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Updated: Mar 16, 2026
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Short-Term Estrogen Withdrawal Increases Adiposity in Healthy Men
Jing Chao1, Katya B Rubinow1, Mario Kratz1
1Center for Research in Reproduction and Contraception (J.C., K.B.R., S.T.P., J.K.A.) and Diabetes Institute, Division of Metabolism, Endocrinology, and Nutrition (K.B.R. and S.T.P.) and Division of Gerontology & Geriatric Medicine (A.M.M.), Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195; The Fred Hutchinson Cancer Research Center (M.K.); and the Geriatric Research, Education and Clinical Center (A.M.M.), VA Puget Sound Health Care System, Seattle, Washington 98108.
Context:
T deprivation increases risk of insulin resistance in men, but whether this risk is independent of changes in body composition is unknown. Further, the metabolic roles of T and its metabolite estradiol have not been clearly defined in men.
Objective:
This study sought to establish the effects of selective sex steroid withdrawal on insulin sensitivity in healthy men.
Design, Setting, And Participants:
This was a double-blinded, placebo-controlled, randomized trial at an academic medical center of 56 healthy men, 19-55 years of age.
Interventions:
Subjects received the GnRH antagonist acyline plus one of the following: placebo gel (Castrate), 1.25 g testosterone gel (Low T/E), 5 g testosterone gel (Normal T/E), or 5 g testosterone gel with letrozole (Normal T/Low E) daily for 4 weeks. Body composition and glucose tolerance were assessed at baseline and end of treatment.
Main Outcome Measure:
Insulin sensitivity was quantified by the Matsuda index.
Results:
Predicted circulating sex steroid concentrations were achieved in all treatment groups. The time-by-group interaction for Matsuda index did not achieve significance in overall repeated measures ANOVA (baseline vs week 4; P = .16). A significant time-by-group interaction was observed for fat mass (P = .003), with changes in fat mass attributable predominantly to estrogen exposure in linear regression analysis (P = .016). A time-by-group interaction also was observed for lean mass (P = .03) and influenced by androgen exposure (P = .003).
Conclusions:
Short-term sex steroid withdrawal in healthy men causes adverse changes in body composition. These findings support the role of estradiol as a determinant of adiposity in men.
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