Selective Estrogen Receptor Modulators (SERMs)

SERMs are estrogen agonist/antagonists. They bind estrogen receptors and activate estrogenic pathways in some tissues while blocking them in others. Tamoxifen competes with estrogen for the receptor in breast tissue, lowering estrogen-receptor–driven growth there, yet in bone it stimulates estrogen receptors, and the uterine cancers it can cause may be related to its estrogen-like effect. Ospemifene acts as an estrogen in the endometrium. Clomiphene acts on estrogen-receptor–containing tissues including the hypothalamus and pituitary, where blocking estrogen feedback raises gonadotropins.

Two related drugs are taught elsewhere. Raloxifene, which acts as an estrogen on bone but blocks it in the uterus and breast, is on the Bone & Calcium Agents page, and bazedoxifene, paired with conjugated estrogens in Duavee to protect the endometrium, is on the Menopausal Hormone Therapy page.

Tamoxifen (tablets and the Soltamox oral liquid) treats estrogen receptor–positive metastatic breast cancer, is used as adjuvant treatment of early-stage estrogen receptor–positive breast cancer, reduces the risk of invasive breast cancer after surgery and radiation for ductal carcinoma in situ (DCIS), and reduces the incidence of breast cancer in women at high risk. Its boxed warning is serious and sometimes fatal uterine malignancies, stroke and pulmonary embolism; benefits and risks are discussed with women taking it for DCIS or risk reduction, while for most patients already diagnosed with breast cancer the benefits outweigh the risks.

Tamoxifen is extensively metabolized; CYP2D6 forms its potent active metabolite endoxifen, so strong CYP2D6 inhibitors such as paroxetine and fluoxetine lower endoxifen levels, though the effect on efficacy is not well established. Toremifene (Fareston) treats metastatic breast cancer in postmenopausal women with estrogen receptor–positive or unknown tumors. Its boxed warning is QT prolongation, which can cause torsade de pointes; it is not used with congenital or acquired long QT, uncorrected hypokalemia or uncorrected hypomagnesemia, and QT-prolonging drugs and strong CYP3A4 inhibitors are avoided.

Clomiphene (Clomid) treats ovulatory dysfunction in women who want to become pregnant. With its estrogen receptors occupied by clomiphene, the hypothalamus no longer senses estrogen’s negative feedback, so FSH and LH rise; follicles grow, estradiol rises, and a gonadotropin surge leads to follicular rupture. Other causes of infertility are excluded or treated first, and a pelvic examination precedes each course.

Its warnings follow from stimulating the ovary. Ovarian enlargement and ovarian hyperstimulation syndrome (OHSS) can occur and may progress rapidly; early warning signs are abdominal pain and distention, nausea, vomiting, diarrhea and weight gain. Multiple pregnancy is more likely. Visual symptoms — blurring, spots or flashes — mean stopping the drug and a prompt eye examination, and long-term cyclic therapy beyond about six cycles is not recommended.

Ospemifene (Osphena) is an oral estrogen agonist/antagonist that treats moderate to severe dyspareunia and vaginal dryness, symptoms of vulvar and vaginal atrophy due to menopause. Because it acts as an estrogen in the endometrium, its boxed warning covers endometrial cancer (abnormal genital bleeding is evaluated, including endometrial sampling) and cardiovascular disorders — the stroke and DVT seen with estrogen-alone therapy.

It is contraindicated with undiagnosed abnormal genital bleeding, estrogen-dependent neoplasia, active or past DVT, PE, stroke or MI, and in pregnancy, and it is not used with known, suspected or past breast cancer, with severe hepatic impairment, or together with estrogens or other estrogen agonist/antagonists.