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The risks and benefits of hormone replacement therapy (HRT) need to be put in perspective. In the analysis of clinical trials, emphasis is often placed on relative risks, statistical significance and 95% confidence intervals, whereas, from a clinical perspective, more may be gained from a consideration of the absolute and attributable risks of therapy. The Council for International Organizations of Medical Sciences recommended that the frequency of adverse events be categorized as "rare" if less than 1/1000 but more than 1/10,000, and as "very rare" if less than 1/10,000. In the analyses of the Women's Health Initiative (WHI), the attributable risks were "appreciable" (i.e. more than 1/1000) only in women aged over 70 years, with the exception of the risks of venous thromboembolism and stroke. The women in the WHI trial do not represent the relatively younger, healthy, postmenopausal women most commonly prescribed HRT, who are probably at much lower risk. Moreover, the WHI trial did not take into account the benefit of relief of menopausal symptoms, which is, for many women, paramount and outweighs the "rare" long-term risks. Age may be a useful guide to risks and some simple guidelines for management, based on age, are suggested. Many women have been denied or have discontinued HRT because of the fear of risks, which may not have been put in perspective or fully understood. The care of postmenopausal women is not static, and sufficient has now been learned to enable each menopausal woman, with the help of her medical adviser, to come to a balanced and reasonable decision.
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PMID:Hormone replacement therapy: time to move on? 1677 59

Oral administration of conjugated equine estrogens (CEE) with and without the synthetic progestin medroxyprogesterone acetate (MPA) in postmenopausal women is associated with side-effects that include increased risk of stroke and breast cancer. The current evidence that transdermal administration of estradiol may provide a safer alternative to orally administered CEE is reviewed. Transdermally administered estradiol has been shown to be an efficacious treatment for hot flushes possibly without the increase in blood clotting that is associated with administration of oral CEE. Further, natural progesterone may have a more beneficial spectrum of physiological effects than synthetic progestins. The substantial differences between CEE compared with estradiol and estriol, as well as the differences between synthetic MPA and natural progesterone, are detailed. Estriol is an increasingly popular alternative hormone therapy used for menopausal symptoms. There is evidence that estriol, by binding preferentially to estrogen receptor-beta, may inhibit some of the unwanted effects of estradiol. New clinical trials are needed to evaluate the safety and efficacy of topically or transdermally administered combinations of estradiol, estriol and progesterone. Future studies should focus on relatively young women who begin estrogen supplement use near the start of menopause.
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PMID:Hormone replacement therapy in menopausal women: Past problems and future possibilities. 1713 36

Menopause occurs naturally when the ovary ceases folliculogenesis, or artificially by surgical and/or medical ablation of the ovarian function. Menopause is a hypoestrogenic state, which may adversely affect estrogen target tissues, such as the brain, skeleton and skin, as well as the cardiovascular and genitourinary systems, with resultant frequency and severity of climacteric symptoms. The climacteric symptoms, however, vary significantly among women. For decades, hormone therapy (HT) has been the mainstay and is considered the most effective for managing menopausal symptoms. The prolonged use of either single estrogen therapy or a combination therapy of estrogen and progestogen (EPT) might be associated with a slightly increased risk of breast cancer and many resultant adverse events, such as coronary heart disease, stroke and venous thromboembolism. Perhaps because the clear benefits are limited to these end points of HT in treating menopausal women, the relatively significant adverse event profiles of these women may not be enough to trigger primary care physicians to be more aggressive than they have been to date in treating climacteric symptoms of postmenopausal women. However, severe climacteric symptoms really disturb the woman's life. Some epidemiologic studies have shown that the increased risk for breast cancer after 5 years of combined EPT is similar in magnitude to other lifestyle variables, such as 10-year delayed menopause, fewer pregnancies and reduced breastfeeding, postmenopausal obesity, excessive alcohol or cigarette use, and lack of regular exercise. Furthermore, elevated serum concentrations of either endogenous or exogenous (replaced by HT) sex hormone in either pre- or postmenopausal women are associated with an increased risk of breast cancer. Finally, the increased breast cancer risk diminishes soon after discontinuing hormones, and largely disappears by 5 years after cessation. Taken together, low-dose conventional HT can be used with symptomatic menopausal women, but is worthy of further evaluation because we found the following potential benefits, including (i) low-dose oral EPT appears to be effective for the alleviation of climacteric symptoms; (ii) it has a good tolerability profile with a low incidence of the most common and problematic side effects, such as breast tenderness and an increased mammographic density. Altogether, when compared with the standard dose HT, physicians may prefer to use low-dose HT initially in managing the climacteric symptoms of postmenopausal women. Time will prove.
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PMID:Standard and low-dose hormone therapy for postmenopausal women--focus on the breast. 1763 20

In recent years, isoflavones have increased in popularity as an alternative to estrogen therapy, particularly after the Women's Health Initiative demonstrated an increased risk of breast cancer, stroke, and heart attacks in response to estrogen and progesterone intervention. Isoflavones are heterocyclic phenols with structural similarity to estradiol-17beta and selective estrogen receptor modulators. Actions at the cellular level depend on the target tissue, receptor status of the tissue, and the level of endogenous estrogen. Clinical studies of soy-based diets evaluating the relation between soy consumption and serum lipid concentrations revealed that soy consumption significantly decreased total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. Epidemiological studies suggest a protective effect of soy protein on breast tissue as evidenced by the lower rates of breast cancer in East Asian countries where soy is a predominant part of the diet. Soy products also alleviate menopausal symptoms by reducing hot flashes. However, whether these biological effects of soy products originated from isoflavones is not clear. Furthermore, data available from human studies on the effect of isoflavones on osteoporosis are limited, and additional studies are needed to support a role in osteoporosis prevention. To date, no adverse effects of short- or long-term use of soy proteins are known in humans, and the only adverse effects known are those reported in animals. In conclusion, isoflavones are biologically active compounds, and current data are insufficient to draw definitive conclusions regarding the use of isoflavones as an alternative to estrogen for hormone replacement in postmenopausal women. Large, long-term intervention studies examining adverse effects and disease outcomes are needed before definitive conclusion can be drawn.
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PMID:Soy isoflavones as safe functional ingredients. 1815 25

Bazedoxifene is a third-generation selective estrogen receptor modulator (SERM) that is being developed by Ligand Pharmaceuticals in collaboration with Wyeth. The agent has effects on bone and cardiovascular tissue, but does not affect breast or uterine tissue. Bazedoxifene is in clinical development as a monotherapy for the prevention and treatment of postmenopausal osteoperosis, and in combination with conjugated estrogens for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis. American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth Lederle to Wyeth in March 2002. Wyeth and Ligand entered into a discovery research collaboration for bazedoxifene in September 1994. Under the agreement, Wyeth has worldwide development rights to the compound and is solely responsible for its clinical development. In exchange, Ligand is entitled to milestone and royalty payments associated with development and commercialization achievements. Ligand entered into an agreement with Royalty Pharma in March 2002 whereby Royalty Pharma purchased the rights to a share of Ligand's entitlement to milestone and royalty payments. Under the agreement, Ligand received $US6 million from Royalty Pharma in exchange for a 0.25% stake in net sales of three SERM products (lasofoxifene, bazedoxifene and bazedoxifene/Premarin) for a period of 10 years. Subsequently, Ligand and Royalty Pharma further amended their existing royalty agreement for three SERM products in November 2004. Under the revised agreement, Royalty Pharma would purchase an additional 1.625% of the SERM products' net sales for $US32.5 million, which represents an acceleration of the previous option timetable and an increase in the royalty amount as well as aggregate purchase price. Consequently, Royalty Pharma increased its rights to a total of 3.0125% of net sales of each SERM product for 10 years following first commercial sale of each product and has no further options. Ligand retains an approximately equal portion of lasofoxifene and other SERM's net sales going forward and for periods that could exceed 10 years. The royalty rates owed to Royalty Pharma for the royalties just purchased could be reduced by one-third if product sales exceed certain thresholds. Payments from the royalty purchase are non-refundable, regardless of whether the products ever become successfully launched or not. Milestone payments owed by Ligand's partners as products achieve development and regulatory targets would be paid to Ligand as earned, and are not included in this amended agreement. The US FDA issued a second approvable for bazedoxifene in December 2007, after Wyeth submitted additional study reports from two completed clinical studies for the prevention of postmenopausal osteoporosis. The study reports provided data from two studies conducted in Asia and will form part of a complete response to safety and efficacy issues raised in an initial approvable letter issued by the FDA in April 2007. Prior to approval of the NDA, the FDA must also analyse final safety and efficacy data from a completed phase III trial, and complete an acceptable establishment evaluation on the manufacturing facilities for bazedoxifene. In January 2008, Wyeth stated that the FDA expects to convene an Advisory Committee meeting in July 2008 to review both the treatment and prevention of osteoporosis indications for bazedoxifene. While the second approvable letter issued by the FDA expressed concerns about the incidence of stroke and venous thrombotic events, Wyeth has reported that no additional studies would be needed. Initial filing of the NDA in June 2006 triggered a milestone payment from Wyeth to Ligand.A 2-year, randomized, phase III trial (study 300) has been conducted to compare bazedoxifene (10, 20 and 40 mg) and raloxifene (60 mg) in 1583 patients for the prevention of osteoporosis. Data presented in September 2007 demonstrated that bazedoxifene treatment prevented bone loss, reduced bone turnover, and was generally well tolerated in postmenopausal women with normal or low bone mineral density. Wyeth submitted an NDA to the FDA in July 2007 to gain marketing approval for bazedoxifene as a treatment for postmenopausal osteoporosis. In January 2008, Wyeth stated that the FDA expects to convene an Advisory Committee meeting in July 2008 to review both the treatment and prevention of osteoporosis indications for bazedoxifene. Wyeth has completed a phase III trial comparing bazedoxifene with raloxifene and placebo in 7492 patients with moderate-to-severe postmenopausal osteoporosis. The three-year, randomized, double-blind study commenced in October 2001, and was conducted at sites in the US. Data presented in September 2007 indicated that bazedoxifene showed significant risk reduction for new vertebral fractures, compared with placebo. In addition, Wyeth conducted a phase II trial in Japan to investigate bazedoxifene dose-response in 375 patients with postmenopausal osteoporosis. The randomized, double-blind, placebo-controlled, parallel assignment study commenced in August 2003 and is no longer recruiting patients. The patent covering bazedoxifene will expire in 2017 with the potential for extension.
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PMID:Bazedoxifene: bazedoxifene acetate, TSE 424, TSE-424, WAY 140424. 1845 72

Available biochemical and clinical data are sufficiently compelling to recommend low dose or transdermal hormone therapy for the management of menopausal symptoms when possible. Women initiating low dose or transdermal hormone therapy are not at increased risk of cardiovascular disease, stroke, venous thrombotic disease, and breast cancer. Evidence suggests that these outcomes are favorably affected by low-dose hormone therapy and persist with continuation of therapy.
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PMID:Hormone therapy and stroke. 1867 52

The use of aromatase inhibitors (AIs) as adjuvant endocrine therapy for hormone-sensitive breast cancer is increasing, as these drugs are more effective than tamoxifen alone in improving disease-free survival in breast cancer patients-whether used in lieu of tamoxifen as upfront therapy or after tamoxifen treatment periods of 2 years or longer. AIs differ from tamoxifen in their mechanism of action, effectively suppressing estrogen levels in postmenopausal women to near-undetectable levels. AI-associated adverse events largely mimic menopausal symptoms, including hot flashes, losses in bone mineral density, gynecologic symptoms, and arthralgias. The AIs lack the infrequent but potentially serious adverse events associated with tamoxifen (eg, endometrial cancer, thromboembolic events, and stroke). Large randomized studies of AIs in the adjuvant setting have not demonstrated an adverse effect on lipids and cardiovascular health, but postmenopausal women receiving AIs are at risk for age-related changes in lipid parameters and an increased risk for cardiovascular events. To optimize the overall benefits of adjuvant endocrine therapy with an AI, patients should be monitored for bone loss and cardiovascular risk factors, and symptoms such as joint pain and vaginal dryness should be anticipated and managed proactively.
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PMID:Safety of adjuvant endocrine therapy in postmenopausal women with breast cancer. 1906 May 94

Many women are now using herbal medicines to try to relieve menopausal symptoms such as hot flushes and night sweats, in light of recent evidence suggesting that hormone replacement therapy (HRT) may increase the likelihood of breast cancer, ovarian cancer, venous thromboembolism, heart attacks and stroke. or example, one survey has suggested that around 40% of women in the UK have used complementary and alternative treatments for their menopausal symptoms.7 Here we review the efficacy and safety of herbal medicines for the relief of such symptoms.
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PMID:Herbal medicines for menopausal symptoms. 2017 71

This Practice Point commentary discusses a double-blind, placebo-controlled trial by Cummings et al. that investigated the effects of tibolone 1.25 mg per day in 4,534 postmenopausal women (mean age 68 years) with osteoporosis. Tibolone is a synthetic steroid with estrogenic, progestational and androgenic effects. It has been used as an alternative to estrogen to treat menopausal symptoms for 30 years. Cummings et al. found that tibolone reduced the incidence of vertebral fractures by 45%, nonvertebral fractures by 26%, breast cancer by 68% and colon cancer by 69%. The trial was discontinued 2 months before a median treatment time of 3 years because the major end point (reduction of fractures) was reached. In addition, tibolone increased the risk of stroke, although the absolute risk was small. Similarly to other compounds with estrogenic activity that increase the risk of stroke, such as estrogen and selective estrogen-receptor modulators, clinicians must weigh the risks and benefits of therapy for individual patients. This risk might be lower in women aged 50-60 years than in those aged >60 years.
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PMID:Does tibolone reduce the risk of fracture in older postmenopausal women with osteoporosis? 1870 72

From 2002 to 2008, reports from the Women's Health Initiative (WHI) claimed that hormone replacement therapy (HRT) significantly increased the risks of breast cancer development, cardiac events, Alzheimer disease, and stroke. These claims alarmed the public and health professionals alike, causing an almost immediate and sharp decline in the numbers of women receiving HRT. However, the actual data in the published WHI articles reveal that the findings reported in press releases and interviews of the principal investigators were often distorted, oversimplified, or wrong. This review highlights the history of research on HRT, including a timeline of studies that have or have not found a link between HRT and breast cancer; discusses how to distinguish important, robust findings from those that are trivial; closely examines the WHI findings on HRT and breast cancer, most of which are weak or statistically insignificant; reviews the current thinking about possible links of HRT with cardiovascular disease and cognitive functioning; and reports research on the benefits of HRT, notably relief of menopausal symptoms, that affect a woman's quality of life. On these complicated matters, physicians and the public must be cautious about accepting "findings by press release" in determining whether to prescribe or take HRT.
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PMID:Hormone replacement therapy: real concerns and false alarms. 1967 54


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