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Menopause
Matters
Postmenopausal
Hormone Therapy:
Clarifying the Role
Wulf H. Utian, MD, PhD
After more than 2 years since the publication of results on estrogen therapy (ET) and estrogen plus progestin (EPT) from the Women's Health Initiative (WHI), women continue to look to their clinicians to sort out fact from fiction and allay their concerns, all the while being bombarded by negative reports from the lay media. Meanwhile, clinicians struggle to translate newly published data—some of which are conflicting—into their clinical practices in order to devise the safest and most effective course of treatment for their patients' individual needs.
To this end, The North American Menopause Society (NAMS) has published its third report on this topic, titled "Recommendations for Estrogen and Progestogen Use in Peri- and Postmenopausal Women: October 2004 Position Statement of The North American Menopause Society."1 The report, released on October 6, 2004, is the work of a NAMS-convened Hormone Therapy Panel, composed of experts in several related fields who carefully reviewed recently published studies to determine the need for new recommendations and for revisions of previous recommendations since publication of the Society's 2003 report.2
While the substance of this latest report remains similar to that of the 2003 report, the primary
clinical question put to the 2004 Panel was to differentiate the risk-benefit ratio of postmenopausal ET/EPT for disease prevention and treatment of specific menopause-related symptoms.
An expanded introductory section explains the terminology used to define and interpret risk and encourages use of international standards to quantify risk. The Panel emphasized that the practice of medicine must be based on the interpretation of the entire body of evidence, rather than on a single trial, noting that there will never be sufficient clinical trials to cover all populations, regimens, and eventualities.
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NEW RECOMMENDATIONS
The following are some of the important revisions contained in the latest NAMS Position Statement:
For women who require drug therapy for osteoporosis risk reduction (including those at high risk for fracture in the next 5 to 10 years), ET/EPT may still be considered, weighing its risks and benefits as well as those of alternate therapies. There is definitive evidence that both ET alone and EPT reduce the risk for postmenopausal osteoporotic fracture.
Breast cancer risk probably increases with EPT use beyond 5 years. In absolute terms, this risk is small (four to six cases of additional invasive cancers per 10,000 women using EPT for 5 years or more) and of possible statistical significance.3 There is no mortality difference between EPT users and nonusers. Women in the estrogen-only arm of the WHI had no increase in breast cancer risk after an average of 6.8 years of use.4 Available evidence also suggests that use of estrogen alone for fewer than 5 years has little impact on breast cancer risk, but questions persist despite the WHI results. A large observational study5 has shown that 25 years of ET use is not associated with changes in breast cancer risk.
No ET or EPT regimen should be used for primary or secondary prevention of coronary heart disease (CHD). The role of ET and EPT in the primary prevention of CHD remains unclear, especially in younger women who begin therapy early and continue for a number of years. In the WHI,6 ET/EPT did not reduce the incidence of CHD.
Estrogen plus progestin should not be initiated after age 65 years for primary prevention of dementia as doing so may increase the risk of dementia during the ensuing 5 years in this population. There is insufficient evidence to either support or refute the benefits or risks of ET/EPT for this indication when therapy is initiated during the menopausal transition or in early postmenopause. Estrogen therapy does not appear to convey direct benefit or harm for treatment of dementia due to Alzheimer disease.
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ONGOING RECOMMENDATIONS
As in 2003, the 2004 Position Statement stresses the need for an individualized approach to treatment, based on a woman's unique treatment goals and potential benefits and risks. The following points and recommendations continue to be emphasized in the most recent Position Statement:
Treatment of moderate to severe menopausal symptoms (ie, vasomotor symptoms, sleep disruption from vasomotor symptoms) remains the primary indication for systemic ET and EPT. Every systemic ET/EPT product is government-approved for this indication.
Every systemic and local ET/EPT product is government-approved for treating moderate symptoms of vulvar and vaginal atrophy. When hormones are considered solely for this indication, local ET is generally recommended.
A general guiding principle regarding duration of therapy should be for the lowest effective dose and shortest amount of time consistent with treatment goals.
Provided the woman is well aware of the potential risks and benefits, and that there is clinical supervision, extended use of the lowest effective ET/EPT dose for treatment goals is acceptable in women who believe the benefits outweigh the risks, and for those at high risk of osteoporotic fracture who also have moderate to severe menopausal symptoms. It also is acceptable for further prevention of established bone loss when alternate therapies are not appropriate or cause side effects, or when outcomes of extended use of those therapies are not known.
Although specific compounds, doses, and routes of administration may have different outcomes, clinical trial results for one agent should be generalized to all agents within the same family in the absence of data for each specific product. This proviso also applies to the so-called bioidentical products.
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QUESTIONS REMAIN
Panelists were divided on whether there is definitive evidence for early increased CHD risk with use of hormone therapy (HT). The Panel also was unable to reach consensus on whether women doing well on long-term HT should discontinue. There was, however, agreement that the risks and benefits need to be discussed on an individual basis. Panelists also were divided with respect to agreeing on the best way to discontinue HT when needed (abrupt cessation versus dose tapering).
On the question of whether continuous-combined EPT has an effect different from that of continuous estrogen with sequential progestogen, the evidence was insufficient to reach a consensus. Conflicting data precluded a consensus related to adverse breast cancer and cardiovascular outcomes associated with ET/EPT. The Panel recommends further research on these and other issues about which consensus could not be reached.
The full report, as well as other information about menopause, may be accessed on the NAMS Web site (www.menopause.org).
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Wulf H. Utian, MD, PhD, is Arthur H. Bill Professor Emeritus of Reproductive Biology and Obstetrics and Gynecology, Case Western Reserve University School of Medicine; president, Rapid Medical Research; and consultant in Women's Health, Cleveland Clinic Foundation, Cleveland, Ohio. Dr Utian is executive director and honorary founding president of NAMS. He served as NAMS president from 1989 to 1992 and has been a member of the NAMS Board of Trustees since 1989.
References
- The North American Menopause Society. Recommendations for estrogen and progestogen use in peri- and postmenopausal women: October 2004 position statement of The North American Menopause Society. Menopause. 2004;11(6):589-600.
- The North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: September 2003 position statement of The North American Menopause Society. Menopause. 2003;10(6):497-506
- Chlebowski RT, Hendrix SL, Langer RD, et al; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative randomized trial. JAMA. 2003;289(24): 3243-3253.
- Anderson GL, Limacher M, Assaf AR, et al; 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; 291(14):1701-1712.
- Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003; 362(9382):419-427.
- Manson JE, Hsia J, Johnson KC, et al; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349(6):523-534.
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