Estrogen, Insulin Sensitivity, and Diabetes: Is Timing Everything?

JoAnn E. Manson, MD, DrPH


February 11, 2016

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Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women's Hospital. I'd like to talk with you about estrogen, insulin sensitivity, and diabetes. Is timing everything? Is there a hypothesis for a critical window of opportunity for estrogen and glucose metabolism as there is for estrogen and coronary heart disease?

A recent report from the Journal of Clinical Endocrinology & Metabolism by Pereira and colleagues[1] from the University of Colorado would suggest that this is the case. They did a randomized controlled trial, which was relatively short-term and small, enrolling 46 women. Half of the women were earlier in menopause—within 6 years of onset—and the other half were older and more distant from menopause by at least a decade. They were treated with high-dose transdermal estradiol at a dose of 150 µg/day for a week, and had insulin sensitivity testing before and after the estradiol treatment. They had a test called the insulin-mediated glucose disposal rate (GDR) as measured by sophisticated testing with a hyperinsulinemic-euglycemic clamp.

What they found was that the younger women had improvements in their GDR and insulin sensitivity, whereas the older women, more distant from the onset of menopause, had worsening and actual deterioration of their GDR and insulin sensitivity. These findings suggest that there were differences by age and time since menopause.

There are several large randomized controlled trials of hormone therapy that have looked at type 2 diabetes as an outcome. These trials have generally found benefits. The Heart and Estrogen/progestin Replacement Study (HERS) in older women showed a lower risk for type 2 diabetes with combination oral estrogen plus progestin,[2] and the two trials from the Women's Health Initiative[3,4]—estrogen plus progestin and estrogen alone given orally—were associated with a lower risk for diabetes. The Women's Health Initiative was large enough to look at differences by age group. The results were mixed. The estrogen-alone trial did show a reduced risk for diabetes across all age groups.[4] However, the estrogen-plus-progestin trial suggested that the reduced risk for diabetes was in the younger women, who were below 70 years old.[3] For women who were above 70 years old, there was a borderline increased risk for diabetes. That was somewhat suggestive of a difference by age. Overall, the results have been mixed but supportive of the benefits of hormone therapy for reducing diabetes risk among younger women fairly consistently.

Now, would these findings then support the initiation of hormone therapy for the express purpose of trying to prevent diabetes? We think that's probably not optimal because hormone therapy is associated with risks. There is an increased risk for venous thrombosis and a slight increase in the risk for stroke, but these findings do provide further reassurance for the initiation of hormone therapy in early menopause and recently menopausal women who have other indications for hormone therapy, such as hot flashes and other symptoms where hormone therapy would be indicated. These findings support not withholding treatment due to concerns about increased cardiometabolic risk with hormone therapy in these younger and generally healthy women.

Thank you so much for your attention. This is JoAnn Manson.


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