Menopause

For recently postmenopausal women, oral combined hormone therapy may help with symptoms of depression and anxiety. But hormone therapy did not produce any changes in cognition.

In a large, randomized controlled trial of oral and transdermal estrogens compared with each other and placebo, Carey Gleason, Ph.D., of the University of Wisconsin, Madison, and colleagues found that exogenous estrogen had no effect on cognitive performance in recently postmenopausal women over a 4-year study period. For women taking low-dose oral conjugated equine estrogens, a small to moderate improvement in some mood symptoms occurred; women receiving estrogen via a transdermal patch did not see this improvement in mood.

The results were published in PLOS Medicine (PLoS. Med. 2015;12:e1001833 [doi:10.1371/journal.pmed.1001833]).

Previous studies had shown mixed findings of the effects of menopausal hormone therapy on cognition, largely depending on whether treatment was initiated early on or later in menopause.

The 693 participants in the Kronos Early Estrogen Prevention Study - Cognitive and Affective Study (KEEPS-Cog) were a mean 52.6 years old, and the average time since the last menstrual period was 1.4 years. Enrollees were randomized to one of three study arms where they received either a 0.45 mg/day oral conjugated equine estrogen tablet, 200 mg/day cyclical progesterone capsule, and a placebo skin patch; or a 50 microgram/day transdermal estradiol patch, 200 mg/day cyclical progesterone capsule, and a placebo tablet; or a placebo tablet, capsule and patch. Treatment lasted for 4 years.

Cognitive status was measured over the 4 years using the Modified Mini-Mental State (3MS) exam and an additional battery of cognitive tests that assessed verbal learning, auditory attention and working memory, visual attention and executive function, and mental and linguistic flexibility. The Profile of Mood States (POMS) was used to evaluate mood. This test, designed to detect specific affective states in nondepressed individuals, assessed levels of tension-anxiety, depression-dejection, anger-hostility, fatigue, vigor, and confusion-bewilderment.

Dr. Gleason and her colleagues found no improvement in cognitive function with either formulation of menopausal hormone therapy.

“Contrary to our hypothesis, treatment with t-E2 [transdermal estrogen] did not improve cognition in recently postmenopausal women,” the researchers wrote.

For women taking oral estrogen, POMS subscores for tension-anxiety and depression-dejection showed significant improvement over time (for both, P < 0.001). The effect was not seen for transdermal estrogen; Dr. Gleason and her colleagues hypothesized that differences in the formulations of the two products, which resulted in different levels of estradiol versus estrone in participants, may have contributed to the result.

Most of the study’s enrollees were white women with low risk for cardiovascular disease, and most participants had at least a bachelor’s degree, so the generalizability of the KEEPS-Cog findings may be limited. Also, the study’s length and design did not permit assessment of dementia or other clinical diagnoses.

The KEEPS-Cog study, said Dr. Gleason and colleagues, can be incorporated into clinical decision making for women deciding whether to use menopausal hormone therapy. Using these results, a younger woman in good cardiovascular health “can weigh the known risks of [menopausal hormone therapy] against potential benefits for her unique symptom profile, and make an informed decision as to whether she would benefit from [menopausal hormone therapy] or whether she would prefer to manage symptoms through other means.”

The study was supported by the National Institutes of Health; the parent KEEPS trial was also supported by the Aurora Foundation. Dr. Cedars, Dr. Asthana, Dr. Santoro, and Dr. Taylor reported grant support and other financial relationships with pharmaceutical companies. The other authors reported no relevant financial disclosures.

For recently postmenopausal women, oral combined hormone therapy may help with symptoms of depression and anxiety. But hormone therapy did not produce any changes in cognition.

In a large, randomized controlled trial of oral and transdermal estrogens compared with each other and placebo, Carey Gleason, Ph.D., of the University of Wisconsin, Madison, and colleagues found that exogenous estrogen had no effect on cognitive performance in recently postmenopausal women over a 4-year study period. For women taking low-dose oral conjugated equine estrogens, a small to moderate improvement in some mood symptoms occurred; women receiving estrogen via a transdermal patch did not see this improvement in mood.

The results were published in PLOS Medicine (PLoS. Med. 2015;12:e1001833 [doi:10.1371/journal.pmed.1001833]).

Previous studies had shown mixed findings of the effects of menopausal hormone therapy on cognition, largely depending on whether treatment was initiated early on or later in menopause.

The 693 participants in the Kronos Early Estrogen Prevention Study - Cognitive and Affective Study (KEEPS-Cog) were a mean 52.6 years old, and the average time since the last menstrual period was 1.4 years. Enrollees were randomized to one of three study arms where they received either a 0.45 mg/day oral conjugated equine estrogen tablet, 200 mg/day cyclical progesterone capsule, and a placebo skin patch; or a 50 microgram/day transdermal estradiol patch, 200 mg/day cyclical progesterone capsule, and a placebo tablet; or a placebo tablet, capsule and patch. Treatment lasted for 4 years.

Cognitive status was measured over the 4 years using the Modified Mini-Mental State (3MS) exam and an additional battery of cognitive tests that assessed verbal learning, auditory attention and working memory, visual attention and executive function, and mental and linguistic flexibility. The Profile of Mood States (POMS) was used to evaluate mood. This test, designed to detect specific affective states in nondepressed individuals, assessed levels of tension-anxiety, depression-dejection, anger-hostility, fatigue, vigor, and confusion-bewilderment.

Dr. Gleason and her colleagues found no improvement in cognitive function with either formulation of menopausal hormone therapy.

“Contrary to our hypothesis, treatment with t-E2 [transdermal estrogen] did not improve cognition in recently postmenopausal women,” the researchers wrote.

For women taking oral estrogen, POMS subscores for tension-anxiety and depression-dejection showed significant improvement over time (for both, P < 0.001). The effect was not seen for transdermal estrogen; Dr. Gleason and her colleagues hypothesized that differences in the formulations of the two products, which resulted in different levels of estradiol versus estrone in participants, may have contributed to the result.

Most of the study’s enrollees were white women with low risk for cardiovascular disease, and most participants had at least a bachelor’s degree, so the generalizability of the KEEPS-Cog findings may be limited. Also, the study’s length and design did not permit assessment of dementia or other clinical diagnoses.

The KEEPS-Cog study, said Dr. Gleason and colleagues, can be incorporated into clinical decision making for women deciding whether to use menopausal hormone therapy. Using these results, a younger woman in good cardiovascular health “can weigh the known risks of [menopausal hormone therapy] against potential benefits for her unique symptom profile, and make an informed decision as to whether she would benefit from [menopausal hormone therapy] or whether she would prefer to manage symptoms through other means.”

The study was supported by the National Institutes of Health; the parent KEEPS trial was also supported by the Aurora Foundation. Dr. Cedars, Dr. Asthana, Dr. Santoro, and Dr. Taylor reported grant support and other financial relationships with pharmaceutical companies. The other authors reported no relevant financial disclosures.

For recently postmenopausal women, oral combined hormone therapy may help with symptoms of depression and anxiety. But hormone therapy did not produce any changes in cognition.

In a large, randomized controlled trial of oral and transdermal estrogens compared with each other and placebo, Carey Gleason, Ph.D., of the University of Wisconsin, Madison, and colleagues found that exogenous estrogen had no effect on cognitive performance in recently postmenopausal women over a 4-year study period. For women taking low-dose oral conjugated equine estrogens, a small to moderate improvement in some mood symptoms occurred; women receiving estrogen via a transdermal patch did not see this improvement in mood.

The results were published in PLOS Medicine (PLoS. Med. 2015;12:e1001833 [doi:10.1371/journal.pmed.1001833]).

Previous studies had shown mixed findings of the effects of menopausal hormone therapy on cognition, largely depending on whether treatment was initiated early on or later in menopause.

The 693 participants in the Kronos Early Estrogen Prevention Study - Cognitive and Affective Study (KEEPS-Cog) were a mean 52.6 years old, and the average time since the last menstrual period was 1.4 years. Enrollees were randomized to one of three study arms where they received either a 0.45 mg/day oral conjugated equine estrogen tablet, 200 mg/day cyclical progesterone capsule, and a placebo skin patch; or a 50 microgram/day transdermal estradiol patch, 200 mg/day cyclical progesterone capsule, and a placebo tablet; or a placebo tablet, capsule and patch. Treatment lasted for 4 years.

Cognitive status was measured over the 4 years using the Modified Mini-Mental State (3MS) exam and an additional battery of cognitive tests that assessed verbal learning, auditory attention and working memory, visual attention and executive function, and mental and linguistic flexibility. The Profile of Mood States (POMS) was used to evaluate mood. This test, designed to detect specific affective states in nondepressed individuals, assessed levels of tension-anxiety, depression-dejection, anger-hostility, fatigue, vigor, and confusion-bewilderment.

Dr. Gleason and her colleagues found no improvement in cognitive function with either formulation of menopausal hormone therapy.

“Contrary to our hypothesis, treatment with t-E2 [transdermal estrogen] did not improve cognition in recently postmenopausal women,” the researchers wrote.

For women taking oral estrogen, POMS subscores for tension-anxiety and depression-dejection showed significant improvement over time (for both, P < 0.001). The effect was not seen for transdermal estrogen; Dr. Gleason and her colleagues hypothesized that differences in the formulations of the two products, which resulted in different levels of estradiol versus estrone in participants, may have contributed to the result.

Most of the study’s enrollees were white women with low risk for cardiovascular disease, and most participants had at least a bachelor’s degree, so the generalizability of the KEEPS-Cog findings may be limited. Also, the study’s length and design did not permit assessment of dementia or other clinical diagnoses.

The KEEPS-Cog study, said Dr. Gleason and colleagues, can be incorporated into clinical decision making for women deciding whether to use menopausal hormone therapy. Using these results, a younger woman in good cardiovascular health “can weigh the known risks of [menopausal hormone therapy] against potential benefits for her unique symptom profile, and make an informed decision as to whether she would benefit from [menopausal hormone therapy] or whether she would prefer to manage symptoms through other means.”

The study was supported by the National Institutes of Health; the parent KEEPS trial was also supported by the Aurora Foundation. Dr. Cedars, Dr. Asthana, Dr. Santoro, and Dr. Taylor reported grant support and other financial relationships with pharmaceutical companies. The other authors reported no relevant financial disclosures.

As new options for managing menopausal symptoms emerge, so do data on their efficacy and safety. In this article, I highlight the following publications:

After long-term follow-up of WHI participants, a “critical window” of HT timing is revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, an October 2013 publication from the Journal of the American Medical Association, which details 13-year follow-up of WHI HT clinical trial participants, better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95–1.45) and 0.94 in the ET arm (95% CI, 0.78–1.14). In both arms, women given HT had reduced risks of vasomotor symptoms, hip fractures, and diabetes, and increased risks of stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 years at baseline, the risk of cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk of breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11–1.48). In contrast, in the ET arm, a significantly reduced risk of breast cancer materialized (HR, 0.79; 95% CI, 0.65–0.97) (TABLE).

To put into perspective the elevated risk of breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming 1 glass of wine daily and lower than the HR noted with 2 glasses daily.¹ Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk of adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women aged 50 to 59 years at baseline. In the EPT arm, the risk of MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risks of stroke, VTE, and gallbladder disease.

EPT increased the risk of breast cancer in all age groups. However, the lower absolute risks of adverse events in younger women, together with the generally more favorable HRs for many outcomes in the younger women, resulted in substantially lower rates of adverse events attributable to HT in the younger age group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar below).
 

What this EVIDENCE means for practice
Long-term follow-up of women who participated in the WHI clarifies the benefit-risk profile of systemic HT, underscoring that the benefit-risk ratio is greatest in younger menopausal women.

Because the safety of HT is greater in women nearer the onset of menopause, as well as in those at lower baseline risk of cardiovascular disease (CVD), individualized risk assessment may improve the benefit-risk profile and safety of HT. One approach to decision-making for women with bothersome menopausal symptoms is the MenoPro app, a free mobile app from the North American Menopause Society, with modes for both clinicians and patients.

In hysterectomized women, supraphysiologic doses of testosterone improve parameters of sexual function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612–623.

No formulation of testosterone is approved by the US Food and Drug Administration (FDA) for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.²

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0 mg, 6.0 mg, 12.5 mg, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were 5 to 6 times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the 2 highest doses of testosterone.

What this EVIDENCE means for practice
Although this well-executed study was small and short-term, it confirms that, in menopausal women receiving estrogen, testosterone can enhance parameters of sexuality. It is unfortunate that the dose needed to achieve this benefit results in markedly supraphysiologic serum testosterone levels.

One important caveat raised by this trial: It did not specifically recruit participants with low sexual desire. Therefore, it remains unknown whether lower doses of testosterone might provide benefits in women with low baseline libido. Regrettably, no randomized trials have addressed the long-term benefits and risks of use of testosterone among menopausal women.

ACOG offers valuable guidance on management of menopausal symptoms
ACOG Practice Bulletin No. 141: management of menopausal symptoms. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(1):202–216.

Despite findings from new studies, optimal management of menopausal symptoms remains controversial. In January 2014, ACOG issued guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65 years
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for ­Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.³ Along with many of the clinicians reading this Update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65 years. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

Three new options for menopausal HT
The ACOG Practice Bulletin describes 3 formulations for the treatment of menopausal symptoms that have recently become available:

Steer patients clear of compounded formulations
Every week I encounter patients who have recently visited physicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

What this EVIDENCE means for practice
ACOG’s Practice Bulletin provides useful guidance for clinicians regarding treatment of menopausal symptoms. Besides clarifying that systemic HT should not be arbitrarily discontinued at age 65 and that FDA-approved HT is preferable to compounded HT, this publication details newer (including nonhormonal) formulations for treating menopausal symptoms as well as traditional HT formulations, including useful dosing information. 

Is menopausal HT safe in statin users?
Berglind IA, Andersen M, Citarella A, Linder M, Sundström A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376.

Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publications of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women 40 to 74 years old who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of 4 years after beginning statins until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62 years, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks of mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk of CVD, compared with other estrogens⁴).

What this EVIDENCE means for practice
This important study provides strong evidence that, for menopausal women with bothersome vasomotor symptoms or an elevated risk for osteoporosis, concomitant use of statins should not be considered a contraindication to HT.

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

As new options for managing menopausal symptoms emerge, so do data on their efficacy and safety. In this article, I highlight the following publications:

After long-term follow-up of WHI participants, a “critical window” of HT timing is revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, an October 2013 publication from the Journal of the American Medical Association, which details 13-year follow-up of WHI HT clinical trial participants, better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95–1.45) and 0.94 in the ET arm (95% CI, 0.78–1.14). In both arms, women given HT had reduced risks of vasomotor symptoms, hip fractures, and diabetes, and increased risks of stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 years at baseline, the risk of cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk of breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11–1.48). In contrast, in the ET arm, a significantly reduced risk of breast cancer materialized (HR, 0.79; 95% CI, 0.65–0.97) (TABLE).

To put into perspective the elevated risk of breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming 1 glass of wine daily and lower than the HR noted with 2 glasses daily.¹ Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk of adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women aged 50 to 59 years at baseline. In the EPT arm, the risk of MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risks of stroke, VTE, and gallbladder disease.

EPT increased the risk of breast cancer in all age groups. However, the lower absolute risks of adverse events in younger women, together with the generally more favorable HRs for many outcomes in the younger women, resulted in substantially lower rates of adverse events attributable to HT in the younger age group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar below).
 

What this EVIDENCE means for practice
Long-term follow-up of women who participated in the WHI clarifies the benefit-risk profile of systemic HT, underscoring that the benefit-risk ratio is greatest in younger menopausal women.

Because the safety of HT is greater in women nearer the onset of menopause, as well as in those at lower baseline risk of cardiovascular disease (CVD), individualized risk assessment may improve the benefit-risk profile and safety of HT. One approach to decision-making for women with bothersome menopausal symptoms is the MenoPro app, a free mobile app from the North American Menopause Society, with modes for both clinicians and patients.

In hysterectomized women, supraphysiologic doses of testosterone improve parameters of sexual function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612–623.

No formulation of testosterone is approved by the US Food and Drug Administration (FDA) for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.²

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0 mg, 6.0 mg, 12.5 mg, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were 5 to 6 times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the 2 highest doses of testosterone.

What this EVIDENCE means for practice
Although this well-executed study was small and short-term, it confirms that, in menopausal women receiving estrogen, testosterone can enhance parameters of sexuality. It is unfortunate that the dose needed to achieve this benefit results in markedly supraphysiologic serum testosterone levels.

One important caveat raised by this trial: It did not specifically recruit participants with low sexual desire. Therefore, it remains unknown whether lower doses of testosterone might provide benefits in women with low baseline libido. Regrettably, no randomized trials have addressed the long-term benefits and risks of use of testosterone among menopausal women.

ACOG offers valuable guidance on management of menopausal symptoms
ACOG Practice Bulletin No. 141: management of menopausal symptoms. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(1):202–216.

Despite findings from new studies, optimal management of menopausal symptoms remains controversial. In January 2014, ACOG issued guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65 years
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for ­Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.³ Along with many of the clinicians reading this Update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65 years. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

Three new options for menopausal HT
The ACOG Practice Bulletin describes 3 formulations for the treatment of menopausal symptoms that have recently become available:

Steer patients clear of compounded formulations
Every week I encounter patients who have recently visited physicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

What this EVIDENCE means for practice
ACOG’s Practice Bulletin provides useful guidance for clinicians regarding treatment of menopausal symptoms. Besides clarifying that systemic HT should not be arbitrarily discontinued at age 65 and that FDA-approved HT is preferable to compounded HT, this publication details newer (including nonhormonal) formulations for treating menopausal symptoms as well as traditional HT formulations, including useful dosing information. 

Is menopausal HT safe in statin users?
Berglind IA, Andersen M, Citarella A, Linder M, Sundström A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376.

Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publications of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women 40 to 74 years old who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of 4 years after beginning statins until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62 years, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks of mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk of CVD, compared with other estrogens⁴).

What this EVIDENCE means for practice
This important study provides strong evidence that, for menopausal women with bothersome vasomotor symptoms or an elevated risk for osteoporosis, concomitant use of statins should not be considered a contraindication to HT.

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

As new options for managing menopausal symptoms emerge, so do data on their efficacy and safety. In this article, I highlight the following publications:

After long-term follow-up of WHI participants, a “critical window” of HT timing is revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, an October 2013 publication from the Journal of the American Medical Association, which details 13-year follow-up of WHI HT clinical trial participants, better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95–1.45) and 0.94 in the ET arm (95% CI, 0.78–1.14). In both arms, women given HT had reduced risks of vasomotor symptoms, hip fractures, and diabetes, and increased risks of stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 years at baseline, the risk of cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk of breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11–1.48). In contrast, in the ET arm, a significantly reduced risk of breast cancer materialized (HR, 0.79; 95% CI, 0.65–0.97) (TABLE).

To put into perspective the elevated risk of breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming 1 glass of wine daily and lower than the HR noted with 2 glasses daily.¹ Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk of adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women aged 50 to 59 years at baseline. In the EPT arm, the risk of MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risks of stroke, VTE, and gallbladder disease.

EPT increased the risk of breast cancer in all age groups. However, the lower absolute risks of adverse events in younger women, together with the generally more favorable HRs for many outcomes in the younger women, resulted in substantially lower rates of adverse events attributable to HT in the younger age group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar below).
 

What this EVIDENCE means for practice
Long-term follow-up of women who participated in the WHI clarifies the benefit-risk profile of systemic HT, underscoring that the benefit-risk ratio is greatest in younger menopausal women.

Because the safety of HT is greater in women nearer the onset of menopause, as well as in those at lower baseline risk of cardiovascular disease (CVD), individualized risk assessment may improve the benefit-risk profile and safety of HT. One approach to decision-making for women with bothersome menopausal symptoms is the MenoPro app, a free mobile app from the North American Menopause Society, with modes for both clinicians and patients.

In hysterectomized women, supraphysiologic doses of testosterone improve parameters of sexual function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612–623.

No formulation of testosterone is approved by the US Food and Drug Administration (FDA) for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.²

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0 mg, 6.0 mg, 12.5 mg, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were 5 to 6 times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the 2 highest doses of testosterone.

What this EVIDENCE means for practice
Although this well-executed study was small and short-term, it confirms that, in menopausal women receiving estrogen, testosterone can enhance parameters of sexuality. It is unfortunate that the dose needed to achieve this benefit results in markedly supraphysiologic serum testosterone levels.

One important caveat raised by this trial: It did not specifically recruit participants with low sexual desire. Therefore, it remains unknown whether lower doses of testosterone might provide benefits in women with low baseline libido. Regrettably, no randomized trials have addressed the long-term benefits and risks of use of testosterone among menopausal women.

ACOG offers valuable guidance on management of menopausal symptoms
ACOG Practice Bulletin No. 141: management of menopausal symptoms. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(1):202–216.

Despite findings from new studies, optimal management of menopausal symptoms remains controversial. In January 2014, ACOG issued guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65 years
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for ­Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.³ Along with many of the clinicians reading this Update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65 years. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

Three new options for menopausal HT
The ACOG Practice Bulletin describes 3 formulations for the treatment of menopausal symptoms that have recently become available:

Steer patients clear of compounded formulations
Every week I encounter patients who have recently visited physicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

What this EVIDENCE means for practice
ACOG’s Practice Bulletin provides useful guidance for clinicians regarding treatment of menopausal symptoms. Besides clarifying that systemic HT should not be arbitrarily discontinued at age 65 and that FDA-approved HT is preferable to compounded HT, this publication details newer (including nonhormonal) formulations for treating menopausal symptoms as well as traditional HT formulations, including useful dosing information. 

Is menopausal HT safe in statin users?
Berglind IA, Andersen M, Citarella A, Linder M, Sundström A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376.

Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publications of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women 40 to 74 years old who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of 4 years after beginning statins until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62 years, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks of mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk of CVD, compared with other estrogens⁴).

What this EVIDENCE means for practice
This important study provides strong evidence that, for menopausal women with bothersome vasomotor symptoms or an elevated risk for osteoporosis, concomitant use of statins should not be considered a contraindication to HT.

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

SAN FRANCISCO – The use of unopposed topical vaginal estrogen is not associated with an increased risk of endometrial hyperplasia or cancer, findings from a large database review suggest.

Yearly disease incidence between 2006 and 2012 among women aged 46 years or older from the Kaiser Permanente Northern California membership database did not differ significantly by number of dispensed vaginal estrogen prescriptions over a 3-year period, Dr. Kathryn M. Gunnison reported at the annual meeting of the American College of Obstetricians and Gynecologists.

Yearly incidence per 10,000 women was 1.86-18.23 in those who received four or more prescriptions, 7.29-15.01 in those who received one to three prescriptions, and 8.74-10.86 in those who received no prescriptions, said Dr. Gunnison of Kaiser Permanente Medical Center, Santa Clara, Calif.

The overall incidence rates in the groups, respectively, were 9.96, 10.25, and 9.96 per 10,000 women, she said.

Dr. Gunnison and her colleagues used ICD-9 codes and the Kaiser Permanente Northern California Cancer Registry to identify the first date of endometrial hyperplasia or cancer in the yearly population, and pharmacy records were reviewed to identify dispensed vaginal estrogen prescriptions in the 3 years prior to diagnosis of endometrial hyperplasia or cancer; those exposed within 2 years prior to diagnosis were excluded, as were those who used systemic estrogen.

Between 450,000 and 530,000 women met the selection criteria for each year during the study period, and the use of vaginal estrogen increased slightly over the study period. Between 26,000 and 34,000 women filled one to three prescriptions during the study years, and between 9,300 and 23,000 filled four or more prescriptions.

The overall annual incidence of endometrial hyperplasia or cancer increased over the study period, which is consistent with national data. The incidence rose from 8.96 per 10,000 women in 2006 to 10.56 per 10,000 women in 2012, but did not differ significantly by number of prescriptions filled.

“So we think our data suggest that the use of unopposed topical vaginal estrogen is not associated with an increased risk for endometrial hyperplasia or cancer over a 3-year period. However, further studies are needed,” Dr. Gunnison said, noting that the current study is limited by the retrospective, descriptive study design, and by the fact that the estrogen delivery method was not examined. The study also did not control for potential confounders.

Despite these limitations, it is the first study to look at vaginal estrogen use for more than 1 year, she said.

The findings are encouraging, she said, since many women choose low-dose topical vaginal estrogen because of concerns about potential adverse effects from systemic estrogen.

Dr. Gunnison reported having no financial disclosures.

[email protected]

SAN FRANCISCO – The use of unopposed topical vaginal estrogen is not associated with an increased risk of endometrial hyperplasia or cancer, findings from a large database review suggest.

Yearly disease incidence between 2006 and 2012 among women aged 46 years or older from the Kaiser Permanente Northern California membership database did not differ significantly by number of dispensed vaginal estrogen prescriptions over a 3-year period, Dr. Kathryn M. Gunnison reported at the annual meeting of the American College of Obstetricians and Gynecologists.

Yearly incidence per 10,000 women was 1.86-18.23 in those who received four or more prescriptions, 7.29-15.01 in those who received one to three prescriptions, and 8.74-10.86 in those who received no prescriptions, said Dr. Gunnison of Kaiser Permanente Medical Center, Santa Clara, Calif.

The overall incidence rates in the groups, respectively, were 9.96, 10.25, and 9.96 per 10,000 women, she said.

Dr. Gunnison and her colleagues used ICD-9 codes and the Kaiser Permanente Northern California Cancer Registry to identify the first date of endometrial hyperplasia or cancer in the yearly population, and pharmacy records were reviewed to identify dispensed vaginal estrogen prescriptions in the 3 years prior to diagnosis of endometrial hyperplasia or cancer; those exposed within 2 years prior to diagnosis were excluded, as were those who used systemic estrogen.

Between 450,000 and 530,000 women met the selection criteria for each year during the study period, and the use of vaginal estrogen increased slightly over the study period. Between 26,000 and 34,000 women filled one to three prescriptions during the study years, and between 9,300 and 23,000 filled four or more prescriptions.

The overall annual incidence of endometrial hyperplasia or cancer increased over the study period, which is consistent with national data. The incidence rose from 8.96 per 10,000 women in 2006 to 10.56 per 10,000 women in 2012, but did not differ significantly by number of prescriptions filled.

“So we think our data suggest that the use of unopposed topical vaginal estrogen is not associated with an increased risk for endometrial hyperplasia or cancer over a 3-year period. However, further studies are needed,” Dr. Gunnison said, noting that the current study is limited by the retrospective, descriptive study design, and by the fact that the estrogen delivery method was not examined. The study also did not control for potential confounders.

Despite these limitations, it is the first study to look at vaginal estrogen use for more than 1 year, she said.

The findings are encouraging, she said, since many women choose low-dose topical vaginal estrogen because of concerns about potential adverse effects from systemic estrogen.

Dr. Gunnison reported having no financial disclosures.

[email protected]

SAN FRANCISCO – The use of unopposed topical vaginal estrogen is not associated with an increased risk of endometrial hyperplasia or cancer, findings from a large database review suggest.

Yearly disease incidence between 2006 and 2012 among women aged 46 years or older from the Kaiser Permanente Northern California membership database did not differ significantly by number of dispensed vaginal estrogen prescriptions over a 3-year period, Dr. Kathryn M. Gunnison reported at the annual meeting of the American College of Obstetricians and Gynecologists.

Yearly incidence per 10,000 women was 1.86-18.23 in those who received four or more prescriptions, 7.29-15.01 in those who received one to three prescriptions, and 8.74-10.86 in those who received no prescriptions, said Dr. Gunnison of Kaiser Permanente Medical Center, Santa Clara, Calif.

The overall incidence rates in the groups, respectively, were 9.96, 10.25, and 9.96 per 10,000 women, she said.

Dr. Gunnison and her colleagues used ICD-9 codes and the Kaiser Permanente Northern California Cancer Registry to identify the first date of endometrial hyperplasia or cancer in the yearly population, and pharmacy records were reviewed to identify dispensed vaginal estrogen prescriptions in the 3 years prior to diagnosis of endometrial hyperplasia or cancer; those exposed within 2 years prior to diagnosis were excluded, as were those who used systemic estrogen.

Between 450,000 and 530,000 women met the selection criteria for each year during the study period, and the use of vaginal estrogen increased slightly over the study period. Between 26,000 and 34,000 women filled one to three prescriptions during the study years, and between 9,300 and 23,000 filled four or more prescriptions.

The overall annual incidence of endometrial hyperplasia or cancer increased over the study period, which is consistent with national data. The incidence rose from 8.96 per 10,000 women in 2006 to 10.56 per 10,000 women in 2012, but did not differ significantly by number of prescriptions filled.

“So we think our data suggest that the use of unopposed topical vaginal estrogen is not associated with an increased risk for endometrial hyperplasia or cancer over a 3-year period. However, further studies are needed,” Dr. Gunnison said, noting that the current study is limited by the retrospective, descriptive study design, and by the fact that the estrogen delivery method was not examined. The study also did not control for potential confounders.

Despite these limitations, it is the first study to look at vaginal estrogen use for more than 1 year, she said.

The findings are encouraging, she said, since many women choose low-dose topical vaginal estrogen because of concerns about potential adverse effects from systemic estrogen.

Dr. Gunnison reported having no financial disclosures.

[email protected]

Direct immunoassays shouldn’t be used to measure estrogens and their metabolites in patients with very low estrogen concentrations, according to a report published online April 7 in the Journal of Clinical Endocrinology and Metabolism.

“The inaccuracy of direct immunoassays is especially problematic in ... men, postmenopausal women, those taking aromatase inhibitors, and prepubertal children. Thus, the use of current direct assays for measuring estradiol concentrations in these groups of patients should be discouraged,” wrote Dr. Laurence Demers of the Pennsylvania State University, Hershey, and his associates.

Mass spectrometry has better sensitivity and specificity, but mass spectrometers are expensive, and assays to quantify estrogen metabolites are demanding. Because of that, many labs continue to use direct immunoassays even when they’re not the best choice.

The report summarized the consensus from a 2014 meeting of experts in Bethesda, MD., on the measurement of the estrogens and their metabolites. In general, participants agreed that measurements need to be standardized and improved (J. Clin. Endocrinol. Metab. 2015 April 7 [doi:10.1210/jc.2015-1040]).

“Assay inaccuracy complicates the comparison of results obtained from different laboratories, from the same laboratory over time, or from different epidemiological and clinical studies and constrains the application of guidelines to ... patients. A set of clinical practice guidelines cannot be implemented unless the assays used are accurate and precise,” according to the investigators.

Even so, “measurement of estradiol is challenging because the physiologically relevant concentration range spans at least four orders of magnitude ... an assay that is suitable for use for diagnosis and management of infertility in adult women may not meet performance specifications for use when evaluating the onset of puberty in a child,” they said.

Current estradiol assays are particularly problematic in postmenopausal women and children, where sensitivity is critical. Reference ranges haven’t been established for either group. The Centers for Disease Control and Prevention are working to address those and other problems under a Hormone Standardization Program.

Meanwhile, “use of currently available direct estradiol immunoassays appears to compromise assay specificity, probably due to antibody cross-reactivity, matrix effects, and suboptimal sensitivity. These direct assays usually yield higher values than [do] those measured by methods with superior specificity, including immunoassays preceded by organic solvent extraction, liquid chromatography, or gas or liquid chromatography mass spectrometry assays,” the authors said.

There’s a need “for a study to evaluate the different approaches for validation of estrogen assay accuracy. It [is also] recommended that journals require a statement regarding accuracy assessment for estrogen and estrogen metabolite assays with a long-term goal of requiring measurements using accurate assays,” they said.

The Bethesda meeting was sponsored primarily by the Endocrine Society, the American Association for Clinical Chemistry, and the Partnership for Accurate Testing of Hormones. One of the nine authors – Dr. Richard J. Santen of the University of Virginia, Charlottesville – has been a Pfizer adviser and is the principal investigator on a grant from the company to his university. The other authors have no disclosures.

[email protected]

Direct immunoassays shouldn’t be used to measure estrogens and their metabolites in patients with very low estrogen concentrations, according to a report published online April 7 in the Journal of Clinical Endocrinology and Metabolism.

“The inaccuracy of direct immunoassays is especially problematic in ... men, postmenopausal women, those taking aromatase inhibitors, and prepubertal children. Thus, the use of current direct assays for measuring estradiol concentrations in these groups of patients should be discouraged,” wrote Dr. Laurence Demers of the Pennsylvania State University, Hershey, and his associates.

Mass spectrometry has better sensitivity and specificity, but mass spectrometers are expensive, and assays to quantify estrogen metabolites are demanding. Because of that, many labs continue to use direct immunoassays even when they’re not the best choice.

The report summarized the consensus from a 2014 meeting of experts in Bethesda, MD., on the measurement of the estrogens and their metabolites. In general, participants agreed that measurements need to be standardized and improved (J. Clin. Endocrinol. Metab. 2015 April 7 [doi:10.1210/jc.2015-1040]).

“Assay inaccuracy complicates the comparison of results obtained from different laboratories, from the same laboratory over time, or from different epidemiological and clinical studies and constrains the application of guidelines to ... patients. A set of clinical practice guidelines cannot be implemented unless the assays used are accurate and precise,” according to the investigators.

Even so, “measurement of estradiol is challenging because the physiologically relevant concentration range spans at least four orders of magnitude ... an assay that is suitable for use for diagnosis and management of infertility in adult women may not meet performance specifications for use when evaluating the onset of puberty in a child,” they said.

Current estradiol assays are particularly problematic in postmenopausal women and children, where sensitivity is critical. Reference ranges haven’t been established for either group. The Centers for Disease Control and Prevention are working to address those and other problems under a Hormone Standardization Program.

Meanwhile, “use of currently available direct estradiol immunoassays appears to compromise assay specificity, probably due to antibody cross-reactivity, matrix effects, and suboptimal sensitivity. These direct assays usually yield higher values than [do] those measured by methods with superior specificity, including immunoassays preceded by organic solvent extraction, liquid chromatography, or gas or liquid chromatography mass spectrometry assays,” the authors said.

There’s a need “for a study to evaluate the different approaches for validation of estrogen assay accuracy. It [is also] recommended that journals require a statement regarding accuracy assessment for estrogen and estrogen metabolite assays with a long-term goal of requiring measurements using accurate assays,” they said.

The Bethesda meeting was sponsored primarily by the Endocrine Society, the American Association for Clinical Chemistry, and the Partnership for Accurate Testing of Hormones. One of the nine authors – Dr. Richard J. Santen of the University of Virginia, Charlottesville – has been a Pfizer adviser and is the principal investigator on a grant from the company to his university. The other authors have no disclosures.

[email protected]

Direct immunoassays shouldn’t be used to measure estrogens and their metabolites in patients with very low estrogen concentrations, according to a report published online April 7 in the Journal of Clinical Endocrinology and Metabolism.

“The inaccuracy of direct immunoassays is especially problematic in ... men, postmenopausal women, those taking aromatase inhibitors, and prepubertal children. Thus, the use of current direct assays for measuring estradiol concentrations in these groups of patients should be discouraged,” wrote Dr. Laurence Demers of the Pennsylvania State University, Hershey, and his associates.

Mass spectrometry has better sensitivity and specificity, but mass spectrometers are expensive, and assays to quantify estrogen metabolites are demanding. Because of that, many labs continue to use direct immunoassays even when they’re not the best choice.

The report summarized the consensus from a 2014 meeting of experts in Bethesda, MD., on the measurement of the estrogens and their metabolites. In general, participants agreed that measurements need to be standardized and improved (J. Clin. Endocrinol. Metab. 2015 April 7 [doi:10.1210/jc.2015-1040]).

“Assay inaccuracy complicates the comparison of results obtained from different laboratories, from the same laboratory over time, or from different epidemiological and clinical studies and constrains the application of guidelines to ... patients. A set of clinical practice guidelines cannot be implemented unless the assays used are accurate and precise,” according to the investigators.

Even so, “measurement of estradiol is challenging because the physiologically relevant concentration range spans at least four orders of magnitude ... an assay that is suitable for use for diagnosis and management of infertility in adult women may not meet performance specifications for use when evaluating the onset of puberty in a child,” they said.

Current estradiol assays are particularly problematic in postmenopausal women and children, where sensitivity is critical. Reference ranges haven’t been established for either group. The Centers for Disease Control and Prevention are working to address those and other problems under a Hormone Standardization Program.

Meanwhile, “use of currently available direct estradiol immunoassays appears to compromise assay specificity, probably due to antibody cross-reactivity, matrix effects, and suboptimal sensitivity. These direct assays usually yield higher values than [do] those measured by methods with superior specificity, including immunoassays preceded by organic solvent extraction, liquid chromatography, or gas or liquid chromatography mass spectrometry assays,” the authors said.

There’s a need “for a study to evaluate the different approaches for validation of estrogen assay accuracy. It [is also] recommended that journals require a statement regarding accuracy assessment for estrogen and estrogen metabolite assays with a long-term goal of requiring measurements using accurate assays,” they said.

The Bethesda meeting was sponsored primarily by the Endocrine Society, the American Association for Clinical Chemistry, and the Partnership for Accurate Testing of Hormones. One of the nine authors – Dr. Richard J. Santen of the University of Virginia, Charlottesville – has been a Pfizer adviser and is the principal investigator on a grant from the company to his university. The other authors have no disclosures.

[email protected]

AT ENDO 2015

SAN DIEGO – Hormone therapy in postmenopausal women does not seem to affect risk of mortality, results from a meta-analysis demonstrated.

“Most menopausal women suffer from a lot of bothersome symptoms, like hot flashes, sleep problems, and night sweats,” Dr. Khalid Benkhadra said during a press briefing at the meeting of the Endocrine Society. “Hormone therapy is usually very effective in alleviating these symptoms. However, women are usually concerned about the long-term safety [of HT].”

Doug Brunk/Frontline Medical News

To assess all-cause and specific mortality associated with hormone therapy in postmenopausal women, Dr. Benkhadra and his associates searched databases for randomized trials published before August 2013 that compared hormone therapy with placebo or no treatment, with a follow-up of at least 6 months. The databases included MEDLINE and the Cochrane Central Register of Controlled Trials.

The outcome of interest was death from any cause, death from cardiac events, and death from breast cancer, lung cancer, ovarian cancer, colorectal cancer, and stroke.

The final meta-analysis included 43 clinical trials involving more than 52,000 women, mean age 62 years. Dr. Benkhadra, a research fellow at Mayo Clinic, Rochester, Minn., reported that no statistically significant association was observed between the use of hormone therapy and all-cause mortality (risk ratio, 0.99), with no significant interaction based on hormone type or preexisting heart disease. In addition, no association was observed between use of hormone therapy and death from myocardial infarction (RR, 1.04), stroke (RR, 1.49), and breast cancer (RR, 0.93), nor lung cancer, ovarian cancer, and colorectal cancer. “In each of these categories, there was no significant effect of HR on the risk of dying,” Dr. Benkhadra said. “Results were similar for estrogen only versus combined estrogen and progesterone therapy.”

He acknowledged certain limitations of the study, including the fact that the evidence in the 43 trials was rated as “low to moderate” and the length of follow-up was limited to 5 years.

Based on the findings, he concluded that postmenopausal women with bothersome symptoms “can engage with their physician in shared decision making to discuss treatment [with HT].”

Dr. Benkhadra reported having no relevant financial conflicts.

[email protected]

On Twitter @dougbrunk

AT ENDO 2015

SAN DIEGO – Hormone therapy in postmenopausal women does not seem to affect risk of mortality, results from a meta-analysis demonstrated.

“Most menopausal women suffer from a lot of bothersome symptoms, like hot flashes, sleep problems, and night sweats,” Dr. Khalid Benkhadra said during a press briefing at the meeting of the Endocrine Society. “Hormone therapy is usually very effective in alleviating these symptoms. However, women are usually concerned about the long-term safety [of HT].”

Doug Brunk/Frontline Medical News

To assess all-cause and specific mortality associated with hormone therapy in postmenopausal women, Dr. Benkhadra and his associates searched databases for randomized trials published before August 2013 that compared hormone therapy with placebo or no treatment, with a follow-up of at least 6 months. The databases included MEDLINE and the Cochrane Central Register of Controlled Trials.

The outcome of interest was death from any cause, death from cardiac events, and death from breast cancer, lung cancer, ovarian cancer, colorectal cancer, and stroke.

The final meta-analysis included 43 clinical trials involving more than 52,000 women, mean age 62 years. Dr. Benkhadra, a research fellow at Mayo Clinic, Rochester, Minn., reported that no statistically significant association was observed between the use of hormone therapy and all-cause mortality (risk ratio, 0.99), with no significant interaction based on hormone type or preexisting heart disease. In addition, no association was observed between use of hormone therapy and death from myocardial infarction (RR, 1.04), stroke (RR, 1.49), and breast cancer (RR, 0.93), nor lung cancer, ovarian cancer, and colorectal cancer. “In each of these categories, there was no significant effect of HR on the risk of dying,” Dr. Benkhadra said. “Results were similar for estrogen only versus combined estrogen and progesterone therapy.”

He acknowledged certain limitations of the study, including the fact that the evidence in the 43 trials was rated as “low to moderate” and the length of follow-up was limited to 5 years.

Based on the findings, he concluded that postmenopausal women with bothersome symptoms “can engage with their physician in shared decision making to discuss treatment [with HT].”

Dr. Benkhadra reported having no relevant financial conflicts.

[email protected]

On Twitter @dougbrunk

AT ENDO 2015

SAN DIEGO – Hormone therapy in postmenopausal women does not seem to affect risk of mortality, results from a meta-analysis demonstrated.

“Most menopausal women suffer from a lot of bothersome symptoms, like hot flashes, sleep problems, and night sweats,” Dr. Khalid Benkhadra said during a press briefing at the meeting of the Endocrine Society. “Hormone therapy is usually very effective in alleviating these symptoms. However, women are usually concerned about the long-term safety [of HT].”

Doug Brunk/Frontline Medical News

To assess all-cause and specific mortality associated with hormone therapy in postmenopausal women, Dr. Benkhadra and his associates searched databases for randomized trials published before August 2013 that compared hormone therapy with placebo or no treatment, with a follow-up of at least 6 months. The databases included MEDLINE and the Cochrane Central Register of Controlled Trials.

The outcome of interest was death from any cause, death from cardiac events, and death from breast cancer, lung cancer, ovarian cancer, colorectal cancer, and stroke.

The final meta-analysis included 43 clinical trials involving more than 52,000 women, mean age 62 years. Dr. Benkhadra, a research fellow at Mayo Clinic, Rochester, Minn., reported that no statistically significant association was observed between the use of hormone therapy and all-cause mortality (risk ratio, 0.99), with no significant interaction based on hormone type or preexisting heart disease. In addition, no association was observed between use of hormone therapy and death from myocardial infarction (RR, 1.04), stroke (RR, 1.49), and breast cancer (RR, 0.93), nor lung cancer, ovarian cancer, and colorectal cancer. “In each of these categories, there was no significant effect of HR on the risk of dying,” Dr. Benkhadra said. “Results were similar for estrogen only versus combined estrogen and progesterone therapy.”

He acknowledged certain limitations of the study, including the fact that the evidence in the 43 trials was rated as “low to moderate” and the length of follow-up was limited to 5 years.

Based on the findings, he concluded that postmenopausal women with bothersome symptoms “can engage with their physician in shared decision making to discuss treatment [with HT].”

Dr. Benkhadra reported having no relevant financial conflicts.

[email protected]

On Twitter @dougbrunk

For women in midlife, an earlier age of onset of vasomotor symptoms – hot flashes and night sweats – was linked to impaired endothelial function, a very early marker for cardiovascular disease.

In the first of two related studies, an earlier age of onset for vasomotor symptoms (VMS) was associated with increased endothelial dysfunction as measured by brachial artery ultrasound. Greater frequency of hot flashes was associated with endothelial dysfunction for younger but not older participants in the second study.

Though more than 70% of women experience VMS during perimenopause and menopause, these symptoms largely have been viewed as a quality of life issue. However, this emerging research might mean that early onset of of hot flashes might serve a potential marker for increased risk for cardiovascular disease, said Rebecca C. Thurston, Ph.D., associate professor of psychiatry, psychology, and epidemiology at the University of Pittsburgh. Her work was presented in a briefing in advance of the annual meeting of the American College of Cardiology in San Diego.

Dr. Thurston and her colleagues drew from the Women’s Ischemia Syndrome Evaluation (WISE) study to evaluate 104 women at four study sites. Participants were postmenopausal and at least 50 years old, could not be on hormone replacement therapy, and had their ovaries. Women with any signs or symptoms of ischemia were excluded, and multiple potential confounders were assessed in the study’s extensive evaluation. Women were stratified by onset of VMS by self-report into three groups: those who never had VMS, those whose VMS began at age 42 or earlier, and those whose VMS began after the age of 42.

Women in the WISE study underwent brachial artery ultrasound to assess brachial artery flow mediated dilation (FMD), a known preclinical disease marker that has been linked to clinical outcomes. Lower FMD scores indicate poorer endothelial function. Women in the group with the earliest onset of VMS had significantly lower FMD values (P = 0.038), indicating poorer endothelial dysfunction. The effect persisted even after controlling for potentially confounding factors.

The second trial, the MSHeart Study, enrolled 189 women aged 40-60. All were nonsmokers with no history of CVD. All of the women had intact uteri and ovaries, and enrollees could not be using hormones or other medications that could affect vascular function (beta-blockers, calcium channel blockers, insulin, or selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors). Participants again underwent extensive evaluation.

Women in the MSHeart Study received a full 24 hours of objective physiologic hot flash monitoring via an external monitoring system as well as FMD evaluation by brachial artery ultrasound. Women were stratified by age into three groups: younger than 53, 53-56, and greater than age 56.

For the youngest group of women in the second study, increased frequency of objectively verified hot flashes was associated with lower FMD and poorer endothelial dysfunction (P < 0.05). The association was not significant for either of the older two groups when taken separately; however, when pooled data for participants of all ages were considered, the interaction between age and hot flash frequency was associated with reduced FMD (P = 0.02). These associations held true after adjusting for the covariates of age, race, BMI, blood vessel diameter, menopausal stage, and any prior hormone use.

These two studies, said Dr. Thurston, “may point to subgroups of women that need targeted cardiovascular prevention” by identifying early VMS as a mechanistic pathway for endothelial dysfunction. Dr. Richard Chazal, ACC vice president and session moderator, noted that the MSHeart Study in particular succeeded in “leveraging physiologic symptoms and markers, as well as the flow mediated functional dilation that we all would expect.”

The studies were sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health.

For women in midlife, an earlier age of onset of vasomotor symptoms – hot flashes and night sweats – was linked to impaired endothelial function, a very early marker for cardiovascular disease.

In the first of two related studies, an earlier age of onset for vasomotor symptoms (VMS) was associated with increased endothelial dysfunction as measured by brachial artery ultrasound. Greater frequency of hot flashes was associated with endothelial dysfunction for younger but not older participants in the second study.

Though more than 70% of women experience VMS during perimenopause and menopause, these symptoms largely have been viewed as a quality of life issue. However, this emerging research might mean that early onset of of hot flashes might serve a potential marker for increased risk for cardiovascular disease, said Rebecca C. Thurston, Ph.D., associate professor of psychiatry, psychology, and epidemiology at the University of Pittsburgh. Her work was presented in a briefing in advance of the annual meeting of the American College of Cardiology in San Diego.

Dr. Thurston and her colleagues drew from the Women’s Ischemia Syndrome Evaluation (WISE) study to evaluate 104 women at four study sites. Participants were postmenopausal and at least 50 years old, could not be on hormone replacement therapy, and had their ovaries. Women with any signs or symptoms of ischemia were excluded, and multiple potential confounders were assessed in the study’s extensive evaluation. Women were stratified by onset of VMS by self-report into three groups: those who never had VMS, those whose VMS began at age 42 or earlier, and those whose VMS began after the age of 42.

Women in the WISE study underwent brachial artery ultrasound to assess brachial artery flow mediated dilation (FMD), a known preclinical disease marker that has been linked to clinical outcomes. Lower FMD scores indicate poorer endothelial function. Women in the group with the earliest onset of VMS had significantly lower FMD values (P = 0.038), indicating poorer endothelial dysfunction. The effect persisted even after controlling for potentially confounding factors.

The second trial, the MSHeart Study, enrolled 189 women aged 40-60. All were nonsmokers with no history of CVD. All of the women had intact uteri and ovaries, and enrollees could not be using hormones or other medications that could affect vascular function (beta-blockers, calcium channel blockers, insulin, or selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors). Participants again underwent extensive evaluation.

Women in the MSHeart Study received a full 24 hours of objective physiologic hot flash monitoring via an external monitoring system as well as FMD evaluation by brachial artery ultrasound. Women were stratified by age into three groups: younger than 53, 53-56, and greater than age 56.

For the youngest group of women in the second study, increased frequency of objectively verified hot flashes was associated with lower FMD and poorer endothelial dysfunction (P < 0.05). The association was not significant for either of the older two groups when taken separately; however, when pooled data for participants of all ages were considered, the interaction between age and hot flash frequency was associated with reduced FMD (P = 0.02). These associations held true after adjusting for the covariates of age, race, BMI, blood vessel diameter, menopausal stage, and any prior hormone use.

These two studies, said Dr. Thurston, “may point to subgroups of women that need targeted cardiovascular prevention” by identifying early VMS as a mechanistic pathway for endothelial dysfunction. Dr. Richard Chazal, ACC vice president and session moderator, noted that the MSHeart Study in particular succeeded in “leveraging physiologic symptoms and markers, as well as the flow mediated functional dilation that we all would expect.”

The studies were sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health.

For women in midlife, an earlier age of onset of vasomotor symptoms – hot flashes and night sweats – was linked to impaired endothelial function, a very early marker for cardiovascular disease.

In the first of two related studies, an earlier age of onset for vasomotor symptoms (VMS) was associated with increased endothelial dysfunction as measured by brachial artery ultrasound. Greater frequency of hot flashes was associated with endothelial dysfunction for younger but not older participants in the second study.

Though more than 70% of women experience VMS during perimenopause and menopause, these symptoms largely have been viewed as a quality of life issue. However, this emerging research might mean that early onset of of hot flashes might serve a potential marker for increased risk for cardiovascular disease, said Rebecca C. Thurston, Ph.D., associate professor of psychiatry, psychology, and epidemiology at the University of Pittsburgh. Her work was presented in a briefing in advance of the annual meeting of the American College of Cardiology in San Diego.

Dr. Thurston and her colleagues drew from the Women’s Ischemia Syndrome Evaluation (WISE) study to evaluate 104 women at four study sites. Participants were postmenopausal and at least 50 years old, could not be on hormone replacement therapy, and had their ovaries. Women with any signs or symptoms of ischemia were excluded, and multiple potential confounders were assessed in the study’s extensive evaluation. Women were stratified by onset of VMS by self-report into three groups: those who never had VMS, those whose VMS began at age 42 or earlier, and those whose VMS began after the age of 42.

Women in the WISE study underwent brachial artery ultrasound to assess brachial artery flow mediated dilation (FMD), a known preclinical disease marker that has been linked to clinical outcomes. Lower FMD scores indicate poorer endothelial function. Women in the group with the earliest onset of VMS had significantly lower FMD values (P = 0.038), indicating poorer endothelial dysfunction. The effect persisted even after controlling for potentially confounding factors.

The second trial, the MSHeart Study, enrolled 189 women aged 40-60. All were nonsmokers with no history of CVD. All of the women had intact uteri and ovaries, and enrollees could not be using hormones or other medications that could affect vascular function (beta-blockers, calcium channel blockers, insulin, or selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors). Participants again underwent extensive evaluation.

Women in the MSHeart Study received a full 24 hours of objective physiologic hot flash monitoring via an external monitoring system as well as FMD evaluation by brachial artery ultrasound. Women were stratified by age into three groups: younger than 53, 53-56, and greater than age 56.

For the youngest group of women in the second study, increased frequency of objectively verified hot flashes was associated with lower FMD and poorer endothelial dysfunction (P < 0.05). The association was not significant for either of the older two groups when taken separately; however, when pooled data for participants of all ages were considered, the interaction between age and hot flash frequency was associated with reduced FMD (P = 0.02). These associations held true after adjusting for the covariates of age, race, BMI, blood vessel diameter, menopausal stage, and any prior hormone use.

These two studies, said Dr. Thurston, “may point to subgroups of women that need targeted cardiovascular prevention” by identifying early VMS as a mechanistic pathway for endothelial dysfunction. Dr. Richard Chazal, ACC vice president and session moderator, noted that the MSHeart Study in particular succeeded in “leveraging physiologic symptoms and markers, as well as the flow mediated functional dilation that we all would expect.”

The studies were sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health.