ObjectiveThis study was designed to compare the bleeding profiles of conjugated equine estrogens 0.625 mg in combination with 2.5 mg medroxyprogesterone acetate (Prempro; CEE/MPA group), the most widely prescribed continuous combined hormone replacement therapy (CCHRT) in the United States, with 17&bgr;-estradiol 1 mg combined with 0.5 mg norethindrone acetate (Activella; E2/NETA group), a newly available CCHRT preparation, over a 6-month period.DesignThis study was a prospective, randomized, multicenter, double-blind, controlled trial. A total of 438 healthy postmenopausal women were randomized and received treatment (Activellan= 217, Prempron= 221). Each woman recorded bleeding diaries daily. Total cholesterol, triglycerides, and endometrial biopsies were obtained at screening and end-of-trial visits.ResultsThe more favorable bleeding profile was found in the E2/NETA (Activella) group. The differences in bleeding patterns were most marked in the first 3 months of treatment in women who were 1–2 years from last menses, with no bleeding in 71.4% vs. 40.0%; (p= 0.005) and with no bleeding and no spotting in 54.8% vs. 17.1%; (p= 0.001). Triglycerides fell by 8.5% in the E2/NETA group and increased by 11.7% in the CEE/MPA group (p< 0.001). Total cholesterol declined by 9.1% and 6.9%, respectively.ConclusionThe most important factor in the continuation of HRT is uterine bleeding. E2/NETA has significantly less bleeding than the most commonly prescribed CCHRT CEE/MPA, therefore; E2/NETA should be associated with improved continuation rates. The patient taking E2/NETA will receive effective treatment for her menopausal symptoms with less bleeding.