Selective estrogen modulators in menopause

Hypoestrogenism is the primary etiologic factor for osteoporosis and related fractures, as well as for a number of clinical symptoms that can reduce the quality of life in postmenopausal women. Alternative to classical hormone replacement therapy (HRT) are needed for women that cannot or don't want to be treated with hormones. Selective estrogen receptor modulators (SERMs) are compounds that lack the steroid structure of estrogens, but interact with estrogen receptors (ERs) as agonists or antagonists depending on the target tissue. Tamoxifen, the first generation of SERMs, has been used for decades in the primary prevention and treatment of breast cancer. Tamoxifen exerts positive estrogenic effect on bone protecting bone mineral density (BMD). However, tamoxifen acts as agonist also on the endometrium, leading to an increased risk of endometrial hyperplasia and cancer. In addition, tamoxifen administration is associated with significantly increased risks of stroke, venous thromboembolism, including both deep-vein thrombosis and pulmonary emboli. Thus, these actions, in addition to the increased risk of and hot flushes, prevent the use of tamoxifen for the prevention of osteoporosis. Further generations of SERM, Raloxifene and bazedoxifene were developed for the prevention and treatment of postmenopausal osteoporosis and are now licensed for this indication. In addition. Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer. On the other hand, the available data indicate that Bazedoxifene exerts a greater anti-fracture activity than Raloxifene. At variance of tamoxifen, both raloxifene and bazedoxifene reduce the risk of endometrial hyperplasia and cancer. However, they are associated with a significant increase the risks of venous thromboembolic events. Although raloxifene and Bazedoxifene prevent postmenopausal osteoporosis, they have not been associated with reductions in climacteric symptoms, particularly hot flushes. In order to find a new approach for menopausal management, SERMs have been combined with estrogens, creating a tissue selective estrogen complex (TSEC) to achieve a favorable clinical profile based on the blended tissue selective activity profiles of the components. Bazedoxifene in association with conjugated estrogens (BZA/CE) is the first TSEC evaluated in an extensive clinical program. BZA/CE administration decreases bone turnover, with an increase in lumbar spine and total hip BMD. The magnitude of these effects are similar to those exerted by HRT and greater than that observed with Raloxifene and Bazedoxifene alone. In addition, BZA/CE significantly reduced the severity and frequency of hot flushes and improved measures of vaginal atrophy and quality-of-life scores, including that for sleep likewise HRT. BZA/CE administration prevents endometrial proliferation, with high rates of amenorrhea over one year. Taken together, all the available data indicate that BZA/CE combination is effective and safe for the treatment for climacteric women, improving the overall quality of life, while protecting the skeleton. The high amenorrhea rate may increase compliance, avoiding the bleedings and side effects related to progestin administration. Further studies are needed to evaluate the ultimate effects of BZA/CE combination on clinical outcomes, such as CVD events, breast and endometrial cancer.