The effect of estradiol and a combined estradiol progestagen preparation on insulin sensitivity in healthy postmenopausal women

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 th ese effects. We have examined the effects of transdermal estradiol and oral norethisterone on insulin sensitivity using the hyperinsulinemic euglycemi c clamp method by performing a randomized, double blind, placebo-controlled study in 22 healthy women after a surgically induced menopause. After base line measurements, subjects were randomized to receive either transdermal 1 7 beta-estradiol (50 mu g) or matching placebo patches for 6 weeks. The sub jects were then further randomized to receive either estradiol in combinati on with oral norethisterone (1 mg) or a matching oral placebo preparation, crossing over after 6 weeks, with assessment insulin sensitivity at the end of each treatment. No significant increase in insulin sensitivity was obse rved after 6 weeks of transdermal 17 beta-estradiol treatment (95% confiden ce interval, -0.54, 1.86; P = 0.27). Addition of norethisterone for a furth er 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 transderm al 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 be nefit. It is therefore unlikely that effects on insulin sensitivity contrib ute appreciably to the cardioprotective benefits attributed to hormone repl acement therapy.