Menopause, Estrogens, and Glucose Homeostasis in Women

  • Franck Mauvais-Jarvis
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1043)


Randomized trials suggest that menopausal hormone therapy (MHT) prevents type 2 diabetes. Still, the mechanisms of these antidiabetic effects are a matter of controversy. This chapter provides an analysis of epidemiological and clinical evidence and proposes a mechanism for the effect of menopause and MHT on type 2 diabetes development and prevention. It discusses the beneficial role of estradiol on glucose homeostasis that is lost at menopause and improved by MHT, which delays type 2 diabetes. This chapter aims to reconcile differences among studies of the effect of menopause and MHT formulations on type 2 diabetes and argues that discrepancies arise from physiological differences in methods used to assess glucose homeostasis.



This work was supported by grants from the National Institutes of Health (DK074970, DK107444), the American Diabetes Association (7-13-BS-101), and the VA Merit Review Award (BX003725).


  1. Andersson, B., Mattsson, L. A., Hahn, L., Marin, P., Lapidus, L., Holm, G., Bengtsson, B. A., & Bjorntorp, P. (1997). Estrogen replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in postmenopausal women with noninsulin-dependent diabetes mellitus. The Journal of Clinical Endocrinology and Metabolism, 82, 638–643.PubMedGoogle Scholar
  2. Bonds, D. E., Lasser, N., Qi, L., Brzyski, R., Caan, B., Heiss, G., Limacher, M. C., Liu, J. H., Mason, E., Oberman, A., O’sullivan, M. J., Phillips, L. S., Prineas, R. J., & Tinker, L. (2006). The effect of conjugated equine oestrogen on diabetes incidence: The women’s health initiative randomised trial. Diabetologia, 49, 459–468.CrossRefPubMedGoogle Scholar
  3. Brand, J. S., Van Der Schouw, Y. T., Onland-Moret, N. C., Sharp, S. J., Ong, K. K., Khaw, K. T., Ardanaz, E., Amiano, P., Boeing, H., Chirlaque, M. D., Clavel-Chapelon, F., Crowe, F. L., De Lauzon-Guillain, B., Duell, E. J., Fagherazzi, G., Franks, P. W., Grioni, S., Groop, L. C., Kaaks, R., Key, T. J., Nilsson, P. M., Overvad, K., Palli, D., Panico, S., Quiros, J. R., Rolandsson, O., Sacerdote, C., Sanchez, M. J., Slimani, N., Teucher, B., Tjonneland, A., Tumino, R., Van Der, A. D., Feskens, E. J., Langenberg, C., Forouhi, N. G., Riboli, E., & Wareham, N. J. (2013). Age at menopause, reproductive life span, and type 2 diabetes risk: Results from the EPIC-InterAct study. Diabetes Care, 36, 1012–1019.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Brussaard, H. E., Gevers Leuven, J. A., Frolich, M., Kluft, C., & Krans, H. M. (1997). Short-term oestrogen replacement therapy improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM. Diabetologia, 40, 843–849.CrossRefPubMedGoogle Scholar
  5. Cagnacci, A., Soldani, R., Carriero, P. L., Paoletti, A. M., Fioretti, P., & Melis, G. B. (1992). Effects of low doses of transdermal 17 beta-estradiol on carbohydrate metabolism in postmenopausal women. The Journal of Clinical Endocrinology and Metabolism, 74, 1396–1400.PubMedGoogle Scholar
  6. De Lauzon-Guillain, B., Fournier, A., Fabre, S., Simon, N., Mesrine, S., Boutron-Ruault, M. C., Balkau, B., & Clavel-Chapelon, F. (2009). Menopausal hormone therapy and new-onset diabetes in the French Etude Epidemiologique de Femmes de la Mutuelle Generale de l’Education Nationale (E3N) cohort. Diabetologia, 52, 2092–2100.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Espeland, M. A., Hogan, P. E., Fineberg, S. E., Howard, G., Schrott, H., Waclawiw, M. A., & Bush, T. L. (1998). Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI investigators. Postmenopausal estrogen/Progestin interventions. Diabetes Care, 21, 1589–1595.CrossRefPubMedGoogle Scholar
  8. Friday, K. E., Dong, C., & Fontenot, R. U. (2001). Conjugated equine estrogen improves glycemic control and blood lipoproteins in postmenopausal women with type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism, 86, 48–52.PubMedGoogle Scholar
  9. Godsland, I. F., Gangar, K., Walton, C., Cust, M. P., Whitehead, M. I., Wynn, V., & Stevenson, J. C. (1993). Insulin resistance, secretion, and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism, 42, 846–853.CrossRefPubMedGoogle Scholar
  10. Godsland, I. F., Manassiev, N. A., Felton, C. V., Proudler, A. J., Crook, D., Whitehead, M. I., & Stevenson, J. C. (2004). Effects of low and high dose oestradiol and dydrogesterone therapy on insulin and lipoprotein metabolism in healthy postmenopausal women. Clinical Endocrinology, 60, 541–549.CrossRefPubMedGoogle Scholar
  11. Hodis, H. N., Mack, W. J., Lobo, R. A., Shoupe, D., Sevanian, A., Mahrer, P. R., Selzer, R. H., Liu, C. R.,. C. R., Liu, C. H.,. C. H., & Azen, S. P. (2001). Estrogen in the prevention of atherosclerosis. A randomized, double- blind, placebo-controlled trial. Annals of Internal Medicine, 135, 939–953.CrossRefPubMedGoogle Scholar
  12. Kanaya, A. M., Herrington, D., Vittinghoff, E., Lin, F., Grady, D., Bittner, V., Cauley, J. A., & Barrett-Connor, E. (2003). Glycemic effects of postmenopausal hormone therapy: The heart and Estrogen/progestin replacement study. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine, 138, 1–9.CrossRefPubMedGoogle Scholar
  13. Kim, D. J., & Barrett-Connor, E. (2006). Association of serum proinsulin with hormone replacement therapy in nondiabetic older women: The Rancho Bernardo study. Diabetes Care, 29, 618–624.CrossRefPubMedGoogle Scholar
  14. Liu, S., Kilic, G., Meyers, M. S., Navarro, G., Wang, Y., Oberholzer, J., & Mauvais-Jarvis, F. (2013). Oestrogens improve human pancreatic islet transplantation in a mouse model of insulin deficient diabetes. Diabetologia, 56, 370–381.CrossRefPubMedGoogle Scholar
  15. Lobo, R. A., Bush, T., Carr, B. R., & Pickar, J. H. (2001). Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertility and Sterility, 76, 13–24.CrossRefPubMedGoogle Scholar
  16. Manson, J. E., Chlebowski, R. T., Stefanick, M. L., Aragaki, A. K., Rossouw, J. E., Prentice, R. L., Anderson, G., Howard, B. V., Thomson, C. A., Lacroix, A. Z., Wactawski-Wende, J., Jackson, R. D., Limacher, M., Margolis, K. L., Wassertheil-Smoller, S., Beresford, S. A., Cauley, J. A., Eaton, C. B., Gass, M., Hsia, J., Johnson, K. C., Kooperberg, C., Kuller, L. H., Lewis, C. E., Liu, S., Martin, L. W., Ockene, J. K., O’sullivan, M. J., Powell, L. H., Simon, M. S., Van Horn, L., Vitolins, M. Z., & Wallace, R. B. (2013). Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA, 310, 1353–1368.CrossRefPubMedGoogle Scholar
  17. Manson, J. E., Rimm, E. B., Colditz, G. A., Willett, W. C., Nathan, D. M., Arky, R. A., Rosner, B., Hennekens, C. H., Speizer, F. E., & Stampfer, M. J. (1992). A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent diabetes mellitus. Annals of Epidemiology, 2, 665–673.CrossRefPubMedGoogle Scholar
  18. Margolis, K. L., Bonds, D. E., Rodabough, R. J., Tinker, L., Phillips, L. S., Allen, C., Bassford, T., Burke, G., Torrens, J., & Howard, B. V. (2004). Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: Results from the Women’s Health Initiative hormone trial. Diabetologia, 47, 1175–1187.CrossRefPubMedGoogle Scholar
  19. Mauvais-Jarvis, F. (2013). Novel link between inflammation, endothelial dysfunction, and muscle insulin resistance. Diabetes, 62, 688–690.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Mauvais-Jarvis, F. (2016). Role of sex steroids in beta cell function, growth, and survival. Trends in Endocrinology and Metabolism, 27(12), 844–855.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Mauvais-Jarvis, F., Clegg, D. J., & Hevener, A. L. (2013). The role of estrogens in control of energy balance and glucose homeostasis. Endocrine Reviews, 34, 309–338.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Mauvais-Jarvis, F., Kulkarni, R. N., & Kahn, C. R. (2002). Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance. Clinical Endocrinology, 57, 1–9.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. Muka, T., Asllanaj, E., Avazverdi, N., Jaspers, L., Stringa, N., Milic, J., Ligthart, S., Ikram, M. A., Laven, J. S. E., Kavousi, M., Dehghan, A., & Franco, O. H. (2017). Age at natural menopause and risk of type 2 diabetes: A prospective cohort study. Diabetologia. 60(10), 1951–1960. PMID: 28721436.Google Scholar
  25. Muscelli, E., Kozakova, M., Flyvbjerg, A., Kyriakopoulou, K., Astiarraga, B. D., Glintborg, D., Konrad, T., Favuzzi, A., & Petrie, J. (2009). The effect of menopause on carotid artery remodeling, insulin sensitivity, and plasma adiponectin in healthy women. American Journal of Hypertension, 22, 364–370.CrossRefPubMedGoogle Scholar
  26. Paoletti, A. M., Pilloni, M., Orru, M., Floris, S., Pistis, M., Guerriero, S., Ajossa, S., & Melis, G. B. (2002). Efficacy and safety of oral and transdermal hormonal replacement treatment containing levonorgestrel. Maturitas, 42, 137–147.CrossRefPubMedGoogle Scholar
  27. Pentti, K., Tuppurainen, M. T., Honkanen, R., Sandini, L., Kroger, H., Alhava, E., & Saarikoski, S. (2009). Hormone therapy protects from diabetes: The Kuopio osteoporosis risk factor and prevention study. European Journal of Endocrinology, 160, 979–983.CrossRefPubMedGoogle Scholar
  28. Pereira, R. I., Casey, B. A., Swibas, T. A., Erickson, C. B., Wolfe, P., & Van Pelt, R. E. (2015). Timing of estradiol treatment after menopause may determine benefit or harm to insulin action. The Journal of Clinical Endocrinology and Metabolism, 100, 4456–4462.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Salpeter, S. R., Walsh, J. M., Ormiston, T. M., Greyber, E., Buckley, N. S., & Salpeter, E. E. (2006). Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes, Obesity & Metabolism, 8, 538–554.CrossRefGoogle Scholar
  30. Santen, R. J., Allred, D. C., Ardoin, S. P., Archer, D. F., Boyd, N., Braunstein, G. D., Burger, H. G., Colditz, G. A., Davis, S. R., Gambacciani, M., Gower, B. A., Henderson, V. W., Jarjour, W. N., Karas, R. H., Kleerekoper, M., Lobo, R. A., Manson, J. E., Marsden, J., Martin, K. A., Martin, L., Pinkerton, J. V., Rubinow, D. R., Teede, H., Thiboutot, D. M., & Utian, W. H. (2010). Postmenopausal hormone therapy: An endocrine society scientific statement. The Journal of Clinical Endocrinology and Metabolism, 95, s1–s66.CrossRefPubMedGoogle Scholar
  31. Spencer, C. P., Godsland, I. F., Cooper, A. J., Ross, D., Whitehead, M. I., & Stevenson, J. C. (2000). Effects of oral and transdermal 17beta-estradiol with cyclical oral norethindrone acetate on insulin sensitivity, secretion, and elimination in postmenopausal women. Metabolism, 49, 742–747.CrossRefPubMedGoogle Scholar
  32. Tiano, J. P., & Mauvais-Jarvis, F. (2012). Importance of oestrogen receptors to preserve functional beta-cell mass in diabetes. Nature Reviews. Endocrinology, 8, 342–351.CrossRefPubMedGoogle Scholar
  33. Toth, M. J., Sites, C. K., Eltabbakh, G. H., & Poehlman, E. T. (2000). Effect of menopausal status on insulin-stimulated glucose disposal: Comparison of middle-aged premenopausal and early postmenopausal women. Diabetes Care, 23, 801–806.CrossRefPubMedGoogle Scholar
  34. Walton, C., Godsland, I. F., Proudler, A. J., Wynn, V., & Stevenson, J. C. (1993). The effects of the menopause on insulin sensitivity, secretion and elimination in non-obese, healthy women. European Journal of Clinical Investigation, 23, 466–473.CrossRefPubMedGoogle Scholar
  35. Xu, B., Lovre, D., & Mauvais-Jarvis, F. (2015). Effect of selective estrogen receptor modulators on metabolic homeostasis. Biochimie, 124, 92–97.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Medicine, Section of Endocrinology and MetabolismTulane University Health Sciences Center, School of MedicineNew OrleansUSA

Personalised recommendations