Menopausal hormone therapy and type 2 diabetes prevention: evidence, mechanisms, and clinical implications

Mauvais-Jarvis, Franck; Manson, JoAnn E.; Stevenson, John C.; Fonseca, Vivian A.

doi:10.1210/er.2016-1146

Cited by 341Menopause: Health Impacts and TreatmentsEstrogen and related hormone effectsHormonal and reproductive studies

Menopausal hormone therapy and type 2 diabetes prevention: evidence, mechanisms, and clinical implications

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Mauvais-Jarvis, Franck, Manson, JoAnn E., Stevenson, John C., Fonseca, Vivian A.·2017·Endocrine Reviews

DOI 10.1210/er.2016-1146PMC PMC5460681

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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.

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Estrogen replacement therapy in postmenopausal women can promote weight loss and improve metabolic markers including fat distribution, notably by increasing subcutaneous fat and reducing visceral fat mass.
“Studies generally show that estrogen replacement therapy in postmenopausal women can promote weight loss and improve metabolic markers including fat distribution, notably by increasing subcutaneous fat and reducing visceral fat mass (201–203).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [201]
The section “Effect of MHT on energy balance and adipose tissue mass” (page unavailable) reports that most long-term studies found reduced abdominal fat deposition and that large trials found reduced total and intra-abdominal fat. “Mechanisms of Antidiabetic Actions of MHT” also mentions reductions in BMI and waist circumference. Our copy does not establish the claimed increase in subcutaneous fat or a general weight-loss effect; it notes that some estrogen regimens increased fat mass. (LLM, conf=0.86)
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Minireview: Estrogenic Protection of β-Cell Failure in Metabolic Diseases
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Original ArticlesComparison of Estimates of Insulin Sensitivity in Pre- and Postmenopausal Women Using the Insulin Tolerance Test and the Frequently Sampled Intravenous Glucose Tolerance Test
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Role of Sex Steroids in β Cell Function, Growth, and Survival
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17??-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality1
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Impaired estrogen receptor action in the pathogenesis of the metabolic syndrome
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Glucose effectiveness assessed under dynamic and steady state conditions. Comparability of uptake versus production components.
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Effects of oral and transdermal 17beta-estradiol with cyclical oral norethindrone acetate on insulin sensitivity, secretion, and elimination in postmenopausal women.
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Reproductive history and risk of type 2 diabetes mellitus in postmenopausal women: findings from the Women's Health Initiative
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Changes in Cardiovascular Risk Factors by Hysterectomy Status With and Without Oophorectomy
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Bilateral Oophorectomy and the Risk of Incident Diabetes in Postmenopausal Women
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Conjugated Equine Estrogen Improves Glycemic Control and Blood Lipoproteins in Postmenopausal Women with Type 2 Diabetes1
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Effects of percutaneous estradiol and conjugated estrogens on the level of plasma proteins and triglycerides in postmenopausal women
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Menopausal hormone therapy and new-onset diabetes in the French Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) cohort
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Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance
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The Effect of Estradiol and a Combined Estradiol/Progestagen Preparation on Insulin Sensitivity in Healthy Postmenopausal Women
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A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes.
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Algorithm and mobile app for menopausal symptom management and hormonal/non-hormonal therapy decision making
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Calculated Pattern of Intraportal Insulin Appearance Without Independent Assessment of C-Peptide Kinetics
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Association between earlier age at natural menopause and risk of diabetes in middle-aged and older Chinese women: The Dongfeng–Tongji cohort study
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Hormone therapy protects from diabetes: the Kuopio osteoporosis risk factor and prevention study
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Effect of selective estrogen receptor modulators on metabolic homeostasis
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Absorption of percutaneous oestradiol in postmenopausal women
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The effect of selective estrogen receptor modulators on type 2 diabetes onset in women: Basic and clinical insights
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Oophorectomy promotes islet amyloid formation in a transgenic mouse model of Type II diabetes
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Low-dose hormone therapy and carbohydrate metabolism
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Sexual Dimorphism of Pancreatic β-Cell Degeneration in Transgenic Mice Expressing an Insulin-rasHybrid Gene*
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Effect of oral estrogen on substrate utilization in postmenopausal women
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The Islet Estrogen Receptor-α Is Induced by Hyperglycemia and Protects Against Oxidative Stress-Induced Insulin-Deficient Diabetes
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Is Estradiol a Biomarker of Type 2 Diabetes Risk in Postmenopausal Women?
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Efficacy and safety of oral and transdermal hormonal replacement treatment containing levonorgestrel
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Novel Link Between Inflammation, Endothelial Dysfunction, and Muscle Insulin Resistance
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Effects of tibolone and cyclic hormone replacement therapy on glucose metabolism in non-diabetic obese postmenopausal women: a randomized study
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Association of Serum Proinsulin With Hormone Replacement Therapy in Nondiabetic Older Women
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Research works printed but not linked: 2

Lindheim SR, Buchanan TA, Duffy DM, Vijod MA, Kojima T, Stanczyk FZ, Lobo RA. Comparison of esti- mates of insulin sensitivity in pre-and postmenopausal women using the insulin tolerance test and the fre- quently sampled intravenous glucose tolerance test. J Soc Gynecol Investig. 1994;1(2):150-154.
Xu B, Allard C, Mauvais-Jarvis F. Estrogen complexes improve the unfolded protein response and prevent ER-stress induced beta cell failure in Akita mice. Di- abetes. 2015;64:A35.

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Authors: Mauvais-Jarvis, F., Manson, J. E., Stevenson, J. C., & Fonseca, V. A.
Affiliations: Department of Medicine, Division of Endocrinology and Metabolism, School of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112
Brigham and Women's Hospital (US)
Royal Brompton Hospital (GB)
Tulane University (US)
ORCID: Manson, JoAnn E.
Stevenson, John C.
Fonseca, Vivian A.
Venue: Endocrine Reviews
Publisher: The Endocrine Society
Published: 2017-03-08
Volume: 38
Issue: 3
Pages: 173-188
ISSN: 0163-769X (ISSN-L)
1945-7189
DOI: 10.1210/er.2016-1146
PMC: PMC5460681
OpenAlex: W2606520020
Cited by: 341
References: 146
Citations by year: 2026: 34 · 2025: 42 · 2024: 22 · 2023: 38 · 2022: 48 · 2021: 46 · 2020: 39 · 2019: 35 · 2018: 24 · 2017: 13
FWCI: 4.43
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Endocrine Reviews (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: American Diabetes Association (7-13-BS-101, DK074970)
Abbott Laboratories
Pfizer
Tulane University
National Institutes of Health (HHSN268201100001C, CA-138962)
National Heart, Lung, and Blood Institute (HHSN2682011-00001I, R01HL034594)
National Cancer Institute (U01CA138962, R01CA138962)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107444, R01DK074970)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Keywords: hormone replacement therapy, type 2 diabetes prevention, menopause, endogenous estradiol, insulin secretion, insulin sensitivity, glucose effectiveness, energy expenditure, body fat distribution, progestogens, menopausal symptoms
MeSH terms: Diabetes Mellitus, Type 2, Estrogens, Female, Humans, Menopause, Estrogen Replacement Therapy, Randomized Controlled Trials as Topic, Hormone Replacement Therapy

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Menopausal hormone therapy and type 2 diabetes prevention: evidence, mechanisms, and clinical implications

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