Selective estrogen receptor modulator

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists (e.g., full agonists and silent antagonists), SERMs are more tissue-specific, allowing them to selectively inhibit or stimulate estrogen-like action in various tissues.

SERMs are used for various estrogen-related diseases, including treatment of ovulatory dysfunction in the management of infertility treatment, prevention of postmenopausal osteoporosis, treatment and risk reduction of breast cancer, and treatment of dyspareunia due to menopause. SERMs are also used in combination with conjugated estrogens indicated for the management of estrogen deficiency symptoms and of vasomotor symptoms associated with menopause.

SERMs are also being explored for gender-affirming hormone therapy in some non-binary transgender individuals that were assigned male at birth. Unlike full estrogen receptor agonists like estradiol which cause the broad development of feminine secondary sex characteristics, SERMs can be used to achieve partial feminization in individuals who wish to develop certain feminine traits such as softer skin and feminine body fat distribution without significant breast growth while avoiding the hypogonadic symptoms associated with the use of puberty blockers alone. Unlike bioidentical estrogens, SERMs themselves do not suppress testosterone production by downregulating the HPG axis and therefore are used alongside antiandrogens such as cyproterone acetate or spironolactone, or GnRH agonists. The off-label use of SERMs for gender-affirming hormone therapy is still relatively new and uncommon as there is limited research into efficacy including the degree of physical effects and long-term safety.

Tamoxifen is a first-line hormonal treatment for ER-positive metastatic breast cancer. It is used for breast cancer risk reduction in women at high risk, and as adjuvant treatment for axillary node-negative and node-positive ductal carcinoma in situ. Tamoxifen treatment is also used for the treatment of osteoporosis and blood lipids in postmenopausal women. Adverse effects of tamoxifen include hot flashes and an increase in the risk of developing endometrial cancer compared to women of similar age.

Toremifene, a chlorinated tamoxifen derivative developed to avoid hepatic carcinomas, was associated with fewer DNA adducts in the liver than tamoxifen in preclinical studies. It is used as endocrine therapy for women with estrogen or progesterone receptor-positive, stage 4 or recurrent metastatic breast cancer and has demonstrated similar efficacy compared to tamoxifen as adjuvant treatment of breast cancer and in the treatment of metastatic breast cancer.

Raloxifene is used for the prevention and treatment of postmenopausal osteoporosis and breast cancer prevention in high-risk postmenopausal women with osteoporosis. Preclinical and clinical reports suggest that it is considerably less potent than estrogen for the treatment of osteoporosis. It is associated with an acceptable endometrial profile and has not demonstrated tamoxifen-like effects on the uterus, but has been associated with adverse effects such as venous thromboembolism and vasomotor symptoms, including hot flushes.

Ospemifene is an analogous metabolite of toremifene. Unlike tamoxifen, toremifene is not a rat hepatocarcinogen, and therefore ospemifene would also be a safer SERM than tamoxifen. It is used for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy associated with menopause. Clinical data on breast cancer are not available, but both in vitro and in vivo data suggest that ospemifene may have chemopreventive activity in breast tissue.

Bazedoxifene is used for treatment of osteoporosis in postmenopausal women at increased risk of fracture. It has been shown to be relatively safe and well-tolerated. It shows no breast or endometrial stimulation and in the first two years the small increase is better in venous thromboembolism, and similar in the long term to other SERMs. The advantage of bazedoxifene over raloxifene is that it increases endothelial nitric oxide synthase activity and does not antagonize the effect of 17β-estradiol on vasomotor symptoms.