Menopausal Hormone Therapy and Type 2 Diabetes Prevention: Evidence, Mechanisms, and Clinical Implications

Abstract

Type 2 diabetes has reached epidemic proportions in the United States. Large, randomized controlled trials suggest that menopausal hormone therapy (MHT) delays the onset of type 2 diabetes in women. However, the mechanisms and clinical implications of this association are still a matter of controversy. This review provides an up-to-date analysis and integration of epidemiological, clinical, and basic studies, and proposes a mechanistic explanation for the effect of menopause and MHT on type 2 diabetes development and prevention. We discuss the beneficial effects of endogenous estradiol with respect to insulin secretion, insulin sensitivity, and glucose effectiveness; we also discuss energy expenditure and adipose distribution, both of which are affected by menopause and improved by MHT, which thereby decreases the incidence of type 2 diabetes. We reconcile differences among studies that investigated the effect of menopause and MHT formulations on type 2 diabetes. We argue that discrepancies arise from physiological differences in methods used to assess glucose homeostasis, ranging from clinical indices of insulin sensitivity to steady-state methods to assess insulin action. We also discuss the influence of the route of estrogen administration and the addition of progestogens. We conclude that, although MHT is neither approved nor appropriate for the prevention of type 2 diabetes due to its complex balance of risks and benefits, it should not be withheld from women with increased risk of type 2 diabetes who seek treatment for menopausal symptoms.

Copyright © 2017 Endocrine Society.

Figures

Figure 1.

Effects of MHT on glucose homeostasis. The weight of evidence argues for a beneficial role of MHT on pancreatic β cells, skeletal muscle, liver, and adipose tissue in postmenopausal women. This is associated with decreased abdominal fat, decreased fasting glucose and insulin, improved glucose effectiveness and insulin sensitivity, and a reduced incidence of diabetes.

Figure 2.

Comparison of transdermal E2 and oral CE delivery. Transdermal E2 delivery provides the ability to administer unmetabolized E2, at lower doses, directly to the blood stream, with enhanced delivery to nonhepatic tissues and with minimal stimulation of hepatic protein production, but lower suppression of HGP and the low-density lipoprotein (LDL)/high-density lipoprotein (HDL) cholesterol ratio compared with oral estrogen delivery. In contrast, oral estrogen (CE or E2) delivery leads to first-pass hepatic metabolism and necessitates higher doses of estrogen to achieve efficient delivery to nonhepatic tissues. Oral estrogen delivery also leads to increased hepatic production of coagulation and inflammatory factors, but better suppression of HGP and the LDL/HDL cholesterol ratio than oral delivery. TG, triglycerides.