Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women

Arch Intern Med. 2000 Nov 27;160(21):3315-25. doi: 10.1001/archinte.160.21.3315.


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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Apolipoprotein A-I / blood
  • Blood Coagulation Factors / metabolism
  • Blood Glucose / metabolism
  • C-Peptide / blood
  • Cardiovascular Diseases / etiology*
  • Cardiovascular Diseases / prevention & control*
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Double-Blind Method
  • Drug Administration Schedule
  • Estradiol / administration & dosage*
  • Estrogen Replacement Therapy*
  • Female
  • Glycated Hemoglobin / metabolism
  • Humans
  • Insulin / blood
  • Lipids / blood*
  • Lipoprotein(a) / blood
  • Middle Aged
  • Norethindrone / administration & dosage*
  • Norethindrone / analogs & derivatives
  • Norethindrone Acetate
  • Postmenopause / blood*
  • Risk Factors
  • Treatment Outcome
  • Triglycerides / blood


  • Apolipoprotein A-I
  • Blood Coagulation Factors
  • Blood Glucose
  • C-Peptide
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Glycated Hemoglobin A
  • Insulin
  • Lipids
  • Lipoprotein(a)
  • Triglycerides
  • Estradiol
  • Norethindrone Acetate
  • Norethindrone