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Cited by 95Hormonal and reproductive studiesHypothalamic control of reproductive hormonesGrowth Hormone and Insulin-like Growth Factors

Late‐onset hypogonadism: metabolic impact

Open access
Grossmann, M., Ng Tang Fui, M., Cheung, A. S.·2020·Andrology
DOI 10.1111/andr.12705
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Abstract

Background: Obesity and dysglycemia (comprising insulin resistance, the metabolic syndrome and type 2 diabetes), that is diabesity, are associated with reduced circulating testosterone and, in some men, clinical features consistent with androgen deficiency. Objective: To review the metabolic impact of late‐onset hypogonadism. Methods: Comprehensive literature search with emphasis on recent publications. Results: Obesity is one of the strongest modifiable risk factors for late‐onset hypogonadism, and coexisting diabetes leads to further hypothalamic‐pituitary‐testicular axis suppression. The hypothalamic‐pituitary‐testicular axis suppression is functional and hence potentially reversible, and occurs predominantly at the level of the hypothalamus. While definitive mechanistic data are lacking, the evidence suggests that hypothalamic‐pituitary‐testicular axis suppression is mediated by dysregulation of pro‐inflammatory cytokines leading to hypothalamic inflammation. Dysregulation of central leptin and insulin signaling may also contribute. In contrast, recent data challenge the paradigm that estradiol excess is a major contributor to hypothalamic‐pituitary‐testicular axis suppression. Instead, relative estradiol signaling deficiency may contribute to metabolic dysregulation in men with diabesity. While weight loss and optimization of comorbidities can reverse functional hypothalamic‐pituitary‐testicular axis suppression, testosterone treatment leads to metabolically favorable changes in body composition and to improvements in insulin resistance. Discussion: The relationship between diabesity and late‐onset hypogonadism is bidirectional. Preliminary evidence suggests that, in carefully selected men, lifestyle measures and testosterone treatment may have additive effects. Conclusions: While recent research has provided new insights into mechanistic and clinical aspects of diabesity‐associated late‐onset hypogonadism, more evidence from well‐designed large trials is needed to guide the optimal clinical approach to such men.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes evidence that obesity and dysglycemia (“diabesity”) suppress the hypothalamic-pituitary-testicular axis, while low testosterone may also promote metabolic dysfunction. It concludes that testosterone treatment consistently improves body composition and modestly improves insulin resistance, but not glycemic control, and that more large trials are needed.

Key findings

  • Obesity is a dominant modifiable risk factor for low testosterone: in EMAS, men with BMI >30 kg/m² had 30% lower testosterone, equivalent to almost 3 decades of aging, and a 13-fold increase in LOH prevalence versus BMI <25 kg/m².
  • Diabetes adds a modest testosterone reduction: obese men with diabetes had 0.8 nmol/L lower total testosterone than obese men without diabetes; a meta-analysis attributed a 2.98 nmol/L relative reduction in total testosterone to T2DM, and free testosterone was 32 pmol/L lower in men with T2DM.
  • Weight loss raises testosterone modestly: diet-associated ~10% body weight loss increased testosterone by 2.87 nmol/L (95% CI 1.68; 4.07), while bariatric surgery (~30% weight loss) increased total testosterone by 8.73 nmol/L (95% CI 6.51; 10.95); in one RCT, an 11 kg diet-induced weight loss raised testosterone by only 2.9 nmol/L and was not sustained 18 months after trial end.
  • Testosterone treatment effects are mixed: a meta-analysis of 7 placebo-controlled double-blind RCTs found improved insulin resistance (pooled MD −1.58, 95% CI −2.25; −0.91, p<0.001) but no HbA1c improvement (MD −0.15, 95% CI −0.39; 0.10, p=0.25); a larger meta-analysis of 59 trials (~5,100 older men) found decreased fat mass (SMD −0.34, 95% CI −0.48; −0.20, p<0.001), increased lean mass (0.55, 95% CI 0.3–0.72, p<0.001), and improved HOMA-IR (−0.80, 95% CI −1.16; −0.45, p<0.001).

Methods

  • Narrative review based on multiple PubMed searches using terms including “testosterone,” “estradiol,” “obesity,” “diabetes,” “insulin resistance,” “metabolic syndrome,” and “late onset hypogonadism” to June 2019, with emphasis on work published from 2016 onwards.
  • The review considers epidemiologic studies, mechanistic preclinical and human studies, clinical trials, meta-analyses, and registry studies; it is not a systematic review or meta-analysis.
  • Main synthesis focuses on the bidirectional relationship between diabesity and late-onset hypogonadism, including HPT-axis suppression mechanisms, SHBG and estradiol roles, and metabolic effects of testosterone treatment.

Limitations

  • Stated: definitive mechanistic data are lacking; observational studies cannot establish causality or direction; estradiol was often measured by immunoassay, which lacks accuracy in men; more evidence from well-designed large trials is needed.
  • Stated for included trials: heterogeneity in inclusion criteria and testosterone formulations, short duration (often <12 months; mean 8.7 months in one meta-analysis), small samples, participants not uniformly hypogonadal, and generally well-controlled diabetes at baseline.
  • Stated for registry studies: observational design, lack of randomization or blinding, baseline imbalances, and lack of information on concomitant cardiometabolic medications; evident from the text, the review itself is not systematic and does not report formal risk-of-bias assessment.

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Integrity signals

Registry

Crossref · 10.1111/andr.12705

Cites

79 of 79 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 114 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    Obesity is one of the strongest modifiable risk factors for LOH.

    “Obesity is one of the strongest modifiable risk factors for LOH, and coexisting diabetes leads to further hypothalamic-pituitary-testicular (HPT) axis suppression.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In the most recent meta-analysis, the relative reduction of total testosterone concentrations attributable to T2DM (irrespective of BMI) was 2.98 nmol/L, measured by immunoassays in most studies.

    “Indeed in the most recent meta-analysis, the relative reduction of total testosterone concentrations attributable to T2DM (irrespective of BMI) was relatively modest, 2.98 nmol/L, measured by immunoassays in most studies (Zhang, et al., 2019)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhang, et al., 2019

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  • Premisecitation

    LOH related to diabesity usually presents as the secondary (central) form.

    “While age-related HPT axis changes manifest predominantly as primary and compensated forms, LOH related to diabesity usually presents as the secondary (central) form (Kaufman, et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kaufman, et al., 2019

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  • Interpretationnone given

    HPT axis suppression is mediated by dysregulation of pro-inflammatory cytokines leading to hypothalamic inflammation.

    “While definitive mechanistic data are lacking, the evidence suggests that HPT axis suppression is mediated by dysregulation of pro-inflammatory cytokines leading to hypothalamic inflammation.”
    Quote in the paperNot a substantial claim
  • Interpretationnone given

    Preliminary evidence suggests that, in carefully selected men, lifestyle measures and testosterone treatment may have additive effects.

    “Preliminary evidence suggests that, in carefully selected men, lifestyle measures and testosterone treatment may have additive effects.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 57
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisenone given

    Obesity and dysglycemia (diabesity) are associated with reduced circulating testosterone and, in some men, clinical features consistent with androgen deficiency.

    “Obesity and dysglycemia (comprising insulin resistance, the metabolic syndrome and type 2 diabetes), i.e. diabesity, are associated with reduced circulating testosterone and, in some men, clinical features consistent with androgen deficiency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The HPT axis suppression is functional and hence potentially reversible.

    “The HPT axis suppression is functional and hence potentially reversible, and occurs predominantly at the level of the hypothalamus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the presence of obesity, type 2 diabetes is associated with an additional reduction in testosterone, although this reduction is comparatively modest.

    “In the presence of obesity, type 2 diabetes (T2DM) is associated with an additional reduction in testosterone, although this reduction is comparatively modest; in one large study in obese men, those with diabetes had a 0.8 nmol/L lower total testosterone concentration (by LCMS) compared to obese men without diabetes (Dhindsa, et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dhindsa, et al., 2010

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    Premisecitation

    In EMAS, obese men (BMI >30 kg/m2) had a 30% lower testosterone concentration, a reduction equivalent to almost 3 decades of aging, and a 13-fold increase in LOH prevalence compared to men with a BMI of <25 kg/m2.

    “In the European Male Ageing Study (EMAS), obese men (body mass index (BMI) >30 kg/m 2 ) had a 30% lower testosterone concentration (measured by liquid chromatography/mass spectrometry (LCMS)), a reduction equivalent to almost 3 decades of aging, and a 13-fold increase in LOH prevalence compared to men with a BMI of <25 kg/m 2 (Wu, et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wu, et al., 2010

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Sexual symptoms are the most specific symptoms for LOH.

    “noting that causality is not always certain and that sexual symptoms are the most specific (Wu, et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wu, et al., 2010

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Dysregulation of central leptin and insulin signalling may also contribute to HPT axis suppression.

    “Dysregulation of central leptin and insulin signalling may also contribute.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Weight loss and optimisation of comorbidities can reverse functional HPT axis suppression.

    “While weight loss and optimisation of comorbidities can reverse functional HPT axis suppression, testosterone treatment leads to metabolically favourable changes in body composition, and to improvements in insulin resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the meta-analysis, men with diabetes had lowered free testosterone concentrations (by 32 pmol/L) compared to men without T2DM, suggesting an SHBG-independent association.

    “In the aforementioned metaanalysis, men with diabetes also had lowered free testosterone concentrations (by 32 pmol/L) compared to men without T2DM (Zhang, et al., 2019), suggesting an SHBG-independent association.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhang, et al., 2019

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  • May combine two claims.

    Premisenone given

    Testosterone treatment leads to metabolically favourable changes in body composition and to improvements in insulin resistance.

    “While weight loss and optimisation of comorbidities can reverse functional HPT axis suppression, testosterone treatment leads to metabolically favourable changes in body composition, and to improvements in insulin resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    Free testosterone was derived differently in individual studies, calculated by various formulae and from different immunoassays, limiting the precision of these findings.

    “Free testosterone was derived differently in individual studies, calculated by various formulae and from different immunoassays, limiting the precision of these findings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Observational studies suggest that low testosterone is associated with, and predicts future adverse metabolic outcomes, such as insulin resistance, the metabolic syndrome, T2DM and obesity.

    “In summary, observational studies suggest that low testosterone is associated with, and predicts future adverse metabolic outcomes, such as insulin resistance, the metabolic syndrome, T2DM and obesity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Free testosterone predicted incident metabolic syndrome in a patient level meta-analysis, although more weakly than total testosterone or SHBG.

    “Likewise, free testosterone predicted incident metabolic syndrome in a patient level meta-analysis, although more weakly than total testosterone or SHBG (Brand, et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brand, et al., 2014

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    Premisecitation

    In a prospective cohort study of 5,350 men, low total testosterone and low SHBG were associated with an increased risk of future T2DM development, while free testosterone and LH were not predictive.

    “In contrast, in a prospective cohort study of 5,350 men, while low total testosterone and low SHBG were associated with an increased risk of future T2DM development, free testosterone and LH were not predictive (Holmboe, et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Holmboe, et al., 2016

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    Premisecitation

    In a recent prospective study of 141 younger mostly insulin resistant men, insulin resistance predicted hypogonadism somewhat more strongly (risk ratio=2.2) than hypogonadism predicted insulin resistance (risk ratio=1.3) (p=0.03).

    “Consistent with earlier work, in a recent prospective study of 141 younger (mean age 43 years) mostly insulin resistant men, insulin resistance (measured using an octreotidebased pancreatic suppression test) predicted hypogonadism (defined as a total testosterone <10.4 nmol/L) somewhat more strongly (risk ratio= 2.2) than hypogonadism predicted insulin resistance (risk ratio=1.3)(p=0.03)(Contreras”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Contreras, et al., 2018

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  • May combine two claims.

    Interpretationreasoning

    While some of the low testosterone-diabesity associations reflect lowered SHBG, the observational data strongly suggest androgen-diabesity interactions that are independent of SHBG.

    “In summary, while some of the low testosterone-diabesity associations reflect lowered SHBG, the observational data strongly suggest androgen-diabesity interactions that are independent of SHBG.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a larger prospective study among 1,400 Swedish men, low baseline testosterone predicted insulin resistance, but high insulin resistance at baseline did not predict low testosterone at follow-up.

    “However in a larger prospective study among 1,400 Swedish men (mean age 58 years), low baseline testosterone predicted insulin resistance (measured by HOMA-IR), but high insulin resistance at baseline did not predict low testosterone at follow-up (Ottarsdottir, et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ottarsdottir, et al., 2018

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    Premisecitation

    In a recent bi-directional Mendelian study, a genetically instrumented increase in BMI was associated with a decrease in serum testosterone, whereas no association was seen for genetically instrumented testosterone with BMI.

    “In a recent bi-directional Mendelian study, a genetically instrumented increase in BMI was associated with a decrease in serum testosterone, whereas no association was seen for genetically instrumented testosterone with BMI (Eriksson, et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Eriksson, et al., 2017

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    Premisecitation

    Only metabolically unhealthy, but not metabolically healthy obese men had worse self-reported and objective sexual function compared to nonobese men.

    “Only metabolically unhealthy, but not metabolically healthy obese men had worse self-reported and objective (by penile doppler ultrasound) sexual function compared to nonobese men.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lotti, et al., 2019

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    Interpretationcitation

    There is stronger clinical evidence that obesity (and to a lesser extent diabetes, especially if poorly controlled) has a greater effect on reducing testosterone, compared to the lesser effect that low testosterone has on promoting diabesity.

    “Overall, there is stronger clinical evidence that obesity (and to a lesser extent diabetes, especially if poorly controlled (Grossmann and Matsumoto, 2017)) has a greater effect on reducing testosterone, compared to the lesser effect that low testosterone has on promoting diabesity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grossmann and Matsumoto, 2017

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  • May combine two claims.

    Premisecitation

    Infusing the proinflammatory cytokine interleukin-2 at a relatively low dose reduced LH stimulated testosterone secretion and augmented testosterone-mediated negative LH feedback.

    “A recent experimental study in adult men reported that infusing the proinflammatory cytokine interleukin-2 (IL-2) at a relatively low dose reduced LH stimulated testosterone secretion and augmented testosterone-mediated negative LH feedback (Veldhuis and Bowers, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Veldhuis and Bowers, 2009

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    Premisecitation

    Greater treatment effects were seen in men with a baseline C-reactive protein >2mg/L (2.14 nmol/L, 95%CI 0.1; 4.9, p=0.04) or a BMI>40 kg/m2 (2.64 nmol/L, 95%CI 0.2; 5.9, p=0.04).

    “Greater treatment effects were seen in men with a baseline C-reactive protein >2mg/L (2.14 nmol/L, 95%CI 0.1; 4.9, p=0.04) or a BMI>40 kg/m 2 (2.64 nmol/L, 95%CI 0.2; 5.9, p=0.04) (Ebrahimi, et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ebrahimi, et al., 2018

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    Premisecitation

    High fat diet-induced hypogonadotropic hypogonadism in male rabbits was associated with increased hypothalamic inflammation, increased hypothalamic expression of pro-inflammatory cytokines and reduced expression of the kisspeptin-1 receptor.

    “This study demonstrated that high fat diet-induced hypogonadotropic hypogonadism was associated with increased hypothalamic inflammation, increased hypothalamic expression of pro-inflammatory cytokines and reduced expression of the kisspeptin-1 receptor (Morelli, et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Morelli, et al., 2014

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  • May combine two claims.

    Premisecitation

    Fat mass increased by 3.5 kg [95%CI 2.0; 5.0] and lean mass decreased by 1.5 kg (95%CI 0.2; 1.8), associated with a 30% increase in insulin resistance (measured by HOMA-IR).

    “Fat mass increased by 3.5 kg [95%CI 2.0; 5.0] and lean mass decreased by 1.5 kg (95%CI 0.2; 1.8), associated with a 30% increase in insulin resistance (measured by HOMA-IR) (Cheung, et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cheung, et al., 2016

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    Premisecitation

    Testosterone has been reported to reduce pro-inflammatory cytokines in vitro and in vivo, to increase insulin sensitivity in both muscle and adipose tissue and to promote catecholamine-induced lipolysis.

    “For example, reviewed in detail elsewhere (Dhindsa, et al., 2018, Gianatti and Grossmann, 2019, Grossmann, 2018, Rastrelli, et al., 2018), testosterone has been reported to reduce pro-inflammatory cytokines in vitro and in vivo, to increase insulin sensitivity in both muscle and adipose tissue and to promote catecholamine-induced lipolysis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dhindsa, et al., 2018

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    • cites Gianatti and Grossmann, 2019

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    • cites Grossmann, 2018

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    Premisecitation

    In an RCT in obese men with experimentally induced hypogonadism, testosterone plus dutasteride reduced fat mass and improved insulin sensitivity whereas testosterone plus anastrozole did not; testosterone alone reduced fat mass but had no effects on insulin sensitivity.

    “Using hyperglycemic-euglycemic clamps, they found that testosterone plus dutasteride reduced fat mass and improved insulin sensitivity whereas testosterone plus anastrozole did not.Testosterone alone reduced fat mass but had no effects on insulin sensitivity (Juang, Peng, Allehmazedeh, Shah, Coviello and Herbst, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Juang, et al., 2013

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Reduced tissue receptor-mediated signalling may augment the effects of reduced circulating sex steroids in some hypogonadal men.

    “This suggests that, if confirmed, reduced tissue receptor-mediated signalling may augment the effects of reduced circulating sex steroids in some hypogonadal men (Ghanim, et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ghanim, et al., 2018

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    Premisecitation

    Insulin resistance has been documented in aromatase-deficient men and in a variety of tissue-specific estrogen alpha receptor male knock out mice, collectively suggesting that estrogen alpha receptor signalling in liver, brain, skeletal muscle and adipose tissue may favour insulin sensitivity.

    “Insulin resistance has also been documented in aromatase-deficient men and in a variety of tissue-specific estrogen alpha receptor male knock out mice, collectively suggesting that estrogen alpha receptor signalling in liver, brain, skeletal muscle and adipose tissue may favour insulin sensitivity (Russell and Grossmann, 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Russell and Grossmann, 2019

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    Premisecitation

    Testosterone treatment has no consistent effects on visceral adipose tissue mass and on glycemic control, measured by HbA1c.

    “In contrast, testosterone treatment has no consistent effects on visceral adipose tissue mass and on glycemic control, measured by HbA1c.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In a recent experimental RCT using hyperinsulinemic-euglycemic clamps, aromatase inhibitor treatment reduced insulin-stimulated glucose disposal, inferring a beneficial metabolic role for estradiol.

    “In a recent experimental RCT using hyperinsulinemic-euglycemic clamps, aromatase inhibitor treatment reduced insulin-stimulated glucose disposal, again inferring a beneficial metabolic role for estradiol (Gibb, et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gibb, et al., 2016

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    Premisecitation

    A meta-analysis restricted to placebo-controlled double-blind RCTs (n=7) concluded that testosterone treatment modestly improved insulin resistance, compared to placebo, pooled mean difference (MD) -1.58 (95%CI -2.25; -0.91, p<0.001) but did not improve glycemic (HbA1c) control, MD -0.15 (95%CI -0.39; 0.10), p=0.25.

    “A meta-analysis restricted to placebo-controlled double-blind RCTs (n=7) concluded that testosterone treatment modestly improved insulin resistance, compared to placebo, pooled mean difference (MD) -1.58 (95%CI -2.25; -0.91, p<0.001) but did not improve glycemic (HbA1c) control, MD -0.15 (95%CI -0.39; 0.10), p=0.25 (Grossmann, et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grossmann, et al., 2015

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    Premisecitation

    HOMA-IR improved (-0.80 (95%CI 1.16; -0.45, p<0.001), as did fasting glycemia (-0.34 mM (95%CI -5.1; -0.17, p<0.001).

    “HOMA-IR improved, (-0.80 (95%CI 1.16; -0.45, p<0.001), as did fasting glycemia (-0.34 mM (95%CI -5.1; -0.17, p<0.001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Corona, et al., 2016

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    Premisecitation

    Overall, findings suggested that testosterone treatment consistently and modestly increases lean mass (by about 2kg), decreases fat mass (by about 2kg), and modestly improves insulin resistance in most but not all studies.

    “Overall, findings suggested that testosterone treatment consistently and modestly increases lean mass (by about 2kg), decreases fat mass (by about 2kg), and modestly improves insulin resistance in most but not all studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Overall the bulk of the evidence suggests that in men, testosterone reduces fat mass by both androgen receptor and estrogen receptor signalling, and that aromatization of testosterone to estradiol is required to improve glucose metabolism.

    “Overall the bulk of the evidence suggests that in men, testosterone reduces fat mass by both androgen receptor and estrogen receptor signalling, and that aromatization of testosterone to estradiol is required to improve glucose metabolism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a secondary analysis of a subgroup of 134 nondiabetic men enrolled in the TEAM trial, with a mean baseline age of 66 years, BMI of 28 kg/m2 and total testosterone of 11.4 nmol/L, 3 years of topical testosterone gel (achieving mean serum testosterone 16.6 nmol/L in the testosterone group) had no effect on body weight, or on insulin sensitivity, evaluated by octreotide insulin suppression testing

    “In a secondary analysis of a subgroup of 134 nondiabetic men enrolled in the Testosterone Effects on Atherosclerosis in Aging Men (TEAM) trial, with a mean baseline age of 66 years, BMI of 28 kg/m 2 and total testosterone of 11.4 nmol/L, 3 years of topical testosterone gel (achieving mean serum testosterone 16.6 nmol/L in the testosterone group) had no effect on body weight, or on insulin”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huang, et al., 2018

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  • May combine two claims.

    Premisecitation

    In uncontrolled observational studies, testosterone therapy (long acting intramuscular testosterone undecanoate) in a cohort of 411 obese men with hypogonadism was associated with weight loss ranging from ~15 to 30 kg and decreases in waist circumference >10 cm over mean 6 years.

    “In uncontrolled observational studies, the effects of testosterone therapy (using long acting intramuscular testosterone undecanoate) have been impressive; in a cohort of 411 obese men selected from a urology registry with a baseline mean age of 59 years and hypogonadism (defined as testosterone <12.1 nmol/L and presence of symptoms measured with the Aging Males' symptom scale (AMS)), testosterone”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Saad, et al., 2016

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    Premisecitation

    Men receiving testosterone had improvements in lipid parameters, reduced incidence of acute myocardial infarction and reduced mortality relative to controls.

    “Men receiving testosterone had improvements in lipid parameters, reduced incidence of acute myocardial infarction and reduced mortality relative to controls (Yassin, et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yassin, et al., 2019

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    Study design and conductcitation

    Limitations of these studies include the observational nature with lack of randomization or blinding, baseline imbalances in clinical characteristics and lack of information regarding concomitant cardiometabolic medications and their changes.

    “Limitations of these studies include the observational nature with lack of randomization or blinding, baseline imbalances in clinical characteristics (Yassin, et al., 2019) and lack of information regarding concomitant cardiometabolic medications and their changes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yassin, et al., 2019

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  • May combine two claims.

    Interpretationreasoning

    Weight loss has not been documented in RCTs, attributed to their shorter duration.

    “The fact that weight loss has not been documented in RCTs was attributed to their shorter duration”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    Men participating in the trials were not uniformly hypogonadal (mean baseline total testosterone was 11.6 nmol/L) and mean trial duration was only 8.7 months.

    “Men participating in the trials were not uniformly hypogonadal (mean baseline total testosterone was 11.6 nmol/L) and mean trial duration was only 8.7 months (Corona, et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Corona, et al., 2016

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    Premisecitation

    A subsequent magnetic resonance analysis of this cohort demonstrated no effect of testosterone treatment on metabolically adverse hepatic or visceral fat, but testosterone decreased the potentially insulin sensitizing adipokine adiponectin.

    “A subsequent magnetic resonance analysis of this cohort demonstrated no effect of testosterone treatment on metabolically adverse hepatic or visceral fat, but testosterone decreased the potentially insulin sensitizing adipokine adiponectin (Magnussen, et al., 2017).”
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    • cites Magnussen, et al., 2017

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    Premisecitation

    In contrast, a 24-week clamp study enrolling 44 hypogonadal men (defined as free testosterone < 225 pmol/L with a mean age 55 years, BMI 40 kg/m2, HOMA-IR of 3.9, and HbA1c of 7.0%) while similarly demonstrating no change in visceral hepatic fat, found a 32% increase in insulin sensitivity with intramuscular testosterone treatment (p=0.03 for comparison with placebo), in association with up

    “In contrast, a 24-week clamp study enrolling 44 hypogonadal men (defined as free testosterone < 225 pmol/L with a mean age 55 years, BMI 40 kg/m 2 , HOMA-IR of 3.9, and HbA1c of 7.0%) while similarly demonstrating no change in visceral hepatic fat, found a 32% increase in insulin sensitivity with intramuscular testosterone treatment (p=0.03 for comparison with placebo), in association with up”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dhindsa, et al., 2016

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  • May combine two claims.

    Study design and conductnone given

    Limitations inherent in the meta-analyzed studies include heterogeneity in inclusion criteria and testosterone treatment formulations.

    “Limitations inherent in the meta-analyzed studies include heterogeneity in inclusion criteria and testosterone treatment formulations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the large Testosterone trial which included 788 men older than 65 years (at baseline, 72% were obese, and 37% had diabetes) with a serum testosterone of <9.51 mmol/L averaged from 2 measurements, 12 months of testosterone treatment (adjusted to mid-normal concentrations for healthy men) modestly reduced insulin resistance, HOMA-IR -0.6, p=0.03, but did not have an effect on body weight or waist

    “In the large Testosterone trial which included 788 men older than 65 years (at baseline, 72% were obese, and 37% had diabetes) with a serum testosterone of <9.51 mmol/L averaged from 2 measurements, 12 months of testosterone treatment (adjusted to mid-normal concentrations for healthy men) modestly reduced insulin resistance, HOMA-IR -0.6, p=0.03, but did not have an effect on body weight or waist”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mohler, et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In one 24-week study of 39 men with a bioavailable testosterone of 7.3 nmol/L (mean age 60 years, BMI 31 kg/m2, HOMA-IR of 3.5 and HbA1c of 6.5%), testosterone gel treatment, despite expected changes in body composition (increase in lean mass by 1.9kg and decrease in fat mass by 1.3kg), had no effect on insulin sensitivity assessed by clamp, nor on HOMA-IR or on HbA1c

    “In one 24-week study of 39 men with a bioavailable testosterone of 7.3 nmol/L (mean age 60 years, BMI 31 kg/m 2 , HOMA-IR of 3.5 and HbA1c of 6.5%), testosterone gel treatment, despite expected changes in body composition (increase in lean mass by 1.9kg and decrease in fat mass by 1.3kg), had no effect on insulin sensitivity assessed by clamp, nor on HOMA-IR or on HbA1c (Magnussen, et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Magnussen, et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    90% of men in the testosterone group achieved a HbA1c <5.7%, whereas in 40% of controls HbA1c increased to more than 6.5%.

    “90% of men in the testosterone group achieved a HbA1c <5.7%, whereas in 40% of controls HbA1c increased to more than 6.5%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yassin, et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In summary, the overall evidence from clinical trials suggests that testosterone has consistent effects on body composition that may be expected to be metabolically favorable, in particular increases in lean mass and decreases in total fat mass.

    “In summary, the overall evidence from clinical trials suggests that testosterone has consistent effects on body composition that may be expected to be metabolically favorable, in particular increases in lean mass and decreases in total fat mass.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both groups had improvements in HOMA-IR, HbA1c and lipid parameters.

    “While both groups had improvements in HOMA-IR, HbA1c and lipid parameters”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ng Tang Fui, et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the meta-analysis by Corona, if only men with a baseline testosterone <12 nmol/L were considered, similar reductions in total cholesterol (-0.35 mmol/L) and triglycerides (-0.22 mmol/L) were observed, and again, no effect on HDL or LDL cholesterol.

    “In the aforementioned metaanalysis by Corona, if only men with a baseline testosterone <12 nmol/L were considered, similar reductions in total cholesterol (-0.35 mmol/L) and triglycerides (-0.22 mmol/L) were observed, and again, no effect on HDL or LDL cholesterol (Corona, et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Corona, et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Testosterone treatment was associated with slight, but significant decreases in total cholesterol (-0.16 mmol/L), in HDL cholesterol (-0.05 mmol/L), and in LDL cholesterol (-0.06 mmol/L) in the T-trials.

    “a recent analysis of the T-trials reported that testosterone treatment was associated with slight, but significant decreases in total cholesterol (-0.16 mmol/L), in HDL cholesterol (-0.05 mmol/L), and in LDL cholesterol (-0.06 mmol/L).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mohler, et al., 2018

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The clinical significance of these lipid changes is uncertain.

    “The authors concluded that the clinical significance of these changes is uncertain (Mohler, et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mohler, et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Testosterone treatment prevented diet-associated loss of lean mass, and while placebo-treated men lost both muscle and fat, the weight loss in testosterone treated men was almost entirely loss of body fat.

    “Thus, testosterone treatment prevented diet-associated loss of lean mass, and while placebo-treated men lost both muscle and fat, the weight loss in testosterone treated men was almost entirely loss of body fat (Ng Tang Fui, et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ng Tang Fui, et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effects of testosterone treatment on body composition were not sustained, with no between group differences 18 months after trial cessation.

    “The effects of testosterone treatment on body composition were not sustained, with no between group differences 18 months after trial cessation (Ng Tang Fui, et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ng Tang Fui, et al., 2017

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    There are also many experimental preclinical and clinical studies suggesting mechanisms by which testosterone, either directly or via aromatization to estradiol, improves body composition and glucose metabolism by signaling in multiple somatic tissues.

    “However, there are also many experimental preclinical and clinical studies suggesting mechanisms by which testosterone, either directly or via aromatization to estradiol, improves body composition and glucose metabolism by signaling in multiple somatic tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In most but not all studies testosterone treatment improves insulin resistance to a modest degree, but effects on glycemic control remain inconsistent.

    “In most but not all studies testosterone treatment improves insulin resistance to a modest degree, but effects on glycemic control remain inconsistent.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    This is reminiscent of trials of testosterone therapy focusing on other outcomes where, for example effects on lean mass and strength are mostly consistent, effects on functional performance or fall frequency are not established.

    “This is reminiscent of trials of testosterone therapy focusing on other outcomes where, for example effects on lean mass and strength are mostly consistent, effects on functional performance or fall frequency are not established (Bhasin, et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bhasin, et al., 2018

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The overall evidence is compatible with hypotheses (yet to be tested) that men with lower testosterone, who are more overweight/obese and more insulin resistant may have more marked responses especially if they are treated for longer durations with effective testosterone treatment achieving consistently therapeutic testosterone concentrations.

    “The overall evidence is compatible with hypotheses (yet to be tested) that men with lower testosterone, who are more overweight/obese and more insulin resistant may have more marked responses especially if they are treated for longer durations with effective testosterone treatment achieving consistently therapeutic testosterone concentrations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Mechanistic studies have reported plausible mechanisms by which diabesity suppresses the HPT axis, including hypothalamic inflammation, dysregulation of leptin and CNS insulin signaling.

    “Mechanistic studies have reported plausible mechanisms by which diabesity suppresses the HPT axis, including hypothalamic inflammation, dysregulation of leptin and CNS insulin signaling.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The lack of evidence for glycemic outcomes in RCTs may be because of their short duration and the enrolment of men with well controlled diabetes who are unlikely to derive a benefit.

    “The lack of evidence for glycemic outcomes in RCTs may be because of their short duration and the enrolment of men with well controlled diabetes who are unlikely to derive a benefit.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The effects of testosterone in men with more poorly controlled T2DM remains unknown.

    “Moreover, the effects of testosterone in men with more poorly controlled T2DM remains unknown.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Current Endocrine Society guidelines no longer recommend routine testosterone testing in men with T2DM, and recommend against testosterone treatment in asymptomatic men for the purpose of improving glucometabolic outcomes.

    “In the light of recent studies, current Endocrine Society guidelines no longer recommend routine testosterone testing in men with T2DM, and recommend against testosterone treatment in asymptomatic men for the purpose of improving glucometabolic outcomes (Bhasin, et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bhasin, et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    In clinical trials among men with dysglycemia overall, testosterone treatment has very consistent effects on body composition (increased lean mass, reduced fat mass, inconsistent effects on ectopic fat), less consistent effects on insulin resistance and no consistent effect on glycemic control.

    “In clinical trials among men with dysglycemia overall, testosterone treatment has very consistent effects on body composition (increased lean mass, reduced fat mass, inconsistent effects on ectopic fat), less consistent effects on insulin resistance and no consistent effect on glycemic control.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    From a clinical perspective, while substantial weight loss achievable by bariatric surgery in obese men can restore eugonadism in a substantial proportion of men, the lesser weight loss generally achievable with lifestyle measures has only modest effect on serum testosterone.

    “From a clinical perspective, while substantial weight loss achievable by bariatric surgery in obese men can restore eugonadism in a substantial proportion of men, the lesser weight loss generally achievable with lifestyle measures has only modest effect on serum testosterone.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    This trial is not designed to evaluate long term outcomes such as cardiovascular events or mortality.

    “However, this trial is not designed to evaluate long term outcomes such as cardiovascular events or mortality (Wittert, et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wittert, et al., 2018

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    T4DM is a large (>1,000 men) 2-year RCT that tests the hypothesis that testosterone treatment prevents the development of T2DM in high risk men over and above the effects of a lifestyle program alone.

    “T4DM is a large (>1,000 men) 2-year RCT that tests the hypothesis that testosterone treatment prevents the development of T2DM in high risk men over and above the effects of a lifestyle program alone.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wittert, et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    In summary, there is a strong inverse association of endogenous testosterone with diabesity, including simple obesity, and, to a lesser extent, with the full spectrum of dysglycemia from insulin resistance to the metabolic syndrome and established T2DM.

    “In summary, there is a strong inverse association of endogenous testosterone with diabesity, including simple obesity, and, to a lesser extent, with the full spectrum of dysglycemia from insulin resistance to the metabolic syndrome and established T2DM.”
    Quote in the paperNot a substantial claim
65 of 65

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Male Obesity-Associated Secondary Hypogonadism (MOSH) can worsen body composition, with further diminishment of SM mass, quality, and function through impaired muscle protein synthesis and myogenic differentiation, and stimulation of adipogenesis.

    “In turn, MOSH can worsen body composition, with further diminishment of SM mass, quality, and function through impaired muscle protein synthesis and myogenic differentiation, and stimulation of adipogenesis [43,77].”

    From Optimised Skeletal Muscle Mass as a Key Strategy for Obesity Management (2025) · cites this paper as [77]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • There are several postulated mechanisms by which obesity may mediate HPT axis suppression including leptin resistance and/or dysregulated insulin signaling.

    “There are several postulated mechanisms by which obesity may mediate HPT axis suppression including leptin resistance and/or dysregulated insulin signaling. 66 , 67”

    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 [67]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The reported HOMA-IR estimate falls outside its confidence interval

    Minor

    The reported HOMA-IR effect of -0.80 is outside the stated 95% confidence interval, whose endpoints are 1.16 and -0.45. The endpoints are also printed in reverse numerical order.

1 of 1

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Authors
Grossmann, M., Ng Tang Fui, M., & Cheung, A. S.
Affiliations
  • The University of Melbourne (AU)
  • Department of Medicine Austin Health University of Melbourne Melbourne Vic. Australia
Corresponding author
Grossmann, M.
ORCID
Venue
Andrology
Publisher
Wiley
Published
2019-09-25
Volume
8
Issue
6
Pages
1519-1529
ISSN
  • 2047-2919 (ISSN-L)
  • 2047-2927
DOI
10.1111/andr.12705
OpenAlex
W2972475462
Semantic Scholar
23c947d7eca1e14d28f622bc7f84595e8a26e928
Cited by
95
References
79
Citations by year
2026: 6 · 2025: 12 · 2024: 19 · 2023: 16 · 2022: 13 · 2021: 12 · 2020: 17
FWCI
1.62
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Andrology (publishedVersion)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
Funders
National Health and Medical Research Council (1024139)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords
andropause, diabesity, obesity, type 2 diabetes, insulin resistance, metabolic syndrome, testosterone, leptin signaling, insulin signaling, inflammatory cytokines, hypothalamic inflammation, estradiol, body composition, weight loss
MeSH terms
Animals, Diabetes Mellitus, Type 2, Energy Metabolism, Humans, Hypogonadism, Insulin Resistance, Male, Obesity, Prognosis, Risk Factors, Testosterone, Biomarkers, Age of Onset, Risk Assessment, Hormone Replacement Therapy, Metabolic Syndrome

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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