The Women's Health Initiative comprised two parallel trials. The first randomized women with an intact uterus to conjugated equine estrogens plus medroxyprogesterone acetate versus placebo; this arm was stopped early when breast cancer incidence in the hormone therapy group crossed the predefined stopping threshold. The second randomized hysterectomized women to conjugated equine estrogens alone versus placebo; this arm showed no increase in breast cancer — and a non-significant trend toward reduction.

These two arms must never be conflated. The breast cancer signal in the Women's Health Initiative came from the medroxyprogesterone acetate component, not from estrogen alone. Applying the combined arm risk data to other hormone therapy regimens — particularly transdermal estradiol plus micronized progesterone, which was not tested in the Women's Health Initiative — is not pharmacologically justified.

The cardiovascular risk-benefit of hormone therapy depends critically on when it is started relative to menopause. Women who begin hormone therapy within 10 years of menopause onset, or before age 60, show a neutral or favorable cardiovascular profile. Women who begin more than 10 years after menopause, or after age 60, show net cardiovascular harm — particularly increased coronary events and stroke. The Women's Health Initiative enrolled women with a mean age of 63, more than a decade past the mean menopause age of 51, which means the trial was not designed to answer the question most relevant to symptomatic perimenopausal women.

Current guidance holds that for healthy women under 60 or within 10 years of menopause who have bothersome vasomotor symptoms, the benefits of hormone therapy outweigh the risks in the absence of specific contraindications. Hormone therapy should not be withheld based on age alone if the woman is within this therapeutic window.

The type of progestin in a combined hormone therapy regimen modifies the breast cancer risk signal. Medroxyprogesterone acetate is associated with a breast cancer risk increase in combined hormone therapy regimens. Micronized progesterone is not associated with a statistically significant breast cancer risk increase in large observational datasets. When a woman with an intact uterus requires systemic progestin to protect the endometrium, micronized progesterone is the preferred choice in women prioritizing breast cancer risk minimization.

Tamoxifen is a selective estrogen receptor modulator that produces tissue-selective effects depending on which tissue's receptor conformation and coactivator environment it encounters. In breast tissue it acts as an estrogen receptor antagonist — blocking estradiol-driven proliferation — making it the standard adjuvant hormonal therapy for premenopausal women with hormone receptor-positive breast cancer, used for 5 to 10 years depending on recurrence risk. In bone it acts as a partial agonist, maintaining bone mineral density in postmenopausal women. In the uterus it acts as a partial agonist, producing endometrial stimulation and increasing the risk of endometrial hyperplasia and endometrial carcinoma with long-term use. Uterine cancer risk is the primary serious adverse effect of tamoxifen.

Tamoxifen itself has low estrogen receptor affinity. Its anticancer activity depends on conversion to its active metabolite endoxifen by the cytochrome P450 2D6 enzyme. Patients who are cytochrome P450 2D6 poor metabolizers (carrying two non-functional alleles) achieve much lower endoxifen levels and have higher breast cancer recurrence rates on tamoxifen.

The clinical consequence: potent cytochrome P450 2D6 inhibitors co-prescribed with tamoxifen substantially reduce endoxifen levels and may compromise the oncological benefit of therapy. Paroxetine and fluoxetine — two selective serotonin reuptake inhibitors commonly used for vasomotor symptoms in breast cancer survivors — are potent cytochrome P450 2D6 inhibitors and should not be co-prescribed with tamoxifen. Venlafaxine (a serotonin-norepinephrine reuptake inhibitor) is a much weaker inhibitor and is the preferred agent for vasomotor symptoms in women on tamoxifen. Gabapentin is also a safe alternative.

Raloxifene differs from tamoxifen in one clinically decisive way: it antagonizes the estrogen receptor in both breast and uterus, rather than acting as a partial agonist in the uterus. As a result, raloxifene does not carry the endometrial cancer risk associated with tamoxifen, making it the preferred selective estrogen receptor modulator for breast cancer chemoprevention in postmenopausal women. Raloxifene is also approved for osteoporosis prevention and treatment in postmenopausal women through its bone agonist activity. It is somewhat less effective than tamoxifen at reducing non-invasive ductal carcinoma in situ, but produces fewer thromboembolic events and no uterine cancer risk. Like all selective estrogen receptor modulators, raloxifene carries a venous thromboembolism risk similar to oral estrogen and is contraindicated in women with active or prior venous thromboembolism.

Ospemifene is an oral selective estrogen receptor modulator approved for moderate to severe dyspareunia due to vulvovaginal atrophy in postmenopausal women. It acts as an estrogen receptor agonist in vaginal epithelium (improving lubrication and reducing dyspareunia) and as an estrogen receptor antagonist in breast tissue. Unlike vaginal estrogen preparations, ospemifene is taken orally and achieves systemic absorption. It carries a venous thromboembolism risk and is contraindicated in women with prior venous thromboembolism or estrogen-sensitive malignancy. Hot flushes are the most common adverse effect.