Context: The incidence of endometrial cancer may be different with medroxyprogesterone acetate (MPA) vs natural progesterone (P4) when used with estrogens for endometrial protection. The WHI reported a lower incidence of endometrial cancer vs placebo in women using 0.625 mg/day conjugated equine estrogens (CEE) and 2.5 mg/day MPA followed for a median intervention of 5.6 years and median cumulative follow-up of 13 years . The REPLENISH trial showed for the first time [3-5] that P4 continuously combined with 17β-estradiol (E2) provides adequate endometrial protection . Objective: To compare the separately conducted REPLENISH and Women’s HOPE trials in terms of endometrial protection and uterine bleeding. Methods: The REPLENISH (NCT01942668) study was a 12-month, randomized, double-blind, placebo-controlled, multicenter trial that examined an investigational continuous-combined oral E2/P4 (TX-001HR, TherapeuticsMD, Inc) for the treatment of moderate-to-severe vasomotor symptoms in menopausal women . The Women’s HOPE trial [6,7] was a 12-month, randomized, double-blind, placebo-controlled, multicenter trial that evaluated continuous-combined CEE/MPA in menopausal women. Endometrial biopsies were performed and evaluated similarly in both studies. Patients: Menopausal women with an intact uterus. Interventions: Continuous-combined, oral E2/P4 (1.0 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg) , or CEE/MPA (0.625 mg/2.5 mg, 0.45 mg/2.5 mg, 0.45 mg/1.5 mg, 0.3 mg/1.5 mg) [6,7]. Main Outcome Measure: Comparison of endometrial hyperplasia and uterine bleeding data. Results: Incidence rates of endometrial hyperplasia at 12 months were below 1% with all doses evaluated in both REPLENISH and Women’s HOPE trials. Cumulative amenorrhea rates with E2/P4 at 12 months were high (56–73% vs 81% with placebo) and had increased over time; rates with CEE/MPA ranged from 22–45% vs 68% with placebo. Conclusions: When given continuously, specific combinations/doses of solubilized E2 and P4 provided endometrial protection (similar to MPA) and resulted in favorable amenorrhea rates. 1. Chlebowski RT et al. J Nat Cancer Inst. 2016;108:djv350. 2. Archer DF et al. Endoc Rev. 2017;38:3. 3. Allen NE et al. Am J Epidemiol. 2010;172:1394-1403. 4. Fournier A et al. Am J Epidemiol. 2014;180:508-517. 5. Sjögren LL et al. Maturitas. 2016;91:25-35. 6. Pickar JH et al. Fertil Steril. 2001;76:25-31. 7. Archer DF et al. Fertil Steril. 2001;75:1080-1087.