Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women.
OBJECTIVE
To evaluate the influence of 2 continuous combined estrogen-progestin replacement products, compared with unopposed estrogen and placebo, on cardiovascular risk markers in postmenopausal women in a randomized, double-blind, placebo-controlled trial.


METHODS
Two hundred seventy healthy postmenopausal women were randomly assigned to 1 of 4 treatment groups: placebo, unopposed 17-beta estradiol (1 mg), 1 mg of 17-beta estradiol with 0.25 mg of norethindrone acetate, or 1 mg of 17-beta estradiol with 0.5 mg of norethindrone acetate. The primary outcome variable was change from baseline in low-density lipoprotein cholesterol concentration. Additional outcome variables included changes in other serum lipid levels, hemostatic variables, and indicators of carbohydrate metabolism.


RESULTS
The low-density lipoprotein cholesterol level was reduced to a similar degree in all groups receiving active treatment (10%-14% from baseline; P =.001 for 17-beta estradiol with 0.5 mg of norethindrone acetate, P =.004 for 17-beta estradiol with 0.25 mg of norethindrone acetate, and P =. 001 for 1 mg of 17-beta estradiol vs placebo). Compared with unopposed 17-beta estradiol, 17-beta estradiol with 0.5 mg of norethindrone acetate enhanced the reductions in total cholesterol and apolipoprotein B levels (P<.01 vs 17-beta estradiol). 17-beta Estradiol plus norethindrone blunted or reversed the increases in levels of high-density lipoprotein cholesterol, apolipoprotein A-I, and triglycerides produced by 17-beta estradiol alone. Effects of 17-beta estradiol plus norethindrone on hemostatic variables were similar to those of 17-beta estradiol except for factor VII activity, which was significantly reduced with 17-beta estradiol combined with 0.25 mg (P<.01) and 0.5 mg (P<.05) of norethindrone acetate. 17-beta Estradiol plus norethindrone appeared to blunt reductions in C-peptide and insulin levels produced by unopposed 17-beta estradiol but did not elevate these values compared with placebo.


CONCLUSIONS
17-beta Estradiol plus norethindrone produced favorable changes in most cardiovascular risk markers evaluated and has a profile distinct from that of unopposed 17-beta estradiol. The impact of these differences on cardiovascular events warrants investigation. Arch Intern Med. 2000;160:3315-3325.
Davidson
M H
MH
Nutrition and Metabolism Research Unit, Chicago Center for Clinical Research, 515 N State St, 27th Floor, Chicago, IL 60610, USA.
Maki
K C
KC
Marx
P
P
Maki
A C
AC
Cyrowski
M S
MS
Nanavati
N
N
Arce
J C
JC
D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood; D001779:Blood Coagulation Factors / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000517:prevention & control*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004958:Estradiol / Q000008:administration & dosage*; D015914:Estrogen Replacement Therapy; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood*; D017270:Lipoprotein(a) / Q000097:blood; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage* / Q000031:analogs & derivatives; D000077563:Norethindrone Acetate; D017698:Postmenopause / Q000097:blood*; D012307:Risk Factors; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D001779:Blood Coagulation Factors; D001786:Blood Glucose; D002096:C-Peptide; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004958:Estradiol; D006442:Glycated Hemoglobin; D007328:Insulin; D008055:Lipids; D017270:Lipoprotein(a); D009640:Norethindrone; D000077563:Norethindrone Acetate; D014280:Triglycerides