Estrogen modulators compared — estrogens, SERMs, aromatase inhibitors and GnRH analogs

Estrogens act by binding nuclear receptors — estrogen receptors α and β, in proportions that vary from tissue to tissue. Estrogen therapy simply supplies the hormone. SERMs bind the same receptors but activate estrogenic pathways in some tissues while blocking them in others: tamoxifen competes with estrogen in breast tissue yet stimulates estrogen receptors in bone, and raloxifene is an estrogen agonist in bone and an antagonist in the uterus and breast.

The other two classes take estrogen away. Before menopause the ovary is the main source; after menopause the principal source is conversion of adrenal and ovarian androgens by aromatase in peripheral tissues such as fat — the enzyme that aromatase inhibitors block. GnRH analogs act upstream: continuous agonist exposure downregulates pituitary GnRH receptors after an initial stimulation, and antagonists block them at once, so LH, FSH and ovarian estradiol fall.

Aromatase inhibitors are drugs for after menopause. Before menopause, lowering estrogen removes its negative feedback on the pituitary, gonadotropin secretion rises and the ovary is stimulated — so their breast cancer indications are labeled for postmenopausal women, and the same ovarian stimulation is used off-label to induce ovulation. Clomiphene, a SERM, reaches the same rise in gonadotropins by occupying hypothalamic estrogen receptors, and it is the labeled drug for ovulatory dysfunction.

GnRH analogs, by contrast, create a hypoestrogenic state in premenopausal women — the point of using them for endometriosis and fibroids; goserelin is also labeled for advanced breast cancer in pre- and perimenopausal women. In postmenopausal women, estrogen therapy lowers the gonadotropins that rise when ovarian estrogen is lost.

Endometrium. Estrogen alone makes the lining grow unopposed, with an endometrial cancer risk about 2 to 12 times that of non-users, so a progestin is added for a woman with a uterus — or, in Duavee, bazedoxifene acts as an antagonist in the uterus. Tamoxifen’s partial estrogenic effect causes hyperplasia and polyps, and its boxed uterine malignancies may be related to the same effect; ospemifene is an endometrial agonist with an endometrial-cancer box. Raloxifene is an antagonist in the uterus, and compared with tamoxifen, anastrozole caused fewer endometrial cancers.

Breast. In the WHI, estrogen plus progestin increased invasive breast cancer, while estrogen alone was not associated with an increase. Tamoxifen is an antagonist in breast tissue, raloxifene reduces the risk of invasive breast cancer in postmenopausal women, and aromatase inhibitors slow estrogen-driven growth of hormone receptor-positive cancer by lowering serum estrogen.

Bone. Estrogens are labeled for prevention of postmenopausal osteoporosis, and raloxifene inhibits bone resorption and increases bone mineral density. Tamoxifen stimulates bone estrogen receptors after menopause, but adjuvant tamoxifen in premenopausal women has been associated with lumbar-spine bone loss. Taking estrogen away costs bone: aromatase inhibitors lower bone mineral density and increase fractures — density fell on anastrozole while it rose on tamoxifen — and in women GnRH analogs cause bone loss that may not fully reverse, which add-back therapy reduces.

The boxed warnings follow the drug. Estrogens carry the WHI boxes — endometrial cancer, stroke, DVT, pulmonary embolism, myocardial infarction, breast cancer and probable dementia, worded by product — and oral estrogen raises clotting factors in the liver, which transdermal estradiol bypasses. Tamoxifen is boxed for uterine malignancies, stroke and pulmonary embolism, raloxifene for venous thromboembolism and death from stroke, ospemifene for endometrial cancer with estrogen-alone stroke and DVT risks, and toremifene for QT prolongation. The relugolix and elagolix combinations with estradiol and norethindrone (Myfembree, Oriahnn) carry an estrogen-progestin box for thromboembolic disorders and vascular events.

The estrogen-lowering drugs bring deprivation instead: aromatase inhibitors cause arthralgia (the commonest reason to stop), bone loss and, with anastrozole and letrozole, raised cholesterol, but fewer hot flashes, venous clots and ischemic strokes than tamoxifen. GnRH agonists add an initial flare, and in men on androgen deprivation the labels warn of hyperglycemia, cardiovascular events and QT prolongation.