Diabetes mellitus is a pertinent concern as it may advance into renal failure and cardiovascular disease, the leading cause of death among women. Moreover, this issue affects millions of females all over the world, with more than 50 million women expected to be postmenopausal by 20201,2.
Several clinical studies have supported the correlation between menopause and type 2 diabetes.
One such study published in Diabetic Medicine found that women who had lower estradiol (E2) levels in the early phases of menopausal transition had a 47% higher risk of developing type 2 diabetes than women with higher E2 levels in pre-menopausal3. This finding is consistent with the known link between obesity and diabetes, as obesity also impacts hormone levels.
Research by Duke Appiah and colleagues discovered that women who underwent bilateral ovariectomy, which forces early menopause, had a 57% greater chance of being diagnosed with type 2 diabetes than women who went through menopause naturally4.
Furthermore, in the European Journal of Clinical Investigation, Walton et al. found that postmenopausal women experienced a 30% decrease in glucose effectiveness as compared to premenopausal women. Glucose effectiveness is defined as the ability of glucose to regulate its own uptake and production in response to fluctuating insulin levels. This indicates that menopause affects the way in which glucose behaves in the body, thus providing support for the alleged association between menopause and the development of type 2 diabetes.
Walton et al. also concluded that menopause may change the way in which insulin is secreted by the pancreas and ultimately metabolized5.
A growing number of research points to the fact that hormone replacement therapy, or HRT, may reduce the risk of type 2 diabetes following menopause.
To understand how E2 can impact glucose metabolism, Gupte et al. dissected large clinical trials and found that a reduction of the amount of E2 and impairment of its action in the body leads to a decrease in a woman’s metabolic rate. This in turn leads to higher cholesterol levels, increased visceral fat, and metabolic syndrome6.
These findings may give insight to the astounding discovery from a large prospective cohort study that women who are current users of HRT have a 62% lower incidence of type 2 diabetes than those who do not currently use HRT7.
Researchers from Stanford University School of Medicine analyzed statistical data from 1966 to 2004 in order to quantify effects on metabolic syndrome of HRT in postmenopausal women. The results, published in Diabetes, Obesity and Metabolism, concluded that women without type 2 diabetes at baseline exhibited declined fasting insulin and glucose levels that led to a 13% drop in insulin resistance when taking HRT.
The same study found that HRT reduced the incidence of new-onset diabetes by 30%.
Furthermore, women with concurrent type 2 diabetes experienced a 36% reduction in their Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) when using HRT8.
Similar results were exhibited in PEPI (Postmenopausal Estrogen/Progestin Intervention Study) clinical research, a randomized trial comparing women taking oral conjugated equine estrogen (CEE) alone or with medroxyprogesterone acetate (MPA) versus placebo. The PEPI trial showed improved metabolic parameters amongst HRT users of CEE with or without MPA, such as, enhanced insulin sensitivity and diminished fasting insulin and glucose levels9.
The rising concern of cardiovascular disease in women and its connection to uncontrolled diabetes prompted the publication of HERS (Heart and Estrogen/progestin Replacement Study), a large, randomized, double-blind, placebo-controlled trial.
The HERS study examined the incidence of type 2 diabetes among postmenopausal women with coronary artery disease and found that 4 years of HRT use had reduced the incidence of type 2 diabetes by 35% as compared to a placebo. The HRT group also experienced lower fasting glucose levels than those in the placebo group10.
In a study of women with type 2 diabetes who took oral estradiol, Brussaard et al. found that HbA1c levels were significantly decreased.
Furthermore, the use of estradiol-only HRT was shown to enhance the ability of insulin to suppress hepatic glucose production11.
Researchers believe that menopause increases the risk of developing type 2 diabetes largely because of the role estradiol plays in the regulation of glucose metabolism in the body.
Estradiol greatly impacts the maintenance of glucose homeostasis throughout multiple organ systems in the body. It does this by mediating effects on the body via three different receptors: G protein-coupled E2 receptor1, E2-alpha receptors and E2-beta receptors. The number of estradiol receptors across different tissues, as well as their distribution, will impact the function of the hormone. Activities of estradiol also depend on its bioavailability, which is directly related to levels of sex hormone binding globulin, or SHBG6.
Estradiol impacts the action of insulin both directly and indirectly. Direct impacts are related to estradiol’s actions on insulin-sensitive tissues, while indirect impacts are related to estradiol’s regulation of oxidative stress and other factors that contribute to insulin resistance6.>
The E2-alpha is the most important of the three estrogen receptors for insulin-glucose homeostasis. Studies show that a deficiency of E2-alpha is associated with high insulin levels, impaired glucose metabolism and increased insulin resistance12.
Estradiol also has a pronounced effect on overall metabolism and fat accumulation, both of which are associated with the development of type 2 diabetes. Effects of estradiol on metabolism are controlled by the hypothalamus, with estradiol playing a role in the regulation of appetite13. Throughout the earlier stages of life, women accumulate mostly subcutaneous fat, which is fat deposited just under the skin. However, after menopause, accumulation of visceral fat increases. Visceral fat, which is fat surrounding the internal organs, is more dangerous and increases the risk of serious complications like metabolic syndrome and cardiovascular disease. This occurs because estradiol influences the balance of lipid storage between visceral and subcutaneous regions6.
Furthermore, fluctuations in estradiol may be to blame for other symptoms women experience during menopause, including fatigue, muscle weakness, reduced stamina and propensity to gain weight. All of these symptoms may be attributed to dysfunction of mitochondria, the powerhouse for ATP or energy production. As estradiol plays an important regulatory role in mitochondrial function, it stands to reason that disturbances in estradiol levels could contribute to these issues5.
According to clinical studies published by Wang et al. and Duckles, et al., estradiol is believed to influence mitochondrial biogenesis, generation membrane potential, the production of ATP and the regulation of calcium14,15. In addition, O’Lone et al. and Chen et al. report that estradiol is defending against oxidative stress16,17.
Estrogen HRT may be produced in a number of ways, such as by using non-human sources. However, bioidentical HRT may be more beneficial than other forms of HRT for patients who want to decrease their risk of type 2 diabetes. The added benefits of bioidentical estrogen HRT are related to its composition, which is identical to that of the estrogen produced in the human body.
Research has shown the effects of estrogen therapy to be dose-dependent. Thus, compounding pharmacies that produce HRT unique for each woman based on her history and comorbidities may be the best option for postmenopausal patients.
1. Mauvais-Jarvis, F., Manson, J. E., Stevenson, J. C., & Fonseca, V. A. (2017). Menopausal Hormone Therapy and Type 2 Diabetes Prevention: Evidence, Mechanisms, and Clinical Implications. Endocrine reviews, 38(3), 173–188. doi:10.1210/er.2016-114
2. Brand, J. S., et. al. (2013). Age at Menopause, Reproductive Life Span, and Type 2 Diabetes Risk: results from the EPIC-InterAct study. Diabetes care, 36(4), 1012–1019. doi:10.2337/dc12-1020
3. Park, S. K., et. al. (2017). Association between changes in oestradiol and follicle-stimulating hormone levels during the menopausal transition and risk of diabetes. Diabetic Medicine, 34(4), 531–538. doi:10.1111/dme.13301
4. Appiah, D., Winters, S. J., & Hornung, C.A. (2014). Bilateral Oophorectomy and the Risk of Incident Diabetes in Postmenopausal Women. Diabetes Care, 37(3), 725–733. doi: 10.2337/dc13-1986
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11. Brussaard, H., Leuven, J., Frölich, M. et al. Diabetologia (1997). Short-term estrogen replacement therapy improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM. Diabetologia, 40: 843.
12. Foryst-Ludwig, A., Clemenz, M., Hohmann, S., Hartge, M., Sprang, C., Frost, N., … Kintscher, U. (2008). Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS genetics, 4(6), e1000108. doi:10.1371/journal.pgen.1000108
13. Clegg, D. J., Brown, L. M., Woods, S. C., & Benoit, S. C. (2006). Gonadal Hormones Determine Sensitivity to Central Leptin and Insulin. Diabetes, 55(4), 978–987. doi: 10.2337/diabetes.55.04.06.db05-1339
14. Wang, J., Green, P. S., & Simpkins, J. W. (2001). Estradiol protects against ATP depletion, mitochondrial membrane potential decline and the generation of reactive oxygen species induced by 3-nitroproprionic acid in SK-N-SH human neuroblastoma cells. Journal of Neurochemistry, 77(3), 804–811. doi: 10.1046/j.1471-4159.2001.00271.x
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16. O’Lone, R., et. al. (2007). Estrogen Receptors α and β Mediate Distinct Pathways of Vascular Gene Expression, Including Genes Involved in Mitochondrial Electron Transport and Generation of Reactive Oxygen Species. Molecular Endocrinology, 21(6),1281–96
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