Article

Endometrial safety: a key hurdle for selective estrogen receptor modulators in development.

University of Virginia, Charlottesville, VA, USA.
Menopause (New York, N.Y.) (Impact Factor: 2.81). 01/2010; 17(3):642-53. DOI: 10.1097/gme.0b013e3181c4f1d6
Source: PubMed

ABSTRACT Selective estrogen receptor modulators (SERMs) have the ability to provide mixed functional estrogen receptor (ER) agonist or antagonist activity, depending on the target tissue. Tamoxifen, the first SERM available for clinical use, is regarded as a highly effective agent for the prevention and treatment of breast cancer. However, tamoxifen exhibits ER agonist activity in the uterus and is associated with an increased risk of endometrial hyperplasia and malignancy. Endometrial safety has been an important consideration in the clinical development of SERMs, with improved benefit-risk profiles. Raloxifene, which is currently approved for the prevention and treatment of postmenopausal osteoporosis and for the prevention of breast cancer, seems to have neutral effects on the uterus. Promising results have been observed with the targeted development of newer and more tissue-specific SERMs, many of which are under investigation for postmenopausal osteoporosis. Of the newer SERMs in development, lasofoxifene has been shown to reduce fracture risk and decrease the incidence of breast cancer but has been associated with an increased incidence of vaginal bleeding, endometrial thickening, and endometrial polyps. Lasofoxifene and ospemifene have shown beneficial effects on the vaginal epithelium. Phase 3 clinical data have shown that bazedoxifene is effective in preventing and treating postmenopausal osteoporosis, without adverse effects on the endometrium or breast. Arzoxifene has been evaluated in phase 3 trials for postmenopausal osteoporosis and has been studied for the treatment of uterine malignancies but is no longer in clinical development. Further investigation of newer SERMs is warranted to more clearly define the endometrial safety of these agents.

0 Followers
 · 
138 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bazedoxifene (Conbriza®, Viviant®) is the first third-generation selective estrogen receptor modulator (SERM) and it is approved for the treatment of postmenopausal osteoporosis in the EU and Japan. Bazedoxifene contains an indole-based core binding domain that binds with high affinity to estrogen receptors and exhibits favourable effects on bone and lipid profiles, with no clinically relevant endometrial or breast stimulation. Oral bazedoxifene once daily reduced the incidence of new vertebral fractures in patients with postmenopausal osteoporosis in a large, well designed trial of 3 years’ duration; both bazedoxifene and raloxifene were significantly more effective than placebo. Neither bazedoxifene nor raloxifene reduced the incidence of nonvertebral fractures in the overall study population; however, bazedoxifene, but not raloxifene, reduced the rate of nonvertebral fractures in high-risk patients. Moreover, data from patients who continued to receive the drug during a 2-year extension phase of this trial indicate that bazedoxifene continues to provide protection against new vertebral fractures for up to 5 years. Bazedoxifene also increases bone mineral density and reduces the levels of bone turnover markers. Bazedoxifene was generally well tolerated and did not detrimentally affect the reproductive tract or breast tissue in clinical trials, thereby demonstrating a favourable risk-benefit profile. A pharmacoeconomic analysis conducted from an EU perspective predicted bazedoxifene to be cost effective in some EU countries.Therefore, bazedoxifene presents another useful option for the treatment of post-menopausal osteoporosis, especially in those at high risk for osteoporotic fracture.
    Drugs 01/2011; 71(16). DOI:10.2165/11207420-000000000-00000 · 4.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is one of the most common malignant tumours in women. More than a century ago it was noted that oophorectomy helps some but not all breast cancer patients. Further milestones in the development of endocrine treatment included the discovery of oestrogen receptors in breast tumours, introduction of tamoxifen, pharmacological ovarian ablation, and inhibitors of oestrogen biosynthesis in postmenopausal women. Each of these steps led to improvement in outcomes of breast cancer. However, despite the success of endocrine treatment, resistance remains an important clinical issue. There are no reliable markers for predicting endocrine resistance in ER-positive tumours and there is no rational targeted treatment of tumours, which do not respond (primary resistance) or progress after initial response (secondary resistance).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Soyfoods have long been prized among vegetarians for both their high protein content and versatility. Soybeans differ markedly in macronutrient content from other legumes, being much higher in fat and protein, and lower in carbohydrate. In recent years however, soyfoods and specific soybean constituents, especially isoflavones, have been the subject of an impressive amount of research. Nearly 2,000 soy-related papers are published annually. This research has focused primarily on the benefits that soyfoods may provide independent of their nutrient content. There is particular interest in the role that soyfoods have in reducing risk of heart disease, osteoporosis and certain forms of cancer. However, the estrogen-like effects of isoflavones observed in animal studies have also raised concerns about potential harmful effects of soyfood consumption. This review addresses questions related to soy and chronic disease risk, provides recommendations for optimal intakes, and discusses potential contraindications. As reviewed, the evidence indicates that, with the exception of those individuals allergic to soy protein, soyfoods can play a beneficial role in the diets of vegetarians. Concerns about adverse effects are not supported by the clinical or epidemiologic literature. Based on the soy intake associated with health benefits in the epidemiologic studies and the benefits noted in clinical trials, optimal adult soy intake would appear to be between two and four servings per day.
    Nutrients 08/2010; 2(8):855-88. DOI:10.3390/nu2080855 · 3.15 Impact Factor