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Estrogen, HRT, and mood disorders

Vol. 2, No. 12 / December 2003

“Minding menopause” (CURRENT PSYCHIATRY, October 2003) provided an interesting and useful look at how to diagnose and treat menopause-related psychiatric symptoms.

However, Dr. Brizendine’s statement that “…the Women’s Health Initiative (WHI) trial reported that estrogen’s health risks…exceeded potential benefit during 5 years of therapy” requires some clarification.

After a mean of 5.2 years of follow-up, the WHI reported an increased risk of major cardiovascular events, breast cancer, and pulmonary emboli in the trial arm evaluating estrogen plus progestin versus placebo.1 The reduced incidence of hip fractures and colorectal cancers did not outweigh the adverse events. The results of the trial’s estrogen-versus-placebo arm (in women without a uterus) have not yet been reported.

Hormone replacement therapy, or HRT (estrogen plus progestin), is clearly no longer indicated to prevent chronic diseases in healthy postmenopausal women. 2 Given the increase in breast cancer and symptomatic gallstones in patients taking estrogen,3 and uncertainty over how estrogen affects cardiovascular status, most clinicians now avoid estrogen for primary prevention, at least until the WHI reports its estrogen-only trial results.

As long as the risks and benefits are carefully explained, HRT can still be used to treat hot flashes.4 Although HRT does not have a clinically meaningful effect on health-related quality of life, it does reduce moderate to severe vasomotor symptoms.5

For now, the risks of estrogen therapy (in women without a uterus) should be presumed to be at least as serious as those of combined estrogen/progestin therapy. Though challenging, psychiatrists who treat menopause-related hot flashes and mood symptoms need to clearly understand the risks and benefits of estrogen and estrogen/progestin therapy.

Michael Rack MD
Assistant professor of internal medicine and psychiatry
University of Mississippi School of Medicine
Jackson, MS


  1. Yusuf S, Anand S. Hormone replacement therapy: a time for pause. CMAJ 2002;167:357–9.
  2. Day A. Lessons from the Women’s Health Initiative: Primary prevention and gender health. CMAJ 2002;167:361–2.
  3. Gupta G, Aronow WS. Hormone replacement therapy. An analysis of efficacy based on evidence. Geriatrics 2002;57(8):18–20, 23–4.
  4. Sherman FT. Hormone replacement therapy. The sudden halt of a clinical trial shakes long held beliefs. Geriatrics 2002;57(8):7.
  5. Hays J, Ockene JK, Brunner RL, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348:1839–54.

Dr. Brizendine responds

Dr. Rack is right that the WHI has so far documented dangers of estrogen-progestin but not estrogen alone.

The WHI results clearly indicate that the risks of more than 5 years of estrogen-progestin HRT outweigh the benefits for the average woman. While we still don’t know the risks of estrogen-only therapy, the WHI trial’s estrogen-only arm—scheduled for completion in 2005—will provide valuable information on the safety of estrogen alone for women without a uterus.

It is somewhat comforting that after 7 years, predetermined risk limits have not forced termination of the estrogen-only trial. More than 6,500 women will soon enter their eighth year in the estrogen-only trial. Most physicians now feel they can treat severe hot flashes for up to 5 years with:

  • estrogen in women without a uterus
  • estrogen-progestin in women with a uterus.

In either case, patients must have no other contraindications to taking estrogen, including breast cancer risk, history of blood clotting, and gallbladder disease.

Women who cannot or will not take estrogen but have severe hot flashes may wish to try a selective serotonin reuptake inhibitor (SSRI) for hot flashes. Based on clinical experience, women with mood symptoms and hot flashes are likely to respond best to an SSRI.

Many women ages 40 to 60 develop mood symptoms during their perimenopause and menopause transitions. Familiarity with use of estrogen and SSRIs in this patient population is critical. Psychiatrists should be able to knowledgeably discuss the risks and benefits of HRT with patients, but HRT prescription is best left up to the patient’s Ob/Gyn or primary practitioner.

Louann Brizendine, MD
Clinical professor of psychiatry
Director, Women’s Mood and Hormone Clinic
University of California-San Francisco Medical School

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