Beyond estrogen: advances in tissue selective estrogen complexes and selective estrogen receptor modulators

Pinkerton JV1Conner EA1.

Climacteric. 2019 Apr;22(2):140-147. doi: 10.1080/13697137.2019.1568403.


Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have variable estrogen agonist and antagonist activities in different target tissues. Tamoxifen is an anti-estrogen in the breast used for treatment and prevention of breast cancer, with estrogen agonist activity in the uterus. Raloxifene prevents and treats osteoporosis and prevents breast cancer, and can be safely combined with vaginal but not systemic estrogen. The tissue selective estrogen complex combines conjugated equine estrogens (CEE) with the SERM bazedoxifene (BZA). The five Selective Estrogen Menopause and Response to Therapy studies, with up to 2 years of data, demonstrated that CEE/BZA 0.45 mg/BZA 20 mg improved vasomotor symptoms and vulvovaginal atrophy, prevented bone loss, and was neutral on breast tenderness, breast density, with breast cancer incidence similar to placebo. Protection against estrogen-induced endometrial hyperplasia and cancer was found, with similar amenorrhea rates to placebo. Ospemifene is approved to treat dyspareunia, with potential benefits on bone and the breast, while lasofoxifene is being developed to treat resistant estrogen receptor-positive breast cancer in women. Estetrol is an estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered a weak estrogen, but it appears to have dual weak estrogenic/anti-estrogenic features.

Summary: clinical considerations The decision about therapy for postmenopausal women should be based on the individual woman’s health risks, needs for treatment, and preferences. However, beyond traditional estrogen, with or without progestogen treatment if a woman has a uterus, there are newer therapies that allow specific tissues to be targeted. These include various SERMs and the novel TSEC, with ongoing development of E4 and other selective options. The overall effect of a therapy on both targeted and non-targeted tissues needs to be taken into account to assess the benefit-to-risk profile of different therapies and overall tolerability

Toremifene is used primarily as an adjunct for ER-positive breast cancer, while tamoxifen is used for both prevention and as adjuvant treatment for ER breast cancer. Tamoxifen has positive effects on bone and possibly vaginal tissues, but an increased risk of endometrial effects including endometrial cancer and VTEs. Raloxifene is used for the prevention and treatment of osteoporosis and for chemoprophylaxis of breast cancer in postmenopausal women at high risk for breast cancer. Raloxifene is associated with mild increases in hot flushes, VTE, and endometrial polyps, but not an increase in endometrial hyperplasia or cancer. Raloxifene appears safe when used with low-dose vaginal estrogen therapies for vaginal atrophy but has been associated with an increase in endometrial hyperplasia when combined with systemic estradiol. Ospemifene is an oral SERM approved for relief of postmenopausal dyspareunia with improvement in postmenopausal vaginal atrophy and dryness. Ospemifene increases hot flushes, primarily in women discontinuing systemic hormone therapy, which resolve over 4 weeks. Like other oral synthetic SERMs, concern exists for an increased risk of VTE. The TSEC CEE 0.45 mg/BZA 20mg effectively relieves hot flushes, night sweats, and sleep disruptions and improves quality of life, with prevention of bone loss and relief of VVA, without stimulation of the endometrium or breast tissue. Spotting and amenorrhea were similar to placebo. Effects on the breast were similar to placebo for breast tenderness, breast density changes, and breast cancer incidence in trials up to 2 years, unlike the increase in mammographic density typically seen with estrogen–progestin therapy. The lack of significant breast tenderness or vaginal bleeding with CEE/BZA provides a major benefit in tolerability. The longer-term impact on risk of breast cancer awaits larger, long-term studies. E4 has weak estrogen agonist/antagonist properties and is being developed as an oral contraceptive and menopausal therapy, differentiated due to its minimal coagulation effects.


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