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"Timing Hypothesis" for Hormone Therapy: Still Viable, or Time to Let Go?

In a new analysis, researchers examine outcomes associated with HT use in the early postmenopausal period.

Postmenopausal hormone therapy was associated with an unfavorable balance of benefits and harms in findings from the landmark Women's Health Initiative (WHI) randomized trials, published in 2002 for estrogen-progestin¹ and in 2004 for estrogen alone.² At enrollment, women in these trials ranged in age from 50 to 79 (average age, 63), and only about one third were 50 to 59. Thus, soon after the initial WHI findings were published, researchers and clinicians began to wonder whether the outcomes were applicable to women who start HT shortly after menopause. This issue seemed particularly relevant for coronary heart disease (CHD), because previous observational studies had suggested that HT use lowered risk for coronary disease; conversely, combination HT with estrogen-progestin led to excess risk for coronary events in the WHI trial.

In subsequent WHI analyses, data trends suggested that HT did not lead to excess coronary risk when it was started close to menopause.³ Although this finding did not reach statistical significance, the idea that HT was safe or even beneficial (from the coronary perspective) when started shortly after menopause gained some currency and became known as the "timing hypothesis." This hypothesis was promoted by some WHI researchers,⁴ but others remained skeptical.⁵ Notably, WHI researchers who advanced the timing hypothesis did not advocate prescribing HT to prevent coronary disease; rather, they suggested that "health care providers need not be unduly concerned about coronary risk" when they prescribe short-term HT to recently menopausal women for relief from vasomotor symptoms.⁴

To address the timing hypothesis more conclusively, the WHI researchers now have published new data from both the WHI randomized trials (which involved >17,000 women) and a parallel WHI observational study of nearly 100,000 women. Information on date of menopause and hormone use before enrollment in the WHI was used to calculate a "gap time" between menopause and first use of HT. The analysis is quite complex: Essentially, the researchers noted trends toward excess risk for CHD, venous thromboembolism, and breast cancer among early users of estrogen-progestin, and trends toward elevated risk for stroke and venous thromboembolism among early users of estrogen alone. A caveat is that the authors don't indicate whether the excess CHD events actually occurred during the first several years of HT use (i.e., when women were still in their fifties) or later on. Nevertheless, the authors conclude that "... the unfavorable balance of benefits and risks observed in the [estrogen-progestin] trial as a whole also applies to recently menopausal women .... WHI data provide little support for the estrogen timing hypothesis concerning CHD risk ...."⁶

However, the timing hypothesis is not dead and buried. Primate studies and other lines of basic research suggest that estrogen slows initial development of atherosclerotic plaques. In addition, the specific hormones used in the WHI (conjugated equine estrogens and medroxyprogesterone) might have harmful effects that are not shared by estradiol and progesterone. Randomized trials — for example, the KEEPS and ELITE trials — are in progress to study the effects of HT on surrogate endpoints (e.g., carotid intima-media thickness) in recently postmenopausal women.

But, until new trials with clinical endpoints are completed, a prudent conclusion is that clinical research has not identified a window of time after menopause during which HT can confidently be considered to be free of risk.⁷ Women of any age who receive HT for symptom relief still should be informed of all potential risks, including CHD.

— Allan S. Brett, MD

Published in Journal Watch General Medicine September 17, 2009

Citation(s):

1. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002 Jul 17; 288:321.

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• Medline abstract (Free)

2. The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA 2004 Apr 14; 291:1701.

• Original article (Subscription may be required)
• Medline abstract (Free)

3. Rossouw JE et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007 Apr 4; 297:1465.

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• Medline abstract (Free)

4. Manson JE and Bassuk SS. Invited commentary: Hormone therapy and risk of coronary heart disease — Why renew the focus on the early years of menopause? Am J Epidemiol 2007 Sep 1; 166:511.

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5. Barrett-Connor E. Hormones and heart disease in women: The timing hypothesis. Am J Epidemiol 2007 Sep 1; 166:506.

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6. Prentice RL et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009 Jul 1; 170:12.

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• Medline abstract (Free)

7. Banks E and Canfell K. Invited commentary: Hormone therapy risks and benefits — The Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis. Am J Epidemiol 2009 Jul 1; 170:24.

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Reader Remarks:

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• Natural hormones
  Steven J. Meyerson, M.D., 18 Sep 2009 9:46 AM EST
  It's too bad the use of semisynthetic hormones and estrogens from a nonhuman source (pregnant mares) has been generalized as... [more]
• combination or sequential HT?
  E. Lerner, 18 Sep 2009 11:42 PM EST
  I have been on HT since I started to go into early menopause maybe 10 or more years. I'm now... [more]
• Retired Gynecologist--no guilt trip for me for replacing estrogen.
  Richard R Thornton, Retired, 22 Sep 2009 2:49 PM EST
  Please read the abstract as well as the summary article to get actual numbers and statistical analysis
  
  I prescribed hormone... [more]