Unscheduled bleeding during initiation of continuous combined hormone replacement therapy: A direct comparison of two combinations of norethindrone acetate and ethinyl estradiol to medroxyprogesterone acetate and conjugated equine estrogens

Objective: To determine whether there are differences between continuous combined hormone replacement therapies on bleeding control. Design: Nine hundred and forty-five postmenopausal women were randomized to one of seven double-blind treatment groups (placebo, 0.25 mg norethindrone acetate (NA)/5 μg ethinyl estradiol (EE), 1 mg NA/5 μg EE, 0.5 mg NA/10 μg EE, 1 mg NA/10 μg EE, 5 μg EE, and 10 μ EE) or unmasked 0.625 mg conjugated equine estrogens (CEE)/2.5 mg medroxyprogesterone acetate (MPA). Treatment was for 12 months; subjects kept daily diaries recording whether they had bleeding and/or spotting. Results: The results focused on currently commercially available hormone replacement therapy products (femhrt [1 mg NA/5 μg EE] and Prempro [0.625 mg CEE/2.5 mg MPA]) as well as a high-dose NA/EE dose combination (1/10) over the first 6 months of use, the most critical period in establishing treatment adherence. At the end of month 6 there was a greater incidence of amenorrhea with both NA/EE dose combinations compared with CEE/MPA (p = 0.009 for 1 mg NA/5 μg EE andp = 0.006 for 1 mg NA/10 μg EE). Statistically significantly more women were amenorrheic at every month based on cumulative amenorrhea for 1 mg NA/5 μg (p < 0.05) compared with CEE/MPA; at months 3 and 6 more women were amenorrheic on 1 mg NA/10 μg EE compared with CEE/MPA using the cumulative amenorrhea parameter. Conclusions: The results indicate that statistically significantly more women attained amenorrhea based on various parameters when administered continuous combined NA/EE compared with CEE/MPA. The potential for long-term treatment compliance based on better bleeding control may optimize the opportunity to prevent osteoporosis as well as other associated health benefits.