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Cited by 246Hormonal and reproductive studiesAdrenal Hormones and DisordersHypothalamic control of reproductive hormones

A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management

Open access
Grossmann, Mathis, Matsumoto, Alvin M.·2017·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2016-3580PMC PMC5477803
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Abstract

Context: Middle-aged and older men (≥50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic–pituitary–testicular axis pathology but have functional hypogonadism that is potentially reversible. Evidence Acquisition: Literature review from 1970 to October 2016. Evidence Synthesis: Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency–like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling. Conclusions: There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy.

AI snapshot

Written from the paper’s full text.

TL;DR

This perspective argues that functional hypogonadism in middle-aged and older men is often nonspecific, modestly low, and potentially reversible, so holistic management—lifestyle, weight loss, exercise, comorbidity optimization, and targeted symptom treatment—should precede or accompany testosterone therapy. Testosterone remains an option in selected men with more severe symptoms and consistently low levels, but evidence for long-term benefits/risks and for alternative testosterone-boosting medications is limited.

Key findings

  • Functional hypogonadism is defined as androgen deficiency–like features plus low serum testosterone without intrinsic structural hypothalamic–pituitary–testicular pathology or specific pathologic suppression, in men aged 50 years or older; community prevalence estimates range from 2.1% to 12.3%.
  • Symptoms are nonspecific: in EMAS, only 9 of 32 candidate androgen-deficiency symptoms were associated with testosterone levels, and only 3 sexual symptoms clustered with low testosterone; even in stringently defined late-onset hypogonadism, 60% had testosterone ≥8.0 nmol/L. Obesity increased late-onset hypogonadism prevalence 13-fold and comorbidities 9-fold, while it was uncommon in lean men (0.4%) or healthy men (0.6%).
  • Weight loss can raise testosterone: a meta-analysis found diet-associated weight loss (mean 9.8%) increased testosterone by 2.9 nmol/L (84 ng/dL) and surgical weight loss (32%) by 8.7 nmol/L (251 ng/dL); in EMAS, 5% weight loss increased total testosterone by 2 nmol/L (58 ng/dL) but not free testosterone, while >15% weight loss increased total testosterone by 5.7 nmol/L (164 ng/dL), LH by 2.2 IU/L, and free testosterone by 52 pmol/L. Lifestyle intervention increased IIEF score by 2.66 in a meta-analysis of four RCTs, whereas PDE5 inhibitors increased IIEF scores by 5.66 to 7.49; sildenafil alone increased testosterone by 30%.
  • In the Testosterone Trials, men with baseline testosterone averaging <9.5 nmol/L (275 ng/dL) had modest sexual-function benefit and some mood/depressive-symptom benefit; short-term adverse-event rates were similar to placebo, but the trial was too small to reliably assess risks. Aromatase inhibitors, selective estrogen receptor modulators, dehydroepiandrosterone, dihydrotestosterone, selective androgen receptor modulators, and human chorionic gonadotropin cannot currently be recommended outside clinical trials due to limited evidence.

Methods

  • Design: narrative perspective/opinion piece, not a systematic review or primary clinical trial.
  • Data/sample: no new sample; the authors synthesize existing observational cohorts (e.g., EMAS, Framingham, Boston Area Community Health), meta-analyses, RCTs (e.g., Testosterone Trials, sildenafil RCT, lifestyle RCTs, bariatric studies), and clinical guidelines.
  • Main analysis: qualitative synthesis and clinical recommendations; no formal meta-analysis or primary data collection.

Limitations

  • Stated: there are not enough clinical trial data to determine whether low testosterone is a marker of poor health or part of a treatable syndrome; causality cannot be inferred from observational studies; the weight-loss meta-analysis was limited to small studies (total <500 patients) with short-term follow-up and heterogeneous designs; a CPAP meta-analysis including 232 men found no consistent effect on testosterone; RCTs of alternative testosterone-boosting agents were small and short-term; the Testosterone Trials were too small to reliably assess risks.
  • Stated: the authors explicitly present their opinion regarding who might benefit from testosterone treatment, and many management recommendations rely on limited or indirect evidence.
  • Evident: as a narrative perspective, the paper lacks a systematic search strategy, formal risk-of-bias assessment, or quantitative synthesis, and it draws on observational/confounded studies and short-term RCTs.

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

Integrity signals

Registry

Crossref · 10.1210/jc.2016-3580

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 104 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Functional hypogonadism is potentially reversible.

    “is potentially reversible”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Matsumoto, 2013, Testosterone administration in older men, Endocrinol Metab Clin North Am source

      Not checked in the free run.

  • Premisecitation

    In such men, hypogonadism is caused by functional HPT axis suppression in the presence of an intact HPT axis.

    “hypogonadism is caused by functional HPT axis suppression in the presence of an intact HPT axis”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tajar, 2010, Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Premisecitation

    Organic hypogonadism typically presents with clinically and biochemically severe androgen deficiency.

    “Whereas organic hypogonadism typically presents with clinically and biochemically severe androgen deficiency”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Matsumoto, 2013, Testosterone administration in older men, Endocrinol Metab Clin North Am source

      Not checked in the free run.

  • Premisecitation

    Some older men present with primary hypogonadism due to testicular failure, evidenced by high gonadotropin levels, reduced testicular response to human chorionic gonadotropin, and reduced Leydig cell mass.

    “some older men presenting with primary hypogonadism due to testicular failure, evidenced by high gonadotropin levels, reduced testicular response to human chorionic gonadotropin, and reduced Leydig cell mass (4, 5).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Harman, 1980, Reproductive hormones in aging men. I. Measurement of sex steroids, basal luteinizing hormone, and Leydig cell response to human chorionic gonadotropin, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [5] Neaves, 1984, Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Premisecitation

    Organic hypogonadism is not usually reversible.

    “and is not usually reversible”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Matsumoto, 2013, Testosterone administration in older men, Endocrinol Metab Clin North Am source

      Not checked in the free run.

  • May combine two claims. 35
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    Organic hypogonadism is underdiagnosed and undertreated.

    “there is evidence that this condition is underdiagnosed and undertreated (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Bojesen, 2003, Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many middle-aged and older men (aged 50 years or older), especially when obese and suffering from comorbid illness, present with clinical features resembling organic androgen deficiency and modestly to occasionally severely low testosterone levels, yet they do not have recognizable intrinsic structural HPT pathology.

    “many middle-aged and older men (defined here as aged 50 years or older), especially when obese and suffering from comorbid illness, present with clinical features resembling organic androgen deficiency and modestly to occasionally severely low testosterone levels, yet they do not have recognizable intrinsic structural HPT pathology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tajar, 2010, Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In EMAS, only nine of 32 candidate symptoms of androgen deficiency were associated with testosterone levels, and of these only three sexual symptoms clustered with low testosterone and had a syndromic association.

    “In the European Male Aging Study (EMAS) a cross-sectional survey of community-dwelling men, only nine of 32 candidate symptoms of androgen deficiency were associated with testosterone levels, and of these only three sexual symptoms clustered with low testosterone and had a syndromic association (10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Wu, 2010, Identification of late-onset hypogonadism in middle-aged and elderly men, N Engl J Med source

      Not checked in the free run.

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

    Premisecitation

    Community prevalence estimates of potentially functional hypogonadism in middle-aged and older men vary from 2.1% to 12.3%.

    “The community prevalence estimates of potentially functional hypogonadism in middle-aged and older men (also referred to as late-onset, age-related, or adult-onset hypogonadism) vary from 2.1% to 12.3% (8–10)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Araujo, 2004, Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [9] Araujo, 2007, Prevalence of symptomatic androgen deficiency in men, J Clin Endocrinol Metab source

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    • cites [10] Wu, 2010, Identification of late-onset hypogonadism in middle-aged and elderly men, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Testosterone levels in men with functional hypogonadism are usually only modestly reduced and fluctuate around the lower limit of normal.

    “Second, testosterone levels in men with functional hypogonadism are usually only modestly reduced and fluctuate around the lower limit of normal.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Wu, 2010, Identification of late-onset hypogonadism in middle-aged and elderly men, N Engl J Med source

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

    Interpretationnone given

    Optimization of lifestyle measures and comorbidities has the potential to improve all symptoms, as well as testosterone levels and general health.

    “Optimization of lifestyle measures and comorbidities has the potential to improve all symptoms, as well as testosterone levels and general health.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Targeted treatment of specific end-organ dysfunction may improve specific clinical features and may also increase testosterone slightly.

    “Targeted treatment of specific end-organ dysfunction also may improve specific clinical features and, as demonstrated with phosphodiesterase-5 (PDE5) inhibitors discussed later (16), may also increase testosterone slightly.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Spitzer, 2012, Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial, Ann Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In EMAS, obesity increased the prevalence of late-onset hypogonadism by 13-fold and comorbidities by ninefold.

    “In EMAS, obesity increased the prevalence of late-onset hypogonadism by 13-fold and comorbidities by ninefold.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Wu, 2010, Identification of late-onset hypogonadism in middle-aged and elderly men, N Engl J Med source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    It is unclear whether lowered testosterone drives ill health or whether obesity and chronic disease cause poor outcomes.

    “Given this coexistence, it is unclear whether the lowered testosterone drives ill health or whether, conversely, obesity and chronic disease cause poor outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Late-onset hypogonadism was uncommon in men who were lean (0.4%) or healthy (0.6%) and was relatively rare in men who were both.

    “Late-onset hypogonadism was uncommon in men who were lean (0.4%) or healthy (0.6%) and was relatively rare in men who were both (10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Wu, 2010, Identification of late-onset hypogonadism in middle-aged and elderly men, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Maintenance of some minimum level of circulating testosterone is clearly important in older men, although the threshold levels below which adverse health outcomes manifest remain unknown.

    “Thus, the maintenance of some minimum level of circulating testosterone is clearly important in older men, although the threshold levels below which adverse health outcomes manifest remain unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the Testosterone Trials of stringently selected symptomatic men with a baseline testosterone averaging <9.5 nmol/L for no apparent reason other than age, testosterone treatment had a modest benefit in sexual function, and some benefit with respect to mood and depressive symptoms.

    “In the Testosterone Trials of stringently selected symptomatic men with a baseline testosterone averaging < 9.5 nmol/L (275 ng/dL) for no apparent reason other than age, testosterone treatment had a modest benefit in sexual function, and some benefit with respect to mood and depressive symptoms (15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Snyder, 2016, Effects of testosterone treatment in older men, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In EMAS, compared with lean weight, overweight (BMI, 25 to 30 kg/m2) was associated with a 2.3 nmol/L reduction and obesity with a 5.1 nmol/L reduction in total testosterone and, respectively, a 17.6 pmol/L and 53.7 pmol/L reduction in free testosterone.

    “In EMAS, compared with lean weight, overweight (BMI, 25 to 30 kg/m2) was associated with a 2.3 nmol/L (66 ng/dL) reduction and obesity with a 5.1 nmol/L (147 ng/dL) reduction in total testosterone and, respectively, a 17.6 pmol/L (5.1 pg/mL) and 53.7 pmol/L (15.5 pg/mL) reduction in free testosterone (6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tajar, 2010, Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weight loss of 5% was associated with an increase in total testosterone [+2 nmol/L] but not in free testosterone.

    “This weight loss of 5% was associated with an increase in total testosterone [+2 nmol/L (+58 ng/dL)] but not in free testosterone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Camacho, 2013, Age-associated changes in hypothalamic–pituitary–testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a meta-analysis, diet-associated weight loss (mean 9.8%) increased testosterone by 2.9 nmol/L and surgical weight loss (32%) by 8.7 nmol/L.

    “In a meta-analysis, diet-associated weight loss (mean 9.8%) increased testosterone by 2.9 nmol/L (84 ng/dL) and surgical weight loss (32%) by 8.7 nmol/L (251 ng/dL) (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Corona, 2013, Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These data suggest that maintaining good health may prevent, or at least decelerate, the age-related decline in testosterone, although causality cannot be inferred from these observational studies.

    “These data suggest that maintaining good health may prevent, or at least decelerate, the age-related decline in testosterone, although causality cannot be inferred from these observational studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In an intensive lifestyle RCT of relatively healthy obese middle-aged men, 15% weight loss increased the mean IIEF score by 3.10, which is clinically meaningful and similar to the increase of 2.64 reported in the Testosterone Trials.

    “In an intensive lifestyle randomized controlled trial (RCT) of relatively healthy obese middle-aged men, 15% weight loss increased the mean International Index of Erectile Function (IIEF) score by 3.10, which is clinically meaningful (23) and similar to the increase of 2.64 reported in the Testosterone Trials, although those men were older (15).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Esposito, 2004, Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial, JAMA source

      Not checked in the free run.

    • cites [15] Snyder, 2016, Effects of testosterone treatment in older men, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During 4.4 years, weight loss of 5% was associated with a significant linear rise in serum sex hormone-binding globulin, probably because insulin resistance improved.

    “During 4.4 years, weight loss of 5% was associated a significant linear rise in serum sex hormone–binding globulin, probably because insulin resistance improved (22).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Camacho, 2013, Age-associated changes in hypothalamic–pituitary–testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This meta-analysis was limited to small studies (total < 500 patients) with short-term follow-up and heterogeneous study designs.

    “However, this meta-analysis was limited to small studies (total < 500 patients) with short-term follow-up and heterogeneous study designs (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Corona, 2013, Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis, Eur J Endocrinol source

      Not checked in the free run.

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

    Interpretationreasoning

    Although such studies have potential for confounding, one may posit that potential testosterone increases achievable with stopping offending medications or optimizing comorbidities could range from 2 to 5 nmol/L.

    “Although such studies have potential for confounding, one may, analogous to weight loss effects, posit that potential testosterone increases achievable with stopping offending medications or optimizing comorbidities could range from 2 to 5 nmol/L (58 to 144 ng/dL).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Optimizing glycemic control may improve testosterone even in men with fairly well controlled diabetes, although observational data do not prove causality.

    “This suggests that optimizing glycemic control may improve testosterone even in men with fairly well controlled diabetes, although such observational data do not prove causality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Even modest exercise can lead to improvement in features of the metabolic syndrome and to improvements in muscle mass, bone density, and physical function in middle-aged and older men with low testosterone.

    “Even modest exercise can lead to improvement in features of the metabolic syndrome (29) and to improvements in muscle mass, bone density, and physical function in such men (30).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Pattyn, 2013, The effect of exercise on the cardiovascular risk factors constituting the metabolic syndrome: a meta-analysis of controlled trials, Sports Med source

      Not checked in the free run.

    • cites [30] Villareal, 2011, Weight loss, exercise, or both and physical function in obese older adults, N Engl J Med source

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  • May combine two claims.

    Premisecitation

    In a 2-year prospective controlled study of gastric bypass surgery in 64 men (age 49 years; BMI, 46 kg/m2), 30% weight loss increased testosterone by 10.8 nmol/L and reduced sexual dissatisfaction by 7.5 on a 20-scale questionnaire.

    “In a 2-year prospective controlled study of gastric bypass surgery in 64 men (age 49 years; BMI, 46 kg/m2), 30% weight loss increased testosterone by 10.8 nmol/L (311 ng/dL) and reduced sexual dissatisfaction by 7.5 on a 20-scale questionnaire (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Hammoud, 2009, Effect of Roux-en-Y gastric bypass surgery on the sex steroids and quality of life in obese men, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In one prospective study, the degree of weight loss and baseline erectile function predicted improved erectile function, whereas changes in reproductive hormones did not.

    “In one prospective study, the degree of weight loss and baseline erectile function predicted improved erectile function, whereas changes in reproductive hormones did not (28).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Mora, 2013, Weight loss is a major contributor to improved sexual function after bariatric surgery, Surg Endosc source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In those whose glycemic control improved over time, testosterone increased, whereas in those whose control worsened, testosterone decreased.

    “In those whose glycemic control improved over time, testosterone increased, whereas in those whose control worsened, testosterone decreased (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Grossmann, 2008, Low testosterone levels are common and associated with insulin resistance in men with diabetes, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In obese men, exercise decreased body weight by 5.9 kg and improved erectile function (2.6 increase in IIEF-5 score).

    “In obese men, exercise decreased body weight by 5.9 kg and improved erectile function (2.6 increase in IIEF-5 score) (31).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Khoo, 2013, Comparing effects of low- and high-volume moderate-intensity exercise on sexual function and testosterone in obese men, J Sex Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although head-to-head studies are lacking, lifestyle interventions appear less effective than PDE5 inhibitors, which increased IIEF scores by 5.66 to 7.49 in a meta-analysis.

    “Although head-to-head studies are lacking, lifestyle interventions appear less effective than PDE5 inhibitors, which increased IIEF scores by 5.66 to 7.49 in a meta-analysis (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Yuan, 2013, Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis, Eur Urol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Men with low to low-normal testosterone levels can respond well to PDE5 inhibitors, consistent with an analysis of 1075 men reporting that baseline testosterone levels did not influence PDE5 inhibitor responsiveness.

    “Thus, men with low to low-normal testosterone levels can respond well to PDE5 inhibitors, consistent with an analysis of 1075 men reporting that baseline testosterone levels did not influence PDE5 inhibitor responsiveness (40).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Mulhall, 2016, Impact of baseline total testosterone level on successful treatment of sexual dysfunction in men taking once-daily tadalafil 5 mg for lower urinary tract symptoms and benign prostatic hyperplasia: an integrated analysis of three randomized controlled trials, J Sex Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a rigorous RCT of 140 middle-aged men (mean age, 55 years) with sexual dysfunction and testosterone < 11.4 nmol/L, erectile function was initially optimized with sildenafil in all men, leading to a large, clinically meaningful improvement in erectile function (+7.7 on the IIEF erectile function domain).

    “In a rigorous RCT of 140 middle-aged men (mean age, 55 years) with sexual dysfunction and testosterone < 11.4 nmol/L (329 ng/dL), erectile function was initially optimized with sildenafil in all men, leading to a large, clinically meaningful improvement in erectile function (+7.7 on the IIEF erectile function domain) (16).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Spitzer, 2012, Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial, Ann Intern Med source

      Not checked in the free run.

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

    Interpretationnone given

    For most symptoms and end-organ deficits associated with lowered testosterone, specific first-line therapies targeting clinical features individually are available.

    “For most symptoms and end-organ deficits associated with lowered testosterone, specific first-line therapies targeting clinical features individually are available.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Middle-aged and older men with lowered testosterone are a heterogeneous population, and the clinical presentation can differ among individuals.

    “Middle-aged and older men with lowered testosterone are a heterogeneous population, and the clinical presentation can differ among individuals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a RCT of 67 men with OSA not treated with CPAP, testosterone treatment did not improve quality of life, neurocognitive function, or sexual function, except for a modest increase in sexual desire.

    “In a RCT of 67 men with OSA not treated with CPAP, testosterone treatment did not improve quality of life, neurocognitive function, or sexual function, except for a modest increase in sexual desire (39).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Melehan, 2016, Increased sexual desire with exogenous testosterone administration in men with obstructive sleep apnea: a randomized placebo-controlled study, Andrology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The increase in testosterone with sildenafil is consistent with evidence that resumption of sexual activity by itself can increase testosterone by 30%.

    “Though sildenafil may have a direct action on the testes (41), this increase is also consistent with evidence that resumption of sexual activity by itself can increase testosterone by 30% (42).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Spitzer, 2013, Sildenafil increases serum testosterone levels by a direct action on the testes, Andrology source

      Not checked in the free run.

    • cites [42] Jannini, 1999, Lack of sexual activity from erectile dysfunction is associated with a reversible reduction in serum testosterone, Int J Androl source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Continuous positive airway pressure (CPAP), the first-line treatment of OSA, improves erectile dysfunction, fatigue, as well as quality of life.

    “Indeed, continuous positive airway pressure (CPAP), the first-line treatment of OSA, improves erectile dysfunction, fatigue, as well as quality of life (36).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Wittert, 2014, The relationship between sleep disorders and testosterone, Curr Opin Endocrinol Diabetes Obes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OSA is frequently associated with low testosterone levels, but multiple additional mechanisms such as sleep fragmentation, shared cardiovascular risk factors, and obesity can explain symptoms such as sexual dysfunction or low energy.

    “OSA is also frequently associated low testosterone levels, but multiple additional mechanisms such as sleep fragmentation, shared cardiovascular risk factors, and obesity can explain symptoms such as sexual dysfunction or low energy (36).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Wittert, 2014, The relationship between sleep disorders and testosterone, Curr Opin Endocrinol Diabetes Obes source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although the precise effect of CPAP on serum testosterone levels requires further study, this suggests that mechanisms other than increasing testosterone, including improved hypoxia and endothelial function, may explain the benefit of CPAP.

    “Although the precise effect of CPAP on serum testosterone levels requires further study, this suggests that mechanisms other than increasing testosterone, including improved hypoxia and endothelial function, may explain the benefit of CPAP (38).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Hoyos, 2015, Does obstructive sleep apnea cause endothelial dysfunction? A critical review of the literature, Sleep Med Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Trials of testosterone treatment were too short and not designed to determine fracture rates.

    “However, trials were too short and not designed to determine fracture rates.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [46] Snyder, 1999, Effect of testosterone treatment on bone mineral density in men over 65 years of age, J Clin Endocrinol Metab

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    • cites [47] Amory, 2004, Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low testosterone levels are associated with reduced bone mineral density and with increased fracture risk.

    “Low testosterone levels are associated with reduced bone mineral density (44) and with increased fracture risk (45).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] Tajar, 2012, Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS), J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [45] LeBlanc, 2009, The effects of serum testosterone, estradiol, and sex hormone binding globulin levels on fracture risk in older men, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The Endocrine Society recommended that men with high fracture risk should receive an agent with proven antifracture activity irrespective of receiving testosterone or not.

    “The Endocrine Society recommended that men with high fracture risk should receive an agent with proven antifracture activity irrespective of receiving testosterone or not (50).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Watts, 2012, Osteoporosis in men: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    RCTs of aromatase inhibitors and selective estrogen receptor modulators have been small and short-term, and clinical outcome data are very limited.

    “RCTs have been small and short-term, and clinical outcome data are very limited (Supplemental Table 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplemental Table 2

      Not checked in the free run.

40 of 40

  • The paper relies on this without support.

    Middle-aged and older men with chronic disease and/or obesity commonly present with nonspecific symptoms and modestly low testosterone levels.

    “Middle-aged and older men with chronic disease and/or obesity commonly present with nonspecific symptoms and modestly low testosterone levels.”

  • The paper relies on this without support.

    In many middle-aged and older men, low testosterone is due to functional HPT axis suppression.

    “Increasing evidence suggests that in many middle-aged and older men low testosterone is due to functional HPT axis suppression.”

  • The paper relies on this without support.

    Low testosterone may contribute to fatigue or poor motivation, reducing the ability to initiate healthy lifestyle measures.

    “low testosterone may contribute to fatigue or poor motivation, reducing the ability to initiate healthy lifestyle measures.”

  • The paper relies on this without support.

    The nonspecific androgen deficiency-like symptoms may, at least in part, be mediated by comorbidities.

    “The nonspecific androgen deficiency-like symptoms may, at least in part, be mediated by comorbidities.”

  • The paper relies on this without support.

    Knowledge that obesity and comorbidities might be causing symptoms and why testosterone levels are low may motivate some men to more actively engage in lifestyle interventions.

    “Knowledge that obesity and comorbidities might be causing symptoms and why testosterone levels are low may motivate some men to more actively engage in lifestyle interventions.”

  • The paper relies on this without support.

    Lifestyle intervention, management of comorbid illnesses, and discontinuation of offending medications may be difficult and many times not possible.

    “lifestyle intervention, management of comorbid illnesses, and discontinuation of offending medications may be difficult and many times not possible.”

  • The paper relies on this without support.

    Substantial weight loss in obese men is required to achieve meaningful increases in testosterone levels.

    “substantial weight loss in obese men is required to achieve meaningful increases in testosterone levels.”

  • The paper relies on this without support.

    Even if successful, lifestyle measures may be insufficient to relieve symptoms and to normalize testosterone levels.

    “Even if successful, such measures may be insufficient to relieve symptoms and to normalize testosterone levels.”

  • The paper relies on this without support.

    In some men, measures to reverse functional hypogonadism may be unsuccessful because implementation is not feasible or they are not achieved or maintained.

    “In some men, measures to reverse functional hypogonadism may be unsuccessful, either because implementation is not feasible (e.g., cessation of opioids in chronic pain or methadone maintenance patients) or they are not achieved or maintained (e.g., sustained weight loss in obese patients).”

  • The paper relies on this without support.

    Significant clinical features consistent with androgen deficiency and/or consistently low testosterone may persist even despite successful implementation of measures to reverse functional hypogonadism.

    “Significant clinical features consistent with androgen deficiency and/or consistently low testosterone may persist even despite successful implementation of these measures.”

  • The paper relies on this without support.

    Organic HPT pathology can be missed.

    “Re-evaluation for organic HPT pathology should be considered, as this can be missed.”

  • The paper relies on this without support.

    Aromatase inhibitors and selective estrogen receptor modulators require residual hypothalamic–pituitary responsiveness and are ineffective in organic hypogonadotrophic and primary hypogonadism.

    “These agents require residual hypothalamic–pituitary responsiveness and are not indicated or are ineffective in organic hypogonadotrophic hypogonadism, and they will not work in primary hypogonadism.”

  • The paper relies on this without support.

    Aromatase inhibitors decrease estradiol levels.

    “aromatase inhibitors decrease estradiol levels”
13 of 13

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?

  • Functional hypogonadism is associated with the use of certain drugs, hyperprolactinemia, obesity and chronic diseases such as type 2 diabetes.

    “As functional hypogonadism is associated with the use of certain drugs, hyperprolactinemia, obesity and chronic diseases, such as type 2 diabetes, treatment of these causes can help normalize testosterone levels [9].”

    From Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy (2020) · cites this paper as [9]

    The Abstract (page not provided) links functional hypogonadism to obesity, comorbid illness, and medications such as opioids or glucocorticoids; “Optimization of Chronic Disease” specifically identifies type 2 diabetes. The paper says these conditions may improve with treatment, but its definition excludes hyperprolactinemia as a specific pathologic cause that should be ruled out. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Treatment of the causes of functional hypogonadism (drugs, hyperprolactinemia, obesity, chronic diseases) can help normalize testosterone levels.

    “As functional hypogonadism is associated with the use of certain drugs, hyperprolactinemia, obesity and chronic diseases, such as type 2 diabetes, treatment of these causes can help normalize testosterone levels [9].”

    From Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy (2020) · cites this paper as [9]

    The Conclusions (page unavailable) say that weight loss and management of comorbidities may reverse HPT-axis suppression enough to normalize testosterone; stopping offending medications may also increase levels, though these measures may be insufficient. The Abstract (page unavailable) treats hyperprolactinemia differently: it is a specific pathology to exclude from the paper’s defined group of men with functional hypogonadism, not one of the causes addressed by those management recommendations. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Functional hypogonadism refers to identical clinical signs and coexisting androgen deficiency without an intrinsic pathology of the HPG axis.

    “Functional hypogonadism on the other hand refers to identical clinical signs and coexisting androgen deficiency without an intrinsic pathology of the HPG axis [165].”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [165]

    The paper’s definition in the Abstract supports the coexistence of androgen deficiency–like features and low testosterone without intrinsic structural HPT-axis pathology in middle-aged or older men. But it does not call the clinical signs identical to those of organic hypogonadism: Table 1 distinguishes their typical symptoms and signs. The definition also excludes specific pathological causes of HPT-axis suppression. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The role of TRT to treat men with functional or late-onset hypogonadism remains controversial because of unclear indications and potential side effects.

    “Moreover, the role of TRT to treat men with functional or late-onset hypogonadism remains controversial because of unclear indications and potential side effects [1,9].”

    From Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy (2020) · cites this paper as [9]

  • Organic hypogonadism is characterized by a structural, congenital or destructive disturbance of the HPG axis, leading to the inability of the gonads to produce a sufficient amount of androgens resulting in clinical signs of androgen deficiency.

    “Organic hypogonadism is characterized by a structural, congenital or destructive disturbance of the hypothalamic–pituitary–gonadal (HPG) axis, leading to the inability of the gonads to produce a sufficient amount of androgens resulting in clinical signs of androgen deficiency.”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [165]

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.

  • Inconsistent free-testosterone unit conversion

    Minor

    The stated 52 pmol/L increase is paired with 52 pg/mL, implying a one-to-one conversion. Elsewhere, the paper pairs 42 pmol/L with 12.1 pg/mL for the same measure.

1 of 1

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Authors
Grossmann, M., & Matsumoto, A. M.
Affiliations
  • The University of Melbourne (AU)
  • University of Washington (US)
Corresponding author
Grossmann, Mathis
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2017-01-18
Volume
102
Issue
3
Pages
1067-1075
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2016-3580
PMC
PMC5477803
OpenAlex
W2773652641
Cited by
246
References
53
Citations by year
2026: 23 · 2025: 27 · 2024: 34 · 2023: 28 · 2022: 33 · 2021: 21 · 2020: 24 · 2019: 25 · 2018: 23 · 2017: 5 · 2016: 1 · 2015: 1
FWCI
3.07
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
functional hypogonadism, androgen deficiency, testosterone replacement therapy, middle-aged and older men, obesity, comorbidities, lifestyle intervention, weight loss, phosphodiesterase-5 inhibitors, erectile dysfunction, hypothalamic-pituitary-testicular axis, drug discontinuation
MeSH terms
Aged, Androgens, Diet Therapy, Humans, Hypogonadism, Erectile Dysfunction, Life Style, Male, Middle Aged, Obesity, Testosterone, Weight Loss, Exercise, Phosphodiesterase 5 Inhibitors

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