Clinical Review


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Does estrogen therapy carry more risk than benefit? The answer depends, new data suggest, on the age of the patient, route of administration, and type of progestin.



The author has received funding from Barr/Duramed, Bayer, and Warner Chilcott. He is a consultant for Barr/Duramed, Bayer, Warner Chilcott, Kenwood, Noven, and Johnson & Johnson. He holds stock with Sanofi Aventis and Procter & Gamble.

Does estrogen therapy carry more risk than benefit? The answer depends, new data suggest, on the age of the patient, route of administration, and type of progestin.

The past 12 months have yielded important new insights into the risks and benefits of menopausal hormone therapy (HT), including

  • landmark reports from the Women’s Health Initiative (WHI) regarding HT and the risk of coronary artery disease
  • data from France on the route of HT and risk of thrombosis and on progestin selection and the risk of breast cancer
  • data from the Mayo Clinic regarding HT use and subsequent risk of dementia and parkinsonism.

User age determines effects of HT on coronary artery disease

Rossouw JE, Prentice PL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477.

Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591–2602.

The WHI clinical trials were designed in 1991 and 1992 primarily to determine whether oral menopausal HT protects against coronary artery disease (CAD), as a large body of literature based on observational studies had suggested. Most of those observational studies had involved unopposed oral estrogen.1

When the estrogen–progestin arm of the WHI was halted in 2002, investigators noted that use of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) overall was associated with a 29% increase in the risk of CAD (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02–1.63) and a more than 200% increase in the risk of venous thromboembolism (HR, 2.11; 95% CI, 1.49–2.87), compared with placebo. Subsequent reports explored this connection from different angles ( see the timeline).

In 2007, important—and, for some, startling—findings were published regarding HT and the risk of CAD, most notably:

  • When estrogen users from both arms of the WHI trial were combined into one group, those who were less than 10 years since the onset of menopause had a HR for CAD of 0.76 (95% CI, 0.5–1.16), and oral HT was associated with six fewer cases of CAD for every 10,000 woman-years of use. Similar findings were reported for women 50 to 59 years old. Among older WHI participants and those more distant from menopause, HT was associated with an elevated risk of CAD.
  • In the same cohort, mean coronary artery calcium scores overall were more favorable among women receiving estrogen than among those randomized to placebo (P=.02). Among women who took the study medication most consistently (at least 80% adherent), an even greater reduction in coronary artery calcification was noted with estrogen use, which was associated with a 61% reduction in the risk of having extensive coronary artery calcification (P=.004). The authors concluded: “… estrogen therapy may have cardioprotective effects in younger (menopausal) women.”

In contrast to earlier WHI reports, which failed to break out risks by user age, these recent publications are consistent with the earlier observational studies of HT and should reassure ObGyns that the patients most likely to experience menopausal symptoms (women in their 50s and early 60s) can use HT without increasing their risk of CAD.

Transdermal estrogen carries a lower risk of VTE than oral administration

Canonico M, Oger E, Plu-Bureau G, et al; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation. 2007;115:840–845.

As I noted earlier in this article, the initial 2002 WHI report found that oral CEE plus MPA doubled the risk of venous thromboembolism (VTE). Although WHI clinical trials did not study transdermal estrogen, an important observational study comparing VTE risk between oral and transdermal estrogen therapy was conducted in France, where use of transdermal estrogen is more common than in the United States.

In a 2007 report from this large multicenter, case-control study (the Estrogen and Thromboembolism Risk study, or ESTHER), oral menopausal estrogen therapy was associated with a fourfold increase in the risk of VTE (including pulmonary embolism and deep venous thrombosis), compared with nonuse (P<.05), whereas use of transdermal estrogen was not associated with any increase in the risk of VTE.

Type of progestin also played a role

This report also assessed VTE by the type of progestin used by women taking combination estrogen–progestin HT. Micronized progesterone and MPA did not affect the risk of VTE, but norethindrone acetate as well as other progestins not used in the United States did appear to elevate VTE risk.

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