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.


METHODS
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 microg ethinyl estradiol (EE), 1 mg NA/5 microg EE, 0.5 mg NA/10 microg EE, 1 mg NA/10 microg EE, 5 microg EE, and 10 micro 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 microg 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 microg EE and p = 0.006 for 1 mg NA/10 microg EE). Statistically significantly more women were amenorrheic at every month based on cumulative amenorrhea for 1 mg NA/5 microg (p < 0.05) compared with CEE/MPA; at months 3 and 6 more women were amenorrheic on 1 mg NA/10 microg 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.
Simon
J A
JA
Women's Health Research Center, Laurel, Maryland, USA.
Symons
J P
JP
D004338:Drug Combinations; D045166:Estradiol Congeners / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D008593:Menopause / Q000187:drug effects*; D008875:Middle Aged; D009640:Norethindrone / Q000031:analogs & derivatives / Q000494:pharmacology*; D000077563:Norethindrone Acetate; D045167:Progesterone Congeners / Q000494:pharmacology*
D004338:Drug Combinations; D045166:Estradiol Congeners; D004966:Estrogens, Conjugated (USP); D045167:Progesterone Congeners; D004997:Ethinyl Estradiol; D000077563:Norethindrone Acetate; D017258:Medroxyprogesterone Acetate; D009640:Norethindrone