Insulin sensitivity is decreased in normal women by doses of ethinyl estradiol used in oral contraceptives

Am J Obstet Gynecol. 1993 Dec;169(6):1540-4. doi: 10.1016/0002-9378(93)90432-i.


Objective: We determined the independent effects of various doses of ethinyl estradiol used in oral contraceptives or norethindrone acetate, as well as their combination, on insulin sensitivity in normal women.

Study design: Thirty-three normal ovulatory female volunteers were recruited for this study. Insulin tolerance tests were performed after carbohydrate loading to determine the kinetic disappearance of glucose and insulin. After initial testing the women were randomized into four groups: ethinyl estradiol 20 micrograms, 35 micrograms, and 50 micrograms and norethindrone 1 mg. Insulin tolerance tests were repeated after 1 month of treatment and again after a second month, when all ethinyl estradiol groups received the addition of norethindrone 1 mg to their doses of ethinyl estradiol. Plasma glucose and insulin were measured, and insulin sensitivity (K(itt) glucose) and the disappearance of insulin (K(itt) insulin) were calculated.

Results: All groups were comparable at baseline, and no significant changes in fasting glucose and insulin were evident with treatment. After ingestion of 50 micrograms ethinyl estradiol the K(itt) glucose value decreased significantly (p < 0.03) and ingestion of 20 micrograms and 35 micrograms showed individual changes, but as groups the changes were not statistically significant. All ethinyl estradiol groups combined had a significant decrease in K(itt) glucose (p < 0.01). Norethindrone 1 mg alone did not change K(itt) glucose values, and after the addition of norethindrone to ethinyl estradiol, K(itt) glucose values normalized. K(itt) insulin values were also lower with treatment but were lower with ethinyl estradiol plus norethindrone compared with ethinyl estradiol alone (p < 0.04), suggesting an attenuation of insulin clearance with the progestin.

Conclusion: Ethinyl estradiol alone decreases insulin sensitivity, and this may occur at lower doses, but norethindrone 1 mg does not appear to do so. However, progestins may alter insulin clearance.

PIP: In southern California, reproductive endocrinologists compared data on 3 normal ovulatory 19-42 year old women blindly randomized into 4 groups to determine the independent effect of ethinyl estradiol and norethindrone acetate, both of which are in oral contraceptives, on glucose tolerance and insulin sensitivity. They used the most simple and rapid of the alternatives to the oral glucose tolerance test--the insulin tolerance test. Women received either 20 mcg/day, 35 mcg/day, or 50 mcg/day of ethinyl estradiol or 1 mg/day of norethindrone acetate. For the 2nd month, all women using ethinyl estradiol also received 1 mg/day of norethindrone acetate. The women in all 4 groups had comparable plasma glucose and insulin values while fasting. Estrogen in the 3 contraceptive doses reduced insulin sensitivity (p 0.03). The effect was not significant at 20 mcg and 35 mcg ethinyl estradiol, but 22.2% and 14.3% of the women receiving 20 mcg and 35 mcg ethinyl estradiol, respectively, did experience some reduction in insulin sensitivity. One mg norethindrone acetate alone did not affect insulin sensitivity, but when it was administered with 50 mcg ethinyl estradiol, insulin sensitivity values returned close to normal. 35 mcg of ethinyl estradiol lowered insulin clearance values (19.17% min vs. 9.53%/min; p 0.03). Addition of 1 mg norethindrone acetate to all ethinyl estradiol groups resulted in even more of a reduction (10.58%/min vs. 8/81%/min; p 0.04), indicating that a progestin reduces insulin clearance. In conclusion, ethinyl estradiol, even at low doses, appears to decrease insulin sensitivity while progestins do not. Yet, progestin appear to affect insulin clearance.

Publication types

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

MeSH terms

  • Adult
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Contraceptives, Oral, Combined / pharmacology*
  • Ethinyl Estradiol / pharmacology*
  • Female
  • Humans
  • Insulin / metabolism*
  • Norethindrone / pharmacology*
  • Pilot Projects
  • Prospective Studies


  • Blood Glucose
  • Contraceptives, Oral, Combined
  • Insulin
  • Ethinyl Estradiol
  • Norethindrone