Selective Estrogen Receptor Modulators (SERMs)

SERMs bind estrogen receptors and activate estrogenic pathways in some tissues while blocking them in others. Estrogen receptors come as two isoforms, α and β, whose expression shapes each tissue’s response. Tamoxifen competes with estrogen at the receptor in breast tissue, which is antiestrogenic and slows tumor-cell cycling; in bone it stimulates estrogen receptors instead, and it has an estrogen-like effect on the uterus. Raloxifene, by contrast, is antagonistic in both the uterus and the breast while acting as an estrogen on bone (Bone & Calcium Agents page), and bazedoxifene in Duavee blocks the endometrium so that conjugated estrogens can be given to a woman with a uterus (Menopausal Hormone Therapy page).

The tissue map explains the warnings. Tamoxifen’s partial estrogenic effect on the uterus underlies its endometrial hyperplasia and polyps, and its endometrial cancers and uterine sarcomas — whose mechanism is unknown — may be related to the same estrogen-like effect; ospemifene is an endometrial agonist, hence its endometrial-cancer box. The bone effect depends on the estrogen background: tamoxifen may help prevent osteoporosis after menopause, yet adjuvant tamoxifen in premenopausal women has been associated with significant lumbar-spine bone loss. In the hypothalamus, receptor occupancy by clomiphene removes estrogen’s negative feedback and drives gonadotropins up.

Tamoxifen is extensively metabolized by CYP3A, CYP2D6, CYP2C9, CYP2C19 and CYP2B6. CYP3A forms N-desmethyltamoxifen, the major plasma metabolite, which has activity similar to tamoxifen. The polymorphic enzyme CYP2D6 forms endoxifen and 4-hydroxytamoxifen, minor metabolites with about 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation. CYP2D6 poor metabolizers have significantly lower endoxifen concentrations than patients with a functional allele.

Two things lower endoxifen: genotype and drugs. Strong CYP2D6 inhibitors such as paroxetine and fluoxetine lower endoxifen levels; the label says the effect on efficacy is not well established. CPIC guidance, built on genotype, advises avoiding moderate and strong CYP2D6 inhibitors in normal metabolizers and recommends alternative hormonal therapy, such as an aromatase inhibitor in postmenopausal women, for poor metabolizers, whose lower endoxifen is linked to a higher risk of recurrence. Strong CYP3A4 inducers such as rifampin also lower tamoxifen, and warfarin’s anticoagulant effect can rise markedly.

The boxed warning names uterine malignancies, stroke and pulmonary embolism, including fatal cases, drawn from the NSABP P-1 risk-reduction trial. Thromboembolic events — DVT and PE — rise further when tamoxifen is given with chemotherapy. For DCIS or risk reduction, a need for warfarin or a past DVT or PE is a §4 contraindication, while for treatment of established breast cancer the benefits usually outweigh the risks. Any abnormal vaginal bleeding is evaluated promptly, and gynecological examinations are annual; routine endometrial sampling in women without symptoms has not been shown to help.

Hot flashes are the commonest effect, followed by vaginal discharge and bleeding, mood changes, nausea and fluid retention. Tamoxifen can also cause cataracts and retinopathy, liver changes up to hepatitis and necrosis, thrombocytopenia and leukopenia, and hypercalcemia in bone metastases; it can cause fetal harm, so non-hormonal contraception continues for 2 months after the last dose. Toremifene, a related triphenylethylene for metastatic disease in postmenopausal women, carries a different box: dose- and concentration-related QT prolongation with torsade de pointes.

Clomiphene is a mixture of two isomers, zuclomiphene and enclomiphene. It binds estrogen receptors in the hypothalamus, pituitary, ovary, endometrium, vagina and cervix and may delay replenishment of intracellular estrogen receptors. With hypothalamic receptors occupied, rising estradiol no longer feeds back to lower FSH and LH. The first event is a rise in pituitary gonadotropins, which drives steroidogenesis and folliculogenesis, a rise in estradiol, and finally a preovulatory gonadotropin surge and follicular rupture.

Stimulating the ovaries brings the warnings. Ovarian enlargement is the commonest adverse event, and ovarian hyperstimulation syndrome can progress within 24 hours to several days to ascites, pleural effusion, oliguria and thrombosis; patients with polycystic ovary syndrome may respond excessively. Multiple pregnancy is more likely. Visual symptoms — blurring, spots or flashes from intensified and prolonged after-images — can rarely persist, so they mean stopping the drug. Zuclomiphene’s long half-life (detectable for more than a month) is why some drug may remain in early pregnancy, and pregnancy is a contraindication.

Ospemifene treats moderate to severe dyspareunia and vaginal dryness, symptoms of vulvar and vaginal atrophy due to menopause — the genitourinary syndrome of menopause. It is an estrogen agonist in the endometrium, so its box carries the same endometrial-cancer warning as unopposed estrogen and the estrogen-alone risks of stroke and DVT; endometrial thickening of 5 mm or more occurred about five times as often as with placebo in its trials.

Its exclusions mirror estrogen’s: undiagnosed genital bleeding, estrogen-dependent neoplasia, past clots, stroke or MI, pregnancy, and — because it was not adequately studied there — breast cancer. It is not combined with estrogens or other estrogen agonist/antagonists. It is metabolized by CYP3A4 and CYP2C9, so fluconazole raises its exposure about 2.7-fold and rifampin lowers it, and both are avoided.