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Rethinking Prophylaxis of Post-menopausal Risks

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 22nd Annual Meeting of the North American Menopause Society

Washington, D.C. / September 21-24, 2011

Washington, D.C. - A more rational approach to hormone replacement therapy, particularly the use of estrogens to maintain function in estrogen-dependent tissues, such as the bone and structures of the urogenital tract, is being driven by several trends. One is that the volatility of debate concerning relative benefits and risks has subsided. A more measured and evidence-based approach is being driven by the need for hormone replacement in many postmenopausal women who are experiencing significant symptoms or who are at risk because of low levels of circulating estrogen. Another is the increasing array of options that provide sufficient estrogen to control estrogen-related health problems but preserve a low risk of adverse events. In Canada, the shifting trends in hormone replacement may be accelerated by an increasing number of therapeutic options now in clinical trials. These options arrive just as the aging population pushes large numbers of women into the candidate age range.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The merits and risks of hormone replacement therapy (HRT) overall and estrogen replacement therapy specifically have been the focus of debate, often in the absence of clear data. The most cited study in this debate is the Woman’s Health Initiative (WHI), which generated its first set of results in 2002 (WHI Writing Group. JAMA 2002;288:321-33). But the data from this study, conducted in healthy postmenopausal women with a mean age of 63.3 years, are often irrelevant to the indications being discussed. Relative to the US, Canada has employed a more rational approach to estrogen replacement both before and after release of the WHI data.

“WHI did not have the bombshell effect in Canada. There are several reasons for this and one is that the Health Protection Branch reacted relatively cautiously to the data. In addition, the CMA [Canadian Medical Association] pointed out that risks were lower in younger women, and this had a calming effect,” stated Dr. Timothy Rowe, Head, Division of Reproductive Endocrinology and Infertility, University of British Columbia, Vancouver. Speaking at NAMS, Dr. Rowe acknowledged that prescriptions of HRT fell after the release of WHI data but not as much as in many other countries, and the decline flattened in 2006. Most of the decline, when it occurred, “was in older females, which was probably appropriate,” he noted.

Why HRT?

The need for estrogen replacement is driven by adverse changes in estrogen-sensitive tissues which begin with the menopause and result in diminished quality of life (QoL) and significant health risks in a large proportion of women. Although the value of HRT in asymptomatic women remains a topic of debate, including one conducted at NAMS, the indications are far clearer in women with symptoms. Calling the postmenopausal estrogen-depleted state an endocrinopathy, Dr. David F. Archer, Professor of Obstetrics and Gynecology, Eastern Virginia School of Medicine, Norfolk, observed that many of the problems, such as vasomotor symptoms or vaginal atrophy, are readily reversed with estrogen, while the risks can generally be reduced or avoided.

“At least 40% of postmenopausal women have clinically significant vaginal atrophy, which results in painful intercourse and urogenital symptoms, including incontinence. This is getting to the level of a public health issue. Only 25% of these women seek medical advice even though the symptoms are readily reversed,” reported Dr. Raquel D. Arias, Associate Professor of Clinical Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles.

Although Dr. Arias acknowledged a decline in hormone use overall, particularly in the US, she reported that use of alternative strategies is increasing. This includes topical application of estrogen, with or without lubricants, in those with dyspareunia due to vaginal atrophy, and use of selective estrogen receptor modulators (SERMs) to prevent bone loss while reducing risk of breast cancer. Recently, a strategy in which a SERM is combined with conjugated estrogens (CEs) has completed a phase III study.

“The goal of estrogen therapy is to improve bone health, improve vasomotor symptoms and avoid urogenital atrophy while avoiding proliferative effects in the endometrium,” explained Dr. JoAnn V. Pinkerton, Medical Director of Midlife Health Center and Professor of Obstetrics and Gynecology, University of Virginia, Charlottesville. “We believe that a novel approach in which a SERM, which protects against breast cancer and does not stimulate the endometrium, is combined with CEs can provide a relatively favourable balance of benefits.”

Results of SMART-5 Combination Therapy

The phase III trial, called SMART-5 (Selective estrogens, Menopause And Response to Therapy-5), was conducted with a single pill combination of bazedoxifene, a third-generation SERM not yet licensed for use, and CEs. The multicentre study randomized 1843 postmenopausal women (mean age 54.2 years) to single-pill combinations of bazedoxifene 20 mg and CE 0.45 mg or CE 0.625 mg, bazedoxifene 20 mg alone, medroxyprogesterone (MPA) 1.5 mg and CE 0.45 mg or placebo. All women had an intact uterus. Even though no progesterone was included in the bazedoxifene arms, it is expected that the protective effect of this SERM against breast tissue proliferation in experimental studies and the absence of endometrial stimulation will allow this agent to be employed safely without progesterone. The primary end point of the study was endometrial hyperplasia. Breast tenderness and breast tissue density were secondary end points.

The rate of endometrial hyperplasia after 12 months of therapy was <1% in all treatment groups including placebo and both of the groups receiving the bazedoxifene/CE combinations. The rates of both breast tenderness and breast density over the 12 months of treatment on the bazedoxifene/CE combinations were also statistically indistinguishable from placebo. Although a substudy conducted in about 25% of patients associated the bazedoxifene/CE combination with an improvement in QoL, the safety observed in this study encourages the trials that are needed to show it is a first-line option in postmenopausal estrogen depletion management.

Vaginal Atrophy, Dyspareunia

Another phase III study using a SERM only also generated encouraging results specifically for the treatment of vaginal atrophy. In this study, conducted with ospemifene, 819 postmenopausal women with moderate-to-severe vaginal dryness at baseline were placed into 2 different subgroups before being randomized to receive 60 mg of the SERM once daily or placebo. One group had dryness only and the other group had dryness and dyspareunia. Reporting only the dyspareunia results, the authors reported significant benefit for this end point as well as on improvement in vaginal pH.

“The study demonstrated that ospemifene provided a significant reduction in the severity scores of dyspareunia relative to placebo over the 12 weeks of the study even though all patients were permitted non-hormonal lubricants as needed,” reported Dr. Gloria A. Bachmann, Professor of Obstetrics and Gynecology and Reproductive Sciences, Robert Wood Johnson Medical School, New Brunswick, New Jersey. “Ospemifene was generally safe and well tolerated with no significant estrogenic or clinically important adverse effects on the endometrial tissue compared with placebo.”

Addressing Menopause-related Symptoms

The volume of studies associating the symptoms of menopause, including dyspareunia, with diminished QoL is large, including several new studies reported here at NAMS. One of these, a retrospective analysis of a health-related employee database with more than 17,000 subjects, found that menopause-related symptoms increased health care costs and number of sick days. In another, increasing severity of vasomotor symptoms correlated with greater loss of productivity and more physician visits.

In Canada, more women will seek and receive care for menopausal symptoms as the message that effective therapies are available is better disseminated, according to Dr. Rowe. He reported that currently there are large discrepancies between provinces in the way menopausal women are managed and how they respond to offers for treatment. For example, 76% of postmenopausal women in Quebec are now offered a prescription for HRT, while 51% of these fill their prescription. In Western Canada, the figures are 71% and 39%, respectively, while only half of women in Ontario are offered the prescription and only half fill it. If vaginal atrophy develops into a major public health issue in an aging population as predicted, these numbers may change.

Summary

The debate about HRT was often more emotional than factual due to biases and specific patient fears. Now that a far larger segment of the female population is reaching the postmenopausal years, it is hoped that more rational dialogue will take place about the significant benefits of treatment in the context of low risks. Moreover, evolving strategies are expanding options for patients to select a regimen that provides the greatest likelihood of a favourable benefit:risk ratio. In Canada, as elsewhere, specific menopausal symptoms should direct the focus of care, but patients should not be left to endure treatable consequences of estrogen depletion.

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