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Cited by 599Menopause: Health Impacts and TreatmentsEstrogen and related hormone effectsHormonal and reproductive studies

Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial

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for the Women’s Health Initiative Investigators, Margolis, K. L., Bonds, D. E., Rodabough, R. J., Tinker, L., Phillips, L. S., Allen, C., Bassford, T. +3 more·2004·Diabetologia
DOI 10.1007/s00125-004-1448-x
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Abstract

Aims/hypothesis Studies examining the effect of postmenopausal hormone therapy on concentrations of glucose, insulin and diabetes incidence have been inconclusive, in part because many of the studies were too small. We examined the effect of oestrogen plus progestin on diabetes incidence and insulin resistance.Methods The study was a randomised, double-blind trial comparing the effect of daily 0.625 mg conjugated equine oestrogens plus 2.5 mg medroxyprogesterone acetate with that of placebo during 5.6 years of follow-up. The participants were 15,641 postmenopausal women enrolled in the Women's Health Initiative Hormone Trial. These women were aged 50 to 79 and all had an intact uterus. Diabetes incidence was ascertained by self-report of treatment with insulin or oral hypoglycaemic medication. Fasting glucose, insulin, and lipoproteins were measured in a random sample at baseline and at 1 and 3 years.Results The cumulative incidence of treated diabetes was 3.5% in the hormone therapy group and 4.2% in the placebo group (hazard ratio 0.79, 95% CI 0.67-0.93, p=0.004). There was little change in the hazard ratio after adjustment for changes in BMI and waist circumference. During the first year of follow-up, changes in fasting glucose and insulin indicated a significant fall in insulin resistance in actively treated women compared to the control subjects (Year 1 to baseline between-group difference -0.22+/-0.10, p=0.03). INTERPRETATIONS/CONCLUSION: These data suggest that combined therapy with oestrogen and progestin reduces the incidence of diabetes, possibly mediated by a decrease in insulin resistance unrelated to body size. Future studies of alternative postmenopausal hormone therapy regimens and selective oestrogen agonists and/or antagonists should consider the effects of these regimens on insulin resistance and diabetes.

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  • Post-menopausal women are at increased risk of developing diabetes, an effect that can be mitigated by estrogen replacement therapy, suggesting an important role for estrogens in diabetes risk.

    “Post-menopausal women are also at increased risk of developing diabetes, an effect that can be mitigated by estrogen replacement therapy (74), suggesting an important role for estrogens in diabetes risk ( Table 1 ).”

    From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [74]

    The Results (page not available) report lower treated-diabetes incidence with oestrogen plus progestin than with placebo in postmenopausal women. The trial did not compare pre- and postmenopausal women, so it does not establish that menopause increases diabetes risk; it also tested combined therapy, not oestrogen alone. (LLM, conf=0.88)

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  • The majority of menopausal hormone therapy trials have been done in women of normal weight (BMI<30); as such, the reported impact of MHT on body weight and adiposity has been modest.

    “The majority of MHT trials have been done in women of normal weight (BMI<30); as such, the reported impact of MHT on body weight and adiposity has been modest (74, 204–206).”

    From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [74]

    The Results report a small reduction in BMI and waist circumference with oestrogen plus progestin, supporting the claim that the observed effects were modest. They give a mean baseline BMI of 28 for this trial, but the paper does not establish that most MHT trials enrolled women with BMI below 30 or that this explains the modest effects. (LLM, conf=0.86)

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Authors
for the Women’s Health Initiative Investigators, 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.
Affiliations
  • Hennepin County Medical Center (US)
  • Fred Hutch Cancer Center (US)
  • Emory University (US)
  • University of Wisconsin–Madison (US)
  • University of Arizona (US)
  • Wake Forest University Health Sciences (US)
  • Howard University (US)
Corresponding author
Margolis, K. L.
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2004-07
Volume
47
Issue
7
Pages
1175-1187
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-004-1448-x
OpenAlex
W2064176291
Cited by
599
References
66
Citations by year
2026: 17 · 2025: 15 · 2024: 27 · 2023: 33 · 2022: 29 · 2021: 30 · 2020: 23 · 2019: 26 · 2018: 23 · 2017: 36 · 2016: 31 · 2015: 25 · 2014: 21 · 2013: 29 · 2012: 30
FWCI
16.95
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Diabetologia (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Health and Human Services
  • National Institutes of Health (5k23hl003996-05, HS-07922)
  • Agency for Healthcare Research and Quality (HS 07922)
  • National Heart, Lung, and Blood Institute (K23 HL03996)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD001457, HD-01457)
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, diabetes incidence, insulin resistance, conjugated equine estrogens, medroxyprogesterone acetate, fasting blood glucose, insulin
MeSH terms
Aged, Alcohol Drinking, Energy Intake, Diabetes Mellitus, Double-Blind Method, Estrogens, Conjugated (USP), Female, Humans, Insulin Resistance, Middle Aged, Smoking, Body Mass Index, Incidence, Medroxyprogesterone Acetate, Patient Selection, Body Size

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