Tissue Selective Estrogen Complexes (TSECs) and the Future of Menopausal Therapy

Abstract

As women age and enter menopause, the decline of ovarian function and the consequent decrease in the circulating levels of estrogens leads to the manifestation of a number of undesirable physiological alterations such as osteoporosis, altered lipid profile, vasomotor instability, vaginal atrophy, and an increased incidence of cardiovascular, metabolic, and neural disorders. Hormone replacement therapy traditionally consisted of the administration of estrogens in conjunction with progestins. The estrogens were thought to be effective in reversing or inhibiting the adverse changes that occur in menopause. Progestins were added solely to inhibit the adverse endometrial effects, including hyperplasia and cancer, observed with estrogen administration alone. However, progestin administration has also been reported to be associated with an increased risk of breast cancer. The controversy surrounding the benefits and risks associated with hormone replacement therapy and the goal of developing a successful therapy devoid of unwanted side effects emphasized the need for alternatives to progestins, which are likely to be responsible for most of the adverse effects of hormone therapy. Appropriately, the discovery of a new class of compounds, the tissue selective estrogen complexes (TSECs) that pair selective estrogen receptor modulators (SERMs) with one or more estrogens to achieve unique estrogen receptor properties that are tissue specific, seems to be the perfect finding for this quest. The SERMs are able to activate or inhibit the activity of estrogen receptors, depending on the tissue targeted, due to their ability to recruit specific comodulator proteins. Since there are known SERMs with concomitant antagonist activity in the uterus and mammary glands and agonist activity in bone and most likely liver, their clinical use to treat menopausal undesired health effects seems appropriate. Unfortunately, SERMs alone cannot counteract the vasomotor instability that comes with decreased ovarian function and therefore do not completely fulfill the therapeutic needs. Thus, the introduction of a new concept for treatment based on the combined use of estrogens and SERMs, the TSECs, allows the achievement of a more favorable clinical profile than either therapy alone. The appropriate pairing of an estrogen and an SERM allows endometrial protection with effective action for other menopausal indications, by exploring the beneficial effects of estrogens while blocking its undesired actions through the SERMs. Although not just any estrogen/SERM combination will provide the anticipated outcome, recent work has shown that a TSEC containing bazedoxifene and conjugated estrogens was able to prevent bone loss and to reduce total cholesterol without uterine stimulation, while its clinical trials demonstrated its efficacy in preventing vasomotor instability. These exciting results suggest that TSECS will be on the forefront of menopausal therapy by defeating its detrimental symptoms, constituting a novel and promising approach for hormone replacement therapy.