Clinical Review

2015 Update on menopause

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The latest guidance on safe use of menopausal hormone therapy

In This Article

  • Testosterone for low desire?
  • ACOG on the management of menopausal symptoms
  • Is concomitant use of hormone therapy and statins a good idea?



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

  • long-term follow-up data from the Women’s Health Initiative (WHI) on the benefits and risks of hormone therapy (HT)
  • a randomized trial of testosterone enanthate to improve sexual ­function among ­hysterectomized women
  • guidance from the American College of Obstetricians and Gynecologists (ACOG) on the management of menopausal symptoms, including advice on individualization of therapy for older women
  • a Swedish study on concomitant use of HT and statins.

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.

The safety of hormone therapy is greater in women nearer the onset of menopause, as well as in those at lower baseline risk of cardiovascular disease, as long-term data from the Women’s Health Initiative demonstrate.

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.


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