From the Editor

Does hormone therapy reduce mortality in recently menopausal women?

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Yes. For postmenopausal women aged 50 to 59 years, hormone therapy reduces the risk of death.



Clinicians work to maximize the quality of life and longevity of every patient. For women with moderate to severe menopausal symptoms, oral estrogen therapy can improve quality of life, but at the cost of significant adverse effects. The Women’s Health Initiative
 (WHI) reported that for postmenopausal women with a uterus, 
conjugated estrogen plus medroxyprogesterone acetate (CEE+MPA) hormone therapy (HT) versus placebo 
significantly increased the risk of 
cardiovascular events (relative risk 
[RR], 1.13), breast cancer (RR, 1.24), 
stroke (RR, 1.37), deep vein thrombosis (RR, 1.87), and pulmonary 
embolism (RR, 1.98).1 In postmeno
pausal women without a uterus, CEE 
HT did not increase the risk of breast 
cancer (RR, 0.79), compared with 
placebo, but it did significantly in
crease the risk of cardiovascular 
events (RR, 1.11), stroke (RR, 1.35), 
deep vein thrombosis (RR, 1.48), and 
pulmonary embolism (RR, 1.35).1

Clinicians prescribing estrogen must individualize therapy according
 to its benefits and risks. An important issue that has received insufficient at
tention is, “What is the effect of HT 
on mortality in recently menopausal women?” Here, I examine this issue.

HT reduces mortality in 
recently menopausal women

Pooling the results of the WHI CEE+MPA and CEE-only trials 
reveals that there were 70 deaths in the HT-treated groups and 98 deaths in the placebo groups among women aged 50 to 59 years.1 With 4,706 and 4,259 women alive at the conclusion of the study in the HT and placebo groups, respectively, the women in the placebo group had significantly more deaths than the women in the HT-treated groups (Fisher exact test, P = .0194, χ2 test with Yates correction, P = .0226).

Using pooled data from the WHI, the RR of death in the HT versus placebo group was estimated at 0.70 (95% confidence interval [CI], 0.51−0.96), representing approximately 5 fewer deaths per 
1,000 women per 5 years of therapy.2 In women aged 60 to 69 years and 70 to 79 years there were no significant differences in death rates between the HT- and placebo-treated women.

My interpretation of these results is that HT likely is associated with a reduced risk of death in recently menopausal women, but not in 
women distant from menopause onset.

Cochrane review of 
HT and mortality

Consistent with the WHI findings, authors of a recent Cochrane 
meta-analysis of 19 randomized trials including 40,410 menopausal women reported that HT significantly increased the risk of stroke (RR, 1.24; 95% CI, 1.10−1.41), venous thromboembolism (RR, 1.92; 95% CI, 1.36−2.69), and pulmonary emboli (RR, 1.81; 95% CI, 1.32−2.48).3 However, among women treated with oral HT within 10 years after the start of menopause, there was a reduced risk of coronary heart disease (RR, 0.52; 95% CI, 0.29−0.96). Using data from 5 clinical trials, the Cochrane meta-analysis researchers reported that, compared with placebo, HT reduced mortality (RR, 0.70; 95% CI, 0.52−0.95).3

Results of the Cochrane meta-analysis are consistent with those of a previous meta-analysis of 
19 randomized trials involving 16,000 women. In this analysis, investigators found a reduced risk of death in recently menopausal women treated with hormone therapy (RR, 0.73; 95% CI, 0.52−0.96).4

Early menopause, 
HT, and mortality

Authors of multiple large epidemiologic studies have reported that early menopause is associated with an increased risk of death if HT is not initiated.5−7 For example, results of a study of women in Olmsted County, Minnesota, conducted from 1950 to 1987, indicated that, for women younger than age 45 years who underwent bilateral oophorectomy, the risk of death was increased among those who did not initiate HT, compared with women who did not undergo oophorectomy (hazard ratio [HR], 1.84; 95% CI, 1.27−2.68; 
P = .001).7

By contrast, women younger than 45 years who underwent bilateral oophorectomy and initiated estrogen therapy did not have an increased risk of death compared with women who did not undergo oophorectomy (HR, 0.65; 95% CI, 0.30−1.41; P = .28).7 An excess number of cardiovascular events appeared to account for the increased mortality among women with early surgical menopause who did not initiate HT.

The “timing hypothesis” proposes that the initiation of HT soon after the onset of menopause is associated with beneficial cardiovascular effects, but initiation more than 10 years after the onset of menopause is not associated with beneficial cardiovascular effects. The timing hypothesis is supported by the finding that, in recently menopausal women, HT is associated with reduced carotid intima-media thickness (CIMT), compared with placebo.8 Greater CIMT thickness is associated with an increased risk of cardiovascular events.

In my experience, few primary care clinicians are aware of these data. Often, these clinicians over-emphasize the risks and withhold HT in this vulnerable group of women.

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