Testosterone with Dutasteride, but Not Anastrazole, Improves Insulin Sensitivity in Young Obese Men: A Randomized Controlled Trial

Juang, Patricia S.; Peng, Susan; Allehmazedeh, Kambiz; Shah, Ansal; Coviello, Andrea D.; Herbst, Karen L.

doi:10.1111/jsm.12368

Cited by 36Hormonal and reproductive studiesAdrenal Hormones and DisordersDiabetes, Cardiovascular Risks, and Lipoproteins

Testosterone with Dutasteride, but Not Anastrazole, Improves Insulin Sensitivity in Young Obese Men: A Randomized Controlled Trial

Juang, Patricia S., Peng, Susan, Allehmazedeh, Kambiz, Shah, Ansal, Coviello, Andrea D., Herbst, Karen L.·2014·The Journal of Sexual Medicine

DOI 10.1111/jsm.12368

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Abstract

Introduction: Testosterone (T) administration to men increases T, estradiol (E2), dihydrotestosterone (DHT), and fat-free mass (FFM), and decreases fat mass (FM) but does not consistently improve insulin sensitivity (IS). Aim: The aim of this study was to examine the effects of T administration in obese, nondiabetic men on body composition and IS, and to determine if inhibition (i) of metabolism of T to E2 with anastrazole or to DHT with dutasteride alters these effects. Methods: This was a 98-day randomized, double-blind, parallel group, placebo-controlled trial of 57 men, 24–51 year, free T in the lower 25% of normal range (<0.33 nmol/L), body mass index ≥30.0 kg/m2. Subjects were randomized to one of four groups: (i) placebo: gel, pills, and injection; (ii) T/DHT/iE2: T gel, anastrazole, and acyline (gonadotropin releasing-hormone antagonist to suppress endogenous T); (iii) T/iDHT/E2: T gel, dutasteride, and acyline; (iv) T/DHT/E2: T gel, placebo pills, and acyline. Main Outcome Measures: Main outcome measures are insulin sensitivity as percent change (%Δ) in glucose disposal rates (GDR) from a two-step euglycemic clamp (GDR1 and 2), and %FM and %FFM by dual X-ray absorptiometry scan. Results: Insulin Sensitivity: %Δ GDR1 differed across groups (P = 0.02, anova) and was significantly higher in the dutasteride (T/iDHT/E2) compared with the placebo and T gel (T/DHT/E2) groups. %ΔGDR2 was higher in the dutasteride (T/iDHT/E2) compared with the anastrazole (T/DHT/iE2) group. Body Composition: T gel alone (T/DHT/E2) or with dutasteride (T/iDHT/E2) significantly increased %FFM (P < 0.05) and decreased %FM (P < 0.05). There was no change in %FFM or %FM after placebo or anastrazole (T/DHT/iE2). Conclusions: The combination of T plus dutasteride improved body composition and IS while T alone improved body composition but not IS, suggesting that when T is administered to men, reduction to DHT attenuates the beneficial effects of aromatization to E2 on IS but not body composition.

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Inhibition of aromatase abrogated the fat-reducing effects of testosterone, but 5αR inhibition did not alter the effects of testosterone.
“Inhibition of aromatase abrogated these effects but consistent with the previous findings of Bhasin et al., 170 5αR inhibition did not alter the effects of testosterone.”
From The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments (2022) · cites this paper as [172]
Patients treated with testosterone exhibited significant reductions in fat mass.
“patients treated with testosterone exhibited significant reductions in fat mass.”
From The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments (2022) · cites this paper as [172]
Mechanistic studies in men where testosterone is administrated concomitantly with an AI suggest that the fat reducing effects of testosterone are at least in part dependent on its aromatization to E2.
“Mechanistic studies in men where testosterone is administrated concomitantly with an AI, 172 , 180 , 181 , 182 , 183 suggest that the fat reducing effects of testosterone are at least in part dependent on its aromatization to E2.”
From The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments (2022) · cites this paper as [172]

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Traish, A. M., Guay, A. T., & Zitzmann, M. (2014) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2014-0025 · Cited by 27 · see citing works
Mechanisms in endocrinology: hypogonadism and metabolic health in men—novel insights into pathophysiology
Miller, C., Madden-Doyle, L., Jayasena, C. N., McIlroy, M., Sherlock, M., & O’Reilly, M. (2024) · European Journal of Endocrinology · doi:10.1093/ejendo/lvae128 · Cited by 25 · see citing works
Obesity, Body Composition, and Sex Hormones: Implications for Cardiovascular Risk
Singh, P., Covassin, N., Marlatt, K. L., Gadde, K. M., & Heymsfield, S. B. (2021) · Comprehensive physiology · doi:10.1002/cphy.c210014 · Cited by 43 · see citing works
Estradiol for the mitigation of adverse effects of androgen deprivation therapy
Russell, N., Cheung, A. S., & Grossmann, M. (2017) · Endocrine Related Cancer · doi:10.1530/erc-17-0153 · Cited by 23 · see citing works
“In obese young men with low-normal or frankly low free T, a 14-week placebo-controlled RCT of an LHRH antagonist with exogenous testosterone gel 10 g/day combined with dutasteride (to inhibit testosterone conversion to the more potent AR agonist dihydrotestosterone, DHT), AI or placebo pill was performed to isolate th…”
MethodInfluential
Testosterone vs. aromatase inhibitor in older men with low testosterone: effects on cardiometabolic parameters
Dias, J. P., Shardell, M. D., Carlson, O. D., Melvin, D., Caturegli, G., Ferrucci, L., Chia, C. W., Egan, J. M., & Basaria, S. (2017) · Andrology · doi:10.1111/andr.12284 · Cited by 22 · see citing works
“In contrast, two recent mechanistic studies in young men showed that withdrawal of estradiol had no impact on insulin sensitivity (Rubinow et al., 2012; Juang et al., 2014); however, the role of estradiol in older men with age-related low testosterone remains unclear.”
Result
The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments
Venkatesh, V. S., Grossmann, M., Zajac, J. D., & Davey, R. A. (2022) · Obesity Reviews · doi:10.1111/obr.13429 · Cited by 22 · see citing works
“,(170) 5αR inhibition did not alter the effects of testosterone.(172) Taken together, this evidence suggests that while DHT does”
Background
Interaction of sex steroid hormones and obesity on insulin resistance and type 2 diabetes in men: the Third National Health and Nutrition Examination Survey
Li, J., Lai, H. C., Chen, S., Zhu, H., & Lai, S. (2016) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2016.10.022 · Cited by 20 · see citing works
Obesity, Body Composition, and Sex Hormones: Implications for Cardiovascular Risk
Singh, P., Covassin, N., Marlatt, K. L., Gadde, K. M., & Heymsfield, S. (2022) · Comprehensive physiology · doi:10.1002/j.2040-4603.2022.tb00200.x · Cited by 16 · see citing works
“Numerous studies reported that T treatment of hypogonadal men led to decreased fat mass and increased lean mass (6, 11, 54, 64, 66, 79, 83, 185, 311, 330, 538, 547, 566, 634).”
Influential
Circulating sex steroids coregulate adipose tissue immune cell populations in healthy men
Rubinow, K. B., Chao, J. H., Hagman, D. K., Kratz, M., Yserloo, B. V., Gaikwad, N. W., Amory, J. K., & Page, S. T. (2017) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00075.2017 · Cited by 11 · see citing works
“These seminal papers showing reductions in fat mass consequent to testosterone therapy have been reproduced in more recent studies, including cohorts of men with T2DM, severe obesity, and older age (7, 28, 29, 33, 42).”
Result
Update on late-onset hypogonadism: current concepts, controversies, clinical diagnosis, pathogenesis, and treatment approaches
Tang, X., Xu, Y., Ou, N., Tang, Y., & Chen, H. (2025) · Sexual Medicine Reviews · doi:10.1093/sxmrev/qeaf043 · Cited by 4 · see citing works
Androgens and Coronary Artery Disease
Wu, F. C. W., & von Eckardstein, A. (2003) · Humana Press eBooks · doi:10.1385/1-59259-388-7:191 · Cited by 13 · see citing works
Correlation Analysis between Hypogonadal Symptoms and Changes in Body Composition and Physical Fitness after Testosterone Treatment in Men with Testosterone Deficiency
Park, T. Y., Choi, M., Kim, D. S., Yeo, J. K., Rajasekaran, M. R., & Park, M. G. (2023) · The World Journal of Men s Health · doi:10.5534/wjmh.220274 · Cited by 2 · see citing works
“Several studies regarding the effects of TT on body composition have reported decreased body fat mass and visceral fat [12,13].”
Background
Other Hormonal Therapies and Men's Health
Hawksworth, D. J., & Burnett, A. L. “. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816665-9.00013-5 · Cited by 2 · see citing works
The effect of testosterone treatment on glucose metabolism and other health outcomes in men with type 2 diabetes: a randomized controlled trial
Gianatti, E. (2016) · Minerva Access (University of Melbourne)
Effect of testosterone therapy combined with a very low caloric diet in obese men: a randomised controlled trial
Fui, M. N. T., & Mark, A. (2017) · Minerva Access (University of Melbourne)

Testosterone with Dutasteride Improves Insulin Sensitivity in Young Obese Men.
Liao, P., & Herbst, K. (2010) · The Endocrine Society's 92nd Annual Meeting, June 19–22, 2010 - San Diego · doi:10.1210/endo-meetings.2010.part3.or2.or42-1
Self-citation
Effect of tadalafil administration on insulin secretion and insulin sensitivity in obese men
González-Ortı́z, M., Martínez‐Abundis, E., Hernández-Corona, D. M., & Ramírez-Rodríguez, A. M. (2017) · Acta Clinica Belgica · doi:10.1080/17843286.2017.1293759 · Cited by 11 · see citing works
OBSERVATIONS Androgen Therapy Improves Insulin Sensitivity and Decreases Leptin Level in Healthy Adult Men With Low Plasma Total
(2016)
The effects of testosterone treatment on body composition and metabolism in middle-aged obese men.
Mårin, P., Holmäng, S., Jönsson, L., Sjöström, L., Kvist, H., Holm, G., Lindstedt, G., & Björntorp, P. A. (1992) · PubMed · Cited by 553 · see citing works
Effects of treatment with testosterone alone or in combination with estrogen on insulin sensitivity in postmenopausal women
Zang, H., Carlström, K., Arner, P., & Hirschberg, A. L. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2005.12.039 · Cited by 70 · see citing works

Authors: Juang, P. S., Peng, S., Allehmazedeh, K., Shah, A., Coviello, A. D., & Herbst, K. L.
Affiliations: University of California San Diego (US)
VA San Diego Healthcare System (US)
Boston University (US)
Corresponding author: Herbst, Karen L.
ORCID: Peng, Susan
Coviello, Andrea D.
Herbst, Karen L.
Venue: The Journal of Sexual Medicine
Publisher: Oxford University Press (OUP)
Published: 2014-02-01
Volume: 11
Issue: 2
Pages: 563-573
ISSN: 1743-6095 (ISSN-L)
1743-6109
DOI: 10.1111/jsm.12368
OpenAlex: W2134463235
Cited by: 36
References: 45
Citations by year: 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2019: 3 · 2018: 2 · 2017: 8 · 2016: 5 · 2015: 4 · 2014: 7
FWCI: 4.20
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations: The Journal of Sexual Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5k23dk065038-06)
National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK 065038-05)
National Center for Research Resources (M01RR000827)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: testosterone, dutasteride, anastrozole, insulin sensitivity, insulin resistance, obesity, young men, body composition, fat-free mass, fat mass, glucose disposal rate, euglycemic clamp, androgen metabolism, aromatase inhibition, 5α-reductase inhibition, testosterone gel, acyline, GnRH antagonist, estradiol
MeSH terms: Dutasteride, Anastrozole, Adult, Azasteroids, Body Composition, Double-Blind Method, Drug Therapy, Combination, Estradiol, Humans, Insulin Resistance, Male, Middle Aged, Nitriles, Obesity, Dihydrotestosterone, Testosterone, Triazoles, Absorptiometry, Photon, Body Mass Index, Young Adult, 5-alpha Reductase Inhibitors

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Testosterone with Dutasteride, but Not Anastrazole, Improves Insulin Sensitivity in Young Obese Men: A Randomized Controlled Trial

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