women treated with testosterone (52%) compared with the placebo-treated women (31%).¹⁸ An appreciable placebo response was seen, typical of most studies of therapies for sexual dysfunction.

Safety concerns

Potential risks of testosterone treatment include acne, hirsutism, irreversible deepening of the voice, and adverse changes in lipids and liver function (TABLE 2).¹⁹ Adverse effects are dose dependent and are unlikely with physiologically dosed testosterone.

A 1-year study of testosterone patches in approximately 800 menopausal women with HSDD (with a subgroup of women followed for an additional year) provides the most comprehensive safety data available.¹⁷ Unwanted hair growth occurred more often in women receiving testosterone, without significant differences in blood biochemistry,hematologic parameters, carbohydrate metabolism, or lipids. Breast cancer was diagnosed in more women receiving testosterone than placebo. Although this finding may have been due to chance, the investigators concluded that long-term effects of testosterone treatment remain uncertain.

The FDA reviewed the data from the testosterone patch studies and determined that testosterone patches were effective for the treatment of HSDD in menopausal women, but more information was needed on long-term safety before approval could be granted. Another company then developed a testosterone gel product that produced similar blood levels as the testosterone patch. It was presumed that there would be similar efficacy; the principal goal of these studies was to examine long-term safety, particularly with respect to breast cancer and cardiovascular disease. Unexpectedly, although it raised testosterone blood levels to the upper limit of normal for young women, the testosterone gel product was no more effective than placebo.²⁰ The clinical trial was ended, with safety data never published.

Continue to: Availability of testosterone formulations

Currently, no androgen therapies are FDA approved for the treatment of female sexual dysfunction. Although the best evidence regarding testosterone efficacy and safety involves the use of testosterone patches (300 μg), appropriately dosed for women, these patches are not currently available. FDA-approved testosterone patches are approved for the treatment of male hypogonadism, but use of these patches in women is not recommended since they would result in very high circulating testosterone levels.

Testosterone subcutaneous implants, pellets, and intramuscular injections also are not recommended for women because of the risk of excessive dosing. Small trials of menopausal women taking oral estrogen with low sexual desire found that oral formulations of testosterone improved libido in this study population.²¹ The combination of esterified estrogens (0.625 mg) and methyltestosterone (1.25 mg) is available as a compounded, non-FDA approved product. Oral androgen formulations generally are not advised, due to potential adverse effects on lipids and liver function.²²

Compounded testosterone products. Ointments and creams may be compounded by prescription (TABLE 3). Product purity, dose, bioavailability, and quality typically are untested, and substantial variability exists between formulations and batches.²³ Applying 1% testosterone cream or gel (0.5 g/day) topically to the thigh or lower abdomen should increase the low testosterone levels typically seen in menopausal women to the higher levels seen in younger women.^24,25 Application to the vulva or vagina is not advised, as it may cause local irritation and is unpredictably absorbed.

Adapting male testosterone products. High-quality FDA-approved testosterone gel formulations are available for male hypogonadism. However, since women have approximately one-tenth the circulating testosterone levels of men, supraphysiologic dosing is a risk when these products are prescribed for women. Most testosterone products approved for men are provided in pumps or packets, and they are difficult to dose-adjust for women. Applying one-tenth the male dose of 1% testosterone gel (Testim), which comes in a resealable unit-dose tube, is an alternative to compounding. For men, the dose is 1 tube per day, so women should make 1 tube last for 10 days by using 3 to 4 drops of testosterone gel per day. Close physical contact must be avoided immediately after application, as topical hormone creams and gels are easily transferred to others. The safety and efficacy of compounded or dose-adjusted male testosterone products used in women are unknown.

Follow treated women closely. Women who elect to use transdermal testosterone therapy should be seen at 8 to 12 weeks to assess treatment response. Regular follow-up visits are required to assess response, satisfaction, and adverse effects, including acne and hirsutism. Since there may be little correlation between serum testosterone levels and the prescribed dose of a compounded testosterone product, testosterone levels should be measured regularly as a safety measure. The goal is to keep serum testosterone concentrations within the normal range for reproductive-aged women to reduce the likelihood of adverse effects. Testosterone levels should not be tested as an efficacy measure, however, as there is no testosterone level that will assure a satisfactory sex life.

CASE Conclusion

After a thorough discussion of high placebo response rates, potential adverse effects, unknown long-term risks, and off-label nature of testosterone use, the patient elects a trial of compounded 1% testosterone cream. Her clinician informs her of the limitations of compounded formulations and the need for regular testing of testosterone levels to prevent supraphysiologic dosing. At a follow-up visit 8 weeks later, she reports improved sexual desire and elects to continue treatment and monitoring. After using testosterone for 2 years, the patient is uncertain that she still is experiencing a significant benefit, stops testosterone treatment, and remains satisfied with her sex life.

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.

CASE Midlife woman with low libido causing distress

At her annual gynecologic visit, a 55-year-old woman notes that she has almost no interest in sex. In the past, her libido was good and relations were pleasurable. Since her mid-40s, she has noticed a gradual decline in libido and orgasmic response. Sexual frequency has declined from once or twice weekly to just a few times per month. She has been married for 25 years and describes the relationship as caring and strong. Her husband is healthy with a good libido; his intermittent erectile dysfunction is treated with a phosphodiesterase-5 inhibitor. The patient’s low libido is distressing, as the decline in sexual frequency is causing some conflict for the couple. She requests that her testosterone level be checked because she heard that treatment with testosterone cream will solve this problem.

Evaluating and treating low libido in menopausal women

Low libido is a very common sexual problem for women. When sexual problems are accompanied by distress, they are classified as sexual dysfunctions. Although ObGyns should discuss sexual concerns at every comprehensive visit, if the patient has no associated distress, treatment is not necessarily indicated. A woman with low libido or anorgasmia who is satisfied with her sex life and is not bothered by these issues does not require any intervention.

Currently, the only indication for testosterone therapy that is supported by clinical trial evidence is low sexual desire with associated distress, known as hypoactive sexual desire disorder (HSDD). Although other sexual problems also commonly occur in menopausal women, such as disorders of orgasm and pain, testosterone is not recommended for these problems. In addition, testosterone is not approved by the US Food and Drug Administration (FDA) for the treatment of female sexual dysfunction.

Routinely inquire about sexual functioning

Ask your patients about sexual concerns at every comprehensive visit. You can easily incorporate into the review of systems a general question, such as, “Do you have any sexual concerns?” If the patient does mention a sexual problem, schedule a separate visit (given appointment time constraints) to address it. History and physical examination information you gather during the comprehensive visit will be helpful in the subsequent problem-focused visit.

Taking a thorough history is key when addressing a patient’s sexual problems, since identifying possible etiologies guides treatment. Often, the cause of female sexual dysfunction is multifactorial and includes physiologic, psychologic, and relationship issues.

Explore potential causes, recommend standard therapies

Common causes of low libido in menopausal women include vasomotor symptoms, insomnia, urinary incontinence, cancer or another major medical problem, weight gain, poor body image, genitourinary syndrome of menopause (GSM) with dyspareunia, fatigue, stress, aging, relationship duration, lack of novelty, relationship conflict, and a partner’s sexual problems. Other common etiologies include depression, anxiety, and substance use disorders, as well as medications used to treat these disorders, including selective serotonin reuptake inhibitors (SSRIs).

Continue to: There are many effective therapies...

There are many effective therapies for low sexual desire to consider prior to initiating a trial of testosterone, which should be considered for HSDD only if the disorder persists after addressing all other possible contributing factors (TABLE 1).

Sex therapy, for example, provides information on sexual functioning and helps improve communication and mutual pleasure and satisfaction. Strongly encourage—if not require—a consultation with a sex therapist before prescribing testosterone for low libido. Any testosterone-derived improvement in sexual functioning will be enhanced by improved communication and additional strategies to achieve mutual pleasure.

Hormone therapy. Vasomotor symptoms, with their associated sleep disruption, fatigue, and reduced quality of life (QOL), often adversely impact sexual desire. Estrogen therapy does not appear to improve libido in otherwise asymptomatic women; however, in women with bothersome vasomotor symptoms treated with estrogen, sexual interest may increase as a result of improved sleep, fatigue, and overall QOL. The benefits of systemic hormone therapy generally outweigh its risks for most healthy women younger than age 60 who have bothersome hot flashes and night sweats.¹

Nonhormonal and other therapies. GSM with dyspareunia is a principal cause of sexual dysfunction in older women.² Many safe and effective treatments are available, including low-dose vaginal estrogen therapy, nonhormonal moisturizers and lubricants, ospemifene, vaginal dehydroepiandrosterone, and pelvic floor physical therapy.³ Urinary incontinence commonly occurs in midlife women and contributes to low libido.⁴

Lifestyle approaches. Address fatigue and stress by having the patient adjust her work and sleep schedules, obtain help with housework and meals, and engage in mind-body interventions, counseling, or yoga. Sexual function may benefit from yoga practice, likely as a result of the patient experiencing reduced stress and enhanced body image. Improving overall health and body image with regular exercise, optimal diet, and weight management may contribute to a more satisfying sex life after the onset of menopause.

Relationship refresh. Women’s sexual interest often declines with relationship duration, and both men and women who are in new relationships generally have increased libido, affirming the importance of novelty over the long term. Couples will benefit from “date nights,” weekends away from home, and trying novel positions, locations, and times for sex. Couple’s counseling may address relationship conflict.

Expert referral. Depression, anxiety, and substance use disorders are prevalent in menopausal women and contribute to sexual dysfunction. Effective therapy is available, although some pharmacologic treatments (including SSRIs) may be an additional cause of sexual dysfunction. In addition to recommending appropriate counseling and support, referring the patient to a psychopharmacologist with expertise in managing sexual adverse effects of medications may optimize care.

Continue to: Sexual function improves, but patient still wants to try testosterone

The patient returns for follow-up visits scheduled specifically to address her sexual concerns. Sex is more comfortable and pleasurable since initiating low-dose vaginal estrogen therapy. Having been on an SSRI since her mid-40s for mild depression, the patient switched to bupropion and notes improved libido and orgasmic response. She is exercising more regularly and working with a nutritionist to address a 15-lb weight gain after menopause. The couple saw a sex therapist and is communicating better about sex with more novelty in their repertoire. They are enjoying a regular date night. Although the patient’s sex life has improved with these interventions, she is still very interested in trying testosterone.

Testosterone’s effects on HSDD in menopausal women

After addressing the many factors that contribute to sexual disinterest, a trial of testosterone may be appropriate for a menopausal woman who continues to experience low libido with associated distress.

Testosterone levels decrease with aging in both men and women. Although testosterone levels decline by approximately 50% with bilateral oophorectomy, there is no decline in androgen levels with natural menopause.⁵ Testosterone circulates tightly bound to sex hormone–binding globulin (SHBG), so free or active testosterone will be reduced by oral estrogens, which increase SHBG levels.⁶ As most menopausal women will have a low testosterone level due to aging, measuring the testosterone level does not provide information about the etiology of the sexual problem.

Although some studies have identified an association between endogenous androgen levels and sexual function, the associations are modest and are of uncertain clinical significance.^7-9 Not surprisingly, other factors, such as physical and psychologic health and the quality of the relationship, often are reported as more important predictors of sexual satisfaction than androgen levels.¹⁰

While endogenous testosterone levels may not correlate with sexual function, clinical trials of carefully selected menopausal women with HSDD have shown that androgen treatment generally results in improved sexual function.¹¹ Studies demonstrate substantial improvements in sexual desire, orgasmic response, and frequency in menopausal women treated with high doses of intramuscular testosterone, which result in supraphysiologic androgen levels.^12,13 While it is interesting that women with testosterone levels in the male low range have sizeable increases in sexual desire and response, long-term use of high-dose testosterone would result in unacceptable androgenic adverse effects and risks.

Continue to: Testosterone in low doses...

Testosterone in low doses. It is more relevant to consider the impact on female sexual function of low doses of testosterone, which raise the reduced testosterone levels seen in older women to the higher levels seen in reproductive-aged women.

A series of double-blind, multicenter, randomized, placebo-controlled trials in menopausal women with HSDD examined the impact on sexual function of a transdermal testosterone patch (300 μg) that increased blood testosterone levels to the upper limit of normal for young women.^14-17 In these studies, compared with placebo, women using testosterone reported significant improvements in sexual desire, arousal, orgasmic response, frequency, and sexually related distress. Findings were consistent in surgically and naturally menopausal women, with and without the use of concurrent estrogen therapy. Improvements were clinically limited, however. On average, testosterone-treated women experienced 1 to 1.5 additional satisfying sexual events in a 4-week period compared with those treated with placebo. The percentage of women reporting a clinically meaningful benefit from treatment was significantly greater in women treated with testosterone (52%) compared with the placebo-treated women (31%).¹⁸ An appreciable placebo response was seen, typical of most studies of therapies for sexual dysfunction.

Safety concerns

Potential risks of testosterone treatment include acne, hirsutism, irreversible deepening of the voice, and adverse changes in lipids and liver function (TABLE 2).¹⁹ Adverse effects are dose dependent and are unlikely with physiologically dosed testosterone.

A 1-year study of testosterone patches in approximately 800 menopausal women with HSDD (with a subgroup of women followed for an additional year) provides the most comprehensive safety data available.¹⁷ Unwanted hair growth occurred more often in women receiving testosterone, without significant differences in blood biochemistry,hematologic parameters, carbohydrate metabolism, or lipids. Breast cancer was diagnosed in more women receiving testosterone than placebo. Although this finding may have been due to chance, the investigators concluded that long-term effects of testosterone treatment remain uncertain.

The FDA reviewed the data from the testosterone patch studies and determined that testosterone patches were effective for the treatment of HSDD in menopausal women, but more information was needed on long-term safety before approval could be granted. Another company then developed a testosterone gel product that produced similar blood levels as the testosterone patch. It was presumed that there would be similar efficacy; the principal goal of these studies was to examine long-term safety, particularly with respect to breast cancer and cardiovascular disease. Unexpectedly, although it raised testosterone blood levels to the upper limit of normal for young women, the testosterone gel product was no more effective than placebo.²⁰ The clinical trial was ended, with safety data never published.

Continue to: Availability of testosterone formulations

Currently, no androgen therapies are FDA approved for the treatment of female sexual dysfunction. Although the best evidence regarding testosterone efficacy and safety involves the use of testosterone patches (300 μg), appropriately dosed for women, these patches are not currently available. FDA-approved testosterone patches are approved for the treatment of male hypogonadism, but use of these patches in women is not recommended since they would result in very high circulating testosterone levels.

Testosterone subcutaneous implants, pellets, and intramuscular injections also are not recommended for women because of the risk of excessive dosing. Small trials of menopausal women taking oral estrogen with low sexual desire found that oral formulations of testosterone improved libido in this study population.²¹ The combination of esterified estrogens (0.625 mg) and methyltestosterone (1.25 mg) is available as a compounded, non-FDA approved product. Oral androgen formulations generally are not advised, due to potential adverse effects on lipids and liver function.²²

Compounded testosterone products. Ointments and creams may be compounded by prescription (TABLE 3). Product purity, dose, bioavailability, and quality typically are untested, and substantial variability exists between formulations and batches.²³ Applying 1% testosterone cream or gel (0.5 g/day) topically to the thigh or lower abdomen should increase the low testosterone levels typically seen in menopausal women to the higher levels seen in younger women.^24,25 Application to the vulva or vagina is not advised, as it may cause local irritation and is unpredictably absorbed.

Adapting male testosterone products. High-quality FDA-approved testosterone gel formulations are available for male hypogonadism. However, since women have approximately one-tenth the circulating testosterone levels of men, supraphysiologic dosing is a risk when these products are prescribed for women. Most testosterone products approved for men are provided in pumps or packets, and they are difficult to dose-adjust for women. Applying one-tenth the male dose of 1% testosterone gel (Testim), which comes in a resealable unit-dose tube, is an alternative to compounding. For men, the dose is 1 tube per day, so women should make 1 tube last for 10 days by using 3 to 4 drops of testosterone gel per day. Close physical contact must be avoided immediately after application, as topical hormone creams and gels are easily transferred to others. The safety and efficacy of compounded or dose-adjusted male testosterone products used in women are unknown.

Follow treated women closely. Women who elect to use transdermal testosterone therapy should be seen at 8 to 12 weeks to assess treatment response. Regular follow-up visits are required to assess response, satisfaction, and adverse effects, including acne and hirsutism. Since there may be little correlation between serum testosterone levels and the prescribed dose of a compounded testosterone product, testosterone levels should be measured regularly as a safety measure. The goal is to keep serum testosterone concentrations within the normal range for reproductive-aged women to reduce the likelihood of adverse effects. Testosterone levels should not be tested as an efficacy measure, however, as there is no testosterone level that will assure a satisfactory sex life.

CASE Conclusion

After a thorough discussion of high placebo response rates, potential adverse effects, unknown long-term risks, and off-label nature of testosterone use, the patient elects a trial of compounded 1% testosterone cream. Her clinician informs her of the limitations of compounded formulations and the need for regular testing of testosterone levels to prevent supraphysiologic dosing. At a follow-up visit 8 weeks later, she reports improved sexual desire and elects to continue treatment and monitoring. After using testosterone for 2 years, the patient is uncertain that she still is experiencing a significant benefit, stops testosterone treatment, and remains satisfied with her sex life.

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.

CASE Midlife woman with low libido causing distress

At her annual gynecologic visit, a 55-year-old woman notes that she has almost no interest in sex. In the past, her libido was good and relations were pleasurable. Since her mid-40s, she has noticed a gradual decline in libido and orgasmic response. Sexual frequency has declined from once or twice weekly to just a few times per month. She has been married for 25 years and describes the relationship as caring and strong. Her husband is healthy with a good libido; his intermittent erectile dysfunction is treated with a phosphodiesterase-5 inhibitor. The patient’s low libido is distressing, as the decline in sexual frequency is causing some conflict for the couple. She requests that her testosterone level be checked because she heard that treatment with testosterone cream will solve this problem.

Evaluating and treating low libido in menopausal women

Low libido is a very common sexual problem for women. When sexual problems are accompanied by distress, they are classified as sexual dysfunctions. Although ObGyns should discuss sexual concerns at every comprehensive visit, if the patient has no associated distress, treatment is not necessarily indicated. A woman with low libido or anorgasmia who is satisfied with her sex life and is not bothered by these issues does not require any intervention.

Currently, the only indication for testosterone therapy that is supported by clinical trial evidence is low sexual desire with associated distress, known as hypoactive sexual desire disorder (HSDD). Although other sexual problems also commonly occur in menopausal women, such as disorders of orgasm and pain, testosterone is not recommended for these problems. In addition, testosterone is not approved by the US Food and Drug Administration (FDA) for the treatment of female sexual dysfunction.

Routinely inquire about sexual functioning

Ask your patients about sexual concerns at every comprehensive visit. You can easily incorporate into the review of systems a general question, such as, “Do you have any sexual concerns?” If the patient does mention a sexual problem, schedule a separate visit (given appointment time constraints) to address it. History and physical examination information you gather during the comprehensive visit will be helpful in the subsequent problem-focused visit.

Taking a thorough history is key when addressing a patient’s sexual problems, since identifying possible etiologies guides treatment. Often, the cause of female sexual dysfunction is multifactorial and includes physiologic, psychologic, and relationship issues.

Explore potential causes, recommend standard therapies

Common causes of low libido in menopausal women include vasomotor symptoms, insomnia, urinary incontinence, cancer or another major medical problem, weight gain, poor body image, genitourinary syndrome of menopause (GSM) with dyspareunia, fatigue, stress, aging, relationship duration, lack of novelty, relationship conflict, and a partner’s sexual problems. Other common etiologies include depression, anxiety, and substance use disorders, as well as medications used to treat these disorders, including selective serotonin reuptake inhibitors (SSRIs).

Continue to: There are many effective therapies...

There are many effective therapies for low sexual desire to consider prior to initiating a trial of testosterone, which should be considered for HSDD only if the disorder persists after addressing all other possible contributing factors (TABLE 1).

Sex therapy, for example, provides information on sexual functioning and helps improve communication and mutual pleasure and satisfaction. Strongly encourage—if not require—a consultation with a sex therapist before prescribing testosterone for low libido. Any testosterone-derived improvement in sexual functioning will be enhanced by improved communication and additional strategies to achieve mutual pleasure.

Hormone therapy. Vasomotor symptoms, with their associated sleep disruption, fatigue, and reduced quality of life (QOL), often adversely impact sexual desire. Estrogen therapy does not appear to improve libido in otherwise asymptomatic women; however, in women with bothersome vasomotor symptoms treated with estrogen, sexual interest may increase as a result of improved sleep, fatigue, and overall QOL. The benefits of systemic hormone therapy generally outweigh its risks for most healthy women younger than age 60 who have bothersome hot flashes and night sweats.¹

Nonhormonal and other therapies. GSM with dyspareunia is a principal cause of sexual dysfunction in older women.² Many safe and effective treatments are available, including low-dose vaginal estrogen therapy, nonhormonal moisturizers and lubricants, ospemifene, vaginal dehydroepiandrosterone, and pelvic floor physical therapy.³ Urinary incontinence commonly occurs in midlife women and contributes to low libido.⁴

Lifestyle approaches. Address fatigue and stress by having the patient adjust her work and sleep schedules, obtain help with housework and meals, and engage in mind-body interventions, counseling, or yoga. Sexual function may benefit from yoga practice, likely as a result of the patient experiencing reduced stress and enhanced body image. Improving overall health and body image with regular exercise, optimal diet, and weight management may contribute to a more satisfying sex life after the onset of menopause.

Relationship refresh. Women’s sexual interest often declines with relationship duration, and both men and women who are in new relationships generally have increased libido, affirming the importance of novelty over the long term. Couples will benefit from “date nights,” weekends away from home, and trying novel positions, locations, and times for sex. Couple’s counseling may address relationship conflict.

Expert referral. Depression, anxiety, and substance use disorders are prevalent in menopausal women and contribute to sexual dysfunction. Effective therapy is available, although some pharmacologic treatments (including SSRIs) may be an additional cause of sexual dysfunction. In addition to recommending appropriate counseling and support, referring the patient to a psychopharmacologist with expertise in managing sexual adverse effects of medications may optimize care.

Continue to: Sexual function improves, but patient still wants to try testosterone

The patient returns for follow-up visits scheduled specifically to address her sexual concerns. Sex is more comfortable and pleasurable since initiating low-dose vaginal estrogen therapy. Having been on an SSRI since her mid-40s for mild depression, the patient switched to bupropion and notes improved libido and orgasmic response. She is exercising more regularly and working with a nutritionist to address a 15-lb weight gain after menopause. The couple saw a sex therapist and is communicating better about sex with more novelty in their repertoire. They are enjoying a regular date night. Although the patient’s sex life has improved with these interventions, she is still very interested in trying testosterone.

Testosterone’s effects on HSDD in menopausal women

After addressing the many factors that contribute to sexual disinterest, a trial of testosterone may be appropriate for a menopausal woman who continues to experience low libido with associated distress.

Testosterone levels decrease with aging in both men and women. Although testosterone levels decline by approximately 50% with bilateral oophorectomy, there is no decline in androgen levels with natural menopause.⁵ Testosterone circulates tightly bound to sex hormone–binding globulin (SHBG), so free or active testosterone will be reduced by oral estrogens, which increase SHBG levels.⁶ As most menopausal women will have a low testosterone level due to aging, measuring the testosterone level does not provide information about the etiology of the sexual problem.

Although some studies have identified an association between endogenous androgen levels and sexual function, the associations are modest and are of uncertain clinical significance.^7-9 Not surprisingly, other factors, such as physical and psychologic health and the quality of the relationship, often are reported as more important predictors of sexual satisfaction than androgen levels.¹⁰

While endogenous testosterone levels may not correlate with sexual function, clinical trials of carefully selected menopausal women with HSDD have shown that androgen treatment generally results in improved sexual function.¹¹ Studies demonstrate substantial improvements in sexual desire, orgasmic response, and frequency in menopausal women treated with high doses of intramuscular testosterone, which result in supraphysiologic androgen levels.^12,13 While it is interesting that women with testosterone levels in the male low range have sizeable increases in sexual desire and response, long-term use of high-dose testosterone would result in unacceptable androgenic adverse effects and risks.

Continue to: Testosterone in low doses...

Testosterone in low doses. It is more relevant to consider the impact on female sexual function of low doses of testosterone, which raise the reduced testosterone levels seen in older women to the higher levels seen in reproductive-aged women.

A series of double-blind, multicenter, randomized, placebo-controlled trials in menopausal women with HSDD examined the impact on sexual function of a transdermal testosterone patch (300 μg) that increased blood testosterone levels to the upper limit of normal for young women.^14-17 In these studies, compared with placebo, women using testosterone reported significant improvements in sexual desire, arousal, orgasmic response, frequency, and sexually related distress. Findings were consistent in surgically and naturally menopausal women, with and without the use of concurrent estrogen therapy. Improvements were clinically limited, however. On average, testosterone-treated women experienced 1 to 1.5 additional satisfying sexual events in a 4-week period compared with those treated with placebo. The percentage of women reporting a clinically meaningful benefit from treatment was significantly greater in women treated with testosterone (52%) compared with the placebo-treated women (31%).¹⁸ An appreciable placebo response was seen, typical of most studies of therapies for sexual dysfunction.

Safety concerns

Potential risks of testosterone treatment include acne, hirsutism, irreversible deepening of the voice, and adverse changes in lipids and liver function (TABLE 2).¹⁹ Adverse effects are dose dependent and are unlikely with physiologically dosed testosterone.

A 1-year study of testosterone patches in approximately 800 menopausal women with HSDD (with a subgroup of women followed for an additional year) provides the most comprehensive safety data available.¹⁷ Unwanted hair growth occurred more often in women receiving testosterone, without significant differences in blood biochemistry,hematologic parameters, carbohydrate metabolism, or lipids. Breast cancer was diagnosed in more women receiving testosterone than placebo. Although this finding may have been due to chance, the investigators concluded that long-term effects of testosterone treatment remain uncertain.

The FDA reviewed the data from the testosterone patch studies and determined that testosterone patches were effective for the treatment of HSDD in menopausal women, but more information was needed on long-term safety before approval could be granted. Another company then developed a testosterone gel product that produced similar blood levels as the testosterone patch. It was presumed that there would be similar efficacy; the principal goal of these studies was to examine long-term safety, particularly with respect to breast cancer and cardiovascular disease. Unexpectedly, although it raised testosterone blood levels to the upper limit of normal for young women, the testosterone gel product was no more effective than placebo.²⁰ The clinical trial was ended, with safety data never published.

Continue to: Availability of testosterone formulations

Currently, no androgen therapies are FDA approved for the treatment of female sexual dysfunction. Although the best evidence regarding testosterone efficacy and safety involves the use of testosterone patches (300 μg), appropriately dosed for women, these patches are not currently available. FDA-approved testosterone patches are approved for the treatment of male hypogonadism, but use of these patches in women is not recommended since they would result in very high circulating testosterone levels.

Testosterone subcutaneous implants, pellets, and intramuscular injections also are not recommended for women because of the risk of excessive dosing. Small trials of menopausal women taking oral estrogen with low sexual desire found that oral formulations of testosterone improved libido in this study population.²¹ The combination of esterified estrogens (0.625 mg) and methyltestosterone (1.25 mg) is available as a compounded, non-FDA approved product. Oral androgen formulations generally are not advised, due to potential adverse effects on lipids and liver function.²²

Compounded testosterone products. Ointments and creams may be compounded by prescription (TABLE 3). Product purity, dose, bioavailability, and quality typically are untested, and substantial variability exists between formulations and batches.²³ Applying 1% testosterone cream or gel (0.5 g/day) topically to the thigh or lower abdomen should increase the low testosterone levels typically seen in menopausal women to the higher levels seen in younger women.^24,25 Application to the vulva or vagina is not advised, as it may cause local irritation and is unpredictably absorbed.

Adapting male testosterone products. High-quality FDA-approved testosterone gel formulations are available for male hypogonadism. However, since women have approximately one-tenth the circulating testosterone levels of men, supraphysiologic dosing is a risk when these products are prescribed for women. Most testosterone products approved for men are provided in pumps or packets, and they are difficult to dose-adjust for women. Applying one-tenth the male dose of 1% testosterone gel (Testim), which comes in a resealable unit-dose tube, is an alternative to compounding. For men, the dose is 1 tube per day, so women should make 1 tube last for 10 days by using 3 to 4 drops of testosterone gel per day. Close physical contact must be avoided immediately after application, as topical hormone creams and gels are easily transferred to others. The safety and efficacy of compounded or dose-adjusted male testosterone products used in women are unknown.

Follow treated women closely. Women who elect to use transdermal testosterone therapy should be seen at 8 to 12 weeks to assess treatment response. Regular follow-up visits are required to assess response, satisfaction, and adverse effects, including acne and hirsutism. Since there may be little correlation between serum testosterone levels and the prescribed dose of a compounded testosterone product, testosterone levels should be measured regularly as a safety measure. The goal is to keep serum testosterone concentrations within the normal range for reproductive-aged women to reduce the likelihood of adverse effects. Testosterone levels should not be tested as an efficacy measure, however, as there is no testosterone level that will assure a satisfactory sex life.

CASE Conclusion

After a thorough discussion of high placebo response rates, potential adverse effects, unknown long-term risks, and off-label nature of testosterone use, the patient elects a trial of compounded 1% testosterone cream. Her clinician informs her of the limitations of compounded formulations and the need for regular testing of testosterone levels to prevent supraphysiologic dosing. At a follow-up visit 8 weeks later, she reports improved sexual desire and elects to continue treatment and monitoring. After using testosterone for 2 years, the patient is uncertain that she still is experiencing a significant benefit, stops testosterone treatment, and remains satisfied with her sex life.

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.

A new diagnostic test that can help clinicians ascertain a patient’s menopausal status has been approved for marketing by the Food and Drug Administration.

The PicoAMH Elisa diagnostic test measures circulating levels of anti-Müllerian hormone (AMH), a granulosa cell product in ovaries that is present only until menopause. In research settings, AMH levels have been used to predict menopause and to confirm the occurrence of menopause; levels have been shown to track well with antral follicle count (J Clin Endocrinol Metab. 2011 Aug 1;96[8]:2532-9).

“Diagnostic results about a woman’s menopausal status may prompt discussions about preventative care for women experiencing menopausal symptoms,” Courtney H. Lias, PhD, director of the division of chemistry and toxicology devices in the FDA’s Center for Devices and Radiological Health, said in a press release announcing the marketing permission. “This test, when used in conjunction with other clinical assessments and laboratory findings, can help inform discussions about preventative care, such as ways to help prevent loss in bone mineral density or to address cardiovascular disease, both of which are known to increase after menopause.”

As Dr. Lias emphasized, the new test is designed to be used along with a thorough clinical assessment and other laboratory tests. Having a reliable test for circulating AMH for clinical use allows measurement of a hormone that, unlike follicle stimulating hormone and luteinizing hormone, does not fluctuate throughout the menstrual cycle for premenopausal women.

JoAnn Pinkerton, MD, executive director of the North American Menopause Society, provided clinical context about the utility of the new assay. “AMH levels appear to provide valuable information about timing of menopause. While not needed for women undergoing a natural menopause at age 51, it will be very helpful for women at risk of early ovarian failure, such as following chemotherapy for cancer or genetic or endocrine reasons,” said Dr. Pinkerton. “Women desiring pregnancy who are skipping periods can be more reassured if their AMH is normal, as studies suggest, that AMH is highly predictive of timing of menopause.”*

In permitting marketing of the PicoAMH Elisa assay, the FDA looked at data drawn from the Study of Women’s Health Across the Nation. For 690 women aged 42-62 years, “the PicoAMH Elisa test performed reasonably well at determining levels of AMH in the blood,” the FDA said in the press release. The test also was able to identify women who had already had their last menstrual period, and to determine women who were at least 5 years away from stopping menstruation, according to the longitudinal study.

The PicoAMH Elisa test will be marketed by Ansh Labs. Since the device’s review went through a de novo premarket pathway designed for novel devices of low to medium risk, there will be an additional set of criteria, called special controls, put in place to monitor the safety and effectiveness of the test.

*This article was updated on 10/26/2018.

A new diagnostic test that can help clinicians ascertain a patient’s menopausal status has been approved for marketing by the Food and Drug Administration.

The PicoAMH Elisa diagnostic test measures circulating levels of anti-Müllerian hormone (AMH), a granulosa cell product in ovaries that is present only until menopause. In research settings, AMH levels have been used to predict menopause and to confirm the occurrence of menopause; levels have been shown to track well with antral follicle count (J Clin Endocrinol Metab. 2011 Aug 1;96[8]:2532-9).

“Diagnostic results about a woman’s menopausal status may prompt discussions about preventative care for women experiencing menopausal symptoms,” Courtney H. Lias, PhD, director of the division of chemistry and toxicology devices in the FDA’s Center for Devices and Radiological Health, said in a press release announcing the marketing permission. “This test, when used in conjunction with other clinical assessments and laboratory findings, can help inform discussions about preventative care, such as ways to help prevent loss in bone mineral density or to address cardiovascular disease, both of which are known to increase after menopause.”

As Dr. Lias emphasized, the new test is designed to be used along with a thorough clinical assessment and other laboratory tests. Having a reliable test for circulating AMH for clinical use allows measurement of a hormone that, unlike follicle stimulating hormone and luteinizing hormone, does not fluctuate throughout the menstrual cycle for premenopausal women.

JoAnn Pinkerton, MD, executive director of the North American Menopause Society, provided clinical context about the utility of the new assay. “AMH levels appear to provide valuable information about timing of menopause. While not needed for women undergoing a natural menopause at age 51, it will be very helpful for women at risk of early ovarian failure, such as following chemotherapy for cancer or genetic or endocrine reasons,” said Dr. Pinkerton. “Women desiring pregnancy who are skipping periods can be more reassured if their AMH is normal, as studies suggest, that AMH is highly predictive of timing of menopause.”*

In permitting marketing of the PicoAMH Elisa assay, the FDA looked at data drawn from the Study of Women’s Health Across the Nation. For 690 women aged 42-62 years, “the PicoAMH Elisa test performed reasonably well at determining levels of AMH in the blood,” the FDA said in the press release. The test also was able to identify women who had already had their last menstrual period, and to determine women who were at least 5 years away from stopping menstruation, according to the longitudinal study.

The PicoAMH Elisa test will be marketed by Ansh Labs. Since the device’s review went through a de novo premarket pathway designed for novel devices of low to medium risk, there will be an additional set of criteria, called special controls, put in place to monitor the safety and effectiveness of the test.

*This article was updated on 10/26/2018.

A new diagnostic test that can help clinicians ascertain a patient’s menopausal status has been approved for marketing by the Food and Drug Administration.

The PicoAMH Elisa diagnostic test measures circulating levels of anti-Müllerian hormone (AMH), a granulosa cell product in ovaries that is present only until menopause. In research settings, AMH levels have been used to predict menopause and to confirm the occurrence of menopause; levels have been shown to track well with antral follicle count (J Clin Endocrinol Metab. 2011 Aug 1;96[8]:2532-9).

“Diagnostic results about a woman’s menopausal status may prompt discussions about preventative care for women experiencing menopausal symptoms,” Courtney H. Lias, PhD, director of the division of chemistry and toxicology devices in the FDA’s Center for Devices and Radiological Health, said in a press release announcing the marketing permission. “This test, when used in conjunction with other clinical assessments and laboratory findings, can help inform discussions about preventative care, such as ways to help prevent loss in bone mineral density or to address cardiovascular disease, both of which are known to increase after menopause.”

As Dr. Lias emphasized, the new test is designed to be used along with a thorough clinical assessment and other laboratory tests. Having a reliable test for circulating AMH for clinical use allows measurement of a hormone that, unlike follicle stimulating hormone and luteinizing hormone, does not fluctuate throughout the menstrual cycle for premenopausal women.

JoAnn Pinkerton, MD, executive director of the North American Menopause Society, provided clinical context about the utility of the new assay. “AMH levels appear to provide valuable information about timing of menopause. While not needed for women undergoing a natural menopause at age 51, it will be very helpful for women at risk of early ovarian failure, such as following chemotherapy for cancer or genetic or endocrine reasons,” said Dr. Pinkerton. “Women desiring pregnancy who are skipping periods can be more reassured if their AMH is normal, as studies suggest, that AMH is highly predictive of timing of menopause.”*

In permitting marketing of the PicoAMH Elisa assay, the FDA looked at data drawn from the Study of Women’s Health Across the Nation. For 690 women aged 42-62 years, “the PicoAMH Elisa test performed reasonably well at determining levels of AMH in the blood,” the FDA said in the press release. The test also was able to identify women who had already had their last menstrual period, and to determine women who were at least 5 years away from stopping menstruation, according to the longitudinal study.

The PicoAMH Elisa test will be marketed by Ansh Labs. Since the device’s review went through a de novo premarket pathway designed for novel devices of low to medium risk, there will be an additional set of criteria, called special controls, put in place to monitor the safety and effectiveness of the test.

*This article was updated on 10/26/2018.

Learn more about NAMS: http://www.menopause.org/home

Learn more about NAMS: http://www.menopause.org/home

Learn more about NAMS: http://www.menopause.org/home

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

An observational study showed that women without meditation training who spent more time in a mindful state had lower ratings on a scale of menopausal symptoms. Furthermore, mindfulness had the greatest positive effect on menopausal symptoms for those women with the highest self-reported stress levels.

“In this cross-sectional study, mindfulness was associated with lower menopausal symptom burden. In women with higher stress, the magnitude of association between mindfulness and menopausal symptoms appeared more robust,” said Richa Sood, MD, speaking at the annual meeting of the North American Menopause Society.

Menopausal symptoms can exist alongside many other midlife issues because women often are trying to keep many balls in the air: This age group may be facing aging parents, a household with teenagers, and work-related pressures, she noted.

Thus, menopausal symptoms can be amplified by stressors. New mood problems – or worsening of preexisting ones – can interfere with work productivity and negatively affect relationships. Life satisfaction can take a steep dive during midlife for some women, said Dr. Sood of the Mayo Clinic, Rochester, Minn.

Could mindfulness be effective for stress management in this complex landscape of physiological and lifespan changes? “Mindfulness is paying attention,” said Dr. Sood. Practitioners of mindfulness focus on purposeful attention, staying in the present moment, and avoiding judgment.

Mindfulness may work as a stress-management tool for a variety of reasons, said Dr. Sood. The technique can help retrain people with tendencies for emotional reactivity in stressful situations; additionally, the focus on the present and on observation, rather than judgment, may help avoid maladaptive rumination.

To see how mindfulness in everyday life could affect the burden of menopausal symptoms, Dr. Sood and her collaborators designed an observational, cross-sectional study of 1,744 women aged 40-64 years.

The investigators used three scales in their assessments. The first, the Menopause Rating Scale (MRS), is an 11-item scale ranging from 0 to 44 that assesses psychological, somatovegetative, and urogenital domains. The second, the Perceived Stress Scale 4 (PSS-4), is a four-item scale that is a global measure of stress over the last 4 weeks, with tallied scores in the 0-16 range. Finally, the Mindful Attention Awareness Scale (MAAS) is a 15-item scale that captures how frequently respondents are in a mindful state during their daily life, with higher scores meaning more mindfulness.

The 1,744 women were seen in a women’s health clinic over the period of one year. Participants were a mean 53.4 years old (standard deviation, 6.1 years). Almost all were white (93%), most were married (82.7%), and most also had at least a 4-year college degree (64.6%) and were employed (65.3%).

The investigators mapped each scale against each of the others, which yielded three plots. In the first, higher MAAS scores were correlated with lower MRS scores (correlation, –0.49; P less than .001), which means that more time in a mindful state was associated with less severe menopausal symptoms.

In the second plot, lower MRS scores were associated with lower PSS-4 scores (correlation, 0.55; P less than .001). The last plot mapped PSS-4 scores against MAAS scores, showing that higher MAAS scores were correlated with lower PSS-4 scores, which means that more time in a mindful state was also associated with less perceived stress (correlation, –0.53; P less than .001).

Most of these associations remained statistically significant after multivariable linear regression analysis and breaking out the subscales of the MRS. Only the association between higher MAAS scores and the somatovegetative domain of the PSS-4 lost significance (P = 0.44).

Next, Dr. Sood and her collaborators probed how higher perceived stress, as measured by higher PSS-4 scores, altered the effects that mindful activity had on menopausal symptoms (as measured by the MRS).

The effect of mindfulness became stronger in the milieu of higher perceived stress. At a relatively low PSS-4 value of 4, the MRS score dropped 1.53 points for each one-point increase in the MAAS total score. However, with a PSS-4 score of 12, the decrease in MRS was 2.27 points for each one-point increase in MAAS, and with the maximum perceived stress score of 16, the MRS fell 2.64 points for each one-point increase in the MAAS score.

These findings are set against the backdrop of previous literature linking mindfulness to positive health behaviors and outcomes, she said, noting that work looking specifically at mindfulness-based stress reduction in peri- and postmenopausal women showed a halving of symptoms and improved quality of life.

Dr. Sood said that the present study was observational only, noting that it looked only at time spent in a mindful state in an untrained cohort of women in midlife. “Trait, or dispositional, mindfulness appears to be protective against stress and symptoms in midlife women,” she commented. “More mindful women may be choosing to shift their attention to more pleasant aspects of life, rather than their symptoms.”

“If you allow me to speculate a bit,” Dr. Sood continued, “the underpinnings of psychological symptoms rest in threat-focused attention and emotional reactivity – so the mindfulness approach appears to fit very well to impact such a change.”

Mindfulness, she added, “might be a tool to impact the emotional component of the overall experience, thereby decreasing the total suffering.” However, she noted that what’s needed are studies with a more heterogeneous population, as well as ones designed to tease out causality. Still, “the current study adds to the wealth of data supporting the role of mindfulness in various settings for impacting positive change in health and behaviors.”

Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.

[email protected]

SOURCE: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.

An observational study showed that women without meditation training who spent more time in a mindful state had lower ratings on a scale of menopausal symptoms. Furthermore, mindfulness had the greatest positive effect on menopausal symptoms for those women with the highest self-reported stress levels.

“In this cross-sectional study, mindfulness was associated with lower menopausal symptom burden. In women with higher stress, the magnitude of association between mindfulness and menopausal symptoms appeared more robust,” said Richa Sood, MD, speaking at the annual meeting of the North American Menopause Society.

Menopausal symptoms can exist alongside many other midlife issues because women often are trying to keep many balls in the air: This age group may be facing aging parents, a household with teenagers, and work-related pressures, she noted.

Thus, menopausal symptoms can be amplified by stressors. New mood problems – or worsening of preexisting ones – can interfere with work productivity and negatively affect relationships. Life satisfaction can take a steep dive during midlife for some women, said Dr. Sood of the Mayo Clinic, Rochester, Minn.

Could mindfulness be effective for stress management in this complex landscape of physiological and lifespan changes? “Mindfulness is paying attention,” said Dr. Sood. Practitioners of mindfulness focus on purposeful attention, staying in the present moment, and avoiding judgment.

Mindfulness may work as a stress-management tool for a variety of reasons, said Dr. Sood. The technique can help retrain people with tendencies for emotional reactivity in stressful situations; additionally, the focus on the present and on observation, rather than judgment, may help avoid maladaptive rumination.

To see how mindfulness in everyday life could affect the burden of menopausal symptoms, Dr. Sood and her collaborators designed an observational, cross-sectional study of 1,744 women aged 40-64 years.

The investigators used three scales in their assessments. The first, the Menopause Rating Scale (MRS), is an 11-item scale ranging from 0 to 44 that assesses psychological, somatovegetative, and urogenital domains. The second, the Perceived Stress Scale 4 (PSS-4), is a four-item scale that is a global measure of stress over the last 4 weeks, with tallied scores in the 0-16 range. Finally, the Mindful Attention Awareness Scale (MAAS) is a 15-item scale that captures how frequently respondents are in a mindful state during their daily life, with higher scores meaning more mindfulness.

The 1,744 women were seen in a women’s health clinic over the period of one year. Participants were a mean 53.4 years old (standard deviation, 6.1 years). Almost all were white (93%), most were married (82.7%), and most also had at least a 4-year college degree (64.6%) and were employed (65.3%).

The investigators mapped each scale against each of the others, which yielded three plots. In the first, higher MAAS scores were correlated with lower MRS scores (correlation, –0.49; P less than .001), which means that more time in a mindful state was associated with less severe menopausal symptoms.

In the second plot, lower MRS scores were associated with lower PSS-4 scores (correlation, 0.55; P less than .001). The last plot mapped PSS-4 scores against MAAS scores, showing that higher MAAS scores were correlated with lower PSS-4 scores, which means that more time in a mindful state was also associated with less perceived stress (correlation, –0.53; P less than .001).

Most of these associations remained statistically significant after multivariable linear regression analysis and breaking out the subscales of the MRS. Only the association between higher MAAS scores and the somatovegetative domain of the PSS-4 lost significance (P = 0.44).

Next, Dr. Sood and her collaborators probed how higher perceived stress, as measured by higher PSS-4 scores, altered the effects that mindful activity had on menopausal symptoms (as measured by the MRS).

The effect of mindfulness became stronger in the milieu of higher perceived stress. At a relatively low PSS-4 value of 4, the MRS score dropped 1.53 points for each one-point increase in the MAAS total score. However, with a PSS-4 score of 12, the decrease in MRS was 2.27 points for each one-point increase in MAAS, and with the maximum perceived stress score of 16, the MRS fell 2.64 points for each one-point increase in the MAAS score.

These findings are set against the backdrop of previous literature linking mindfulness to positive health behaviors and outcomes, she said, noting that work looking specifically at mindfulness-based stress reduction in peri- and postmenopausal women showed a halving of symptoms and improved quality of life.

Dr. Sood said that the present study was observational only, noting that it looked only at time spent in a mindful state in an untrained cohort of women in midlife. “Trait, or dispositional, mindfulness appears to be protective against stress and symptoms in midlife women,” she commented. “More mindful women may be choosing to shift their attention to more pleasant aspects of life, rather than their symptoms.”

“If you allow me to speculate a bit,” Dr. Sood continued, “the underpinnings of psychological symptoms rest in threat-focused attention and emotional reactivity – so the mindfulness approach appears to fit very well to impact such a change.”

Mindfulness, she added, “might be a tool to impact the emotional component of the overall experience, thereby decreasing the total suffering.” However, she noted that what’s needed are studies with a more heterogeneous population, as well as ones designed to tease out causality. Still, “the current study adds to the wealth of data supporting the role of mindfulness in various settings for impacting positive change in health and behaviors.”

Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.

[email protected]

SOURCE: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.

An observational study showed that women without meditation training who spent more time in a mindful state had lower ratings on a scale of menopausal symptoms. Furthermore, mindfulness had the greatest positive effect on menopausal symptoms for those women with the highest self-reported stress levels.

“In this cross-sectional study, mindfulness was associated with lower menopausal symptom burden. In women with higher stress, the magnitude of association between mindfulness and menopausal symptoms appeared more robust,” said Richa Sood, MD, speaking at the annual meeting of the North American Menopause Society.

Menopausal symptoms can exist alongside many other midlife issues because women often are trying to keep many balls in the air: This age group may be facing aging parents, a household with teenagers, and work-related pressures, she noted.

Thus, menopausal symptoms can be amplified by stressors. New mood problems – or worsening of preexisting ones – can interfere with work productivity and negatively affect relationships. Life satisfaction can take a steep dive during midlife for some women, said Dr. Sood of the Mayo Clinic, Rochester, Minn.

Could mindfulness be effective for stress management in this complex landscape of physiological and lifespan changes? “Mindfulness is paying attention,” said Dr. Sood. Practitioners of mindfulness focus on purposeful attention, staying in the present moment, and avoiding judgment.

Mindfulness may work as a stress-management tool for a variety of reasons, said Dr. Sood. The technique can help retrain people with tendencies for emotional reactivity in stressful situations; additionally, the focus on the present and on observation, rather than judgment, may help avoid maladaptive rumination.

To see how mindfulness in everyday life could affect the burden of menopausal symptoms, Dr. Sood and her collaborators designed an observational, cross-sectional study of 1,744 women aged 40-64 years.

The investigators used three scales in their assessments. The first, the Menopause Rating Scale (MRS), is an 11-item scale ranging from 0 to 44 that assesses psychological, somatovegetative, and urogenital domains. The second, the Perceived Stress Scale 4 (PSS-4), is a four-item scale that is a global measure of stress over the last 4 weeks, with tallied scores in the 0-16 range. Finally, the Mindful Attention Awareness Scale (MAAS) is a 15-item scale that captures how frequently respondents are in a mindful state during their daily life, with higher scores meaning more mindfulness.

The 1,744 women were seen in a women’s health clinic over the period of one year. Participants were a mean 53.4 years old (standard deviation, 6.1 years). Almost all were white (93%), most were married (82.7%), and most also had at least a 4-year college degree (64.6%) and were employed (65.3%).

The investigators mapped each scale against each of the others, which yielded three plots. In the first, higher MAAS scores were correlated with lower MRS scores (correlation, –0.49; P less than .001), which means that more time in a mindful state was associated with less severe menopausal symptoms.

In the second plot, lower MRS scores were associated with lower PSS-4 scores (correlation, 0.55; P less than .001). The last plot mapped PSS-4 scores against MAAS scores, showing that higher MAAS scores were correlated with lower PSS-4 scores, which means that more time in a mindful state was also associated with less perceived stress (correlation, –0.53; P less than .001).

Most of these associations remained statistically significant after multivariable linear regression analysis and breaking out the subscales of the MRS. Only the association between higher MAAS scores and the somatovegetative domain of the PSS-4 lost significance (P = 0.44).

Next, Dr. Sood and her collaborators probed how higher perceived stress, as measured by higher PSS-4 scores, altered the effects that mindful activity had on menopausal symptoms (as measured by the MRS).

The effect of mindfulness became stronger in the milieu of higher perceived stress. At a relatively low PSS-4 value of 4, the MRS score dropped 1.53 points for each one-point increase in the MAAS total score. However, with a PSS-4 score of 12, the decrease in MRS was 2.27 points for each one-point increase in MAAS, and with the maximum perceived stress score of 16, the MRS fell 2.64 points for each one-point increase in the MAAS score.

These findings are set against the backdrop of previous literature linking mindfulness to positive health behaviors and outcomes, she said, noting that work looking specifically at mindfulness-based stress reduction in peri- and postmenopausal women showed a halving of symptoms and improved quality of life.

Dr. Sood said that the present study was observational only, noting that it looked only at time spent in a mindful state in an untrained cohort of women in midlife. “Trait, or dispositional, mindfulness appears to be protective against stress and symptoms in midlife women,” she commented. “More mindful women may be choosing to shift their attention to more pleasant aspects of life, rather than their symptoms.”

“If you allow me to speculate a bit,” Dr. Sood continued, “the underpinnings of psychological symptoms rest in threat-focused attention and emotional reactivity – so the mindfulness approach appears to fit very well to impact such a change.”

Mindfulness, she added, “might be a tool to impact the emotional component of the overall experience, thereby decreasing the total suffering.” However, she noted that what’s needed are studies with a more heterogeneous population, as well as ones designed to tease out causality. Still, “the current study adds to the wealth of data supporting the role of mindfulness in various settings for impacting positive change in health and behaviors.”

Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.

[email protected]

SOURCE: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.

Neither age nor previous hormone therapy had statistically significant associations with the effect of intravaginal prasterone on dyspareunia severity, according to a new subgroup analysis of clinical trial data. In a trend that did not reach statistical significance, though, women who were further away from menopause reported numerically smaller improvements in dyspareunia, compared with baseline values, said David F. Archer, MD.

“This was an unexpected finding,” he said in an interview.

In a subgroup analysis of data from two clinical trials of intravaginal prasterone (Intrarosa), Dr. Archer and his colleagues sought to investigate whether age, time since menopause, or any previous use of hormone replacement therapy influenced prasterone’s efficacy in treating dyspareunia.

Dr. Archer and his collaborators pooled data from two prospective, randomized, double-blind, placebo-controlled trials (NCT02013544 and NCT01256684) of intravaginal prasterone dosed at 0.50%, 6.5 mg once daily for 12 weeks; he presented the subgroup analyses at the annual meeting of the North American Menopause Society in San Diego.

For each subgroup, Dr. Archer, a professor of obstetrics and gynecology at Eastern Virginia Medical School, Norfolk, and his coinvestigators compared the mean differences in dyspareunia severity score of women who received prasterone and those who received placebo.

All subgroup analyses used the endpoint of improvement in moderate to severe dyspareunia or whether dyspareunia was the most bothersome symptoms for the women participating in the study. The investigators began by looking at the subgroup of 460 women who were 56 years and older at baseline and compared them with the 180 younger participants.

The 283 older participants who received prasterone saw a decrease of 0.36 points in a dyspareunia severity score versus a 0.44 point decrease for the 123 women aged 55 and younger who received prasterone, a nonsignificant difference between subgroups. The decrease compared with placebo-takers was significant in both cases, however (P = .0003 and P =.0031, respectively).

Looking at time since menopause, Dr. Archer and his collaborators divided participants into 33 individuals who were 1 or 2 years post menopause, 86 women who were 3-5 years post menopause, and 521 women who had experienced menopause at least 6 years before study baseline.

In this analysis, 22 of the earliest postmenopause women received prasterone, seeing a 1.59 point drop in dyspareunia severity. For the 59 women in the prasterone study arms who were 3-5 year past menopause, the decrease from baseline was 0.59 points. Finally, among the 325 women who received prasterone and experienced menopause 6 or more years ago, the decrease was 0.27 points.

Although there was a numeric difference in the change in dyspareunia score severity among these groups, the differences were not statistically significant, said Dr. Archer. Again, though, those who took prasterone had a significant reduction in dyspareunia severity scores when compared with those taking placebo (P less than .0001, P = .0136, and P = .0024, respectively).

In the prasterone study arms, 184 had previously used hormone therapy, and 222 had not. After 12 weeks of intravaginal prasterone, there was no statistically significant difference between the two subgroups, with a decreases in dyspareunia severity scores of 0.45 and 0.32, respectively. The decreases in severity scores when compared with those among women who took placebo were again statistically significant for both subgroups, however (P = .0002 and P = .0057, respectively).

Prasterone is a steroid that is also known as dehydroepiandrosterone (DHEA) and is an endogenous hormone that is a precursor for estrogens and androgens. Prasterone’s mechanism of action to reduce vulvar and vaginal atrophy is not completely understood, according to the Food and Drug Administration.

“The nonstatistically significant smaller effect on dyspareunia observed when treatment is initiated after a longer period after menopause suggests that a longer treatment period could be needed to achieve optimal benefit and that treatment of dyspareunia should be initiated as early as possible after menopause,” said Dr. Archer.

Dr. Archer reported grant support from and consulting relationships with several pharmaceutical companies, including Endoceutics, the producer of Intrarosa intravaginal prasterone.

[email protected]

Neither age nor previous hormone therapy had statistically significant associations with the effect of intravaginal prasterone on dyspareunia severity, according to a new subgroup analysis of clinical trial data. In a trend that did not reach statistical significance, though, women who were further away from menopause reported numerically smaller improvements in dyspareunia, compared with baseline values, said David F. Archer, MD.

“This was an unexpected finding,” he said in an interview.

In a subgroup analysis of data from two clinical trials of intravaginal prasterone (Intrarosa), Dr. Archer and his colleagues sought to investigate whether age, time since menopause, or any previous use of hormone replacement therapy influenced prasterone’s efficacy in treating dyspareunia.

Dr. Archer and his collaborators pooled data from two prospective, randomized, double-blind, placebo-controlled trials (NCT02013544 and NCT01256684) of intravaginal prasterone dosed at 0.50%, 6.5 mg once daily for 12 weeks; he presented the subgroup analyses at the annual meeting of the North American Menopause Society in San Diego.

For each subgroup, Dr. Archer, a professor of obstetrics and gynecology at Eastern Virginia Medical School, Norfolk, and his coinvestigators compared the mean differences in dyspareunia severity score of women who received prasterone and those who received placebo.

All subgroup analyses used the endpoint of improvement in moderate to severe dyspareunia or whether dyspareunia was the most bothersome symptoms for the women participating in the study. The investigators began by looking at the subgroup of 460 women who were 56 years and older at baseline and compared them with the 180 younger participants.

The 283 older participants who received prasterone saw a decrease of 0.36 points in a dyspareunia severity score versus a 0.44 point decrease for the 123 women aged 55 and younger who received prasterone, a nonsignificant difference between subgroups. The decrease compared with placebo-takers was significant in both cases, however (P = .0003 and P =.0031, respectively).

Looking at time since menopause, Dr. Archer and his collaborators divided participants into 33 individuals who were 1 or 2 years post menopause, 86 women who were 3-5 years post menopause, and 521 women who had experienced menopause at least 6 years before study baseline.

In this analysis, 22 of the earliest postmenopause women received prasterone, seeing a 1.59 point drop in dyspareunia severity. For the 59 women in the prasterone study arms who were 3-5 year past menopause, the decrease from baseline was 0.59 points. Finally, among the 325 women who received prasterone and experienced menopause 6 or more years ago, the decrease was 0.27 points.

Although there was a numeric difference in the change in dyspareunia score severity among these groups, the differences were not statistically significant, said Dr. Archer. Again, though, those who took prasterone had a significant reduction in dyspareunia severity scores when compared with those taking placebo (P less than .0001, P = .0136, and P = .0024, respectively).

In the prasterone study arms, 184 had previously used hormone therapy, and 222 had not. After 12 weeks of intravaginal prasterone, there was no statistically significant difference between the two subgroups, with a decreases in dyspareunia severity scores of 0.45 and 0.32, respectively. The decreases in severity scores when compared with those among women who took placebo were again statistically significant for both subgroups, however (P = .0002 and P = .0057, respectively).

Prasterone is a steroid that is also known as dehydroepiandrosterone (DHEA) and is an endogenous hormone that is a precursor for estrogens and androgens. Prasterone’s mechanism of action to reduce vulvar and vaginal atrophy is not completely understood, according to the Food and Drug Administration.

“The nonstatistically significant smaller effect on dyspareunia observed when treatment is initiated after a longer period after menopause suggests that a longer treatment period could be needed to achieve optimal benefit and that treatment of dyspareunia should be initiated as early as possible after menopause,” said Dr. Archer.

Dr. Archer reported grant support from and consulting relationships with several pharmaceutical companies, including Endoceutics, the producer of Intrarosa intravaginal prasterone.

[email protected]

Neither age nor previous hormone therapy had statistically significant associations with the effect of intravaginal prasterone on dyspareunia severity, according to a new subgroup analysis of clinical trial data. In a trend that did not reach statistical significance, though, women who were further away from menopause reported numerically smaller improvements in dyspareunia, compared with baseline values, said David F. Archer, MD.

“This was an unexpected finding,” he said in an interview.

In a subgroup analysis of data from two clinical trials of intravaginal prasterone (Intrarosa), Dr. Archer and his colleagues sought to investigate whether age, time since menopause, or any previous use of hormone replacement therapy influenced prasterone’s efficacy in treating dyspareunia.

Dr. Archer and his collaborators pooled data from two prospective, randomized, double-blind, placebo-controlled trials (NCT02013544 and NCT01256684) of intravaginal prasterone dosed at 0.50%, 6.5 mg once daily for 12 weeks; he presented the subgroup analyses at the annual meeting of the North American Menopause Society in San Diego.

For each subgroup, Dr. Archer, a professor of obstetrics and gynecology at Eastern Virginia Medical School, Norfolk, and his coinvestigators compared the mean differences in dyspareunia severity score of women who received prasterone and those who received placebo.

All subgroup analyses used the endpoint of improvement in moderate to severe dyspareunia or whether dyspareunia was the most bothersome symptoms for the women participating in the study. The investigators began by looking at the subgroup of 460 women who were 56 years and older at baseline and compared them with the 180 younger participants.

The 283 older participants who received prasterone saw a decrease of 0.36 points in a dyspareunia severity score versus a 0.44 point decrease for the 123 women aged 55 and younger who received prasterone, a nonsignificant difference between subgroups. The decrease compared with placebo-takers was significant in both cases, however (P = .0003 and P =.0031, respectively).

Looking at time since menopause, Dr. Archer and his collaborators divided participants into 33 individuals who were 1 or 2 years post menopause, 86 women who were 3-5 years post menopause, and 521 women who had experienced menopause at least 6 years before study baseline.

In this analysis, 22 of the earliest postmenopause women received prasterone, seeing a 1.59 point drop in dyspareunia severity. For the 59 women in the prasterone study arms who were 3-5 year past menopause, the decrease from baseline was 0.59 points. Finally, among the 325 women who received prasterone and experienced menopause 6 or more years ago, the decrease was 0.27 points.

Although there was a numeric difference in the change in dyspareunia score severity among these groups, the differences were not statistically significant, said Dr. Archer. Again, though, those who took prasterone had a significant reduction in dyspareunia severity scores when compared with those taking placebo (P less than .0001, P = .0136, and P = .0024, respectively).

In the prasterone study arms, 184 had previously used hormone therapy, and 222 had not. After 12 weeks of intravaginal prasterone, there was no statistically significant difference between the two subgroups, with a decreases in dyspareunia severity scores of 0.45 and 0.32, respectively. The decreases in severity scores when compared with those among women who took placebo were again statistically significant for both subgroups, however (P = .0002 and P = .0057, respectively).

Prasterone is a steroid that is also known as dehydroepiandrosterone (DHEA) and is an endogenous hormone that is a precursor for estrogens and androgens. Prasterone’s mechanism of action to reduce vulvar and vaginal atrophy is not completely understood, according to the Food and Drug Administration.

“The nonstatistically significant smaller effect on dyspareunia observed when treatment is initiated after a longer period after menopause suggests that a longer treatment period could be needed to achieve optimal benefit and that treatment of dyspareunia should be initiated as early as possible after menopause,” said Dr. Archer.

Dr. Archer reported grant support from and consulting relationships with several pharmaceutical companies, including Endoceutics, the producer of Intrarosa intravaginal prasterone.

[email protected]

There is little justification for the use of vitamin D supplementation for the prevention of fractures or falls or for increasing bone density, according to the authors of a meta-analysis that found no benefits from supplementation.

copyright istock/Thinkstock

A systematic review and meta-analysis, published in the Oct. 4 edition of Lancet Diabetes & Endocrinology, examined 81 randomized controlled trials – involving 53,537 participants – of the effects of vitamin D supplementation on fractures, falls, or bone mineral density.

In the pooled analyses, researchers found that vitamin D supplementation did not reduce total fracture, hip fracture, or falls, even in trials in which participants took doses greater than 800 IU/day. Their results were similar when researchers compared high doses and low doses in their trials.

Similarly, vitamin D supplementation was not associated with any clinically relevant improvements in bone mineral density at any site; lumbar spine, total hip, femoral neck, forearm, or total body.

Even a post hoc analysis of randomized, controlled trials that compared daily high doses with daily low doses, as well as trials that compared intermittent high doses with intermittent low doses found no significant interactions for any outcome.

The paper also explored whether baseline vitamin D levels might influence outcomes. Eighteen trials in the analysis reported the results of subgroup analyses using baseline serum 25-hydroxyvitamin D (25[OH]D); three found no effects of vitamin D supplements in different subgroups of baseline, five studies found no effects of subgroups or interaction with baseline serum 25[OH]D, and one found mixed effects with respect to falls.

The outcomes for bone mineral density, as related to baseline serum 25[OH]D, were slightly more mixed. One trial found a positive effect of vitamin D supplements a bone mineral density for different subgroups of baseline serum, five trials reported mixed effects, and eight trials found no effects.

“The strengths of the current analyses are that they are comprehensive, include all available data from a large number of new trials, and concomitantly assess the major clinical and surrogate endpoints for musculoskeletal health,” wrote Mark J. Bolland, MD, of the department of medicine at the University of Auckland (New Zealand), and his coauthors. “Therefore, there is little justification for the use of vitamin D supplements to maintain or improve musculoskeletal health, and clinical guidelines should reflect these findings.”

They also conducted trial sequential analyses, which is a type of cumulative meta-analysis. For each outcome, they set a relative risk reduction threshold, then progressively reduced that threshold until the optimum sample size for that threshold exceeded the actual sample size.

“The trial sequential analyses are important because they provide estimates about the reliability of current evidence and the likelihood of future trials to change current conclusions,” the authors wrote.

Using this approach, they once again found clear evidence that vitamin D supplementation did not reduce fractures or falls for any measure of relative risk reduction. For hip fracture, the trial sequential analysis even found some uncertainty as to whether vitamin D supplementation might increase the risk of hip fractures.

Given the results of the trial sequential analyses, the authors argued that further similar trials were unlikely to alter their conclusion.

“If a large future trial has markedly different results to the current trials, adding its results will substantially increase the heterogeneity of the trial results, which in turn will reduce the weighting the new large trial receives in the pooled analyses,” they wrote. “Thus, adding a positive result from a large randomized, controlled trial will have only a small effect on the pooled result and is unlikely to alter the conclusions of these meta-analyses.”

They also noted that some of the studies had methodological limitations, and smaller studies of shorter duration tended to have “inflated” effect sizes, such that “the results of small, short-duration studies should be interpreted very cautiously, since they might not be replicated in larger, longer studies.”

The study was funded by the Health Research Council of New Zealand. Two authors declared grants from the Health Research Council during the study, one author is a shareholder in a company that provides bone mineral density measurements, and one reported grants from the Scottish Government Health and Social Care Directorates during the study.

SOURCE: Bolland M et al. Lancet Diabetes Endocrinol. 2018 Oct 4. doi. org/10.1016/S2213-8587(18)30265-1.


 

There is little justification for the use of vitamin D supplementation for the prevention of fractures or falls or for increasing bone density, according to the authors of a meta-analysis that found no benefits from supplementation.

copyright istock/Thinkstock

A systematic review and meta-analysis, published in the Oct. 4 edition of Lancet Diabetes & Endocrinology, examined 81 randomized controlled trials – involving 53,537 participants – of the effects of vitamin D supplementation on fractures, falls, or bone mineral density.

In the pooled analyses, researchers found that vitamin D supplementation did not reduce total fracture, hip fracture, or falls, even in trials in which participants took doses greater than 800 IU/day. Their results were similar when researchers compared high doses and low doses in their trials.

Similarly, vitamin D supplementation was not associated with any clinically relevant improvements in bone mineral density at any site; lumbar spine, total hip, femoral neck, forearm, or total body.

Even a post hoc analysis of randomized, controlled trials that compared daily high doses with daily low doses, as well as trials that compared intermittent high doses with intermittent low doses found no significant interactions for any outcome.

The paper also explored whether baseline vitamin D levels might influence outcomes. Eighteen trials in the analysis reported the results of subgroup analyses using baseline serum 25-hydroxyvitamin D (25[OH]D); three found no effects of vitamin D supplements in different subgroups of baseline, five studies found no effects of subgroups or interaction with baseline serum 25[OH]D, and one found mixed effects with respect to falls.

The outcomes for bone mineral density, as related to baseline serum 25[OH]D, were slightly more mixed. One trial found a positive effect of vitamin D supplements a bone mineral density for different subgroups of baseline serum, five trials reported mixed effects, and eight trials found no effects.

“The strengths of the current analyses are that they are comprehensive, include all available data from a large number of new trials, and concomitantly assess the major clinical and surrogate endpoints for musculoskeletal health,” wrote Mark J. Bolland, MD, of the department of medicine at the University of Auckland (New Zealand), and his coauthors. “Therefore, there is little justification for the use of vitamin D supplements to maintain or improve musculoskeletal health, and clinical guidelines should reflect these findings.”

They also conducted trial sequential analyses, which is a type of cumulative meta-analysis. For each outcome, they set a relative risk reduction threshold, then progressively reduced that threshold until the optimum sample size for that threshold exceeded the actual sample size.

“The trial sequential analyses are important because they provide estimates about the reliability of current evidence and the likelihood of future trials to change current conclusions,” the authors wrote.

Using this approach, they once again found clear evidence that vitamin D supplementation did not reduce fractures or falls for any measure of relative risk reduction. For hip fracture, the trial sequential analysis even found some uncertainty as to whether vitamin D supplementation might increase the risk of hip fractures.

Given the results of the trial sequential analyses, the authors argued that further similar trials were unlikely to alter their conclusion.

“If a large future trial has markedly different results to the current trials, adding its results will substantially increase the heterogeneity of the trial results, which in turn will reduce the weighting the new large trial receives in the pooled analyses,” they wrote. “Thus, adding a positive result from a large randomized, controlled trial will have only a small effect on the pooled result and is unlikely to alter the conclusions of these meta-analyses.”

They also noted that some of the studies had methodological limitations, and smaller studies of shorter duration tended to have “inflated” effect sizes, such that “the results of small, short-duration studies should be interpreted very cautiously, since they might not be replicated in larger, longer studies.”

The study was funded by the Health Research Council of New Zealand. Two authors declared grants from the Health Research Council during the study, one author is a shareholder in a company that provides bone mineral density measurements, and one reported grants from the Scottish Government Health and Social Care Directorates during the study.

SOURCE: Bolland M et al. Lancet Diabetes Endocrinol. 2018 Oct 4. doi. org/10.1016/S2213-8587(18)30265-1.


 

There is little justification for the use of vitamin D supplementation for the prevention of fractures or falls or for increasing bone density, according to the authors of a meta-analysis that found no benefits from supplementation.

copyright istock/Thinkstock

A systematic review and meta-analysis, published in the Oct. 4 edition of Lancet Diabetes & Endocrinology, examined 81 randomized controlled trials – involving 53,537 participants – of the effects of vitamin D supplementation on fractures, falls, or bone mineral density.

In the pooled analyses, researchers found that vitamin D supplementation did not reduce total fracture, hip fracture, or falls, even in trials in which participants took doses greater than 800 IU/day. Their results were similar when researchers compared high doses and low doses in their trials.

Similarly, vitamin D supplementation was not associated with any clinically relevant improvements in bone mineral density at any site; lumbar spine, total hip, femoral neck, forearm, or total body.

Even a post hoc analysis of randomized, controlled trials that compared daily high doses with daily low doses, as well as trials that compared intermittent high doses with intermittent low doses found no significant interactions for any outcome.

The paper also explored whether baseline vitamin D levels might influence outcomes. Eighteen trials in the analysis reported the results of subgroup analyses using baseline serum 25-hydroxyvitamin D (25[OH]D); three found no effects of vitamin D supplements in different subgroups of baseline, five studies found no effects of subgroups or interaction with baseline serum 25[OH]D, and one found mixed effects with respect to falls.

The outcomes for bone mineral density, as related to baseline serum 25[OH]D, were slightly more mixed. One trial found a positive effect of vitamin D supplements a bone mineral density for different subgroups of baseline serum, five trials reported mixed effects, and eight trials found no effects.

“The strengths of the current analyses are that they are comprehensive, include all available data from a large number of new trials, and concomitantly assess the major clinical and surrogate endpoints for musculoskeletal health,” wrote Mark J. Bolland, MD, of the department of medicine at the University of Auckland (New Zealand), and his coauthors. “Therefore, there is little justification for the use of vitamin D supplements to maintain or improve musculoskeletal health, and clinical guidelines should reflect these findings.”

They also conducted trial sequential analyses, which is a type of cumulative meta-analysis. For each outcome, they set a relative risk reduction threshold, then progressively reduced that threshold until the optimum sample size for that threshold exceeded the actual sample size.

“The trial sequential analyses are important because they provide estimates about the reliability of current evidence and the likelihood of future trials to change current conclusions,” the authors wrote.

Using this approach, they once again found clear evidence that vitamin D supplementation did not reduce fractures or falls for any measure of relative risk reduction. For hip fracture, the trial sequential analysis even found some uncertainty as to whether vitamin D supplementation might increase the risk of hip fractures.

Given the results of the trial sequential analyses, the authors argued that further similar trials were unlikely to alter their conclusion.

“If a large future trial has markedly different results to the current trials, adding its results will substantially increase the heterogeneity of the trial results, which in turn will reduce the weighting the new large trial receives in the pooled analyses,” they wrote. “Thus, adding a positive result from a large randomized, controlled trial will have only a small effect on the pooled result and is unlikely to alter the conclusions of these meta-analyses.”

They also noted that some of the studies had methodological limitations, and smaller studies of shorter duration tended to have “inflated” effect sizes, such that “the results of small, short-duration studies should be interpreted very cautiously, since they might not be replicated in larger, longer studies.”

The study was funded by the Health Research Council of New Zealand. Two authors declared grants from the Health Research Council during the study, one author is a shareholder in a company that provides bone mineral density measurements, and one reported grants from the Scottish Government Health and Social Care Directorates during the study.

SOURCE: Bolland M et al. Lancet Diabetes Endocrinol. 2018 Oct 4. doi. org/10.1016/S2213-8587(18)30265-1.


 

Intravenous zoledronate therapy given once every 18 months, with minimal use of calcium supplements, was associated with an increase in bone mass and significantly reduced the risk of vertebral and nonvertebral fractures in postmenopausal women, compared with a placebo, based on data from a 6-year trial of 2,000 ambulatory women aged 65 and older with osteopenia.

The findings were presented at the annual meeting of the American Society for Bone and Mineral Research and published simultaneously in the New England Journal of Medicine.

Bisphosphonates have been shown to prevent fractures in osteoporosis patients, but their effectiveness has not been well studied in patients with osteopenia alone, noted Ian R. Reid, MD, of the University of Auckland, New Zealand, and his colleagues. “Many patients at high risk for fracture do not have T scores of less than –2.5 but rather have osteopenia in combination with other risk factors such as age.”

The researchers randomized 2,000 women aged 65 years and older with osteopenia to receive four infusions of zoledronate or a saline placebo every 18 months. A dietary intake of 1 g of calcium per day was advised, but calcium supplements were not provided; 2% of the women took supplements. Those not taking vitamin D before the trial were given a single 2.5-mg dose of cholecalciferol and a monthly 1.25-mg dose during the trial. Trial participants were followed for 6 years.

Courtesy Dr. Ian Reid

SOURCE: Reid I et al. N Engl J Med. 2018 Oct 1. doi: 10.1056/NEJMoa1808082.

Intravenous zoledronate therapy given once every 18 months, with minimal use of calcium supplements, was associated with an increase in bone mass and significantly reduced the risk of vertebral and nonvertebral fractures in postmenopausal women, compared with a placebo, based on data from a 6-year trial of 2,000 ambulatory women aged 65 and older with osteopenia.

The findings were presented at the annual meeting of the American Society for Bone and Mineral Research and published simultaneously in the New England Journal of Medicine.

Bisphosphonates have been shown to prevent fractures in osteoporosis patients, but their effectiveness has not been well studied in patients with osteopenia alone, noted Ian R. Reid, MD, of the University of Auckland, New Zealand, and his colleagues. “Many patients at high risk for fracture do not have T scores of less than –2.5 but rather have osteopenia in combination with other risk factors such as age.”

The researchers randomized 2,000 women aged 65 years and older with osteopenia to receive four infusions of zoledronate or a saline placebo every 18 months. A dietary intake of 1 g of calcium per day was advised, but calcium supplements were not provided; 2% of the women took supplements. Those not taking vitamin D before the trial were given a single 2.5-mg dose of cholecalciferol and a monthly 1.25-mg dose during the trial. Trial participants were followed for 6 years.

Courtesy Dr. Ian Reid

SOURCE: Reid I et al. N Engl J Med. 2018 Oct 1. doi: 10.1056/NEJMoa1808082.

Intravenous zoledronate therapy given once every 18 months, with minimal use of calcium supplements, was associated with an increase in bone mass and significantly reduced the risk of vertebral and nonvertebral fractures in postmenopausal women, compared with a placebo, based on data from a 6-year trial of 2,000 ambulatory women aged 65 and older with osteopenia.

The findings were presented at the annual meeting of the American Society for Bone and Mineral Research and published simultaneously in the New England Journal of Medicine.

Bisphosphonates have been shown to prevent fractures in osteoporosis patients, but their effectiveness has not been well studied in patients with osteopenia alone, noted Ian R. Reid, MD, of the University of Auckland, New Zealand, and his colleagues. “Many patients at high risk for fracture do not have T scores of less than –2.5 but rather have osteopenia in combination with other risk factors such as age.”

The researchers randomized 2,000 women aged 65 years and older with osteopenia to receive four infusions of zoledronate or a saline placebo every 18 months. A dietary intake of 1 g of calcium per day was advised, but calcium supplements were not provided; 2% of the women took supplements. Those not taking vitamin D before the trial were given a single 2.5-mg dose of cholecalciferol and a monthly 1.25-mg dose during the trial. Trial participants were followed for 6 years.

Courtesy Dr. Ian Reid

SOURCE: Reid I et al. N Engl J Med. 2018 Oct 1. doi: 10.1056/NEJMoa1808082.

Women are at increased risk of developing depression during the perimenopausal transition, which can present with menopausal symptoms and affect women with no previous symptoms of depression, according to recent guidelines on perimenopausal depression copublished in the Journal of Women’s Health and Menopause.

pixelheadphoto/ThinkStock

“Epidemiologic findings, animal data, and clinical observations have shed some light into plausible mechanistic hypotheses on why some, but not all, women may be particularly sensitive to changes in the hormonal milieu experienced premenstrually, during the postpartum period or during the menopause transition,” Pauline M. Maki, PhD, past president of the North American Menopause Society (NAMS) and professor of psychiatry and psychology at the University of Illinois at Chicago, and her colleagues wrote. “The notion of a menopause-associated depression, however, has been the focus of clinical and scientific debate for years. The lack of consensus on this issue has also led to a lack of clarity in how to evaluate and treat depression in women during the menopausal transition and postmenopausal period.”

The guidelines were developed on behalf of the NAMS Board of Trustees and the Women and Mood Disorders Task Force of the National Network of Depression Centers. Dr. Maki and her colleagues convened an 11-person expert panel on perimenopausal depression, which looked at the effects of factors such as epidemiology; clinical presentation; antidepressants; hormone therapy; and other therapies such as exercise, natural health products, and psychotherapy.

Most women who experience perimenopausal depression have previously undergone a major depressive episode (MDE), while major depressive disorder (MDD) onset at midlife is less common. However, even among women with no previous history of depression, the risk of perimenopausal depression – both depressive symptoms and MDE – is elevated for women at midlife. Studies suggest that 45%-68% of perimenopausal women have elevated depression symptoms.

Dr. Maki and her associates cited studies that showed women who underwent surgical menopause in the form of hysterectomy with and without oophorectomy and women with ovarian insufficiency also showed an elevated rate of depression.

Other risk factors for perimenopausal depression included sociodemographic (black race, financial difficulties) and psychosocial factors (adverse life events, low social support), anxiety, and menopausal symptoms such as interrupted sleep and vasomotor symptoms. Risk factors for MDD include use of antidepressants, premenstrual depressive symptoms, anxiety, menopausal sleep disturbance, sociodemographic factors such as high body mass index and black race, and psychosocial factors such as social isolation and upsetting life events.

Depressive symptoms in perimenopause present as classic depressive symptoms but may also be in combination with perimenopausal symptoms such as changes in weight, cognitive shifts, night sweats, hot flashes, and sexual and sleep disturbances. In addition, the stressors of life for women in midlife can further complicate depressive symptoms.

“Many women face a series of stressors including, but not exclusive to, caring for aging parents, death of parents, medical illness in self and family, adjusting to emotional and physical sequelae of surgical menopause and other health issues that are common to this stage of life, children leaving the home, and changes in marital status. With the onset of childbirth at an increasingly later age, women are often faced with the dual responsibility of raising young children amid caring for aging parents while navigating their careers and ensuing challenges,” Dr. Maki and her colleagues wrote. “These multiple demands are often faced without supports in place to identify or address the ensuing distress placed on a woman during this stage.”

Assessment and diagnosis should include factoring all these symptoms in and disentangling menopausal and psychiatric symptoms, evaluating women with past MDEs and MDD for a mood disorder, and use of differential diagnosis for psychiatric symptoms.

There is no menopause-specific mood disorder scale, Dr. Maki and her associates emphasized, but the Patient Health Questionnaire-9 can be used to categorize mood disorder diagnoses. There are “validated menopause symptom and health-related quality of life scales [that] include mood items” such as the Menopause Rating Scale, and the Menopause-Specific Quality of Life Scale.

Frontline treatment of MDE with traditional therapies such as antidepressants, cognitive behavioral therapy, and other psychotherapies is appropriate, while previous antidepressant trial and responses should be followed to find the best efficacy and tolerability for a women with a history of MDD. There is data on some SSRIs and serotonin norepinephrine reuptake inhibitors suggesting efficacy and tolerability at usual doses. Of note, Dr. Maki and her colleagues found estrogen therapy has some evidence for use as an antidepressant, but most studies on hormone therapy examined unopposed estrogen instead of estrogen plus progestogen, which has limited data.

The authors recommended exercise as a complement to psychotherapy and pharmacotherapies for perimenopausal women with depression, but said there is no available evidence to recommend “botanical or complementary/alternative approaches for treating depression related to the perimenopause.”

Several authors have reported honoraria, research support, consulting fees, and grants from numerous pharmaceutical companies, the National Pregnancy Registry for Atypical Antipsychotics; the Brain & Behavior Research Foundation; the Ontario Brain Institute; and the Ontario Ministry of Technology, Innovation, and Science. Six of the authors reported no relevant conflicts of interest.

SOURCE: Maki PM et al. J Womens Health. 2018 Sep 5. doi: 10.1089/jwh.2018.27099.mensocrec.

Women are at increased risk of developing depression during the perimenopausal transition, which can present with menopausal symptoms and affect women with no previous symptoms of depression, according to recent guidelines on perimenopausal depression copublished in the Journal of Women’s Health and Menopause.

pixelheadphoto/ThinkStock

“Epidemiologic findings, animal data, and clinical observations have shed some light into plausible mechanistic hypotheses on why some, but not all, women may be particularly sensitive to changes in the hormonal milieu experienced premenstrually, during the postpartum period or during the menopause transition,” Pauline M. Maki, PhD, past president of the North American Menopause Society (NAMS) and professor of psychiatry and psychology at the University of Illinois at Chicago, and her colleagues wrote. “The notion of a menopause-associated depression, however, has been the focus of clinical and scientific debate for years. The lack of consensus on this issue has also led to a lack of clarity in how to evaluate and treat depression in women during the menopausal transition and postmenopausal period.”

The guidelines were developed on behalf of the NAMS Board of Trustees and the Women and Mood Disorders Task Force of the National Network of Depression Centers. Dr. Maki and her colleagues convened an 11-person expert panel on perimenopausal depression, which looked at the effects of factors such as epidemiology; clinical presentation; antidepressants; hormone therapy; and other therapies such as exercise, natural health products, and psychotherapy.

Most women who experience perimenopausal depression have previously undergone a major depressive episode (MDE), while major depressive disorder (MDD) onset at midlife is less common. However, even among women with no previous history of depression, the risk of perimenopausal depression – both depressive symptoms and MDE – is elevated for women at midlife. Studies suggest that 45%-68% of perimenopausal women have elevated depression symptoms.

Dr. Maki and her associates cited studies that showed women who underwent surgical menopause in the form of hysterectomy with and without oophorectomy and women with ovarian insufficiency also showed an elevated rate of depression.

Other risk factors for perimenopausal depression included sociodemographic (black race, financial difficulties) and psychosocial factors (adverse life events, low social support), anxiety, and menopausal symptoms such as interrupted sleep and vasomotor symptoms. Risk factors for MDD include use of antidepressants, premenstrual depressive symptoms, anxiety, menopausal sleep disturbance, sociodemographic factors such as high body mass index and black race, and psychosocial factors such as social isolation and upsetting life events.

Depressive symptoms in perimenopause present as classic depressive symptoms but may also be in combination with perimenopausal symptoms such as changes in weight, cognitive shifts, night sweats, hot flashes, and sexual and sleep disturbances. In addition, the stressors of life for women in midlife can further complicate depressive symptoms.

“Many women face a series of stressors including, but not exclusive to, caring for aging parents, death of parents, medical illness in self and family, adjusting to emotional and physical sequelae of surgical menopause and other health issues that are common to this stage of life, children leaving the home, and changes in marital status. With the onset of childbirth at an increasingly later age, women are often faced with the dual responsibility of raising young children amid caring for aging parents while navigating their careers and ensuing challenges,” Dr. Maki and her colleagues wrote. “These multiple demands are often faced without supports in place to identify or address the ensuing distress placed on a woman during this stage.”

Assessment and diagnosis should include factoring all these symptoms in and disentangling menopausal and psychiatric symptoms, evaluating women with past MDEs and MDD for a mood disorder, and use of differential diagnosis for psychiatric symptoms.

There is no menopause-specific mood disorder scale, Dr. Maki and her associates emphasized, but the Patient Health Questionnaire-9 can be used to categorize mood disorder diagnoses. There are “validated menopause symptom and health-related quality of life scales [that] include mood items” such as the Menopause Rating Scale, and the Menopause-Specific Quality of Life Scale.

Frontline treatment of MDE with traditional therapies such as antidepressants, cognitive behavioral therapy, and other psychotherapies is appropriate, while previous antidepressant trial and responses should be followed to find the best efficacy and tolerability for a women with a history of MDD. There is data on some SSRIs and serotonin norepinephrine reuptake inhibitors suggesting efficacy and tolerability at usual doses. Of note, Dr. Maki and her colleagues found estrogen therapy has some evidence for use as an antidepressant, but most studies on hormone therapy examined unopposed estrogen instead of estrogen plus progestogen, which has limited data.

The authors recommended exercise as a complement to psychotherapy and pharmacotherapies for perimenopausal women with depression, but said there is no available evidence to recommend “botanical or complementary/alternative approaches for treating depression related to the perimenopause.”

Several authors have reported honoraria, research support, consulting fees, and grants from numerous pharmaceutical companies, the National Pregnancy Registry for Atypical Antipsychotics; the Brain & Behavior Research Foundation; the Ontario Brain Institute; and the Ontario Ministry of Technology, Innovation, and Science. Six of the authors reported no relevant conflicts of interest.

SOURCE: Maki PM et al. J Womens Health. 2018 Sep 5. doi: 10.1089/jwh.2018.27099.mensocrec.

Women are at increased risk of developing depression during the perimenopausal transition, which can present with menopausal symptoms and affect women with no previous symptoms of depression, according to recent guidelines on perimenopausal depression copublished in the Journal of Women’s Health and Menopause.

pixelheadphoto/ThinkStock

“Epidemiologic findings, animal data, and clinical observations have shed some light into plausible mechanistic hypotheses on why some, but not all, women may be particularly sensitive to changes in the hormonal milieu experienced premenstrually, during the postpartum period or during the menopause transition,” Pauline M. Maki, PhD, past president of the North American Menopause Society (NAMS) and professor of psychiatry and psychology at the University of Illinois at Chicago, and her colleagues wrote. “The notion of a menopause-associated depression, however, has been the focus of clinical and scientific debate for years. The lack of consensus on this issue has also led to a lack of clarity in how to evaluate and treat depression in women during the menopausal transition and postmenopausal period.”

The guidelines were developed on behalf of the NAMS Board of Trustees and the Women and Mood Disorders Task Force of the National Network of Depression Centers. Dr. Maki and her colleagues convened an 11-person expert panel on perimenopausal depression, which looked at the effects of factors such as epidemiology; clinical presentation; antidepressants; hormone therapy; and other therapies such as exercise, natural health products, and psychotherapy.

Most women who experience perimenopausal depression have previously undergone a major depressive episode (MDE), while major depressive disorder (MDD) onset at midlife is less common. However, even among women with no previous history of depression, the risk of perimenopausal depression – both depressive symptoms and MDE – is elevated for women at midlife. Studies suggest that 45%-68% of perimenopausal women have elevated depression symptoms.

Dr. Maki and her associates cited studies that showed women who underwent surgical menopause in the form of hysterectomy with and without oophorectomy and women with ovarian insufficiency also showed an elevated rate of depression.

Other risk factors for perimenopausal depression included sociodemographic (black race, financial difficulties) and psychosocial factors (adverse life events, low social support), anxiety, and menopausal symptoms such as interrupted sleep and vasomotor symptoms. Risk factors for MDD include use of antidepressants, premenstrual depressive symptoms, anxiety, menopausal sleep disturbance, sociodemographic factors such as high body mass index and black race, and psychosocial factors such as social isolation and upsetting life events.

Depressive symptoms in perimenopause present as classic depressive symptoms but may also be in combination with perimenopausal symptoms such as changes in weight, cognitive shifts, night sweats, hot flashes, and sexual and sleep disturbances. In addition, the stressors of life for women in midlife can further complicate depressive symptoms.

“Many women face a series of stressors including, but not exclusive to, caring for aging parents, death of parents, medical illness in self and family, adjusting to emotional and physical sequelae of surgical menopause and other health issues that are common to this stage of life, children leaving the home, and changes in marital status. With the onset of childbirth at an increasingly later age, women are often faced with the dual responsibility of raising young children amid caring for aging parents while navigating their careers and ensuing challenges,” Dr. Maki and her colleagues wrote. “These multiple demands are often faced without supports in place to identify or address the ensuing distress placed on a woman during this stage.”

Assessment and diagnosis should include factoring all these symptoms in and disentangling menopausal and psychiatric symptoms, evaluating women with past MDEs and MDD for a mood disorder, and use of differential diagnosis for psychiatric symptoms.

There is no menopause-specific mood disorder scale, Dr. Maki and her associates emphasized, but the Patient Health Questionnaire-9 can be used to categorize mood disorder diagnoses. There are “validated menopause symptom and health-related quality of life scales [that] include mood items” such as the Menopause Rating Scale, and the Menopause-Specific Quality of Life Scale.

Frontline treatment of MDE with traditional therapies such as antidepressants, cognitive behavioral therapy, and other psychotherapies is appropriate, while previous antidepressant trial and responses should be followed to find the best efficacy and tolerability for a women with a history of MDD. There is data on some SSRIs and serotonin norepinephrine reuptake inhibitors suggesting efficacy and tolerability at usual doses. Of note, Dr. Maki and her colleagues found estrogen therapy has some evidence for use as an antidepressant, but most studies on hormone therapy examined unopposed estrogen instead of estrogen plus progestogen, which has limited data.

The authors recommended exercise as a complement to psychotherapy and pharmacotherapies for perimenopausal women with depression, but said there is no available evidence to recommend “botanical or complementary/alternative approaches for treating depression related to the perimenopause.”

Several authors have reported honoraria, research support, consulting fees, and grants from numerous pharmaceutical companies, the National Pregnancy Registry for Atypical Antipsychotics; the Brain & Behavior Research Foundation; the Ontario Brain Institute; and the Ontario Ministry of Technology, Innovation, and Science. Six of the authors reported no relevant conflicts of interest.

SOURCE: Maki PM et al. J Womens Health. 2018 Sep 5. doi: 10.1089/jwh.2018.27099.mensocrec.