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The Role of Endogenous Sex Hormones in the Development of Type 2 Diabetes

Hormonal balance is recognized as a factor in the development of non-communicable diseases, such as type 2 diabetes. The topic is of particular interest regarding the health of peri- and post-menopausal women who experience changes in hormone levels during the menopausal transition and also have increased risk of developing non-communicable diseases, such as cardiovascular disease and diabetes, as they age.

It is known that post-menopausal women have elevated glucose and elevated insulin response, compared to adiposity-matched pre-menopausal women, so it is possible that changes in the levels of specific sex hormones due to the menopausal transition play a role in increasing women’s risk of developing diabetes. Glucose and insulin response increased following a glucose challenge in ERα-knockout mice, mice lacking functional estrogen receptor-α, mice which can serve as a useful model for humans for endocrine research and the role of estrogen on the body. These results indicate that ERα is important for regulating adipose tissue in women. Furthermore, in an eight-year longitudinal cohort study, the Study of Women’s Health Across the Nation (SWAN), women who experienced vasomotor symptoms like hot flashes during the menopausal transition had a higher HOMA index, a measure of insulin resistance, and somewhat higher glucose than those who did not experience vasomotor symptoms. Additionally, as women experience the menopausal transition, they often gain subcutaneous abdominal fat and may also have a significant increase in visceral and subcutaneous abdominal fat, accompanied by a decrease in fat oxidation, all of which may predispose post-menopausal women to obesity, more frequent vasomotor symptoms, elevated glucose, elevated insulin response, and diabetes.

These findings suggest a relationship between endogenous female sex hormones, insulin, and diabetes in menopause, particularly in women experiencing the menopausal transition who are overweight or obese. In an abstract at the 2015 European Society of Cardiology Congress, our colleagues from Erasmus MC presented results from the Rotterdam Study indicating that two female sex hormones were associated with the risk of diabetes among women. Sex-hormone binding globulin (SHBG) was inversely associated with the risk of diabetes, while the free androgen index (FAI), the ratio of total testosterone to SHBG, was positively associated with the risk of diabetes in women. The findings regarding the inverse relationship between SHBG levels and incidence of type 2 diabetes in women were also shown in a 2009 study published in the New England Journal of Medicine and a 2006 meta-analysis published in the Journal of the American Medical Association.

The interaction of endogenous sex hormones and menopausal-associated increases in adiposity suggest something of a “vicious cycle” in which elevated insulin levels reduce levels of SHBG, increasing levels of testosterone and the FAI, and increasing visceral and abdominal adiposity, restarting the cycle again.

Hormone replacement therapy (HRT) may alleviate the symptoms of menopause, but are not meant to reduce the risk of developing diabetes, for example. Current guidelines recommend that clinicians discuss the potential benefits and risks of HRT, and that treatments are reviewed every three months to assess efficacy of therapies and tolerability of symptoms. It has been concluded in the guidelines that taking HRT is not associated with an increased risk of developing type 2 diabetes, but ongoing investigations into the associations of sex hormones with various health outcomes may yield changes in the menopausal health guidelines for women. In the meantime, however, healthy lifestyle behaviors like improved nutrition, sleep, and physical activity are recommended to reduce weight gain and its impact on hormonal health during and beyond the menopausal transition.


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