A randomized, double-blind, placebo-controlled, multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone.
OBJECTIVE
The purpose of this study was to determine the incidence of endometrial hyperplasia in subjects who receive continuous norethindrone acetate and ethinyl estradiol combinations versus unopposed ethinyl estradiol.


METHODS
Nine hundred forty-five postmenopausal women were randomly selected for 12 months of treatment with one of six blinded norethindrone acetate/ethinyl estradiol combinations (milligrams of norethindrone acetate/micrograms of ethinyl estradiol: 0/5, 0.25/5, 1/5, 0/10, 0.5/10, or 1/10) or to open-label 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate. Endometrial hyperplasia and endometrial proliferation were assessed by biopsy at screening, months 6 and 12.


RESULTS
Endometrial hyperplasia developed in 26 subjects: Placebo, 0/5 and 0.25/5 (1 subject each) and 0/10 (23 subjects). Significantly less endometrial proliferation was measured in the 1/5 norethindrone acetate/ethinyl estradiol and other norethindrone acetate/ethinyl estradiol combination groups and in the 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate group, than in unopposed ethinyl estradiol groups (6 months: P <.004; 12 months: P <.001). Treatment with 1/5 norethindrone acetate/ethinyl estradiol and with other norethindrone acetate/ethinyl estradiol combinations significantly reduced endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate (6 and 12 months: P <.02).


CONCLUSIONS
Norethindrone acetate protects the endometrium from estrogen-induced hyperplasia and changes in proliferative status. In addition, norethindrone acetate/ethinyl estradiol-treated subjects had significantly less endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate-treated subjects.
Portman
David J
DJ
Columbus Center for Women's Health Research, OH 43213, USA. ccwhr@earthlink.net
Symons
James P
JP
Wilborn
Walter
W
Kempfert
Nona J
NJ
D004311:Double-Blind Method; D004338:Drug Combinations; D004714:Endometrial Hyperplasia / Q000139:chemically induced / Q000453:epidemiology / Q000473:pathology; D004717:Endometrium / Q000187:drug effects* / Q000473:pathology; D045166:Estradiol Congeners / Q000009:adverse effects*; D004997:Ethinyl Estradiol / Q000009:adverse effects*; D005260:Female; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009640:Norethindrone / Q000009:adverse effects* / Q000031:analogs & derivatives*; D000077563:Norethindrone Acetate; D010919:Placebos / Q000627:therapeutic use; D012449:Safety; D012720:Severity of Illness Index
D004338:Drug Combinations; D045166:Estradiol Congeners; D010919:Placebos; D004997:Ethinyl Estradiol; D000077563:Norethindrone Acetate; D009640:Norethindrone