Postmenopausal hormone therapy (HT)
An association between estrogen replacement therapy and endometrial cancer was reported in 1975  and confirmed soon after.[35,36] In these three studies, the overall risk ratio ranged from 4.5 to 8.0. Further studies documented an association with duration of use (10-fold to 30-fold with 5 years or more of use),[37,38,39,40] and a persistent effect lasting more than 10 years after 1 year's use. When these findings were publicized, prescriptions for estrogen declined sharply, followed rapidly by a drop in endometrial cancer incidence.
Combination estrogen-progestin replacement therapy
Postmenopausal estrogen was long recognized to be associated with the risk of adenomatous hyperplasia, often a precursor of endometrial cancer. In addition, progestational agents were known to be effective in the treatment of uterine neoplasms.[44,45,46] Consequently, improved postmenopausal HT was proposed, combining estrogen and progestin, so as to avoid the endometrial cancer risk associated with unopposed estrogen.[47,48]
The Postmenopausal Estrogen Progestin Interventions Trial  enrolled nearly 600 participants in a 3-year multicenter, double-blind, placebo-controlled trial. Five arms consisted of placebo, daily conjugated equine estrogen (CEE), CEE with progestin (medroxyprogesterone acetate [MPA] for 12 days of a 28-day cycle), CEE with micronized progesterone (MP) for 12 days of a 28-day cycle, or CEE with daily MP. Endometrial biopsies were obtained at baseline, annually, and as clinically indicated. Women on CEE had more pathologic abnormalities than women on placebo (simple hyperplasia: 27.7% vs. 0.8%, adenomatous hyperplasia: 22.7% vs. 0.8%, and atypical hyperplasia: 11.8% vs. 0%, respectively), but women on CEE with progestin did not.
A prospective cohort study was conducted among Swedish women for whom HTs were prescribed. For women using medium-potency unopposed estrogens for 6 years or more, the RR of invasive endometrial cancer was 4.2 (95% CI, 2.5–8.4) while the risk for women using a progestin-combined treatment for the same length of time was unaffected (RR = 1.4; 95% CI, 0.6–3.3).