Androgens: Clinical Research and TherapeuticsVol. 3, No. 1 EditorialOpen AccessCreative Commons licenseHypogonadotropic Hypogonadism in Diabesity: Pathogenic Factors and Therapeutic ImplicationsParesh Dandona, Sandeep Dhindsa, and Husam GhanimParesh Dandona*Address correspondence to: Paresh Dandona, BSc, MBBS, MD, DPhil, FRCP, Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, 1000 Youngs Road, Suite 105, Williamsville, NY 14221, USA. E-mail Address: pdandona@kaleidahealth.orgDivision of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York, USA.Search for more papers by this author, Sandeep Dhindsahttps://orcid.org/0000-0001-9342-9807Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York, USA.Division of Endocrinology, Diabetes and Metabolism, Saint Louis University, St. Louis, Missouri, USA.Search for more papers by this author, and Husam GhanimDivision of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York, USA.Search for more papers by this authorPublished Online:28 Dec 2022https://doi.org/10.1089/andro.2022.0019AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Hypogonadotropic hypogonadism (HH) was found to occur in 33% male patients with type 2 diabetes.1 These patients had low total and free testosterone concentrations with inappropriately low or normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations. Since the occurrence of hypogonadism was not related to either HbA1c or the duration of diabetes but to body mass index (BMI), a study in nondiabetic obese patients was carried out, which revealed a prevalence of HH in 25%.2 Thus, this is the commonest cause of hypogonadism in the community.These observations have added ∼18 million hypogonadal patients in the United States alone, based on the prevalence of type 2 diabetes and obesity. In a study comparing type 1 and type 2 diabetic patients, it was shown that the occurrence of HH was confined to type 2 diabetes.3 Since these observations were made in middle aged to older populations, a study in obese young males between 14 and 20 years of age was conducted.4 These patients were found to have similar prevalence of HH as reflected in the total and free testosterone, LH, and FSH concentrations.In these patients and older patients, testosterone concentrations were found to have an inverse relationship with BMI. Bariatric surgery with weight loss has been shown to raise testosterone concentrations. In the younger population with morbid obesity, the prevalence of HH was 75%.5 After bariatric surgery, testosterone levels normalized in the majority after 2 years and were maintained in those who maintained their weight loss but diminished again if they regained weight. Thus, body weight is a major determinant of plasma testosterone concentrations.It has also been demonstrated that diabetic patients with HH have increased insulin resistance when compared with those without.6 Testosterone patients restore insulin sensitivity as measured by Homeostatic Model Assessment of Insulin Resistance or euglycemic hyperinsulinemic clamps, while simultaneously reducing adiposity and increasing muscle mass. In HH patients, four genes in the insulin signaling pathway, insulin receptor β-subunit, IRS-1, Akt-2, and GLUT-4, had diminished expression. All four genes had normalized expression after testosterone replacement.Thus, testosterone is an insulin sensitizer.7 In addition, testosterone also increases the expression of activated protein kinase that induces an increase in glucose uptake independently of insulin signal transduction.8 Consistent with these observations, testosterone has been shown to prevent the development of diabetes in prediabetic patients, reverse prediabetes into a state of normality, and to reverse diabetes in 33% of patients with diabetes and HH for an 8-year period.9,10In addition to the mentioned effects, testosterone also increased the expression of the androgen receptor, the estrogen receptor, and aromatase, all of which are diminished in HH patients.11 Furthermore, testosterone also exerts anti-inflammatory effects that may be relevant to the inhibition of atherosclerosis and the control/prevention of infections.6 In this context, it is relevant that a very large retrospective study has shown that hypogonadal males have markedly increased cardiovascular mortality, whereas those hypogonadal patients whose testosterone had been replaced appropriately did not have such an increase.12Most recently, hypogonadal males have been shown to have two times higher incidence of hospitalization after COVID-19 infection, as compared with men with normal testosterone concentrations.13 This was independent of other known risk factors for hospitalization, such as age, comorbidities, immunosuppression, or body weight. Hypogonadal men with appropriate testosterone replacement did not experience an increase in these hospitalizations. Clearly, therefore, testosterone also has an anti-inflammatory effect that is clinically relevant.The most recent advance in HH and testosterone replacement was when obese males with either impaired glucose tolerance or early diabetes with testosterone concentrations <400 ng/dL were treated with depot testosterone 1000 mg every 3 months in addition to lifestyle change.14 The control arm was subjected to lifestyle change only with placebo injections. It was observed that plasma glucose concentrations fell, and diabetes was reversed in 21.1% of patients on testosterone as compared with 12.4% on lifestyle alone.There was a decrease in 2 h glucose by 31 mg/dL in the testosterone arm and 17 mg/dL in the control arm. Among the prediabetic patients, 7.6% patients progressed to diabetes in the testosterone arm, whereas 14.9% progressed to diabetes in the control arm. Among the early type 2 diabetic patients, there was a reversal of diabetes in 45.2% in the testosterone arm and only 32.1% in the control arm. In addition, there was a significantly greater reduction in waist circumference, total, and abdominal adiposity in the testosterone arm when compared with the control arm.Furthermore, there was an increase in total and arm muscle mass and the strength of the muscles in the nondominant hand. This large prospectively randomized study confirmed the previous observations in patients who had low normal rather than subnormal testosterone concentrations,14 as already discussed.6,7 An Austrian study has also recently confirmed a relationship between testosterone and insulin sensitivity and related metabolic indices in prediabetic males.15 Clearly, therefore, HH predisposes individuals to an insulin-resistant state and testosterone restores insulin sensitivity and can potentially reverse type 2 diabetes and prediabetes.6,15–17In conclusion, testosterone needs to be measured in all type 2 diabetes and obese patients, and if the concentrations are low, testosterone replacement has to be considered not only for its effects on sexual function but also for its metabolic effects that are profound and widespread.Author Disclosure StatementP.D. receives research support from National Institutes of Health; JDRF, ADA; Novo Nordisk; Bristol Meyer Squibb; AbbVie Pharmaceuticals; and Astra Zeneca, Boehringer Ingelheim Pharmaceuticals and honorarium from Eli Lilly; Novartis; GlaxoSmithKline; Merck; Novo Nordisk; Takeda; and Sanofi-Aventis. S.D. is a consultant for Bayer, Clarus Therapeutics. H.G. has no disclosures.Funding InformationThis study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 grant to PD; R01DK075877).References1. Dhindsa S, Prabhakar S, Sethi M, et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 2004;89(11):5462–5468; doi: 10.1210/jc.2004-0804 Crossref, Medline, Google Scholar2. Dhindsa S, Miller MG, McWhirter CL, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care 2010;33(6):1186–1192; doi: 10.2337/dc09-1649 Crossref, Medline, Google Scholar3. Tomar R, Dhindsa S, Chaudhuri A, et al. Contrasting testosterone concentrations in type 1 and type 2 diabetes. Diabetes Care 2006;29(5):1120–1122; doi: 10.2337/diacare.2951120 Crossref, Medline, Google Scholar4. Chandel A, Dhindsa S, Topiwala S, et al. Testosterone concentration in young patients with diabetes. Diabetes Care 2008;31(10):2013–2017; doi: 10.2337/dc08-0851 Crossref, Medline, Google Scholar5. Dhindsa S, Ghanim H, Jenkins T, et al. High prevalence of subnormal testosterone in obese adolescent males: Reversal with bariatric surgery. Eur J Endocrinol 2022;186(3):319–327; doi: 10.1530/EJE-21-0545 Crossref, Medline, Google Scholar6. Dhindsa S, Ghanim H, Batra M, et al. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care 2016;39(1):82–91; doi: 10.2337/dc15-1518 Crossref, Medline, Google Scholar7. Dandona P, Dhindsa S, Ghanim H, et al. Mechanisms underlying the metabolic actions of testosterone in humans: A narrative review. Diabetes Obes Metab; 2021;23(1):18–28; doi: 10.1111/dom.14206 Crossref, Medline, Google Scholar8. Ghanim H, Dhindsa S, Batra M, et al. Testosterone increases the expression and phosphorylation of AMP kinase alpha in men with hypogonadism and type 2 diabetes. J Clin Endocrinol Metab 2020;105(4); doi: 10.1210/clinem/dgz288 Crossref, Google Scholar9. Haider KS, Haider A, Saad F, et al. Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study. Diabetes Obes Metab 2020;22(11):2055–2068; doi: 10.1111/dom.14122 Crossref, Medline, Google Scholar10. Yassin A, Haider A, Haider KS, et al. Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes: Eight-year data from a registry study. Diabetes Care 2019;42(6):1104–1111; doi: 10.2337/dc18-2388 Crossref, Medline, Google Scholar11. Ghanim H, Dhindsa S, Abuaysheh S, et al. Diminished androgen and estrogen receptors and aromatase levels in hypogonadal diabetic men: Reversal with testosterone. Eur J Endocrinol 2018;178(3):277–283; doi: 10.1530/EJE-17-0673 Crossref, Medline, Google Scholar12. Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 2015;36(40):2706–2715; doi: 10.1093/eurheartj/ehv346 Crossref, Medline, Google Scholar13. Dhindsa S, Champion C, Deol E, et al. Association of male hypogonadism with risk of hospitalization for COVID-19. JAMA Netw Open 2022;5(9):e2229747; doi: 10.1001/jamanetworkopen.2022.29747 Crossref, Medline, Google Scholar14. Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): A randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. Lancet Diabetes Endocrinol 2021;9(1):32–45; doi: 10.1016/S2213-8587(20)30367-3 Crossref, Medline, Google Scholar15. Leutner M, Matzhold C, Bellach L, et al. Increase in testosterone levels is related to a lower risk of conversion of prediabetes to manifest diabetes in prediabetic males. Wien Klin Wochenschr 2022;134(1–2):1–6; doi: 10.1007/s00508-021-01903-1 Crossref, Medline, Google Scholar16. Yeap BB, Wittert GA. Testosterone, diabetes risk, and diabetes prevention in men. Endocrinol Metab Clin North Am 2022;51(1):157–172; doi: 10.1016/j.ecl.2021.11.004 Crossref, Medline, Google Scholar17. Jenkins CR, Rittel A, Sturdivant RX, et al. Glycemic benefits with adherence to testosterone therapy in men with hypogonadism and type 2 diabetes mellitus. Andrology 2021;9(4):1076–1085; doi: 10.1111/andr.12990 Crossref, Medline, Google ScholarCite this article as: Dandona P, Dhindsa S, Ghanim H (2022) Hypogonadotropic hypogonadism in diabesity: pathogenic factors and therapeutic implications, Androgens: Clinical Research and Therapeutics 3.1, 214–216, DOI: 10.1089/andro.2022.0019.Abbreviations UsedBMIbody mass indexFSHfollicle-stimulating hormoneHHhypogonadotropic hypogonadismLHluteinizing hormoneFiguresReferencesRelatedDetails Volume 3Issue 1Dec 2022 Information© Paresh Dandona et al., 2022; Published by Mary Ann Liebert, Inc.To cite this article:Paresh Dandona, Sandeep Dhindsa, and Husam Ghanim.Hypogonadotropic Hypogonadism in Diabesity: Pathogenic Factors and Therapeutic Implications.Androgens: Clinical Research and Therapeutics.Dec 2022.214-216.http://doi.org/10.1089/andro.2022.0019creative commons licensePublished in Volume: 3 Issue 1: December 28, 2022Open accessThis Open Access article is distributed under the terms of the Creative Commons License [CC-BY] ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.PDF download

Paresh Dandona

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Hypogonadotropic Hypogonadism in Diabesity: Pathogenic Factors and Therapeutic Implications

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