A pharmacological review of selective oestrogen receptor modulators

Abstract

Selective oestrogen receptor modulators (SERMs) are structurally diverse non-steroidal compounds that bind to oestrogen receptors and produce oestrogen agonist effects in some tissues and oestrogen antagonist effects in others. SERMs are being evaluated for a number of oestrogen-related diseases, including post-menopausal osteoporosis, hormone-dependent cancers, and cardiovascular disease. Several compounds that exhibit a SERM profile are currently available for clinical use, including clomiphene, tamoxifen, and toremifene (which are triphenylethylenes) and raloxifene (a benzothiophene). Clomiphene is used for the induction of ovulation in sub-fertile women attempting pregnancy. Tamoxifen and toremifene are both used to treat breast cancer. Tamoxifen may have beneficial effects on bone mineral density and serum lipids. The effects of toremifene on serum lipids are similar to that of tamoxifen. Both compounds have stimulatory effects on the endometrium. Raloxifene, indicated for the treatment and prevention of post-menopausal osteoporosis, has beneficial effects on bone mineral density and serum lipids, but does not increase the risk of endometrial hyperplasia or endometrial cancer. Recently, raloxifene was shown to reduce the incidence of vertebral fractures in otherwise healthy women with osteoporosis; in the same study, a reduced incidence of breast cancer was also observed. Similar to oestrogens, SERMs increase the incidence of venous thromboembolism. Several newer compounds that exhibit a SERM profile are also in clinical development, including other triphenylethylenes (droloxifene, idoxifene) and benzothiophenes (LY353381.HCl), benzopyrans (EM-800), and naphthalenes (CP-336,156).

The Estrogen Receptor Pathway in Rhabdomyosarcoma: A Role for Estrogen Receptor-β in Proliferation and Response to the Antiestrogen 4′OH-Tamoxifen

“…Our data shows that the ER pathway in RMS can be modified with the antiestrogen 4OHT, which not only inhibits cell proliferation and colony formation but also induces apoptotic signaling in both the presence and absence of steroids. Tamoxifen and its derivatives are most commonly associated with inhibition of cell growth (35), and findings of 4OHT-induced apoptosis are uncommon but not unprecedented. A recent study has shown that tamoxifen is capable of inducing dose-dependent effects on apoptosis and proliferative arrest when added to growth medium used to culture mesenchyme-derived chondrocytes in rat metatarsal bones (36).…”

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…7) is marketed under the brand names Clomid and Serophene. Since its introduction in the 1960s, clomifene has been used in the management of infertility via induction of ovulation (Goldstein et al, 2000). Clomifene is a mixture E and double-bond Z isomers, one of which is an ER agonist/antagonist and the other a strict antagonist (Glasier, 1990).…”

Twenty-five milligrams of clomiphene citrate presents positive effect on treatment of male testosterone deficiency - a prospective study

“…It competes with estradiol for the estrogen receptors at the level of the hypothalamus and blocks the normal negative feedback mechanism of circulating estradiol on the hypothalamus, preventing estrogen from limiting the production of GnRH. The increase in GnRH level then stimulates the pituitary gland to release more FSH and LH, resulting in an increase in sperm and T production by the testes (7)(8)(9).…”