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Cited by 22Hormonal and reproductive studiesRegulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic Diseases

The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments

Open access
Venkatesh, Varun S., Grossmann, Mathis, Zajac, Jeffrey D., Davey, Rachel A.·2022·Obesity Reviews
DOI 10.1111/obr.13429PMC PMC9286619
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Abstract

Summary: Obesity is associated with hypothalamic–pituitary–testicular axis dysregulation in males. Here, we summarize recent evidence derived from clinical trials and studies in preclinical animal models regarding the role of androgen receptor (AR) signaling in the pathophysiology of males with obesity. We also discuss therapeutic strategies targeting the AR for the treatment of obesity and their limitations and provide insight into the future research necessary to advance this field.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes clinical and preclinical evidence that androgen receptor (AR) signaling, largely via testosterone, reduces fat mass in males, with bone marrow precursor cells emerging as a candidate mediator. It concludes that AR pathways are promising but not yet ready as obesity therapeutics because mechanisms, target tissues, and long-term safety remain unresolved.

Key findings

  • Testosterone treatment generally produces modest fat-mass reductions: a meta-analysis reported a −0.34 standardized mean difference, Isidori et al. reported ~2 kg, and the T4DM trial reported −2.7 kg over 2 years while reducing diabetes risk by 40% relative to placebo.
  • AR inhibition increases fat mass: in a 12-month trial, leuprolide increased whole-body fat mass by 11.2% and bicalutamide by 6.4%, though increased E2 confounds attribution to AR inhibition alone.
  • Preclinical AR knockout models mostly show increased adiposity, but adipocyte-specific ARKOs do not spontaneously become obese; AR expression in bone marrow precursor cells (BMPCs) appears sufficient to attenuate global-ARKO fat mass, while monocyte/macrophage AR deletion has no effect.
  • DHT/5α-reductase signaling is less important for fat mass than testosterone, and aromatization of testosterone to estradiol is required for at least some fat-reducing effects; SARMs may be less potent because they are non-aromatizable.

Methods

  • Narrative review summarizing clinical trials and preclinical animal models on AR signaling in male obesity, including tables of post-2016 testosterone trials, global ARKO models, and bone-marrow AR studies.
  • Evidence base includes randomized controlled trials, meta-analyses, observational registry studies, and genetically modified mouse models; no primary data collection or systematic search strategy is described.
  • Main analysis is qualitative synthesis of reported effects on fat mass, fat depots, metabolic outcomes, and proposed mechanisms, not a meta-analysis.

Limitations

  • The paper states that mechanisms by which testosterone reduces fat mass remain unclear, target tissues/cells are not definitively established, and long-term benefits and cardiovascular risks of testosterone treatment are unknown.
  • It notes substantial heterogeneity across clinical studies (baseline BMI, gonadal status, testosterone formulation, duration), short RCT durations, confounding by E2 in AR-antagonist studies, and contradictory findings on depot-specific fat loss and SHBG causality.
  • Preclinical limitations stated include residual AR activity in Tfm mice, differences in ARKO phenotypes due to genetic background and targeted AR region, incomplete AR knockdown and possible tamoxifen/ER effects in inducible models, and brain expression of the aP2 promoter; evident from the text, the review is not systematic and does not quantify publication bias or evidence certainty.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/obr.13429

Cites

253 of 253 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 190 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Modest obesity is predominantly associated with reduced total testosterone due to insulin resistance associated reductions in SHBG.

    “Modest obesity is predominantly associated with reduced total testosterone due to insulin resistance associated reductions in its carrier protein sex hormone binding globulin (SHBG). 64 , 65”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Cooper LA, Page ST, Amory JK, Anawalt BD, Matsumoto AM. The association of obesity with sex hormone‐binding globulin is stronger than the association with ageing ‐ implications for the interpretation of total testosterone measurements. Clin Endocrinol (Oxf). 2015; 83(6): 828‐ 833. doi: 10.1111/cen.12768 25777143 PMC4782930 source

      Not checked in the free run.

    • cites [65] Peter A, Kantartzis K, Machann J, et al. Relationships of circulating sex hormone‐binding globulin with metabolic traits in humans. Diabetes. 2010; 59(12): 3167‐ 3173. doi: 10.2337/db10-0179 20841609 PMC2992779

      Not checked in the free run.

  • Premisecitation

    Functional hypogonadism can be reversible by treating the disease causing hypothalamic-pituitary suppression, such as weight loss in obesity.

    “Functional hypogonadism occurs in the absence of recognizable disease of the HPT and can be reversible by treating the disease causing hypothalamic–pituitary suppression, such as weight loss in obesity. 50 , 54”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Grossmann M, Matsumoto AM. A perspective on middle‐aged and older men with functional hypogonadism: focus on holistic management. J Clin Endocrinol Metab. 2017; 102(3): 1067‐ 1075. doi: 10.1210/jc.2016-3580 28359097 PMC5477803

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    • cites [54] Corona G, Rastrelli G, Morelli A, et al. Treatment of functional hypogonadism besides pharmacological substitution. World J Mens Health. 2019; 37(3): 256‐ 270. doi: 10.5534/WJMH.190061 PMC7308235 31496147 source

      Not checked in the free run.

  • Premisecitation

    In women, the evidence suggests that androgens are positively associated with fat mass.

    “In contrast, in women, although the role of androgens in regulating fat mass is less clear, the evidence suggests that androgens are positively associated with fat mass.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Janssen I, Powell LH, Jasielec MS, Kazlauskaite R. Covariation of change in bioavailable testosterone and adiposity in midlife women. Obesity. 2015; 23(2): 488‐ 494. doi: 10.1002/oby.20974 25557490 PMC4310763 source

      Not checked in the free run.

    • cites [22] Kalyani RR, Franco M, Dobs AS, et al. The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. J Clin Endocrinol Metab. 2009; 94(11): 4127‐ 4135. doi: 10.1210/jc.2009-0910 19789205 PMC2775652

      Not checked in the free run.

    • cites [23] Dumesic DA, Akopians AL, Madrigal VK, et al. Hyperandrogenism accompanies increased intra‐abdominal fat storage in normal weight polycystic ovary syndrome women. J Clin Endocrinol Metab. 2016; 101(11): 4178‐ 4188. doi: 10.1210/jc.2016-2586 27571186 PMC5095243

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  • Premisecitation

    Obesity is a very common cause of functional hypogonadism.

    “Functional hypogonadism is usually due to hypothalamic–pituitary suppression by extragonadal disease, and obesity is a very common cause.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Grossmann M, Matsumoto AM. A perspective on middle‐aged and older men with functional hypogonadism: focus on holistic management. J Clin Endocrinol Metab. 2017; 102(3): 1067‐ 1075. doi: 10.1210/jc.2016-3580 28359097 PMC5477803

      Not checked in the free run.

    • cites [54] Corona G, Rastrelli G, Morelli A, et al. Treatment of functional hypogonadism besides pharmacological substitution. World J Mens Health. 2019; 37(3): 256‐ 270. doi: 10.5534/WJMH.190061 PMC7308235 31496147 source

      Not checked in the free run.

  • Premisecitation

    Marked obesity (BMI > 35 kg/m2) may lead to genuine suppression of the HPT axis.

    “However, marked obesity (body mass index (BMI) > 35 kg/m2) may lead to genuine suppression of the HPT axis. 56”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Grossmann M. Hypogonadism and male obesity: focus on unresolved questions. Clin Endocrinol (Oxf). 2018; 89(1): 11‐ 21. doi: 10.1111/cen.13723 29683196 source

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  • Classified as probably not a substantial claim. 24
  • May combine two claims. 57
  • The quote only partly states this claim. 1

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

    Premisenone given

    Obesity is associated with hypothalamic-pituitary-testicular axis dysregulation in males.

    “Obesity is associated with hypothalamic–pituitary–testicular axis dysregulation in males.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A bidirectional Mendelian randomization study suggested that the effect of an elevated BMI on low testosterone is more important than the effect of low testosterone on an increased BMI, but requires confirmation in independent samples.

    “While a bidirectional Mendelian randomization study suggested that the effect of an elevated BMI on low testosterone is more important than the effect of low testosterone on an increased BMI, such studies require confirmation in independent samples. 63”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Eriksson J, Haring R, Grarup N, et al. Causal relationship between obesity and serum testosterone status in men: a bidirectional mendelian randomization analysis. PLoS ONE. 2017; 12(4): 1‐ 15. doi: 10.1371/journal.pone.0176277 PMC5407807 28448539 source

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    Premisecitation

    Increases in serum testosterone achieved by lifestyle changes are modest around 3 mM, and difficult to sustain.

    “In contrast, the increases in serum testosterone achieved by lifestyle changes are modest around 3 mM, 60 , 61 and difficult to sustain. 62”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [60] Ng Tang Fui M, Prendergast LA, Dupuis P, et al. Effects of testosterone treatment on body fat and lean mass in obese men on a hypocaloric diet: a randomised controlled trial. BMC Med. 2016; 14: 153. doi: 10.1186/s12916-016-0700-9 27716209 PMC5054608

      Not checked in the free run.

    • cites [61] Corona G, Giagulli VA, Maseroli E, et al. Testosterone supplementation and body composition: results from a meta‐analysis study. Eur J Endocrinol. 2016; 174(3): R99‐ R116. doi: 10.1530/EJE-15-0262 26537862

      Not checked in the free run.

    • cites [62] Ng Tang Fui M, Hoermann R, Zajac JD, Grossmann M. The effects of testosterone on body composition in obese men are not sustained after cessation of testosterone treatment. Clin Endocrinol (Oxf). 2017; 87(4): 336‐ 343. doi: 10.1111/cen.13385 28561278 source

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

    Premisecitation

    Obesity is often associated with lowered testosterone and low to normal gonadotrophin concentrations; however, whether this reflects causality, reverse causality, or merely in-common risk factors remains unclear.

    “Obesity is often associated with lowered testosterone and low to normal gonadotrophin concentrations; however, whether this reflects causality, reverse causality, or merely in‐common risk factors remains unclear. 56 , 57”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Grossmann M. Hypogonadism and male obesity: focus on unresolved questions. Clin Endocrinol (Oxf). 2018; 89(1): 11‐ 21. doi: 10.1111/cen.13723 29683196 source

      Not checked in the free run.

    • cites [57] Glass AR, Swerdloff RS, Bray GA, Dahms WT, Atkinson RL. Low serum testosterone and sex‐hormone‐binding‐globulin in massively obese men. J Clin Endocrinol Metab. 1977; 45(6): 1211‐ 1219. doi: 10.1210/jcem-45-6-1211 338622

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The mechanisms by which testosterone exerts its fat-reducing effects are not well understood.

    “While it is well established that testosterone negatively regulates fat mass in males, the mechanisms by which this hormone exerts its fat‐reducing effects are not well understood.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] Dhindsa S, Ghanim H, Batra M, Dandona P. Hypogonadotropic hypogonadism in men with diabesity. Diabetes Care. 2018; 41(7): 1516‐ 1525. doi: 10.2337/dc17-2510 29934480 PMC6014549

      Not checked in the free run.

    • cites [67] Grossmann M, Ng Tang Fui M, Cheung AS. Late‐onset hypogonadism: metabolic impact. Andrology. 2020; 8(6): 1519‐ 1529. doi: 10.1111/andr.12705 31502758 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The relationship between obesity and testosterone is likely bidirectional because weight loss is associated with an increase in serum testosterone, whereas testosterone treatment reduces fat mass.

    “The relationship is likely bidirectional because on the one hand weight loss is associated with an increase in serum testosterone, whereas on the other hand testosterone treatment reduces fat mass.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In men, circulating androgens are negatively associated with body fat mass, and in particular with intra-abdominal fat mass.

    “In men, circulating androgens have been reported to be negatively associated with body fat mass, and in particular with intra‐abdominal fat mass. 19 , 20”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Pasquali R, Casimirri F, Cantobelli S, et al. Effect of obesity and body fat distribution on sex hormones and insulin in men. Metabolism. 1991; 40(1): 101‐ 104. doi: 10.1016/0026-0495(91)90199-7 1984562

      Not checked in the free run.

    • cites [20] Khaw KT, Barrett‐Connor E. Lower endogenous androgens predict central adiposity in men. Ann Epidemiol. 1992; 2(5): 675‐ 682. doi: 10.1016/1047-2797(92)90012-F 1342319

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

    Premisecitation

    Skinner et al. reported that intramuscular testosterone injections were more effective than transdermal gels at increasing lean body weight.

    “Skinner et al. reported that intramuscular testosterone injections were more effective than transdermal gels at increasing lean body weight. 85”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Skinner JW, Otzel DM, Bowser A, et al. Muscular responses to testosterone replacement vary by administration route: a systematic review and meta‐analysis. J Cachexia Sarcopenia Muscle. 2018; 9(3): 465‐ 481. doi: 10.1002/jcsm.12291 29542875 PMC5989848 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Additional contributing factors to obesity-mediated HPT axis suppression include paternal genetics, leptin resistance, and obesity-associated elevations in pro-inflammatory cytokines.

    “Additional contributing factors include paternal genetics, 68 leptin resistance, 69 and obesity‐associated elevations in pro‐inflammatory cytokines (reviewed in Grossmann 56 ).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [68] Sanchez‐Garrido MA, Ruiz‐Pino F, Velasco I, et al. Intergenerational influence of paternal obesity on metabolic and reproductive health parameters of the offspring: male‐preferential impact and involvement of kiss1‐mediated pathways. Endocrinology. 2018; 159(2): 1005‐ 1018. doi: 10.1210/en.2017-00705 29309558

      Not checked in the free run.

    • cites [69] Izquierdo AG, Crujeiras AB, Casanueva FF, Carreira MC. Leptin, obesity, and leptin resistance: where are we 25 years later? Nutrients. 2019; 11(11): 1‐ 11. doi: 10.3390/nu11112704 PMC6893721 31717265 source

      Not checked in the free run.

    • cites [56] Grossmann M. Hypogonadism and male obesity: focus on unresolved questions. Clin Endocrinol (Oxf). 2018; 89(1): 11‐ 21. doi: 10.1111/cen.13723 29683196 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Baik et al. reported that castrated mice fed a normal diet exhibited increased adiposity and expression of fatty acid synthesis associated genes.

    “Baik et al. reported that castrated mice fed a normal diet exhibited increased adiposity and expression of fatty acid synthesis associated genes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Baik M, Jeong JY, Park SJ, et al. Testosterone deficiency caused by castration increases adiposity in male rats in a tissue‐specific and diet‐dependent manner. Genes Nutr. 2020; 15(1): 1‐ 10. doi: 10.1186/s12263-020-00673-1 32807074 PMC7433145

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The mechanism by which testosterone-related reductions in fat mass translate into metabolic benefits remains to be elucidated and is likely not exclusively ascribed to the loss of fat mass.

    “suggesting that at least in part, the testosterone‐related reductions in fat mass may translate into metabolic benefits, however, the mechanism by which this occurs remains to be elucidated and is likely not exclusively ascribed to the loss of fat mass. 74”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] 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 33338415

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    Premisecitation

    The majority of studies report an increase in whole body adiposity or in specific adipose depots post-ORX; however, a handful of studies either report no change or, in one case, a reduction.

    “The majority of studies report an increase in whole body adiposity or in specific adipose depots post‐ORX 99 , 104 , 105 , 106 , 107 , 108 ; however, a handful of studies either report no change 101 , 102 or, in one case, a reduction. 103”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [99] Vandenput L, Boonen S, Van Herck E, Swinnen JV, Bouillon R, Vanderschueren D. Evidence from the aged orchidectomized male rat model that 17β‐estradiol is a more effective bone‐sparing and anabolic agent than 5α‐dihydrotestosterone. J Bone Miner Res. 2002; 17(11): 2080‐ 2086. doi: 10.1359/jbmr.2002.17.11.2080 12412816 source

      Not checked in the free run.

    • cites [104] Baik M, Jeong JY, Park SJ, et al. Testosterone deficiency caused by castration increases adiposity in male rats in a tissue‐specific and diet‐dependent manner. Genes Nutr. 2020; 15(1): 1‐ 10. doi: 10.1186/s12263-020-00673-1 32807074 PMC7433145

      Not checked in the free run.

    • cites [105] Faust IM, Johnson PR, Kral JG. Effects of castration on adipose tissue growth and regrowth in the male rat. Metabolism. 1984; 33(7): 596‐ 601. doi: 10.1016/0026-0495(84)90055-6 6738360

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

    Interpretationnone given

    The mechanism by which this increase of fat mass occurs due to the reduction of testosterone is unclear.

    “The mechanism by which this increase of fat mass occurs due to the reduction of testosterone is unclear; however, recent studies do give evidence to possible mechanisms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    All guidelines agree that men with true hypogonadism should be offered testosterone treatment, but metabolic benefits are highlighted in some but not all guidelines.

    “While all guidelines agree that men with true hypogonadism should (unless they seek fertility) be offered testosterone treatment, metabolic benefits are highlighted in some 96 but not in all guidelines. 49 , 97”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [96] Garvey WT, Mechanick JI, Brett EM, et al. American association of clinical endocrinologists and American college of endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016; 22(July): 1‐ 203. doi: 10.4158/EP161365.GL 27219496 source

      Not checked in the free run.

    • cites [49] Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an endocrine society. J Clin Endocrinol Metab. 2018; 103(5): 1715‐ 1744. doi: 10.1210/jc.2018-00229 29562364

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    • cites [97] Yeap BB, Grossmann M, McLachlan RI, et al. Endocrine Society of Australia position statement on male hypogonadism (Part 2): treatment and therapeutic considerations. Med J Aust. 2016; 205(5): 228‐ 231. doi: 10.5694/mja16.00448 27581270 source

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

    Interpretationcitation

    These discrepancies may be due to different ages of the animals studied as well as the differing length of the studies.

    “These discrepancies may be due to different ages of the animals studied as well as the differing length of the studies. 102”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Moreau MF, Libouban H, Legrand E, Baslé MF, Audran M, Chappard D. Lean, fat and bone masses are influenced by orchidectomy in the rat. A densitometric X‐ray absorptiometric study. J Musculoskelet Neuronal Interact. 2001; 1(3): 209‐ 20913. 15758494

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  • May combine two claims.

    Interpretationreasoning

    These data provide evidence for a role of testosterone in the inhibition of adipogenesis in pre-adipocytes, but do not explain the action of testosterone to reduce the mass of pre-existing fat depots in humans and rodents.

    “While these data provide evidence for a role of testosterone in the inhibition of adipogenesis in pre‐adipocytes, they do not explain the action of testosterone to reduce the mass of pre‐existing fat depots in humans and rodents.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Other mechanisms by which testosterone may regulate fat mass include modulation of lipid metabolism, alteration of muscle metabolism, and alteration of mitochondrial function; further validation is required.

    “Other mechanisms by which testosterone may regulate fat mass include modulation of lipid metabolism, 114 , 115 alteration of muscle metabolism 116 and alteration of mitochondrial function 117 ; with these actions being extensively reviewed elsewhere 118 but further validation is required.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [114] Maseroli E, Comeglio P, Corno C, et al. Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men. J Endocrinol Invest. 2020; 44(4): 819‐ 842. doi: 10.1007/s40618-020-01381-8 32772323 PMC7946690

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    • cites [115] Høst C, Gormsen LC, Christensen B, et al. Independent effects of testosterone on lipid oxidation and VLDL‐TG production: a randomized, double‐blind, placebo‐controlled, crossover study. Diabetes. 2013; 62(5): 1409‐ 1416. doi: 10.2337/db12-0440 23193189 PMC3636625

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    • cites [116] Sarchielli E, Comeglio P, Filippi S, et al. Testosterone improves muscle fiber asset and exercise performance in a metabolic syndrome model. J Endocrinol. 2020; 245(2): 259‐ 279. doi: 10.1530/JOE-19-0532 32134722

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  • May combine two claims.

    Premisecitation

    Sebo et al. reported that testosterone treatment in male mice reduces ORX and HFD associated weight gain with decreases observed in visceral and subcutaneous fat mass as well as adipocyte size.

    “Sebo et al. reported that testosterone treatment in male mice reduces ORX and HFD associated weight gain with decreases observed in visceral and subcutaneous fat mass as well as adipocyte size. 106”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Sebo ZL, Rodeheffer MS. Testosterone metabolites differentially regulate obesogenesis and fat distribution. Mol Metab. 2021; 44(December 2020): 1‐ 9. doi: 10.1016/j.molmet.2020.101141 PMC7772371 33307216 source

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    Premisecitation

    In a 12-month open-label trial, prostate cancer patients treated with leuprolide monotherapy had an 11.2% increase in whole body fat mass, and those treated with bicalutamide monotherapy had a 6.4% increase.

    “In a 12 month open label trial, Smith et al. reported that patients treated with bicalutamide or leuprolide (a GnRH agonist) monotherapies exhibited an increase in whole body fat mass of 11.2% for leuprolide and 6.4% for bicalutamide.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Smith MR, Goode M, Zietman AL, McGovern FJ, Lee H, Finkelstein JS. Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: Effects on bone mineral density and body composition. J Clin Oncol. 2004; 22(13): 2546‐ 2553. doi: 10.1200/JCO.2004.01.174 15226323 source

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  • May combine two claims.

    Interpretationreasoning

    Adipocyte proliferation is not mediated via the AR expressed in APs but may be mediated by another AR dependent mechanism.

    “inferring that adipocyte proliferation is not mediated via the AR expressed in APs but may be mediated by another AR dependent mechanism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tfm mice have reduced endogenous testosterone levels and develop hepatic steatosis as well as aortic fatty streaks when fed a HFD.

    “Tfm mice have reduced endogenous testosterone levels 129 and develop hepatic steatosis as well as aortic fatty streaks when fed a HFD.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [129] Murphy L, O'Shaughnessy PJ. Testicular steroidogenesis in the testicular feminized (Tfm) mouse: loss of 17α‐hydroxylase activity. J Endocrinol. 1991; 131(3): 443‐ 449. doi: 10.1677/joe.0.1310443 1686053 source

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    • cites [130] Kelly DM, Akhtar S, Sellers DJ, Muraleedharan V, Channer KS, Jones TH. Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse. Endocrine. 2016; 54(2): 504‐ 515. doi: 10.1007/s12020-016-1019-1 27488580 PMC5083771

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    • cites [131] Kelly DM, Nettleship JE, Akhtar S, et al. Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol‐fed androgen deficient mice. Life Sci. 2014; 109(2): 95‐ 103. doi: 10.1016/j.lfs.2014.06.007 24953607 source

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  • May combine two claims. The quote only partly states this claim.

    Interpretationreasoning

    The increase in fat mass reported in AR antagonist studies cannot conclusively be ascribed to inhibition of the AR because AR antagonists also disrupt negative feedback of testosterone on the central HPT axis, resulting in increased circulating E2.

    “Thus, the increase in fat mass reported in these studies cannot conclusively be ascribed to inhibition of the AR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The tamoxifen-inducible Global-ARKO data must be interpreted with caution because AR gene knockdown is not complete (approximately 20% mRNA expression remained) and tamoxifen induction may affect fat mass through ER signaling.

    “These data, however, must be interpreted with some caution as AR gene knockdown is not complete (approximately 20% mRNA expression remained) and the induction of knockdown via tamoxifen, despite the short induction time (4 days), may pose some effect of fat mass through ER signaling.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L. A pharmacological review of selective oestrogen receptor modulators. Hum Reprod Update. 2000; 6(3): 212‐ 224. doi: 10.1093/humupd/6.3.212 10874566 source

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  • May combine two claims.

    Interpretationcitation

    The differences in the fat phenotype of ARKO models may be attributed to differences in genetic background and the region of the AR targeted for deletion.

    “The differences in the fat phenotype of these ARKO models may be attributed to the differences in the genetic background of the mice 126 as well as the region of the AR targeted for deletion”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [126] Russell PK, Mangiafico S, Fam BC, et al. The androgen receptor in bone marrow progenitor cells negatively regulates fat mass. J Endocrinol. 2018; 237(1): 15‐ 27. doi: 10.1530/JOE-17-0656 29386237

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    • cites [145] Notini AJ, Davey RA, McManus JF, Bate KL, Zajac JD. Genomic actions of the androgen receptor are required for normal male sexual differentiation in a mouse model. J Mol Endocrinol. 2005; 35(3): 547‐ 555. doi: 10.1677/jme.1.01884 16326839 source

      Not checked in the free run.

    • cites [139] Sato T, Matsumoto T, Yamada T, Watanabe T, Kawano H, Kato S. Late onset of obesity in male androgen receptor‐deficient (AR KO) mice. Biochem Biophys Res Commun. 2003; 300(1): 167‐ 171. doi: 10.1016/S0006-291X(02)02774-2 12480537

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    aP2-ARKO male mice displayed no difference in adipose weight of the subcutaneous or mesenteric regions and a statistically significant but biologically small reduction in perigonadal fat mass at 12 weeks of age compared with chow fed wild-type controls.

    “aP2‐ARKO male mice generated by McInnes et al. displayed no difference in adipose weight of the subcutaneous or mesenteric regions and a statistically significant but biologically small reduction in perigonadal fat mass at 12 weeks of age compared with chow fed wild‐type controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites McInnes et al.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Findings from a tamoxifen-inducible Global-ARKO model suggest that the obesity phenotype observed in previously published Global-ARKO mouse models is attributed to the loss of AR action pre-pubertally, as post-pubertal knockdown of the AR had no effect on fat mass.

    “findings from a tamoxifen‐inducible Global‐ARKO model suggests that the obesity phenotype observed in the previously published Global‐ARKO mouse models is attributed to the loss of AR action pre‐pubertally as post‐pubertal knockdown of the AR had no effect on fat mass.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Wu J, Henning P, Sjögren K, et al. The androgen receptor is required for maintenance of bone mass in adult male mice. Mol Cell Endocrinol. 2019; 479(May 2018): 159‐ 169. doi: 10.1016/j.mce.2018.10.008 30308267 source

      Not checked in the free run.

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

    Interpretationreasoning

    The discrepancy between muscle-specific ARKO results may be due to different activities of the Cre promoters.

    “This discrepancy may be due to the different activities of the Cre promoters as the improved Cre with increased Cre expression was used to generate the MyoD‐Cre mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The current data do not support the adipocyte or myocyte as the target cells for this AR action, while BMPCs appear to be a strong candidate for further study.

    “While the current data do not support the adipocyte or myocyte as the target cells for this AR action, BMPCs appear to be a strong candidate for further study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Male Col3.6AR-Tg mice displayed reduced visceral fat mass in the gonadal and peri-renal fat depots and smaller adipocyte area in the absence of any changes in serum adipokines.

    “Male Col3.6AR‐Tg mice displayed reduced visceral fat mass in the gonadal and peri‐renal fat depots and smaller adipocyte area in the absence of any changes in serum adipokines.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Semirale AA, Zhang XW, Wiren KM. Body composition changes and inhibition of fat development in vivo implicates androgen in regulation of stem cell lineage allocation. J Cell Biochem. 2011; 112(7): 1773‐ 1786. doi: 10.1002/jcb.23098 21381083 PMC3111903 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Taken together, the evidence suggests that while DHT does not play a role in the fat reducing effects of testosterone, the fat reducing effects of testosterone may require its aromatization to E2.

    “Taken together, this evidence suggests that while DHT does not play role in the fat reducing effects of testosterone, the fat reducing effects of testosterone may require its aromatization to E2”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [172] Juang PS, Peng S, Allehmazedeh K, Shah A, Coviello AD, Herbst KL. Testosterone with dutasteride, but not anastrazole, improves insulin sensitivity in young obese men: a randomized controlled trial. J Sex Med. 2014; 11(2): 563‐ 573. doi: 10.1111/jsm.12368 24344872 source

      Not checked in the free run.

    • cites [170] Bhasin S, Travison TG, Storer TW, et al. Effect of testosterone supplementation with and without a dual 5α‐reductase inhibitor on fat‐free mass in men with suppressed testosterone production: a randomized controlled trial. JAMA ‐ J Am Med Assoc. 2012; 307(9): 931‐ 939. doi: 10.1001/jama.2012.227 PMC6035750 22396515 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    While loss of the AR in bone marrow cells confers a propensity to obesity, this is not mediated by lysozyme 2 expressing monocytes/macrophages, suggesting that another cell type in the bone marrow may be responsible for mediating the fat reducing effects of testosterone.

    “while the loss of the AR in bone marrow cells confers a propensity to obesity, this is not mediated by lysozyme 2 expressing monocytes/macrophages, suggesting that another cell type in the bone marrow may be responsible for mediating the fat reducing effects of testosterone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PC-AR gene replacement mice had an increase in the number of smaller adipocytes and a healthier metabolic profile, characterized by normal serum leptin, elevated serum adiponectin and improved whole-body insulin sensitivity, with higher glucose uptake into subcutaneous and visceral fat than Global-ARKOs.

    “PC‐AR gene replacement mice had an increase in the number of smaller adipocytes and a healthier metabolic profile, characterized by normal serum leptin, elevated serum adiponectin and improved whole‐body insulin sensitivity, with higher glucose uptake into subcutaneous and visceral fat than Global‐ARKOs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Russell PK, Mangiafico S, Fam BC, et al. The androgen receptor in bone marrow progenitor cells negatively regulates fat mass. J Endocrinol. 2018; 237(1): 15‐ 27. doi: 10.1530/JOE-17-0656 29386237

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sebo et al. demonstrated a decrease in subcutaneous fat following DHT treatment in orchidectomized mice fed a HFD, although to a lesser extent than observed with testosterone.

    “Sebo et al. demonstrated a decrease in subcutaneous fat following DHT treatment in orchidectomized mice fed a HFD, although to a lesser extent than observed with testosterone”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Sebo ZL, Rodeheffer MS. Testosterone metabolites differentially regulate obesogenesis and fat distribution. Mol Metab. 2021; 44(December 2020): 1‐ 9. doi: 10.1016/j.molmet.2020.101141 PMC7772371 33307216 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overall, the evidence suggests that 5αR and by extension DHT is less significant in regulating fat mass than testosterone, and that the fat reducing effects of testosterone may not be exclusively mediated through the AR.

    “Overall, the evidence suggests that 5αR and by this extension, DHT, is less significant in regulating fat mass than testosterone, and that the fat reducing effects of testosterone may not be exclusively mediated through the AR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Men with inactivating mutations in the CYP19 gene which encodes aromatase, and men with inactivating mutations of the ERα have increased BMI and abdominal adipose tissue.

    “men with inactivating mutations in the CYP19 gene which encodes aromatase, and men with inactivating mutations of the ERα have increased BMI and abdominal adipose tissue.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Russell N, Grossmann M. Estradiol as a male hormone. Eur J Endocrinol. 2019; 181(1): R23‐ R43. doi: 10.1530/EJE-18-1000 31096185

      Not checked in the free run.

    • cites [180] Jones MEE, Chin Boon W, Proietto J, Simpson ER. Of mice and men: the evolving phenotype of aromatase deficiency. Trends Endocrinol Metab. 2006; 17(2): 55‐ 64. doi: 10.1016/j.tem.2006.01.004 16480891 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    DHT treatment was associated with reduced circulating E2, implying that there was no confounding effect of increased E2 on fat mass, but rather, the effects were directly related to DHT.

    “DHT treatment was associated with reduced circulating E2, implying that there was no confounding effect of increased E2 on fat mass, but rather, the effects were directly related to DHT.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    There have been several reports of 5αR type 1 KO mice with no reports of altered fat including in gonadal depots.

    “There have been also several reports of 5αR type 1 KO mice with no reports of altered fat 176 including in gonadal depots.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [176] Livingstone DEW, Barat P, Di Rollo EM, et al. 5α‐Reductase type 1 deficiency or inhibition predisposes to insulin resistance, hepatic steatosis, and liver fibrosis in rodents. Diabetes. 2015; 64(2): 447‐ 458. doi: 10.2337/db14-0249 25239636

      Not checked in the free run.

    • cites [177] Windahl SH, Andersson N, Börjesson AE, et al. Reduced bone mass and muscle strength in male 5α‐reductase type 1 inactivated mice. PLoS ONE. 2011; 6(6): 1‐ 8. doi: 10.1371/journal.pone.0021402 PMC3120862 21731732 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a randomized, placebo controlled trial of 114 older men, DHT treatment over 2 years increased lean mass but decreased fat mass, akin to the effects of testosterone.

    “Idan et al. reported in a randomized, placebo controlled trial of 114 older men that DHT treatment over 2 years increased lean mass but decreased fat mass, akin to the effects of testosterone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [174] Idan A, Griffiths KA, Harwood DT, et al. Long‐term effects of dihydrotestosterone treatment on prostate growth in healthy, middle‐aged men without prostate disease: a randomized, placebo‐controlled trial. Ann Intern Med. 2010; 153(10): 621‐ 632. doi: 10.7326/0003-4819-153-10-201011160-00004 21079217

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Taken together these data suggest that while DHT may be able to negatively modulate fat mass, its contribution is not as marked as testosterone and may be restricted to subcutaneous depots.

    “Taken together these data suggest that while DHT may be able to negatively modulate fat mass, its contribution is not as marked as testosterone and may be restricted to subcutaneous depots.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    One possible alternative mechanism is that, at least in men, testosterone is converted to E2.

    “One possible alternative mechanism inferred by the work of Juang and Finkelstein could be, at least in men, the conversion of testosterone to E2”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Male aromatase KO mice have increased adiposity compared with controls despite having elevated circulating levels of testosterone due to the lack of negative feedback of E2 on the HPT axis, analogous to men with aromatase deficiency.

    “Male aromatase KO mice have increased adiposity compared with controls despite having elevated circulating levels of testosterone due to the lack of negative feedback of E2 on the HPT axis, 106 , 184 , 185 , 186 , 187 analogous to men with aromatase deficiency.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [106] Sebo ZL, Rodeheffer MS. Testosterone metabolites differentially regulate obesogenesis and fat distribution. Mol Metab. 2021; 44(December 2020): 1‐ 9. doi: 10.1016/j.molmet.2020.101141 PMC7772371 33307216 source

      Not checked in the free run.

    • cites [184] Amano A, Kondo Y, Noda Y, et al. Abnormal lipid/lipoprotein metabolism and high plasma testosterone levels in male but not female aromatase‐knockout mice. Arch Biochem Biophys. 2017; 622: 47‐ 58. doi: 10.1016/j.abb.2017.03.007 28341248 source

      Not checked in the free run.

    • cites [185] Jones MEE, Thorburn AW, Britt KL, et al. Aromatase‐deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci. 2000; 97(23): 12735‐ 12740. doi: 10.1073/pnas.97.23.12735 11070087 PMC18833 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The data from these rare case reports are consistent with the notion that the lifelong absence of E2 signaling in men, via ER alpha may limit fat mass accumulation and promote insulin resistance.

    “Overall, the data from these rare case reports are consistent with the notion that the lifelong absence of E2 signaling in men, via ER alpha may limit fat mass accumulation and promote insulin resistance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Male ERα KO mice have increased fat mass; while in contrast, ERβ KO mice exhibit no fat phenotype.

    “Male ERα KO mice have increased fat mass 204 , 205 , 206 , 207 ; while in contrast, ER β KO mice exhibit no fat phenotype, 207 , 208 , 209”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [204] Park CJ, Zhao Z, Glidewell‐Kenney C, et al. Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα‐null mutant mice. J Clin Invest. 2011; 121(2): 604‐ 612. doi: 10.1172/JCI41702 21245576 PMC3026715 source

      Not checked in the free run.

    • cites [205] Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. Increased adipose tissue in male and female estrogen receptor‐α knockout mice. Proc Natl Acad Sci USA. 2000; 97(23): 12729‐ 12734. doi: 10.1073/pnas.97.23.12729 11070086 PMC18832 source

      Not checked in the free run.

    • cites [206] Couse JF, Korach KS. Erratum: Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev. 1999; 20(3): 358– 417. 10368776 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These data support the notion that in addition to the action of testosterone directly via the AR to decrease fat mass, testosterone can also exert these effects following conversion to E2 and action via the ER.

    “These data support the notion that in addition to the action of testosterone directly via the AR to decrease fat mass, testosterone can also exert these effects following conversion to E2 and action via the ER.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Treatment of intact mice with the aromatase inhibitor letrozole was shown to increase fat mass compared with vehicle-treated mice, and administration of E2 to castrated mice fed a HFD was effective in decreasing diet-induced weight gain.

    “treatment of intact mice with the aromatase inhibitor, letrozole, was shown to increase fat mass compared with vehicle‐treated mice 106 and the administration of E2 to castrated mice fed a HFD was effective in decreasing diet‐induced weight gain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Sebo ZL, Rodeheffer MS. Testosterone metabolites differentially regulate obesogenesis and fat distribution. Mol Metab. 2021; 44(December 2020): 1‐ 9. doi: 10.1016/j.molmet.2020.101141 PMC7772371 33307216 source

      Not checked in the free run.

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

    Interpretationreasoning

    These differences could be partially explained by the differences in age and baseline body composition of the participants in the three trials.

    “These differences could be partially explained by the differences in age and baseline body composition of the participants in the three trials.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Men with inactivating mutations in the ESR2 gene encoding ERβ have not been reported.

    “men with inactivating mutations in the ESR 2 gene encoding ER β have not been, to our knowledge, reported.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The second patient with a mutation in ESR1 had a BMI of 23.7 kg/m2, but also had low serum testosterone due to cryptorchidism.

    “The second patient had a BMI of 23.7 kg/m2, but also had low serum testosterone due to cryptorchidism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Bernard V, Kherra S, Francou B, et al. Familial multiplicity of estrogen insensitivity associated with a loss‐of‐function ESR1 mutation. J Clin Endocrinol Metab. 2017; 102(1): 93‐ 99. doi: 10.1210/jc.2016-2749 27754803 PMC5413105

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These findings which imply that inhibition of E2 promotes fat loss are contrary to Finkelstein's work reporting that E2 is required to mediate the fat reducing action of testosterone.

    “these findings which imply that inhibition of E2 promotes fat loss are contrary to Finkelstein's work 181 reporting that E2 is required to mediate the fat reducing action of testosterone.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Finkelstein JS, Lee H, Burnett‐Bowie S‐AM, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013; 369(11): 1011‐ 1022. doi: 10.1056/nejmoa1206168 24024838 PMC4142768 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In one report, male aromatase KO mice exhibited increased gonadal adipose tissue which was ameliorated by E2 treatment.

    “In one report, male aromatase KO mice exhibited increased gonadal adipose tissue which was ameliorated by E2 treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Van Sinderen ML, Steinberg GR, Jørgensen SB, et al. Hepatic glucose intolerance precedes hepatic steatosis in the male aromatase knockout (ArKO) mouse. PLoS ONE. 2014; 9(2): 1‐ 11. doi: 10.1371/journal.pone.0087230 PMC3919708 24520329 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aromatase inhibitors such as anastrozole have been reported to increase fat loss when combined with weight loss programs in men affected by obesity and in a RCT of older men with hypogonadism.

    “Aromatase inhibitors such as anastrozole have been reported to increase fat loss when combined with weight loss programs in men affected by obesity 198 and in a RCT of older men with hypogonadism.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [198] Colleluori G, Chen R, Turin CG, et al. Aromatase inhibitors plus weight loss improves the hormonal profile of obese hypogonadal men without causing major side effects. Front Endocrinol (Lausanne). 2020; 11(May): 1‐ 12. doi: 10.3389/fendo.2020.00277 32499757 PMC7243137 source

      Not checked in the free run.

    • cites [199] Dias JP, Melvin D, Simonsick EM, et al. Effects of aromatase inhibition vs. testosterone in older men with low testosterone: randomized‐controlled trial. Andrology. 2016; 4(1): 33‐ 40. doi: 10.1111/andr.12126 26588809 PMC5836312 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Studies using AI have inferred the role of E2 by reducing its serum concentrations, and no study in men to date has assessed the direct effects of E2 in the absence of T.

    “studies using AI have inferred the role of E2 by reducing its serum concentrations, and no study in men to date has assessed the direct effects of E2 in the absence of T.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    One patient with a mutation in ESR1 had a BMI in the obese range of 30 kg/m2 and clinical evidence of insulin resistance, although fat mass was not reported.

    “One patient had a BMI in the obese range of 30 kg/m2 and clinical evidence of insulin resistance, 196 although fat mass was not reported.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen‐receptor gene in a man. N Engl J Med. 1994; 331(16): 1056‐ 1061. doi: 10.1056/NEJM199410203311604 8090165 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These data suggest that activation of ERα may play a role in the regulation of fat mass in males, but further study is required to ascertain the contribution of the fat reducing effect ERβ activation and the mechanisms by which it exerts these effects.

    “In summary, these data suggest that activation of ERα may play a role in the regulation of fat mass in males, but further study is required to ascertain the contribution of the fat reducing effect ERβ activation and the mechanisms by which it exerts these effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Despite the absence of any reported changes in fat deposition in global ERβ KO mice, agonistic ERβ-selective ligands have been reported to mitigate diet-induced obesity in male mice.

    “Despite the absence of any reported changes in fat deposition in global ERβ KO mice, agonistic ERβ‐selective ligands have been reported to mitigate diet‐induced obesity in male mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [213] Yepuru M, Eswaraka J, Kearbey JD, et al. Estrogen receptor‐β‐selective ligands alleviate high‐fat diet‐ and ovariectomy‐induced obesity in mice. J Biol Chem. 2010; 285(41): 31292‐ 31303. doi: 10.1074/jbc.M110.147850 20657011 PMC2951204 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ERα but not ERβ regulates fat mass.

    “suggesting that ERα but not ER β regulates fat mass.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SHBG is increased by resistance training with concomitant increases in lean body mass and reductions in total and trunk fat mass.

    “SHBG is increased by resistance training with concomitant increases in lean body mass and reductions in total and trunk fat mass.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [223] Roberts CK, Croymans DM, Aziz N, Butch AW, Lee CC. Resistance training increases SHBG in overweight/obese, young men. Metabolism. 2013; 62(5): 725‐ 733. doi: 10.1016/j.metabol.2012.12.004 23318050 PMC3845495 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Strong interactions between E2 and leptin signaling have been reported in male rats indicating that ER signaling has the potential to also modulate fat mass through indirect mechanisms such as decreasing satiety.

    “strong interactions between E2 and leptin signaling have been reported in male rats 179 indicating that ER signaling has the potential to also modulate fat mass through indirect mechanisms such as decreasing satiety.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Rubinow KB. Estrogens and body weight regulation in men. Adv Exp Med Biol. 2017; 1043: 285‐ 313. doi: 10.1007/978-3-319-70178-3_14 29224100 PMC5835337

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Testosterone has been studied as a potential therapy for hypogonadism-related obesity and has been reported to have moderate efficacy.

    “Testosterone has been studied as a potential therapy for hypogonadism related obesity and has been reported to have moderate efficacy. 74”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] 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 33338415

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BMPCs secrete factors and regulate metabolic function both in a paracrine and endocrine capacity.

    “Additionally BMPCs have also been reported to secrete factors and regulate metabolic function both in a paracrine and endocrine capacity. 238 , 239”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [238] Cheleuitte D, Mizuno S, Glowacki J. In vitro secretion of cytokines by human bone marrow: effects of age and estrogen status. J Clin Endocrinol Metab. 1998; 83(6): 2043‐ 2051. doi: 10.1210/jc.83.6.2043 9626137 source

      Not checked in the free run.

    • cites [239] Tencerova M, Kassem M. The bone marrow‐derived stromal cells: commitment and regulation of adipogenesis. Front Endocrinol. 2016; 7. doi: 10.3389/fendo.2016.00127 PMC5030474 27708616 source

      Not checked in the free run.

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

    Premisecitation

    SHBG may protect against HFD induced obesity through the induction of lipolysis in white adipose tissue, though this finding is contradicted elsewhere.

    “may protect against HFD induced obesity through the induction of lipolysis in white adipose tissue, 229 though this finding is contradicted elsewhere.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [226] Laurent MR, Hammond GL, Blokland M, et al. Sex hormone‐binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis. Sci Rep. 2016; 6(May): 1‐ 12. doi: 10.1038/srep35539 27748448 PMC5066276 source

      Not checked in the free run.

    • cites [229] Saez‐Lopez C, Villena JA, Simó R, Selva DM. Sex hormone‐binding globulin overexpression protects against high‐fat diet‐induced obesity in transgenic male mice. J Nutr Biochem. 2020; 85: 108480. doi: 10.1016/j.jnutbio.2020.108480 32795655 source

      Not checked in the free run.

    • cites [230] Sofer Y, Nevo N, Vechoropoulos M, et al. Human sex hormone‐binding globulin does not provide metabolic protection against diet‐induced obesity and dysglycemia in mice. Endocr Connect. 2018; 7(1): 91‐ 96. doi: 10.1530/EC-17-0240 29141991 PMC5754513

      Not checked in the free run.

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

    Interpretationreasoning

    There is an association between SHBG and obesity, but whether this is causal, due to reverse causality or merely reflects in-common risk factors is not known.

    “This infers there is an association between SHBG and obesity, but whether this is causal, due to reverse causality or merely reflects in‐common risk factors is not known.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Understanding how molecular signaling pathways lead to physiological or pathophysiological changes has long been a key way of identifying therapies for diseases including cancer and diabetes.

    “Understanding how molecular signaling pathways lead to physiological or pathophysiological changes has long been a key way of identifying therapies for diseases including cancer 232 , 233 and diabetes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [232] Dimri M, Satyanarayana A. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. 2020. PMC7072513 32093152 source

      Not checked in the free run.

    • cites [233] Schweizer L, Zhang L. Enhancing cancer drug discovery through novel cell signaling pathway panel strategy.: 53– 59. 10.4137/CGM.S11134 PMC3941151 24665207

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    There are important knowledge gaps regarding the mechanism by which androgens regulate fat mass.

    “However, as highlighted in this review, there are important knowledge gaps with regards to the mechanism by which androgens regulate fat mass and more research is needed in order to inform the utility of targeting the AR signaling pathway as a treatment for obesity.”
    • Also stated in: § CONCLUSION · plain
      “However, as highlighted in this review, there are important knowledge gaps with regards to the mechanism by which androgens regulate fat mass and more research is needed in order to inform the utility of targeting the AR signaling pathway as a treatment for obesity.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Putative mechanisms of SARM selectivity include tissue-specific enzymes, modulated recruitment of coregulators, and activation of unique subcellular signaling cascades.

    “Putative mechanisms of SARM selectivity include tissue specific enzymes, modulated recruitment of coregulators and activation of unique subcellular signaling cascades are some of the putative mechanisms of SARM selectivity, 249 but more research is required to understand these mechanisms and then leverage these unique features to generative more efficacious therapeutics.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [249] Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol. 2018; 465(1): 134‐ 142. doi: 10.1016/j.mce.2017.06.013 28624515 PMC5896569 source

      Not checked in the free run.

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

    Premisecitation

    Leptin was the first identified adipokine thought to have value as a therapeutic.

    “The first identified adipokine that was thought to have value as a therapeutic was leptin, 246 but leptin therapy alone has failed as a therapy for obesity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [246] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372(DECEMBER): 425‐ 432. 7984236 source

      Not checked in the free run.

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

    Premisecitation

    Numerous families of secreted signaling molecules bearing the suffix "-kines," such as myokines, osteokines, adipokines, and hepatokines, have been identified in more recent times.

    “Hormones were identified and subsequently leveraged for use as therapeutics throughout the 20th century but it is only in more recent times that numerous families of secreted signaling molecules bearing the suffix “‐kines” such as myokines, 243 osteokines, adipokines, 244 and hepatokines 245 have been identified. 242”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [243] Guo A, Li K, Xiao Q. Sarcopenic obesity: myokines as potential diagnostic biomarkers and therapeutic targets? Exp Gerontol. 2020; 139(June): 111022. doi: 10.1016/j.exger.2020.111022 32707318 source

      Not checked in the free run.

    • cites [244] Blüher M. Adipokines—removing road blocks to obesity and diabetes therapy. Mol Metab. 2014; 3(3): 230‐ 240. doi: 10.1016/j.molmet.2014.01.005 24749053 PMC3986498 source

      Not checked in the free run.

    • cites [245] Montgomery MK, Bayliss J, Devereux C, et al. SMOC1 is a glucose‐responsive hepatokine and therapeutic target for glycemic control. Sci Transl Med. 2020; 12(559): 1‐ 14. doi: 10.1126/SCITRANSLMED.AAZ8048 32878981 source

      Not checked in the free run.

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

    Premisecitation

    The notion of novel inter-cellular communication molecules forming the basis of novel therapeutics has been previously reported.

    “This notion of novel inter‐cellular communication molecules forming the basis of novel therapeutics have been previously reported. 242”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] Castillo‐Armengol J, Fajas L, Lopez‐Mejia IC. Inter‐organ communication: a gatekeeper for metabolic health. EMBO Rep. 2019; 20(9): 1‐ 16. doi: 10.15252/embr.201947903 PMC6726901 31423716 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The AR signaling pathway elicits its biological effects through both DNA-binding-dependent and non-DNA-binding-dependent pathways, which may be activated by either cytosolically located AR or membrane-localized AR as well as other membrane-localized receptors.

    “The AR signaling pathway elicits its biological effects through both DNA‐binding‐dependent and non‐DNA‐binding‐dependent pathways 32 which may be activated by either cytosolically located AR or membrane localized AR 46 as well as other membrane localized receptors. 35”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [32] Davey RA, Grossmann M. Androgen receptor structure, function and biology: from bench to bedside. Clin Biochem Rev. 2016; 37(1): 3‐ 15. doi: 10.1038/sc.1992.29 27057074 PMC4810760 source

      Not checked in the free run.

    • cites [46] Deng Q, Zhang Z, Wu Y, et al. Non‐genomic action of androgens is mediated by rapid phosphorylation and regulation of androgen receptor trafficking. Cell Physiol Biochem. 2017; 43(1): 223‐ 236. doi: 10.1159/000480343 28854419 source

      Not checked in the free run.

    • cites [35] Thomas P. Membrane androgen receptors unrelated to nuclear steroid receptors. Endocrinology. 2019; 160(4): 772‐ 781. doi: 10.1210/en.2018-00987 30753403

      Not checked in the free run.

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

    Premisecitation

    Hormones were identified and subsequently leveraged for use as therapeutics throughout the 20th century.

    “Hormones were identified and subsequently leveraged for use as therapeutics throughout the 20th century but it is only in more recent times that numerous families of secreted signaling molecules bearing the suffix “‐kines” such as myokines, 243 osteokines, adipokines, 244 and hepatokines 245 have been identified. 242”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] Castillo‐Armengol J, Fajas L, Lopez‐Mejia IC. Inter‐organ communication: a gatekeeper for metabolic health. EMBO Rep. 2019; 20(9): 1‐ 16. doi: 10.15252/embr.201947903 PMC6726901 31423716 source

      Not checked in the free run.

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

    Premisecitation

    Numerous other signaling molecules have been identified but have yet to yield results.

    “Since then, numerous other signaling molecules have been identified but have yet to yield results, 242 suggesting there may be other opportunities that remain to be discovered.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] Castillo‐Armengol J, Fajas L, Lopez‐Mejia IC. Inter‐organ communication: a gatekeeper for metabolic health. EMBO Rep. 2019; 20(9): 1‐ 16. doi: 10.15252/embr.201947903 PMC6726901 31423716 source

      Not checked in the free run.

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

    Premisecitation

    Obesity is a multifactorial disease.

    “Obesity is a multifactorial disease 250 that requires novel therapies in conjunction with current lifestyle and pharmacological interventions in order to be effectively treated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [250] Hruby A, Hu FB. The epidemiology of obesity: a big picture. Pharmacoeconomics. 2015; 33(7): 673‐ 689. doi: 10.1007/s40273-014-0243-x 25471927 PMC4859313

      Not checked in the free run.

74 of 74

  • The paper relies on this without support.

    Findings from rodent models of orchidectomy and testosterone treatment are relevant to human obesity and fat mass regulation.

    “To mimic hypogonadism in men, castration or orchidectomy (ORX) in rodents has been widely utilized.”
1 of 1

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?

  • In obesity, AR activity is significantly reduced in key tissues, contributing to hormonal imbalance and metabolic dysfunction.

    “In obesity, AR activity is significantly reduced in key tissues, contributing to hormonal imbalance and metabolic dysfunction.”

    From Prevention of Diet-Induced Obesity by Phytoecdysteroids 20-Hydroxyecdysone and Calonysterone—Unexpected Modulation of Androgen Balance in Normal and Obese Rats (2026) · cites this paper as [46]

    In “Obesity and hypogonadism” (page unavailable), the review associates obesity with reduced testosterone and, in marked obesity, possible suppression of the HPT axis. In “The androgen receptor (AR)” (page unavailable), it reports that restoring AR in bone-marrow progenitor cells improves metabolic measures in knockout mice. It does not establish that obesity significantly reduces AR activity in key tissues or that such a reduction causes hormonal imbalance and metabolic dysfunction. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Chronic inflammation associated with obesity (e.g., increased IL-6 and TNF-α levels) inhibits AR expression in the hypothalamus and testes.

    “The reason for this phenomenon is that the chronic inflammation associated with obesity (e.g., increased IL-6 and TNF-α levels) inhibits AR expression in the hypothalamus and testes [46].”

    From Prevention of Diet-Induced Obesity by Phytoecdysteroids 20-Hydroxyecdysone and Calonysterone—Unexpected Modulation of Androgen Balance in Normal and Obese Rats (2026) · cites this paper as [46]

    In “Obesity and hypogonadism” (page not available), the review identifies obesity-associated elevations in pro-inflammatory cytokines as a possible contributor to hypothalamic–pituitary–testicular axis suppression. It does not say that IL-6 or TNF-α inhibits androgen receptor expression in the hypothalamus or testes; searches for those cytokines did not locate that mechanism in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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.

  • Castration study is described as using mice instead of rats

    Minor

    The account of Baik et al. calls the animals mice, while the cited paper's title identifies them as male rats.

  • Treatment-group counts exceed the reported registry total

    Minor

    The table reports 823 men, but its treated and untreated groups contain 474 and 395 men, respectively, totaling 869.

    Reported 823 · recomputed 869

  • Fat-loss figure for the cirrhosis trial differs from Table 1

    Minor

    The text attributes a 3.4 kg reduction to reference 81, whereas Table 1 reports a 4.34 kg reduction for that trial. The table's value also exceeds the stated upper end of the 3.4-4.2 kg range.

  • Conclusion reverses the stated effect of absent ERα signaling

    Minor

    The paper says men with inactivating ERα mutations have increased BMI and abdominal adipose tissue, but later concludes that lifelong absence of E2 signaling via ERα may limit fat accumulation.

4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. 10.1016/B978‐0‐12‐801238‐3.64343‐X · DOI
  2. 10.1016/j.steroids.2011.10.013.Tissue · DOI

Cited by

Sorted by citations

Related

Authors
Venkatesh, V. S., Grossmann, M., Zajac, J. D., & Davey, R. A.
Affiliations
The University of Melbourne (AU)
Corresponding author
Venkatesh, Varun S.
ORCID
Venue
Obesity Reviews
Publisher
Wiley
Published
2022-01-27
Volume
23
Issue
6
Pages
e13429-e13429
ISSN
  • 1467-7881 (ISSN-L)
  • 1467-789X
DOI
10.1111/obr.13429
PMC
PMC9286619
OpenAlex
W4210812833
Cited by
22
References
253
Citations by year
2026: 4 · 2025: 2 · 2024: 9 · 2023: 6 · 2022: 1
FWCI
0.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Obesity Reviews (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
Funders
University of Melbourne
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
androgen receptor, obesity, male obesity, hypothalamic-pituitary-testicular axis, androgen signaling, obesity pathogenesis, androgen receptor-targeted therapy, obesity treatment
MeSH terms
Animals, Humans, Male, Obesity, Receptors, Androgen, Testosterone

About these checks

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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