Estrogen arm of WHI suspended; what next?

Early summer should see the publication of a detailed analysis from the estrogen-alone arm of the Women’s Health Initiative (WHI). The study was suspended in February when scientists determined the therapy did not appear to affect heart disease, the major question being evaluated in the trial.1 According to initial data from the halted study, estrogen-alone therapy appears to increase the risk of stroke and decrease the risk of hip fracture, and does not increase the risk of breast cancer.1

The increased risk of stroke in the estrogen-alone study is similar to what was found in the WHI study of estrogen plus progestin when that trial was stopped in July 2002 after 5.6 years of follow-up.2 In that study, women taking estrogen plus progestin had eight more strokes per year per 10,000 women than those taking the placebo.2 The estrogen plus progestin trial was stopped due to an increased risk of breast cancer and because the risk of breast cancer, coronary heart disease, stroke, and blood clots outweighed the beneficial effects on hip fracture and colorectal cancer.

Until the results of the newly suspended trial are analyzed, providers should look to guidance issued by the Food and Drug Administration (FDA) when it comes to use of hormone therapy:

  • Discuss the benefits and risks of using estrogen or estrogen with progestin with postmenopausal women who are using or are considering use of hormone therapy.
  • Hormone therapy products are approved therapies for relief from moderate to severe hot flashes and symptoms of vulvar and vaginal atrophy. Although hormone therapy is effective for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis who cannot take nonestrogen medications.
  • The FDA recommends that estrogens and progestins should be used at the lowest doses for the shortest duration needed to achieve treatment goals.1

Treat the symptoms

While professional societies await publication of the detailed analysis of the estrogen-only arm, they advise members to stay the course with previously issued direction on use of hormone therapy.

The Cincinnati-based North American Menopause Society stands by its September 2003 position statement on estrogen and progestin use in peri- and postmenopausal women. (See "resources" at the end of this article to access the document.) The society will issue further recommendations after the full WHI report is published.3 The Washington, DC-based American College of Obstetricians and Gynecologists also stands by its previous recommendations; it refers members to information issued on following the WHI announcement of July 2002. (See "resources" at the end of this article to access the information.)

"It is important to remember that this is one piece of the puzzle, and the fact remains, from my viewpoint, is that the estrogen data actually should be reassuring because they suggest that estrogen alone has fewer side effects and adverse events associated with it than estrogen and progestin," says Robert Rebar, MD, executive director of the Birmingham, AL-based American Society for Reproductive Medicine.

Explain to women that the estrogen-only arm of the study was not halted because of unexpected adverse outcomes, says Rebar; rather, it was felt that sufficient information had been gathered.

"These [new] results underscore that the appropriate use of hormone therapy is for the treatment of menopausal symptoms," says Susan Wysocki, RNC, NP, president and chief executive officer of the Washington, DC-based National Association of Nurse Practitioners in Women’s Health. "Based on the results of this trial, there is no reason to stop therapy if a woman is being treated for symptoms."

What is next?

According to Rebar, the new WHI findings will cause people to rethink how estrogen should be administered. Questions will arise about the route of administration, whether it should it be used with intermittent progestin, and if so, how frequently and with which progestin, Rebar observes. (See "resources" at the end of this article for a selection of Internet information on hormone therapy.)

The new WHI findings strengthen the perspective that the elevated risk of breast cancer associated with combination hormone therapy appears to result from the progestin, not the estrogen component, comments Andrew Kaunitz, MD, professor and assistant chair in the obstetrics and gynecology department at the University of Florida Health Science Center/Jacksonville. This represents good news for post-hysterectomy women contemplating use of estrogen due to bothersome vasomotor symptoms, Kaunitz notes.

For postmenopausal women with an intact uterus, the new WHI information suggests that clinicians should look for ways to minimize progestin use in women receiving estrogen, he asserts. One way to accomplish this is with use of the progestin-releasing intrauterine system (IUS) (Mirena IUS, Berlex Laboratories, Montville, NJ). The systemic estrogen is used for symptoms, while local progestin is delivered for endometrial protection.

"I am already using this approach in a small number of patients in my practice," says Kaunitz. "I am hopeful that smaller, menopause size progestin-releasing IUSs will be developed to facilitate use in this clinical setting."

Women with osteoporosis who once looked to estrogen therapy for its bone-strengthening properties will take heart in results from a new study that indicates uses of alendronate (Fosamax, Merck Research Laboratories) enabled postmenopausal women to maintain or increase their bone density through 10 years of treatment with no apparent ill effects. The improved bone density persisted even after the drug was stopped and diminished only gradually.4

The new study, the longest clinical trial ever conducted in osteoporosis, found that daily alendronate for 10 years produced increases in bone mineral density at the spine, trochanter, and femoral neck. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit.4

References

1. National Heart, Lung, and Blood Institute Communications Office. NIH asks participants in Women’s Health Initiative estrogen-alone study to stop study pills, begin follow-up phase. Press release. March 2, 2004. Web site: www.nhlbi.nih.gov/new/press/04-03-02.htm.

2. 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; 288:321-333.

3. Edelstein B. The North American Menopause Society issues initial reaction to termination of estrogen-only arm of the Women’s Health Initiative. Press release. March 2, 2004. Web site: www.menopause.org.

4. Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. New Engl J Med 2004; 350:1,189-1,199.

Resources

  • The Women’s Health Initiative web site, operated by the National Heart, Lung, and Blood Institute, offers a question-and-answer section about the suspension of the estrogen-only arm, as well as a physicians’ advisory about the halted study. To review these and other items, visit www.nhlbi.nih.gov/whi.
  • To review the September 2003 position statement on estrogen and progestogen use in peri- and postmenopausal women issued by the North American Menopause Society, go to the organization’s web site, www.menopause.org. Click on "NAMS Position Statement about hormone therapy" to access the document. The web site also offers several resources on menopause treatments.
  • To review recommendations issued by the Washington, DC-based American College of Obstetricians and Gynecologists (ACOG), go to the organization’s web site, www.acog.org. Click on the news release, "ACOG Statement on the NIH Announcement to Halt Estrogen-Only Arm of the WHI Study," then click on "Questions and Answers" at the end of the press release.
  • The Washington, DC-based Association of Reproductive Health Professionals has developed a web-based Hormone Therapy Resource Center (www.arhp.org/hormonetherapy/). The site is designed for health care providers and the general public and is updated daily to include the latest news and research on hormone therapy.