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The Effect of Estradiol and a Combined Estradiol/Progestagen Preparation on Insulin Sensitivity in Healthy Postmenopausal Women

Department of Obstetrics and Gynecology, Queen Mother’s Hospital (A.C.D., H.L., R.N.R., M.J.P., S.M., D.M.H., M.A.L.), Yorkhill, Glasgow, United Kingdom G3 8SJ; and the Department of Medicine and Therapeutics, Western Infirmary (J.R.P., J.M.C.C.), Glasgow, United Kingdom G11 8NT

Address all correspondence and requests for reprints to: Dr. M. A. Lumsden, Department of Obstetrics and Gynecology, The Queen Mother’s Hospital, Yorkhill, Glasgow, United Kingdom G3 8SJ.

Abnormalities of carbohydrate metabolism and insulin sensitivity have been reported in estrogen deficiency. Estrogen replacement appears to result in an improvement in these parameters, although progestagens may antagonize these effects. We have examined the effects of transdermal estradiol and oral norethisterone on insulin sensitivity using the hyperinsulinemic euglycemic clamp method by performing a randomized, double blind, placebo-controlled study in 22 healthy women after a surgically induced menopause. After baseline measurements, subjects were randomized to receive either transdermal 17ß-estradiol (50 µg) or matching placebo patches for 6 weeks. The subjects were then further randomized to receive either estradiol in combination with oral norethisterone (1 mg) or a matching oral placebo preparation, crossing over after 6 weeks, with assessment of insulin sensitivity at the end of each treatment. No significant increase in insulin sensitivity was observed after 6 weeks of transdermal 17ß-estradiol treatment (95% confidence interval, -0.54, 1.86; P = 0.27). Addition of norethisterone for a further 6 weeks had no detectable effect on insulin sensitivity (95% confidence interval, -1.65, 1.10; P = 0.65). The results of this study using transdermal estradiol do not support previous reports that unopposed estrogens exert potentially beneficial effects on insulin sensitivity and suggest that the addition of an oral progestagen confers no clinically important risk or benefit. It is therefore unlikely that effects on insulin sensitivity contribute appreciably to the cardioprotective benefits attributed to hormone replacement therapy.

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