In 2010, the E3N cohort study from France also assessed the risk of thrombosis associated with oral and transdermal HT. Investigators followed more than 80,000 postmenopausal women and found that, unlike oral HT, the transdermal route did not increase the risk of venous thrombosis.
More recent evidence also suggests a safety advantage for transdermal HT. The newest data come from the United Kingdom General Practice Research Database, which includes information on more than 870,000 women who were 50 to 70 years old from 1987 to 2006. Investigators identified more than 15,000 women who were given a diagnosis of stroke during this period and compared the use of HT in these women with that of almost 60,000 women in a control group. The risk of stroke associated with current use of transdermal HT was similar to the risk associated with nonuse of HT. Women who used a patch containing 0.05 mg of estradiol or less had a risk of stroke 19% lower than women who did not use HT.
In contrast, the risk of stroke in users of patches that contained a higher dosage of estradiol was almost twice the risk in nonusers of HT. Current users of oral HT had a risk of stroke 28% higher than that of nonusers of HT.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
The WHI assessed the risks and benefits of oral HT only. Although no randomized, clinical trial has compared cardiovascular risks among users of oral and transdermal HT, I believe that a preponderance of evidence points to a superior safety profile for the transdermal route, particularly at a dosage of 0.05 mg of estradiol or less.
I encourage my patients who are initiating HT to consider the transdermal route—particularly women who have an elevated risk of cardiovascular disease, including those who are overweight, smoke cigarettes, or who have hypertension or diabetes. I suggest the transdermal route despite its higher cost (oral micronized estradiol can be purchased for as little as $4 for a month’s supply at a chain pharmacy).
When a patient prefers to avoid a patch (because of local irritation), I offer her estradiol gel or spray or the vaginal ring. (Femring is systemic estradiol, whereas Estring is local.) These formulations should provide the same safety benefits as the patch.
Estrogen-progestin HT raises the risk of death from breast cancer
Chlebowski RT, Anderson GL, Gass M, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304(15):1684–1692.
Toh S, Hernandez-Diaz S, Logan R, Rossouw JE, Hernan MA. Coronary heart disease in postmenopausal recipients of estrogen plus progestin: does the increased risk ever disappear? Ann Intern Med. 2010;152(4):211–217.
In the estrogen-progestin arm of the WHI, initially published in 2002, the risk of invasive breast cancer was modestly elevated (hazard ratio [HR], 1.26) among women who had used HT longer than 5 years.3
In 2010, investigators reported on breast cancer mortality in WHI participants at a mean follow-up of 11 years. They found that combination HT users had breast cancer histology similar to that of nonusers. However, the tumors were more likely to be node-positive in combination HT users (23.7% vs 16.2%). In addition, breast cancer mortality was slightly higher among users of HT (2.6 vs 1.3 deaths in every 10,000 woman-years) (HR, 1.96; 95% confidence interval, 1.00–4.04).
Earlier observational studies had suggested that the death rate from breast cancer is lower in users of combination HT than in nonusers. Consistent with the UK Million Women Study, however, a 2010 report from the WHI found a higher mortality rate among women who have used HT.4
These new WHI findings reinforce the importance of assessing whether micronized progesterone combined with estrogen might lower the risk of death from breast cancer—a possibility suggested by findings of the French E3N cohort study.5
In addition, given the possibility that HT may be cardioprotective when it is initiated within 10 years after the onset of menopause, a WHI report that addresses long-term all-cause mortality would allow us to better counsel our menopausal patients who are trying to decide whether to start or continue HT. See, for example, the data from the California Teachers Study (below) and the estrogen-alone arm of the WHI (page 46).
WHAT THIS EVIDENCE MEANS FOR PRACTICE
The findings of this important WHI publication have strengthened the resolve of some clinicians to stop prescribing HT for menopausal women. I continue to prescribe HT to patients who have bothersome vasomotor and related symptoms, however. I also counsel women about the other benefits of HT, which include alleviation of genital atrophy and prevention of osteoporotic fractures. For patients considering or using estrogen-progestin HT, I include discussion of the small increase in their risk of developing, and dying from, breast cancer.