Selective estrogen receptor modulators

SERMs bind estrogen receptors (ERα and ERβ) and induce conformational changes that differentially recruit coactivators or corepressors depending on the tissue, resulting in agonist or antagonist activity.

Tamoxifen: Antagonist at breast tissue (used in ER+ breast cancer treatment and chemoprevention in high-risk women), but agonist at endometrium (increases risk of endometrial hyperplasia/cancer) and bone (agonist, reduces osteoporosis risk). Also increases risk of venous thromboembolism. Mechanism: competitively inhibits estrogen binding, blocking proliferative signaling in breast cancer cells.

Raloxifene: Antagonist at breast and endometrium (does NOT increase endometrial cancer risk, making it preferred over tamoxifen for osteoporosis prevention in postmenopausal women without breast cancer history), agonist at bone (prevents osteoporosis). Also increases VTE risk. No hot flash relief; may reduce breast cancer risk.

Clomiphene: Antagonist at hypothalamus, blocking negative feedback of estrogen on GnRH release, leading to increased FSH/LH secretion and ovulation induction. Used to treat infertility due to anovulation (e.g., PCOS). Can cause ovarian hyperstimulation syndrome and multiple gestations.

Clinical pearls: Tamoxifen requires CYP2D6 for conversion to active metabolite (endoxifen); poor metabolizers may have reduced efficacy. Both tamoxifen and raloxifene increase VTE risk and hot flashes (tamoxifen only). SERMs are distinct from aromatase inhibitors (which block estrogen synthesis entirely) and pure antiestrogens like fulvestrant (ER antagonist/degrader with no agonist activity).

High-yield boards association: tamoxifen = breast cancer risk reduction but endometrial cancer risk increase; raloxifene = osteoporosis treatment without endometrial risk; clomiphene = ovulation induction.