From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition

Abstract

The female life expectancy rose from an average of 48 years to over 80 years in a century. The decline in the endogenous production of estrogen (especially the main circulating physiological hormone, 17β-estradiol, E2) at menopause (51 years on average) often leads to functional disorders affecting the quality of life. Estrogen deficiency impacts different tissues and results in an increase of various diseases, such as osteoporosis or cardiovascular diseases. Hormone therapy (HT) for menopause is a rather new challenge which experienced vagaries following the women’s health initiative (WHI) study conducted in largely post-menopausal women. In the first part of this review, we will try to summarize the main conclusions of the WHI trials, in particular the timing effect as well as the deleterious impact of the associated progestin, medroxyprogesterone acetate (MPA).Hormone therapy, particularly the conjugated equine estrogen (CEE) combined with the MPA favor the occurrence of breast cancer, whereas conversely selective estrogen receptor modulators (SERMs, such as tamoxifen or raloxifene) that block the activity of estrogen receptor alpha (ERa) prevent the risk of recurrence of ERa-positive breast cancers. A new strategy of ERa modulation called tissue selective estrogen complex (TSEC), combines (1) CEE to maintain the benefits of estrogen (climacteric symptoms and prevention of osteoporosis) and (2) bazedoxifene, which is not only a SERM, but which also induces a rapid degradation of ERa in the uterus and in the breast, thereby prevents the stimulatory effects of estrogens on epithelial proliferation of these two sex targets. In the second part of this review, we will summarize the recognized benefits of the TSEC approach, and our current knowledge of its potential benefits and risks.