Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials
Open accessAbstract
Introduction: Male hypogonadism is a common condition, with an increasing body of literature on diagnosis, implications, and management. Given the significant variability in testosterone (T) from a physiologic and assay perspective, a thorough understanding of factors affecting T values and study methodology is essential to interpret reported study outcomes appropriately. However, despite the large number of publications on T, there are no reference materials consolidating all relevant and potentially confounding factors necessary to interpret T studies appropriately. Aims: To create a resource document that reviews sources of T variability, free vs total T, assay techniques and questionnaires, and study methodology relevant to interpreting outcomes. Methods: A PubMed search was performed of all the T literature published on T variability, assay techniques, and T-specific questionnaires. Results were summarized in the context of their impact on interpreting T literature outcomes and methodology. Main Outcome Measures: Effect of various factors on T variability and their relevance to study methodology and outcomes. Results: Several factors affect measured T levels, including aging, circadian rhythms, geography, genetics, lifestyle choices, comorbid conditions, and intraindividual daily variability. The utility of free T over total T is debatable and must be compared using appropriate threshold levels. Among various assay techniques, mass spectrometry and equilibrium dialysis are gold standards. Calculated empirical estimates of free T also are commonly used and accepted. Hypogonadism-specific questionnaires have limited utility in screening for hypogonadism, and their role as objective end points for quantifying symptoms remains unclear. Numerous aspects of study methodology can directly or indirectly affect reported outcomes, including design (randomized, prospective, retrospective), duration, populations studied (age, comorbid conditions), low T threshold, therapeutic agent used, objective measurements and end points selected, and statistical interpretation. Conclusion: Critical appraisal of the T literature requires an understanding of numerous factors resulting in T variability, study design and methodology, and limitations of assay techniques and objective measurement scales.
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- Premisecitation
Despite similar daily patterns, elderly males had significant blunting of peak versus trough testosterone levels, with differences of 61-205 ng/dl compared with 141-354 ng/dl in younger men.
“Despite similar patterns of variation throughout the day, elderly males experienced significant blunting of peak versus trough levels, with differences in high and low values of 61–205 ng/dl (2.1–7.1 nmol/L) compared to 141–354 ng/dl (4.9–12.3 nmol/L) in younger men.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [42] Shi, 2013, Longitudinal changes in testosterone over five years in community-dwelling men, J Clin Endocrinol Metab source
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- Premisecitation
The European Male Aging Study identified age-related increases in symptomatic hypogonadism, with rates of 0.1% among men aged 40-49, 0.6% among 50-59, 3.2% among 60-69, and 5.1% among 70-79.
“The European Male Aging Study (EMAS) also identified age-related increases in symptomatic hypogonadism, with rates of 0.1% among 40–49 year old men rising to 0.6% (50–59), 3.2% (60–69), and 5.1% (70–79).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Wu, 2010, Identification of late-onset hypogonadism in middle-aged and elderly men, N Engl J Med source
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- Premisecitation
Numerous studies have consistently found age-dependent decreases in testosterone.
“Numerous studies have consistently identified age-dependent decreases in T.”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [35] Muehlenbein, 2010, Toward quantifying the usage costs of human immunity: Altered metabolic rates and hormone levels during acute immune activation in men, Am J Hum Biol source
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- cites [36] Travison, 2007, The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men, J Clin Endocrinol Metab source
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- cites [37] Yeap, 2012, Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men, J Clin Endocrinol Metab source
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- cites [38] Bhasin, 2011, Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts, J Clin Endocrinol Metab source
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- cites [39] Feldman, 2002, Age trends in the level of serum testosterone and other hormones in middle-aged men: Longitudinal results from the Massachusetts male aging study, J Clin Endocrinol Metab source
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- cites [40] Ferrini, 1998, Sex hormones and age: A cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men, Am J Epidemiol source
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- Premisecitation
Men with low numbers of CAG repeats, indicating improved androgen receptor function, may have improved response rates to testosterone supplementation.
“Men with low numbers of CAG repeats (improved AR function) may also experience improved response rates to T supplementation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Dhiman, 2011, Predictors of pilosebaceous unit responsiveness to testosterone therapy in patients with hypogonadotrophic hypogonadism, Andrologia source
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- Premisecitation
Studies of CAG repeats and hypogonadal symptoms found findings similar to those in men with low testosterone, including depressed mood, anxiety, impaired spermatogenesis, and loss of bone mineral density.
“Results demonstrated findings similar to those observed in men with low T, including depressed mood, anxiety, impaired spermatogenesis, and loss of bone mineral density (BMD), among others.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [31] Mifsud, 2001, Trinucleotide (CAG) repeat polymorphisms in the androgen receptor gene: Molecular markers of risk for male infertility, Fertil Steril source
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- cites [32] Zitzmann, 2001, The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males, Clin Endocrinol source
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- cites [33] Schneider, 2011, Sex hormone levels, genetic androgen receptor polymorphism, and anxiety in >/=50-year-old males, J Sex Med source
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- Interpretationreasoning
Many aspects of study methodology can directly or indirectly affect reported outcomes.
“Numerous aspects of study methodology may directly or indirectly impact reported outcomes including design (randomized, prospective, retrospective), duration, populations studied (age, comorbid conditions), low T threshold, therapeutic agent utilized, objective measures/end-points selected, and statistical interpretation.”
Quote in the paperSubstantial claim - Premisecitation
One study of 325 men over age 40 with self-reported very good or excellent health found no significant differences in testosterone levels based on age.
“One study comparing 325 men >age 40 years with self-reported “very good” or “excellent” health demonstrated no significant differences in T levels based on age.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Harman, 2001, Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging, J Clin Endocrinol Metab source
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- Interpretationcitation
The effect of age as an independent risk factor for decreasing testosterone remains controversial.
“Despite the observed decrease in TT and fT levels in aging males, the effect of age as an independent risk factor for decreasing T remains controversial.”
Quote in the paperNot a substantial claim - Premisenone given
Relatively limited data exist on the effect of testosterone supplementation on hypogonadism-associated comorbidities.
“relatively limited data are available regarding the effect of T supplementation on these conditions.”
Quote in the paperSubstantial claim - Premisecitation
Moderate alcohol use has not been associated with altered testosterone levels.
“In contrast to smoking, moderate alcohol use has not been associated with altered T levels.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [76] Rohrmann, 2007, Serum estrogen, but not testosterone, levels differ between black and white men in a nationally representative sample of Americans, J Clin Endocrinol Metab source
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- cites [78] Wu, 1995, Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada, Cancer Epidemiol Biomarkers Prev
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- Interpretationcitation
Data on the effect of smoking on testosterone levels are contradictory.
“Contradictory data are available on the effect of smoking on T levels.”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [68] Nicolau, 1984, Circadian and circannual rhythms of hormonal variables in elderly men and women, Chronobiol Int source
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- cites [76] Rohrmann, 2007, Serum estrogen, but not testosterone, levels differ between black and white men in a nationally representative sample of Americans, J Clin Endocrinol Metab source
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- cites [77] Litman, 2006, Serum androgen levels in black, Hispanic, and white men, J Clin Endocrinol Metab source
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- cites [78] Wu, 1995, Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada, Cancer Epidemiol Biomarkers Prev
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- cites [79] Harris, 1998, The heritability of testosterone: A study of Dutch adolescent twins and their parents, Behav Genet source
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- cites [80] Hoekstra, 2006, Heritability of testosterone levels in 12-year-old twins and its relation to pubertal development, Twin Res Hum Genet source
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- Interpretationcitation
Geographical location appears to have a significant impact on testosterone levels.
“In contrast to the minimal variations noted among different ethnicities, geographical location appears to have a significant impact on T levels.”
Quote in the paperNot a substantial claim - Premisecitation
Development of additional chronic illnesses or increasing medication use results in a more rapid age-associated decline in testosterone.
“Similarly, development of additional chronic illnesses or increasing medication use results in a more rapid age-associated decline in T.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [68] Nicolau, 1984, Circadian and circannual rhythms of hormonal variables in elderly men and women, Chronobiol Int source
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- Premisecitation
A study of 16 men found that 50% of men identified as hypogonadal on one measurement were eugonadal on repeat testing.
“A similar study of 16 men found that 50% of men who were identified as hypogonadal (defined as <300 ng/dl [10.4 nmol/L]) on one given measurement were noted to be eugonadal on repeat testing.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64] Jeng, 2014, Association of cigarette smoking with reproductive hormone levels and semen quality in healthy adult men in Taiwan, J Environ Sci Health A Tox Hazard Subst Environ Eng source
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- Interpretationcitation
Combined results suggest that ethnicity alone is not likely a significant factor causing testosterone variability.
“These combined results suggest that ethnicity alone is not likely a significant factor resulting in T variability.”
Quote in the paperSubstantial claim - Premisecitation
Exercise is independently associated with increasing testosterone levels.
“In addition to weight loss, exercise is independently associated with increasing T levels.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [72] Bremner, 1983, Loss of circadian rhythmicity in blood testosterone levels with aging in normal men, J Clin Endocrinol Metab source
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- cites [73] Crawford, 2007, The association of time of day and serum testosterone concentration in a large screening population, BJU Int source
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- cites [74] Diver, 2003, Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men, Clin Endocrinol source
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- cites [75] Axelsson, 2005, Effects of acutely displaced sleep on testosterone, J Clin Endocrinol Metab source
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- Premisecitation
A study of saliva-based free testosterone in 783 male twins found significant decreases in free testosterone after waking from sleep, with 32-39% of the total decline occurring within 30 minutes of waking.
“One study, which obtained saliva-based fT assessments in 783 male twins, demonstrated significant decreases in fT following waking from sleep, with 32–39% of the total decline occurring within 30 minutes of waking.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Sartorius, 2009, Predictive accuracy and sources of variability in calculated free testosterone estimates, Ann Clin Biochem source
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- Premisecitation
Men performing 236 minutes of moderate-intensity exercise had greater testosterone increases, 59 ng/dl versus 23 ng/dl, than those performing 105 minutes.
“Men performing 236 minutes of moderate-intensity exercise experienced greater increases in T (59 ng/dl versus 23 ng/dl [2 vs 0.8 nmol/L]) over those performing 105 minutes.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [72] Bremner, 1983, Loss of circadian rhythmicity in blood testosterone levels with aging in normal men, J Clin Endocrinol Metab source
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- Interpretationreasoning
Given discrepant and inconsistent findings, there are insufficient data to support or refute seasonal variability in testosterone levels.
“Given the discrepant and inconsistent findings, there are insufficient data to support or refute seasonal variability in T levels.”
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One study of eight healthy males assessed on two separate days found a 32% absolute variation in reported testosterone results.
“One study of eight healthy males undergoing T assessments on two separate days noted a 32% absolute variation in reported results”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [65] Halmenschlager, 2009, Evaluation of the effects of cigarette smoking on testosterone levels in adult men, J Sex Med source
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- Premisecitation
Results showed greater variation between serial intra-individual measurements than from differences in assays themselves.
“Results demonstrated greater variation between serial intra-individual measurements than from differences in assays themselves.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [67] Ruhayel, 2007, Seasonal variation in serum concentrations of reproductive hormones and urinary excretion of 6-sulfatoxymelatonin in men living north and south of the Arctic Circle: A longitudinal study, Clin Endocrinol source
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- Interpretationcitation
Intra-individual variability is a significant factor that must be considered when interpreting testosterone values.
“Intra-individual variability is another significant factor, which must be taken into account when interpreting T values.”
Quote in the paperSubstantial claim - Interpretationreasoning
These combined findings highlight the difficulty of establishing standardized reference ranges given the decline in testosterone with aging and the lack of defined age-specific cut-points for various symptoms.
“These combined findings highlight the difficulty in establishing standardized reference ranges, given the declining T associated with aging and the lack of defined, age-specific cut-points for various symptomatology.”
Quote in the paperSubstantial claim - Premisecitation
At lower total testosterone levels (216-346 ng/dl), free testosterone was superior to total testosterone alone.
“At lower TT levels (216–346ng/dl [7.5–12 nmol/L]), fT was found to be superior to TT alone.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [106] Hammes, 2005, Role of endocytosis in cellular uptake of sex steroids, Cell source
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- Premisecitation
A major challenge in testosterone interpretation is significant variability among laboratories and assay techniques.
“One of the challenges with T interpretation is the significant variability existing among laboratories and various assay techniques.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [86] Nanjee, 1985, Plasma free testosterone—is an index sufficient?, Ann Clin Biochem source
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- cites [87] Sodergard, 1982, Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature, J Steroid Biochem source
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- cites [88] Vermeulen, 1999, A critical evaluation of simple methods for the estimation of free testosterone in serum, J Clin Endocrinol Metab source
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- Premisecitation
A subset of patients describing themselves as in excellent or very good health had similar mean, 97.5%, and 2.5% total testosterone levels compared with the entire cohort.
“Of interest, a subset of patients describing themselves as in excellent or very good health had similar mean, 97.5%, and 2.5% TT levels compared to the entire cohort (mean-406, 97.5%–739, 2.5%–184 ng/dl [14.1, 25.6, and 6.4 nmol/L]).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Muehlenbein, 2010, Toward quantifying the usage costs of human immunity: Altered metabolic rates and hormone levels during acute immune activation in men, Am J Hum Biol source
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- Premisecitation
At lower concentrations, immunoassays show particularly significant variation among techniques, with equivalent samples producing 2.7-14.3 fold variations in reported results.
“At lower concentrations, IA demonstrate particularly significant variations among techniques, with equivalent samples resulting in 2.7–14.3 fold variations in reported results.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [88] Vermeulen, 1999, A critical evaluation of simple methods for the estimation of free testosterone in serum, J Clin Endocrinol Metab source
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- Premisecitation
Other studies have shown increased associations between free testosterone and comorbid conditions including depression and hypogonadal symptoms.
“Other studies have also demonstrated increased associations between fT and other comorbid conditions, including depression and hypogonadal symptoms.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Araujo, 2007, Prevalence of symptomatic androgen deficiency in men, J Clin Endocrinol Metab source
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- cites [97] Wang, 2008, Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations, Eur J Endocrinol source
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- Premisecitation
The CDC requires certifying facilities to report total testosterone values within ±6.4% of samples tested ranging from 2.50-1000 ng/dl.
“Currently, the CDC requires that a certifying facility report TT values within ±6.4% of samples tested ranging from 2.50–1000 ng/dl (0.9–35 nmol/L).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [91] Rosner, 2007, Position statement: Utility, limitations, and pitfalls in measuring testosterone: An Endocrine Society position statement, J Clin Endocrinol Metab source
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- Premisecitation
A study of non-obese healthy men aged 19-40 from the Framingham Heart Study reported calculated free testosterone levels of 70 pg/ml.
“A second study of non-obese healthy men aged 19–40 years from the Framingham Heart Study reported calculated fT levels of 70 pg/ml (242.7 pmol/L).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Travison, 2007, The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men, J Clin Endocrinol Metab source
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- Premisecitation
Testosterone circulates in plasma as free molecule (2%) or complexed with albumin (50%), SHBG (44%), or corticosteroid-binding globulin (4%).
“Testosterone circulates in the plasma as either a free molecule (fT - 2%) or complexed with varying affinities to proteins including albumin (loosely bound - 50%), SHBG (tightly bound - 44%), or corticosteroid-binding globulin (loosely bound - 4%).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [94] Vesper, 2007, Reference materials and commutability, Clin Biochem Rev
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- Premisecitation
Over the past 10 years, mass spectrometry, particularly liquid chromatography tandem mass spectrometry, has become increasingly adopted because of high throughput, limited sample preparation, and high sensitivity and specificity at low and high testosterone concentrations.
“However, over the past 10 years, MS, and in particular liquid chromatography tandem mass spectrometry (LC-MS/MS), has become increasingly adopted due to its high throughput, limited requirement for sample preparation, and high sensitivity/specificity at low and high T concentrations.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [82] Ahokoski, 1998, Biological day-to-day variation and daytime changes of testosterone, follitropin, lutropin and oestradiol-17beta in healthy men, Clin Chem Lab Med source
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- cites [84] Lima, 2000, Decreased androgen levels in massively obese men may be associated with impaired function of the gonadostat, Int J Obes Relat Metab Disord source
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- Premisecitation
Recent data have identified cellular uptake of SHBG-bound testosterone with resultant physiologic hormonal activity.
“The relevance of fT versus TT is also debatable, as recent data have identified cellular uptake of SHBG-bound T with resultant physiologic hormonal activity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [101] van den Beld, 2000, Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men, J Clin Endocrinol Metab
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- Premisecitation
Current guidelines from ASA, EAA, EAU, ISA, and ISSAM have adopted the strategy of using free testosterone as a confirmatory marker in borderline low total testosterone.
“Current guidelines from the ASA, EAA, EAU, ISA, and ISSAM have adopted this strategy of using fT as a confirmatory marker in cases of borderline low TT.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Bhasin, 2010, Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline, J Clin Endocrinol Metab source
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- Premisecitation
A study of 3690 elderly community-dwelling men with mean age 77 found a mean total testosterone of 378 ng/dl, with upper and lower reference ranges of 693 and 145 ng/dl.
“A second study evaluating 3690 elderly (mean age 77), community-dwelling men identified a mean TT of 378 ng/dl (13.1 nmol/L), with upper (97.5%) and lower (2.5%) reference ranges of 693 and 145 ng/dl (24 and 5 nmol/L), respectively.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] Muehlenbein, 2010, Toward quantifying the usage costs of human immunity: Altered metabolic rates and hormone levels during acute immune activation in men, Am J Hum Biol source
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- Premisecitation
Limited data comparing total or free testosterone with clinical variables in elderly males show a stronger relationship between calculated bioavailable testosterone and muscle strength, bone mineral density, and fat mass than with total testosterone.
“Limited data comparing the association of TT or fT to clinical variables in elderly males have demonstrated a stronger relationship between calculated bioavailable T and muscle strength, bone mineral density, and fat mass compared to TT.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [96] Control CfD
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- Premisecitation
In a cohort of 456 men aged 19-40 from the Framingham Heart Study Generation 3, mean total testosterone was 724 ng/dl, with upper and lower intervals of 1197 and 348 ng/dl.
“Mean TT was 724 ng/dl (25.1 nmol/L), with upper (97.5%) and lower (2.5%) intervals noted to be 1197 and 348 ng/dl (41.5 and 12.1 nmol/L), respectively.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Travison, 2007, The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men, J Clin Endocrinol Metab source
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- Premisenone given
Few studies discussing testosterone supplementation report details about the specific testing modality used.
“Few studies discussing T supplementation report details on specifics of the testing modality itself.”
Quote in the paperSubstantial claim - Premisenone given
Despite increasing literature on SHBG polymorphisms and hypogonadal conditions, limited data exist on their impact in hypogonadal men receiving testosterone supplementation.
“Despite an increasing body of literature on the impact of SHBG polymorphisms on hypogonadal-related conditions, limited data are currently available on their impact in hypogonadal men undergoing T supplementation.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Systematic reviews and meta-analyses of randomized controlled trials (level Ia) are of significantly greater value and reliability than retrospective series (level 2b).
“As such, systematic reviews and meta-analyses of RCTs (level Ia) are of significantly greater value and reliability than retrospective series (level 2b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [122] Medicine CfEB, 2009
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- Premisecitation
One study found the MMAS inferior as a screening modality for low bioavailable testosterone because of relatively lower sensitivity (60%).
“In comparing the AMS, ADAM, and MMAS scales on ability to identify low bioavailable T levels, one study noted inferiority of the MMAS scale as a screening modality due to a relatively lower sensitivity (60%).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [115] Morley, 2006, Comparison of screening questionnaires for the diagnosis of hypogonadism, Maturitas source
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- Premisecitation
In a prospective study, young and elderly men treated with clomiphene citrate 50 mg/day for two months showed an approximately 870 ng/dL increase in the youthful group versus 489 ng/dL in elderly males.
“Tenover and colleagues prospectively treated young and elderly (mean age 29 years vs. 73 years) men with clomiphene citrate 50mg/day for two months.128 Results demonstrated an approximately 870ng/dl (30.2 nmol/L) increase in the youthful group compared to 489ng/dl (17 nmol/L) in elderly males.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [128] Tenover, 1991, The effects of normal aging on the response of the pituitary-gonadal axis to chronic clomiphene administration in men, J Androl source
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- Interpretationcitation
The reported increased specificity of free testosterone over total testosterone may reflect inappropriately matched threshold values rather than an intrinsic advantage of free testosterone.
“This observation suggests that the reported increased specificity of fT over TT may reflect inappropriately matched threshold values rather than an intrinsic advantage of fT.”
Quote in the paperSubstantial claim - Premisecitation
In a population-based observational survey of 1,475 men aged 30-79 years, increasing the lower free testosterone threshold (50-60 or 60-70 pg/mL) reduced specificity for symptoms such as low libido (28.1%, 23.9%, and 19.8% for 50, 60, and 70 pg/mL, respectively).
“The authors noted that increasing the lower fT threshold (50–60, or 60–70pg/ml [173.4–208 and 208–242.7 pmol/L]) resulted in reduced specificity for symptoms such as low libido (28.1%, 23.9%, and 19.8% for 50, 60, and 70pg/ml [242.7 pmol/L], respectively).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Araujo, 2007, Prevalence of symptomatic androgen deficiency in men, J Clin Endocrinol Metab source
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- Interpretationnone given
Only randomized controlled trials are able to isolate causative factors.
“Only RCTs are able to isolate causative factors.”
Quote in the paperNot a substantial claim - Premisecitation
A systematic review and meta-analysis of testosterone trials including randomized controlled trials found no significant effect of testosterone supplementation on overall survival.
“In contrast, a systematic review and meta-analysis of T trials, including RCTs demonstrated no significant effect of T supplementation on overall survival.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [124] Fernandez-Balsells, 2010, Clinical review 1: Adverse effects of testosterone therapy in adult men: A systematic review and meta-analysis, J Clin Endocrinol Metab source
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- Premisecitation
A 12-month trial of anastrozole found significant reductions in bone mineral density.
“while Burnett-Bowie’s group identified significant reductions in bone mineral density with therapy.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [125] Leder, 2005, Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men, Osteoporos Int source
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- cites [126] Burnett-Bowie, 2009, Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels, J Clin Endocrinol Metab source
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- Premisecitation
In a 3-month trial of 68 men treated with anastrozole 1 mg/day, there was no change in markers of bone turnover despite greater mean reductions in estradiol.
“Results from the Leder trial reported no change in markers of bone turnover, despite greater mean reductions in estradiol”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [125] Leder, 2005, Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men, Osteoporos Int source
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- cites [126] Burnett-Bowie, 2009, Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels, J Clin Endocrinol Metab source
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- Premisenone given
The preponderance of data has demonstrated an association between aging and low testosterone.
“Although controversial, the preponderance of data have demonstrated an association between aging and low T.”
Quote in the paperNot a substantial claim - Premisecitation
A recent study demonstrated high correlation of hypogonadal symptoms between total and free testosterone when select cutpoints were used: total testosterone 235 ng/dL and free testosterone 98 pg/mL.
“This concept is also highlighted in a recent study demonstrating high correlation of hypogonadal symptoms between TT and fT when select cutpoints were used: TT 235 ng/dl (10.5 nmol/L), fT 98 pg/ml (220 pmol/L).133”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [133] Antonio, Low free testosterone is associated with hypogonadal signs and symptoms in men with normal total testosterone source
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- Interpretationreasoning
Studies reporting consistent early morning sampling with one or more confirmatory tests are more likely to represent a low testosterone population than those with heterogeneous sampling.
“Studies reporting consistent early morning sampling, with one or more confirmatory tests obtained are more likely representative of a low T population rather than those with heterogenous sampling.”
Quote in the paperSubstantial claim - Interpretationreasoning
Participant age is a common confounder in the hypogonadism literature and must be controlled in observational or retrospective studies of hypogonadism-associated conditions.
“Participant age is a common confounder in the hypogonadism literature and must be controlled in observational or retrospective studies of hypogonadism-associated conditions.”
Quote in the paperSubstantial claim- Rests on an assumption: Participant age is a common confounder in the hypogonadism literature.
- Interpretationcitation
The role of questionnaires in identifying improvements with testosterone supplementation is unclear.
“The role for questionnaires in identifying improvements with T supplentation is unclear.”
Quote in the paperSubstantial claim - Interpretationreasoning
Studies of extended duration are likely required to assess changes in cognition, muscle mass, adiposity, bone fracture risk, cardiovascular risk, and comorbid condition sequelae.
“In addition to changes in bone density, studies of extended duration are likely required to assess other factors including changes in cognition, muscle mass, adiposity, bone fracture risks, cardiovascular risk, and comorbid condition sequelae.”
Quote in the paperSubstantial claim - Interpretationreasoning
Potential benefits of testosterone supplementation may be reduced in elderly males because of age-associated impairments in testosterone responsiveness.
“Similarly, although data are lacking, potential benefits of T supplementation may be reduced in elderly males due to age-associated impairments in T responsiveness.”
Quote in the paperNot a substantial claim - Premisecitation
A more recent multi-step model estimating free testosterone using dichotomized analysis of SHBG reported estimates not statistically different from equilibrium dialysis.
“A more recent, multi-step model of estimating fT using a dichotomized analysis of SHBG reported estimates which were not statistically different from those obtained via equilibrium dialysis.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [108] Zakharov, 2015, A multi-step, dynamic allosteric model of testosterone's binding to sex hormone binding globulin, Mol Cell Endocrinol source
Not checked in the free run.
- Interpretationnone given
Methodology for testosterone sampling is important because significant day-to-day, intra-individual, and diurnal variability occurs.
“Methodology for T sampling is also an important aspect of study design, as significant day-to-day, intra-individual and diurnal variability occurs.”
Quote in the paperSubstantial claim - Premisecitation
Among hypogonadism questionnaires, the AMS and ADAM scales show the highest sensitivity (81-97%) but poor specificity (19-39%).
“The sensitivity and specificity of the various scales have been reported, with overall findings demonstrating the highest sensitivities with the AMS and ADAM questionnaires (81–97%) with concomitant poor specificity (19–39%).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [115] Morley, 2006, Comparison of screening questionnaires for the diagnosis of hypogonadism, Maturitas source
Not checked in the free run.
- cites [116] Blumel, 2009, Is the Androgen Deficiency of Aging Men (ADAM) questionnaire useful for the screening of partial androgenic deficiency of aging men?, Maturitas source
Not checked in the free run.
- cites [117] Tancredi, 2004, Interest of the Androgen Deficiency in Aging Males (ADAM) questionnaire for the identification of hypogonadism in elderly community-dwelling male volunteers, Eur J Endocrinol source
Not checked in the free run.
- Premisecitation
In Vigen et al.'s retrospective analysis of a VA population, baseline comorbid states differed significantly between hypogonadal men receiving and not receiving testosterone supplementation, including obesity, obstructed coronary artery status, hypertension, hyperlipidemia, myocardial infarction, and cerebrovascular disease.
“One recent example of poorly matched groupings was the Vigen et al’s retrospective analysis of a VA population, which compared hypogonadal men receiving or not receiving T supplementation.129 Baseline comorbid states were significantly different between groupings, including obesity, obstructed coronary artery status, hypertension, hyperlipidemia, myocardial infarction, and cerebrovascular disease,”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [129] Vigen, 2013, Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels, JAMA source
Not checked in the free run.
- Interpretationreasoning
Use of enzyme immunoassay or radioimmunoassay rather than mass spectrometry may reduce accuracy, particularly at lower testosterone levels.
“This may result in reduced accuracy, particularly at lower T levels.”
Quote in the paperSubstantial claim - Interpretationreasoning
Duration of therapy is significant for trials evaluating testosterone supplementation and prostate cancer, particularly because of the extended natural history of prostate cancer development, progression, and recurrence.
“Duration of therapy is also significant in regards to trials evaluating T supplementation and prostate cancer, particularly given the extended natural history of prostate cancer development, progression, and recurrence.”
Quote in the paperSubstantial claim- Rests on an assumption: The natural history of prostate cancer development, progression, and recurrence is extended enough that long-duration trials are needed to assess testosterone supplementation effects.
- Interpretationreasoning
Comparisons between hypogonadism studies evaluating populations with different comorbid status are of questionable reliability and benefit.
“As such, comparisons between hypogonadism studies evaluating populations of differential comorbid status is of questionable reliability and benefit.”
Quote in the paperSubstantial claim - Interpretationreasoning
Testosterone supplementation in elderly males may exhibit a physiologically blunted effect.
“In addition to the potentially confounding effect of age on associated conditions, T supplementation in elderly males may exhibit a physiologically blunted effect.”
Quote in the paperSubstantial claim- Rests on an assumption: Testosterone supplementation in elderly males may exhibit a physiologically blunted effect.
- Interpretationreasoning
The definition used for total and free testosterone may contribute to reported outcomes.
“The definition utilized for TT and fT may contribute to outcomes reported.”
Quote in the paperSubstantial claim - Interpretationcitation
Use of selective estrogen receptor modulators may result in reduced efficacy in elderly compared with younger males.
“Similarly, the use of alternative T therapies, such as selective estrogen receptor modulators (SERMs) may result in reduced efficacy in elderly compared to younger males.”
Quote in the paperSubstantial claim- Rests on an assumption: Use of selective estrogen receptor modulators may result in reduced efficacy in elderly compared with younger males.
- Interpretationcitation
Use of free testosterone over total testosterone is associated with similar limitations based on the threshold value used.
“The use of fT over TT is also associated with similar limitations based on the threshold value utilized.”
Quote in the paperSubstantial claim - Interpretationreasoning
Contrasting observational and randomized evidence highlights the need for caution in interpreting retrospective series that report observed associations rather than relying on randomized controlled trial data.
“These contrasting studies highlight the need for caution in interpreting results from retrospective series reporting on observed associations rather than relying on RCT data.”
Quote in the paperSubstantial claim - Premisecitation
A 3-year prospective controlled trial of testosterone supplementation in hypogonadal men demonstrated a 5% per year improvement in bone mineral density.
“Inversely, a 3-year prospective, controlled trial of T supplementation in hypogonadal men demonstrated a 5% per year improvement in BMD.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [127] Aversa, 2012, Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: Results from a 36 months controlled study, Aging Male source
Not checked in the free run.
- Interpretationreasoning
Retrospective studies can only identify correlations between low testosterone and comorbid conditions.
“As such, they are only able to identify correlations between low T and comorbid conditions.”
Quote in the paperSubstantial claim - Interpretationreasoning
Associated conditions do not necessarily represent a causative link.
“In these settings, it is important to recognize that associated conditions do not necessarily represent a causative link.”
Quote in the paperSubstantial claim - Interpretationreasoning
A researcher evaluating 20 variables is likely to falsely identify at least one statistically significant outcome by chance alone.
“By definition, a researcher evaluating 20 variables is likely to falsely identify at least one statistically significant outcome, which occurred by chance alone.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Studies of insufficient power that conclude the absence of a particular adverse event with testosterone supplementation are at risk of type-II errors.
“Similarly, studies of insufficient power, which conclude the absence of a particular AE with T supplementation are at risk of type-II errors.”
Quote in the paperSubstantial claim - Interpretationreasoning
Outcome measures with high variability and small changes following intervention require much larger patient populations to detect statistically significant differences.
“Outcome measures with high variability (larger standard deviations among or within a population) and small changes following intervention require much larger patient populations to detect statistically significant differences.”
Quote in the paperSubstantial claim - Interpretationnone given
If an odds ratio includes 1.0, the finding cannot be statistically significant.
“This is significant because if the odds-ratio includes 1.0, by definition the finding cannot be statistically significant.”
Quote in the paperNot a substantial claim - Premisenone given
Several placebo-controlled randomized controlled trials evaluating testosterone supplementation in men with depression have reported seemingly contradictory results.
“Several placebo-controlled RCTs have evaluated the efficacy of T supplementation in men with depression, with seemingly contradictory results reported.”
Quote in the paperSubstantial claim - Interpretationcitation
Men undergoing testosterone supplementation are 3.7 times more likely to experience hematocrits >50% compared with those not receiving testosterone supplementation.
“This suggests that men undergoing T supplementation are 3.7 times more likely to experience hematocrits >50% compared to those not receiving T supplementation.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Outcomes from studies using one form of testosterone supplementation over another should not be used interchangeably, because each treatment results in varying effects on gonadotropins, estradiol, hormonal ratios, and potential unknown factors.
“Outcomes from studies using one form over another should not be used interchangeably, as each treatment results in varying effects on gonadotropins, estradiol, hormonal ratios, and potential unknown factors.”
Quote in the paperSubstantial claim - Premisecitation
Significant variation in bone mineral density among reported therapies evidences that outcomes from different testosterone forms should not be used interchangeably.
“This is evidenced by the significant variation on bone mineral density among the reported therapies.126, 127, 135”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [126] Burnett-Bowie, 2009, Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [127] Aversa, 2012, Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: Results from a 36 months controlled study, Aging Male source
Not checked in the free run.
- cites [135] Moskovic, 2012, Clomiphene citrate is safe and effective for long-term management of hypogonadism, BJU Int source
Not checked in the free run.
- Interpretationnone given
Varying formulations of testosterone supplementation result in different peaks, troughs, and duration of therapeutic levels.
“Similarly, varying formulations of T supplementation result in different peaks, troughs, and duration of therapeutic levels.”
Quote in the paperSubstantial claim - Interpretationnone given
Study duration and the population included are significant factors that may result in inadvertent under- or over-generalization of study findings.
“The study duration and population included also are significant factors, which may result in inadvertent under or over-generalization of study findings.”
Quote in the paperSubstantial claim - Premisecitation
A meta-analysis noted significant benefits in select sub-populations, particularly among those with baseline low testosterone and HIV.
“A meta-analysis of studies noted significant benefits in select sub-populations, particularly among those with baseline low T and HIV.134”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [134] Zarrouf, 2009, Testosterone and depression: Systematic review and meta-analysis, J Psychiatr Pract source
Not checked in the free run.
- Premisecitation
One meta-analysis estimated that 85,862 men would be required in each arm of a 1-year experimental study to identify a 20% increased risk of prostate cancer with 80% power at a 5% significance level.
“As an example, one meta-analyses evaluating prostate-specific events associated with T supplementation estimated that 85,862 men would be required in each arm of a 1-year experimental study to identify a 20% increased risk of prostate cancer with 80% power at a 5% significance level.142”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [142] Calof, 2005, Adverse events associated with testosterone replacement in middle-aged and older men: A meta-analysis of randomized, placebo-controlled trials, J Gerontol A Biol Sci Med Sci source
Not checked in the free run.
- Interpretationcitation
Statistically significant differences do not necessarily correlate with clinically relevant findings.
“Statistically significant differences do not necessarily correlate with clinically relevant findings.”
Quote in the paperSubstantial claim - Premisecitation
In one study, testosterone supplementation was associated with an increased risk of hematocrits >50%, with an odds ratio of 3.7 and a 95% confidence interval of 1.82-7.51.
“For example, T supplementation is associated with an increased risk of hematocrits > 50%, with an odds-ratio of 3.7 and a 95% confidence interval of 1.82–7.51 in one study.142”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [142] Calof, 2005, Adverse events associated with testosterone replacement in middle-aged and older men: A meta-analysis of randomized, placebo-controlled trials, J Gerontol A Biol Sci Med Sci source
Not checked in the free run.
- Interpretationcitation
Studies evaluating the risk of testosterone supplementation on subsequent development of prostate cancer with fewer than the minimum numbers are unlikely to have sufficient power to detect a significant difference, if present.
“Therefore, studies evaluating the risk of T supplementation on subsequent development of prostate cancer which have fewer than the minimum numbers are unlikely to have sufficient power to detect a significant difference, if present.”
Quote in the paperSubstantial claim - Interpretationreasoning
Detecting the impact of testosterone supplementation on prostate cancer progression, recurrence, cancer-specific mortality, and overall mortality requires large patient numbers prospectively evaluated in a randomized controlled trial design over an extended period.
“The ability to detect the impact of T supplementation on prostate cancer progression, recurrence, cancer-specific mortality, and overall mortality requires large patient numbers prospectively evaluated in a RCT design over an extended period of time.”
Quote in the paperSubstantial claim - Interpretationnone given
Data on testosterone supplementation-associated adverse events are frequently limited because of a lack of pre-defined adverse events, exclusion of adverse events as separate study endpoints, and the method of adverse event reporting.
“Data on T supplementation-associated AEs are frequently limited due to a lack of pre-defined AEs, exclusion of AEs as separate study end-points, and method of AE reporting.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The importance of study design and endpoints is particularly relevant in systematic reviews and meta-analyses, because they often extract data from studies of varying endpoints, resulting in decreased methodological quality and reliability.
“The importance of study design and end-points is particularly relevant in regards to systematic reviews and meta-analyses, as often they extract data from studies of varying end-points, with resultant decreased methodological quality and reliability.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 40
- May combine two claims. 93
Probably not a substantial claim: may not pass S4 (based). May combine two claims.
Findingnone givenSeveral factors affect measured testosterone levels, including aging, circadian rhythms, geography, genetics, lifestyle choices, comorbid conditions, and intra-individual daily variability.
“Several factors impact measured T levels including aging, circadian rhythms, geography, genetics, lifestyle choices, comorbid conditions, and intra-individual daily variability.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenThe usefulness of free testosterone relative to total testosterone is debated and should be assessed with suitable threshold values.
“The utility of free T (fT) over total T is debatable and must be compared using appropriate threshold levels.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenMass spectrometry and equilibrium dialysis are regarded as gold-standard assay techniques.
“Among various assay techniques, mass spectrometry and equilibrium dialysis are gold standards.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenHypogonadism-specific questionnaires have limited usefulness for screening for hypogonadism.
“Hypogonadism-specific questionnaires have limited utility in screening for hypogonadism”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenCalculated empirical estimates of free testosterone are commonly used and accepted.
“Calculated empirical estimates of fT are also commonly utilized and accepted.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenMen with 5-alpha reductase inhibitor abnormalities may fail to achieve erectile function benefits from testosterone supplementation despite improvements in other testosterone-related aspects.
“Similarly, men with 5ARI abnormalities may fail to achieve benefits with T supplementation on erectile function, despite improvements in other T-related aspects.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe Massachusetts Male Aging Study found a persistent age-related decrease in testosterone even after controlling for obesity, chronic illness, medication use, and excessive alcohol consumption, although healthier males had attenuation of decline and 10-15% higher testosterone levels.
“Data from the Massachusetts Male Aging Study similarly demonstrated a persistent age-related decrease in T levels even after controlling for obesity, chronic illness, medication use, and excessive alcohol consumption, although an attenuation of rate of decline and 10–15% overall higher T levels were observed among healthier males.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Yeap, 2012, Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
PremisecitationTwo additional longitudinal studies reported a 3.6-3.8 ng/dl/year decrease in total testosterone, with progressive increases in biochemically hypogonadal men: 20% over 60 years, 30% over 70 years, and 50% over 80 years.
“Two additional longitudinal studies reported a 3.6–3.8 ng/dl/year (0.12–0.13 nmol/L/year) decrease in TT, with progressive increases in the number of men characterized as biochemically hypogonadal (defined as TT<325 ng/dl [11.3 nmol/l] or fT<2.5th percentile): 20% (>60 years), 30% (>70 years), and 50% (>80 years).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [39] Feldman, 2002, Age trends in the level of serum testosterone and other hormones in middle-aged men: Longitudinal results from the Massachusetts male aging study, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [40] Ferrini, 1998, Sex hormones and age: A cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men, Am J Epidemiol source
Not checked in the free run.
May combine two claims.
Interpretationnone givenVariations in study methodology, inclusion/exclusion criteria, populations, absence of validated objective measures, and small cohorts have hindered data quality and restricted generalizability.
“Variations in study methodology, inclusion/exclusion criteria, populations evaluated, absence of validated objective measures, and small cohorts have all hindered the quality of data obtained and restricted generalizability of findings.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationA longitudinal cohort of men aged 40-70 reported an estimated total testosterone decrease of 0.8% per year and free testosterone decrease of 2% per year due to increases in SHBG.
“Data from a longitudinal cohort of men aged 40–70 years reported an estimated TT decrease of 0.8%/year, with fT decreasing by 2%/year (due to concomitant increases in SHBG).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Yeap, 2012, Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men, J Clin Endocrinol Metab source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone givenCirculating testosterone can act directly on tissues or be converted to estradiol or dihydrotestosterone via 5-alpha reductase.
“Circulating T may exert a direct effect on tissues/cells, or undergo conversion to downstream hormones estradiol or dihydrotestosterone (DHT) via 5-alpha reductase (5AR).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe prevalence of symptomatic hypogonadism is poorly defined, with estimates of 2.1-17% in population-based surveys of men aged 30-87 years depending on the criterion used.
“The prevalence of symptomatic hypogonadism remains poorly defined, with estimates ranging from 2.1–17% in population-based surveys of men aged 30–87 years depending upon criterion utilized.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [2] Araujo, 2007, Prevalence of symptomatic androgen deficiency in men, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [3] Liu, 2009, The prevalence of and risk factors for androgen deficiency in aging Taiwanese men, J Sex Med source
Not checked in the free run.
- cites [4] 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.
PremisecitationTestosterone levels exhibit time-, sleep-, and age-dependent circadian variations.
“T levels exhibit time, sleep, and age-dependent circadian variations.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [42] Shi, 2013, Longitudinal changes in testosterone over five years in community-dwelling men, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [43] Sartorius, 2012, Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: The healthy man study, Clin Endocrinol source
Not checked in the free run.
- cites [44] Wang, 2004, Measurement of total serum testosterone in adult men: Comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [45] Vesper, 2009, Interlaboratory comparison study of serum total testosterone [corrected] measurements performed by mass spectrometry methods, Steroids source
Not checked in the free run.
May combine two claims.
PremisecitationEarly studies comparing young men aged 25-27 with elderly men aged 71 found peak testosterone concentrations from 3-8 AM, extended to 2 PM in elderly men, and trough levels from early afternoon to late evening.
“Early studies comparing young (mean age 25–27 years) versus elderly males (mean age 71 years) demonstrated peak T concentrations in the 3–8 AM time period (extended to 2 PM in elderly males), with trough levels noted in the early afternoon to late evening.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [42] Shi, 2013, Longitudinal changes in testosterone over five years in community-dwelling men, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [43] Sartorius, 2012, Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: The healthy man study, Clin Endocrinol source
Not checked in the free run.
- cites [44] Wang, 2004, Measurement of total serum testosterone in adult men: Comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [45] Vesper, 2009, Interlaboratory comparison study of serum total testosterone [corrected] measurements performed by mass spectrometry methods, Steroids source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTestosterone and dihydrotestosterone likely have differential roles and expression in various tissues, including prostate, skin, penis, and testicles.
“T and DHT also likely have differential roles and expression in various tissues, including in the prostate, skin, penis, and testicles, among others.”
Quote in the paperNot a substantial claim0 of 8 sources checked- cites [15] Schwartz, 1997, MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen, J Clin Endocrinol Metab
Not checked in the free run.
- cites [24] Borst, 2014, Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: A randomized, controlled trial, Am J Physiol Endocrinol Metab source
Not checked in the free run.
- cites [25] Bang, 2004, Comparative studies on level of androgens in hair and plasma with premature male-pattern baldness, J Dermatol Sci source
Not checked in the free run.
- cites [26] Zhang, 2012, Effects of oral finasteride on erectile function in a rat model, J Sex Med source
Not checked in the free run.
- cites [27] Pinsky, 2011, The effects of chronic 5-alpha-reductase inhibitor (dutasteride) treatment on rat erectile function, J Sex Med source
Not checked in the free run.
- cites [28] Imperato-McGinley, 1974, Steroid 5alpha-reductase deficiency in man: An inherited form of male pseudohermaphroditism, Science source
Not checked in the free run.
- cites [29] Katz, 1997, Paternity by intrauterine insemination with sperm from a man with 5alpha-reductase-2 deficiency, N Engl J Med source
Not checked in the free run.
- cites [30] Ivarsson, 1988, Male pseudohermaphroditism due to 5 alpha-reductase deficiency in a Swedish family, Eur J Pediatr source
Not checked in the free run.
May combine two claims.
PremisecitationTestosterone levels at 4 PM are 20-25% lower in men aged 30-40 and 10% lower in 70-year-old men compared with levels at 8 AM.
“In relative terms, T levels obtained at 4 PM are 20–25% lower in men aged 30–40 and 10% lower in 70 year old men compared to those received at 8 AM.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Steinberger, 1998, Utilization of commercial laboratory results in management of hyperandrogenism in women, Endocr Pract source
Not checked in the free run.
May combine two claims.
PremisecitationA larger study of 1588 men over age 35 followed for 5 years found age was not an independent predictor of decreasing testosterone on multivariate analysis, while obesity, smoking, chronic medical conditions, lifestyle factors, depression, and marital status likely contributed to the decline.
“A larger study evaluating 1588 men >age 35 years over a 5-year period found that age was not an independent predictor of decreasing T on multivariate analysis, while obesity, smoking status, chronic medical conditions, lifestyle factors, depression, and marital status all likely contributed to the observed decline.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Ferrini, 1998, Sex hormones and age: A cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men, Am J Epidemiol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCirculating testosterone is predominantly bound to sex hormone binding globulin and albumin, with small percentages freely circulating or bound to corticosteroid binding globulin.
“Circulating T is predominantly bound to sex hormone binding globulin (SHBG) and albumin, with small percentages freely circulating or associated with corticosteroid binding globulin.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Mazer, 2009, A novel spreadsheet method for calculating the free serum concentrations of testosterone, dihydrotestosterone, estradiol, estrone and cortisol: With illustrative examples from male and female populations, Steroids source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe number of patients diagnosed and treated for hypogonadism over the past decade has increased significantly, with an exponential rise in prescribed testosterone in many developed countries.
“the number of patients diagnosed and treated for hypogonadism over the past decade has increased significantly, with an exponential rise in prescribed T in many developed countries.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [5] Spitzer, 2013, Risks and benefits of testosterone therapy in older men, Nat Rev Endocrinol source
Not checked in the free run.
- cites [6] Baillargeon, 2013, Trends in androgen prescribing in the United States, 2001 to 2011, JAMA Intern Med source
Not checked in the free run.
- cites [7] Handelsman, 2013, Global trends in testosterone prescribing, 2000–2011: Expanding the spectrum of prescription drug misuse, Med J Aust source
Not checked in the free run.
May combine two claims.
PremisecitationA larger analysis of 3690 community-dwelling elderly males with mean age 77 found similar mean testosterone levels among those describing excellent or very good health compared with the overall cohort, suggesting subjective health may not be a significant factor for testosterone levels.
“A larger analysis (n=3690) of community-dwelling, elderly males (mean age 77 years) which demonstrated similar mean T levels (406 vs 378 ng/dl [14.1 vs 13.1 nmol/L]) among those describing excellent or very good health compared to the overall cohort, suggesting that subjective assessment of overall health may not represent a significant factor for T levels.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Muehlenbein, 2010, Toward quantifying the usage costs of human immunity: Altered metabolic rates and hormone levels during acute immune activation in men, Am J Hum Biol source
Not checked in the free run.
Classified as probably not a substantial claim.
Interpretationnone givenThe role of hypogonadism-specific questionnaires as objective endpoints for quantifying symptoms is still unclear.
“their role as objective end-points for quantifying symptoms remains unclear”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationnone givenDiagnosis and treatment of hypogonadism face challenges including variability in testosterone assays, lack of consensus on normal testosterone levels, and poor objective measures for symptoms and therapeutic benefit.
“Several challenges exist in the diagnosis and treatment of hypogonadism including variability in T assays, lack of consensus on normal T levels, and poor objective measures for symptom assessment and therapeutic benefit.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenMen with normal testosterone levels and dysfunctional androgen receptors may have hypogonadal symptoms unresponsive to testosterone supplementation, while men with low testosterone and increased androgen receptor activity may show no testosterone deficiency findings.
“While men with normal T levels and dysfunctional ARs may experience hypogonadal symptoms which are unresponsive to T supplementation, men with low T and increased AR activity may exhibit no findings of T deficiency.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEstradiol, dihydrotestosterone, and 3-alpha androstanediol have established roles in reproductive, bone, hepatic, renal, cardiovascular, dermatologic, prostatic, penile, and central nervous system functions.
“Estradiol, DHT, and the DHT product, 3-alpha androstanediol have established roles in reproductive, bone, hepatic, renal, cardiovascular, dermatologic, prostatic, penile, and central nervous system functions, among others.”
Quote in the paperNot a substantial claim0 of 10 sources checked- cites [11] Carani, 1997, Effect of testosterone and estradiol in a man with aromatase deficiency, N Engl J Med source
Not checked in the free run.
- cites [12] Pentikainen, 2000, Estradiol acts as a germ cell survival factor in the human testis in vitro, J Clin Endocrinol Metab
Not checked in the free run.
- cites [13] Melcangi, 1999, Steroid metabolism and effects in central and peripheral glial cells, J Neurobiol source
Not checked in the free run.
- cites [14] Andersson, 1990, Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases, Proc Natl Acad Sci U S A source
Not checked in the free run.
- cites [15] Schwartz, 1997, MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen, J Clin Endocrinol Metab
Not checked in the free run.
- cites [16] Thigpen, 1993, Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression, J Clin Invest source
Not checked in the free run.
- cites [17] Kim, 2002, Expression of the androgen receptor and 5 alpha-reductase type 2 in the developing human fetal penis and urethra, Cell Tissue Res source
Not checked in the free run.
- cites [18] Amory, 2007, The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [19] Traish, 2007, Testosterone and erectile function: From basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction, Eur Urol source
Not checked in the free run.
- cites [20] Traish, 2006, Are androgens critical for penile erections in humans? Examining the clinical and preclinical evidence, J Sex Med source
Not checked in the free run.
May combine two claims.
PremisecitationPre-adolescent and adolescent males showed genetic contribution rates of 52-66%, with the remaining percentage due to environmental factors.
“Pre-adolescent and adolescent males demonstrated genetic contribution rates of 52–66%, with the remaining percentage due to various environmental factors.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [53] Orwoll, 2010, Evidence for geographical and racial variation in serum sex steroid levels in older men, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [54] Brambilla, 2007, Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men, Clin Endocrinol source
Not checked in the free run.
May combine two claims.
PremisecitationAmong men with testosterone below 250 ng/dl on the first assay, only 40% were confirmed to have a mean testosterone below 250 ng/dl over six visits, and 20% averaged above 300 ng/dl.
“Of interest, among men found to have T < 250 ng/dl (8.7 nmol/L) on the first assay, only 40% were confirmed to have a mean T < 250 ng/dl (8.7 nmol/L) over the six visits, with 20% averaging > 300 ng/dl (10.4 nmol/L).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [67] Ruhayel, 2007, Seasonal variation in serum concentrations of reproductive hormones and urinary excretion of 6-sulfatoxymelatonin in men living north and south of the Arctic Circle: A longitudinal study, Clin Endocrinol source
Not checked in the free run.
May combine two claims.
InterpretationcitationGenetic heritability likely accounts for a significant portion of mean testosterone levels in a select population and of observed diurnal variations.
“Genetic heritability likely accounts for a significant portion of mean T levels in a select population as well as observed diurnal variations.”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [53] Orwoll, 2010, Evidence for geographical and racial variation in serum sex steroid levels in older men, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [54] Brambilla, 2007, Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men, Clin Endocrinol source
Not checked in the free run.
- cites [55] Morley, 2002, Evaluation of assays available to measure free testosterone, Metabolism source
Not checked in the free run.
- cites [56] 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.
- cites [57] 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.
InterpretationreasoningThe effect of seasonal variation on testosterone levels remains controversial, with no definitive evidence available.
“The effect of seasonal variation on T levels remains controversial, with no definitive evidence available at the present time.”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [59] Ahtiainen, 2004, Acute hormonal responses to heavy resistance exercise in strength athletes versus nonathletes, Can J Appl Physiol source
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- cites [60] Cadore, 2008, Hormonal responses to resistance exercise in long-term trained and untrained middle-aged men, J Strength Cond Res source
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- cites [61] Svartberg, 2003, The associations of age, lifestyle factors and chronic disease with testosterone in men: The Tromso Study, Eur J Endocrinol source
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- cites [62] Ponholzer, 2005, Relationship between testosterone serum levels and lifestyle in aging men, Aging Male source
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- cites [63] Field, 1994, The relation of smoking, age, relative weight, and dietary intake to serum adrenal steroids, sex hormones, and sex hormone-binding globulin in middle-aged men, J Clin Endocrinol Metab
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenContemporary assay techniques for total testosterone include immunoassays and mass spectrometry.
“Contemporary assay techniques to assess TT include immunoassays and mass spectrometry (MS).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationBecause of simplicity, ease of use, and high throughput, immunoassays were widely adopted in clinical practice, and most total testosterone reference ranges were established using them.
“Given their simplicity, ease of use, and high-throughput, immunoassays (IA) were widely adopted in clinical practice, with the majority of TT reference ranges established using these techniques.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [82] Ahokoski, 1998, Biological day-to-day variation and daytime changes of testosterone, follitropin, lutropin and oestradiol-17beta in healthy men, Clin Chem Lab Med source
Not checked in the free run.
- cites [83] Valero-Politi, 1993, Within- and between-subject biological variations of follitropin, lutropin, testosterone, and sex-hormone-binding globulin in men, Clin Chem source
Not checked in the free run.
May combine two claims.
PremisecitationIn 25 young men with upper respiratory infections, serial testosterone assessments showed a transient mean 10% decline during the acute phase, with reductions up to 30% in a select cohort.
“Results demonstrated a transient mean 10% decline in T during the acute phase of the illness, with reductions of up to 30% in a select cohort of patients.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [81] Meikle, 1985, Familial factors affecting prostatic cancer risk and plasma sex-steroid levels, Prostate source
Not checked in the free run.
May combine two claims.
PremisecitationOther studies have confirmed increasing testosterone levels during sleep and progressive reductions during waking hours.
“Other studies have confirmed increasing levels of T during sleep, with progressive reductions in T during waking hours.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Brambilla, 2009, The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
PremisecitationCompared with aerobic activity, resistance exercise likely produces greater testosterone improvements, with untrained men having larger increases than those routinely performing resistance exercise.
“Compared to aerobic activity, resistance exercise likely results in greater improvements in T, with untrained men experiencing larger increases compared to those routinely performing resistance exercises.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [73] Crawford, 2007, The association of time of day and serum testosterone concentration in a large screening population, BJU Int source
Not checked in the free run.
- cites [74] Diver, 2003, Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men, Clin Endocrinol source
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- cites [75] Axelsson, 2005, Effects of acutely displaced sleep on testosterone, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
PremisecitationA 4-5 point increase in BMI is roughly equivalent to a 10-year decline in testosterone, while weight loss directly correlates with increasing testosterone.
“A 4–5 point increase in BMI is roughly equivalent to a 10-year decline in T, while weight loss directly correlates with increasing T.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [68] Nicolau, 1984, Circadian and circannual rhythms of hormonal variables in elderly men and women, Chronobiol Int source
Not checked in the free run.
- cites [71] Plymate, 1989, Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men, J Androl source
Not checked in the free run.
May combine two claims.
PremisecitationBased on one sample, 95% confidence limits were 65-153% of the obtained value, while averaging two and three measurements reduced the limit by 30% and 43%, respectively.
“Based on one sample obtained, 95% confidence limits were calculated at 65–153% of the value obtained, while the average of two and three measurements reduced the limit by 30% and 43%, respectively.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [67] Ruhayel, 2007, Seasonal variation in serum concentrations of reproductive hormones and urinary excretion of 6-sulfatoxymelatonin in men living north and south of the Arctic Circle: A longitudinal study, Clin Endocrinol source
Not checked in the free run.
May combine two claims.
PremisecitationObesity and testosterone are inversely correlated, with increasing obesity causing progressive impairments in gonadotropins and testosterone.
“Obesity and T are inversely correlated, with increasing obesity resulting in progressive impairments in gonadotropins and T.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [69] Brambilla, 2007, Lack of seasonal variation in serum sex hormone levels in middle-aged to older men in the Boston area, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [70] Martikainen, 1985, Circannual concentrations of melatonin, gonadotrophins, prolactin and gonadal steroids in males in a geographical area with a large annual variation in daylight, Acta Endocrinol
Not checked in the free run.
May combine two claims.
PremisecitationBoth acute and chronic disease states are associated with decreasing testosterone levels.
“Both acute and chronic disease states are associated with decreasing T levels.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [81] Meikle, 1985, Familial factors affecting prostatic cancer risk and plasma sex-steroid levels, Prostate source
Not checked in the free run.
May combine two claims.
PremisecitationAdult male studies confirmed similar findings, with genetic contribution to testosterone variability of 42-65%.
“Results of adult males have confirmed similar findings, with genetic contribution towards T variability of 42–65%.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [47] Sartorius, 2009, Predictive accuracy and sources of variability in calculated free testosterone estimates, Ann Clin Biochem source
Not checked in the free run.
- cites [55] Morley, 2002, Evaluation of assays available to measure free testosterone, Metabolism source
Not checked in the free run.
- cites [56] 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.
- cites [57] 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.
PremisecitationSHBG, free testosterone, and bioavailable testosterone also show similar circadian variations, with SHBG peaking in the afternoon.
“SHBG, fT, and bioavailable T also exhibit similar circadian variations, with SHBG peaking in the afternoon hours.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [42] Shi, 2013, Longitudinal changes in testosterone over five years in community-dwelling men, J Clin Endocrinol Metab source
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- cites [45] Vesper, 2009, Interlaboratory comparison study of serum total testosterone [corrected] measurements performed by mass spectrometry methods, Steroids source
Not checked in the free run.
May combine two claims.
PremisecitationAfter adjustment for age and body-mass index, testosterone levels were 16% higher in men living in Hong Kong and Japan, while Asian men living in the US had levels similar to other US residents; no differences were noted based on ethnicity alone.
“With adjustment for age and body-mass index, T levels were 16% higher in men living in Hong Kong and Japan, while Asian men living in the US were found to have similar levels to other US residents. No differences were noted in T levels based on ethnicity alone.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52] Ring, 2005, Heritability of plasma sex hormones and hormone binding globulin in adult male twins, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
PremisecitationLifestyle factors are independently associated with variations in testosterone levels and account for a percentage of the observed age-associated decline in testosterone.
“Lifestyle factors are independently associated with variations in T levels and account for a percentage of the observed age-associated decline in T.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [68] Nicolau, 1984, Circadian and circannual rhythms of hormonal variables in elderly men and women, Chronobiol Int source
Not checked in the free run.
May combine two claims.
PremisecitationA meta-analysis of weight loss studies found mean testosterone increases of 83 ng/dl with diet alone and 252 ng/dl with bariatric surgery, with greater improvements after bariatric surgery attributed to more extensive weight loss.
“A meta-analysis of studies reviewing the effect of weight loss on T demonstrated mean T increases of 83 ng/dl (diet alone [2.9 nmol/L]) and 252 ng/dl (bariatric surgery [8.7 nmol/L]), with greater improvements in bariatric surgery attributed to the more extensive weight loss achieved.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [71] Plymate, 1989, Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men, J Androl source
Not checked in the free run.
May combine two claims.
PremisecitationIn a study of 1072 men comparing estimates with assay-determined bioavailable testosterone, total testosterone had high predictability (r2=0.68) and was better than other tested modalities for determining biochemical hypogonadism (AUC: total testosterone 0.93, FAI 0.72, Nanjee and Wheeler 0.91, Vermeulen 0.88).
“Results demonstrated high predictability using TT (r2=0.68), with TT being better than other tested modalities for determining biochemical hypogonadism (area under receiver operative curve; TT=0.93, FAI=0.72, Nanjee and Wheeler calculation=0.91, Vermeulen calculation=0.88).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [106] Hammes, 2005, Role of endocytosis in cellular uptake of sex steroids, Cell source
Not checked in the free run.
May combine two claims.
Premisenone givenEven though mass spectrometry is recognized as a reference technique, its reliability depends on regular calibration maintenance, which is labor intensive and limits consistently high throughput without deterioration.
“And despite the recognition of MS as a reference technique, the reliability of results depends upon regular calibration maintenance, which is labor intensive and limits the ability to achieve consistently high throughputs without deterioration.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenFree testosterone is measured either through direct assays or indirectly through several published calculations.
“Free T is measured either through direct assays or indirectly via several different published calculations.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationComparing immunoassays with gold-standard mass spectrometry, reported variability ranges from −14.1% to +19.2% overall and from −40% to +40% among samples below 100 ng/dl.
“In comparing IA to the gold-standard MS, reported variability ranges from −14.1% to +19.2% in samples overall and −40% to +40% among samples <100 ng/dl (3.5 nmol/L).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [86] Nanjee, 1985, Plasma free testosterone—is an index sufficient?, Ann Clin Biochem source
Not checked in the free run.
- cites [87] Sodergard, 1982, Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature, J Steroid Biochem source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCurrent Endocrine Society guidelines recommend measuring free testosterone in men with low-normal total testosterone in whom SHBG alterations are suspected, with low values established within each laboratory.
“Current Endocrine Society guidelines recommend measuring fT in men with low-normal TT levels in whom SHBG alterations are suspected with low values established within each laboratory.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Bhasin, 2010, Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
PremisecitationNumerous estimating equations have been described, including bioavailable testosterone, free androgen index, and free testosterone index (Vermeulen method), with results suggesting high correlations with direct assays.
“Numerous estimating equations have been described in the literature including bioavailable T (non-SHBG bound T), free androgen index (FAI; 100T/SHBG), and free T index (Vermeulen method), among others, with results suggesting high correlations to direct assays.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [102] Almeida, 2008, Low free testosterone concentration as a potentially treatable cause of depressive symptoms in older men, Arch Gen Psychiatry source
Not checked in the free run.
- cites [103] Brand, 2011, Testosterone, sex hormone-binding globulin and the metabolic syndrome: A systematic review and meta-analysis of observational studies, Int J Epidemiol source
Not checked in the free run.
- cites [104] Coviello, 2012, A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation, PLoS Genet source
Not checked in the free run.
- cites [105] Vanbillemont, 2009, Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle-aged and elderly men, Clin Endocrinol source
Not checked in the free run.
May combine two claims.
PremisecitationLike total testosterone, free testosterone is influenced by diurnal variations and is inversely associated with age and BMI.
“As with TT, fT is influenced by diurnal variations and is inversely associated with age and BMI.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [45] Vesper, 2009, Interlaboratory comparison study of serum total testosterone [corrected] measurements performed by mass spectrometry methods, Steroids source
Not checked in the free run.
- cites [68] Nicolau, 1984, Circadian and circannual rhythms of hormonal variables in elderly men and women, Chronobiol Int source
Not checked in the free run.
May combine two claims.
PremisecitationFree testosterone is a better indicator in young males than in elderly men, suggesting that the age-associated increase in SHBG may further reduce free testosterone specificity.
“Free T is also better indicator in young males as compared to elderly men, suggesting that the age-associated increase in SHBG may further reduce the specificity of fT.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Araujo, 2007, Prevalence of symptomatic androgen deficiency in men, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [98] Bhasin, 2008, The impact of assay quality and reference ranges on clinical decision making in the diagnosis of androgen disorders, Steroids source
Not checked in the free run.
May combine two claims.
PremisecitationIn a community-based sample of 3690 elderly men with mean age 77, calculated free testosterone levels were 24.2 pg/ml, while a separate cohort reporting excellent or very good health had 29.9 pg/ml.
“In a community-based sample of 3,690 elderly men (mean age 77), calculated fT levels were 24.2 pg/ml (83.9 pmol/L), with a separate cohort identifying themselves as being in excellent or very good health reported at 29.9 pg/ml (103.7 pmol/L).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Muehlenbein, 2010, Toward quantifying the usage costs of human immunity: Altered metabolic rates and hormone levels during acute immune activation in men, Am J Hum Biol source
Not checked in the free run.
May combine two claims.
InterpretationcitationThese findings suggest total testosterone may be a better indicator of hypogonadism except in borderline-low total testosterone, where calculated free testosterone or bioavailable testosterone may help confirm diagnosis.
“These findings suggest that TT may be a better indicator of hypogonadism, except in cases of borderline-low TT, where calculated fT or bioavailable T may help to confirm a diagnosis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCombined guidelines from ASA, EAA, EAU, ISA, and ISSAM recommend obtaining free testosterone in men with total testosterone 231-346 ng/dl, with a suggested lower normal threshold of 65 pg/ml.
“The combined guidelines from the ASA, EAA, EAU, ISA, and ISSAM similarly recommend obtaining fT levels in men with TT 231–346ng/dl (8–12 nmol/L), with a suggested threshold of 65 pg/ml (225.4 pmol/L) established as the lower range of normal.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationcitationThe clinical relevance of total versus free testosterone is controversial, with many suggesting free testosterone is more appropriate because SHBG varies with aging, acute and chronic diseases, hormonal alterations, obesity, and normal diurnal rhythms.
“The clinical relevance of TT compared to fT is controversial, with many suggesting that fT is a more appropriate measure of hypogonadism due to SHBG variations occurring with aging, acute/chronic diseases, hormonal alterations, obesity, and normal diurnal rhythms.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [95] Vesper, 2010, Standardization of testosterone measurements in humans, J Steroid Biochem Mol Biol source
Not checked in the free run.
May combine two claims.
PremisecitationLimitations of equilibrium dialysis include increased expense, dependence on total testosterone accuracy, and variations from radiotracer impurities, temperature control, and sample dilution.
“Limitations with this technique include increased expense, dependence on TT accuracy, and variations created by radiotracer impurities, temperature control, and sample dilution, among others.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [83] Valero-Politi, 1993, Within- and between-subject biological variations of follitropin, lutropin, testosterone, and sex-hormone-binding globulin in men, Clin Chem source
Not checked in the free run.
May combine two claims.
PremisecitationMany studies are hindered by heterogeneity in the definition of low free testosterone (50-65 pg/ml), and increasing the threshold for low free testosterone raises sensitivity and reduces specificity compared with total testosterone.
“However, many of these studies are hindered by heterogeneity in the definition for low fT (50–65 pg/ml [173.4–225.4 pmol/L]), with increases in the threshold for low fT resulting in higher sensitivity and reduced specificity when compared to TT.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Araujo, 2007, Prevalence of symptomatic androgen deficiency in men, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
InterpretationcitationGiven the observation of cellular uptake of SHBG-bound testosterone, the optimal method for diagnosing hypogonadism is unclear and the purported advantages of free over total testosterone are in question.
“Given this observation, the optimal method for diagnosing hypogonadism is unclear with the purported advantages of fT over TT currently in question.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningFindings from studies using total testosterone to diagnose hypogonadism should not necessarily be extrapolated to specific free testosterone thresholds, and vice versa.
“Similarly, it is important to recognize that findings of studies which utilize TT to diagnose hypogonadism should not necessarily be extrapolated to suggest that similar results can be expected using specific fT thresholds, and vice-versa.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEndocrine Society guidelines agree on a lower total testosterone threshold for therapeutic consideration of 280-300 ng/dl.
“Similarly, guidelines by the Endocrine Society have agreed upon a lower TT threshold for therapeutic consideration at 280–300 ng/dl (9.7–10.4 nmol/L).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Bhasin, 2010, Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
PremisecitationBoth free and total testosterone are equally associated with BMI, erectile dysfunction, and decreased libido.
“Both fT and TT are equally associated with BMI, ED, and decreased libido.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [70] Martikainen, 1985, Circannual concentrations of melatonin, gonadotrophins, prolactin and gonadal steroids in males in a geographical area with a large annual variation in daylight, Acta Endocrinol
Not checked in the free run.
- cites [76] Rohrmann, 2007, Serum estrogen, but not testosterone, levels differ between black and white men in a nationally representative sample of Americans, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
PremisecitationSHBG polymorphisms directly affect the expression and variability of SHBG itself as well as systemic free testosterone and estradiol.
“Similar to findings with the AR gene, SHBG polymorphisms also directly impact the expression and variability of SHBG itself as well as systemic fT and E2.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [99] Dunn, 1981, Transport of steroid hormones: Binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [100] Hammond, 2012, Evolving utility of sex hormone-binding globulin measurements in clinical medicine, Curr Opin Endocrinol Diabetes Obes source
Not checked in the free run.
May combine two claims.
PremisecitationThere is currently no consensus on accepted lower testosterone limits or established reference intervals.
“Currently, there is no consensus as to the accepted lower T limits or established reference intervals.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [92] Albrecht, 2007, Laboratory testing of gonadal steroids in children, Pediatr Endocrinol Rev
Not checked in the free run.
- cites [93] Wierman, 2006, Androgen therapy in women: An Endocrine Society clinical practice guideline, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
Premisenone givenThe current gold-standard method to measure free testosterone is equilibrium dialysis, which achieves differential passage of free testosterone through a low molecular weight semi-permeable membrane.
“Currently, the gold-standard method to measure fT is equilibrium dialysis, which achieves differential passage of fT via a low molecular weight semi-permeable membrane.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn the largest study evaluating predictive accuracy of free testosterone calculations, Sartorius and colleagues concluded that empirical methods (Ly, Sartorius) are most concordant, while other estimations (Vermeulen, Nanjee and Wheeler, Sodergard) overestimate the true value.
“In the largest study evaluating predictive accuracy of fT calculations, Sartorius and colleagues concluded that empirical methods (Ly, Sartorius) of calculated fT are most concordant, with other estimations (Vermeulen, Nanjee and Wheeler, Sodergard) resulting in overestimation of the true value.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [102] Almeida, 2008, Low free testosterone concentration as a potentially treatable cause of depressive symptoms in older men, Arch Gen Psychiatry source
Not checked in the free run.
- cites [103] Brand, 2011, Testosterone, sex hormone-binding globulin and the metabolic syndrome: A systematic review and meta-analysis of observational studies, Int J Epidemiol source
Not checked in the free run.
- cites [104] Coviello, 2012, A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation, PLoS Genet source
Not checked in the free run.
- cites [105] Vanbillemont, 2009, Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle-aged and elderly men, Clin Endocrinol source
Not checked in the free run.
- cites [107] Morris, 2004, A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men, Eur J Endocrinol source
Not checked in the free run.
May combine two claims.
PremisecitationAdditional factors that may account for variability include specimen handling and preparation, calibration methods, specimen commutability, and interference from matrix material used to store and transport testosterone preparations.
“Additional factors, which may account for variability of results include specimen handling and preparation, calibration methods utilized, specimen commutability, and interference from the matrix material used to store and transport sample T preparations.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [83] Valero-Politi, 1993, Within- and between-subject biological variations of follitropin, lutropin, testosterone, and sex-hormone-binding globulin in men, Clin Chem source
Not checked in the free run.
- cites [89] Ly, 2005, Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays, Eur J Endocrinol source
Not checked in the free run.
- cites [90] Carvalho, 2012, The coming of age of liquid chromatography coupled to tandem mass spectrometry in the endocrinology laboratory, J Chromatogr B source
Not checked in the free run.
May combine two claims.
InterpretationreasoningCurrently available hypogonadism questionnaires are not suitable as screening modalities or as surrogates for hormonal testing.
“Given the variable sensitivities, specificities, inconsistent correlations with biochemical hormonal parameters, and inability to reliably track outcomes with T supplementation, currently available questionnaires are not suitable as screening modalities or as surrogates for hormonal testing.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1] Bhasin, 2010, Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [92] Albrecht, 2007, Laboratory testing of gonadal steroids in children, Pediatr Endocrinol Rev
Not checked in the free run.
May combine two claims.
InterpretationcitationIn Vigen et al., although a higher rate of adverse events was identified in the testosterone supplementation group after statistical manipulation of raw data, the wide discrepancy in groupings makes it unclear whether that group had a higher baseline risk and whether lower testosterone was an indirect indicator of overall comorbid burden.
“Although the authors identified a higher rate of AEs in the T supplementation group (after statistical manipulation of the raw data), given the wide discrepancy in groupings, it is unclear if this group represented men with a higher baseline risk for subsequent events and that a lower T in this group was an indirect indicator of their overall comorbid burdens (despite lower ages).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [129] Vigen, 2013, Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels, JAMA source
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenCommunity-based, military conscript, or similar trials likely yield significant differences in sampling compared with populations common to urologic practices, including men with sexual dysfunction, infertility, or other urologic conditions.
“Community-based, military conscript, or similar trials will likely yield significant differences in sampling when compared to populations common to urologic practices, including those with sexual dysfunction, infertility, or other urologic conditions.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenTo date, no study has compared this new technique with more established empirical methods (Ly, Sartorius).
“To date, no study has compared this new technique with more established empirical methods (Ly, Sartorius).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationCorona and colleagues' meta-analysis of testosterone supplementation on erectile function found improvements in men with lower baseline testosterone and no benefits for treatment of eugonadal men.
“This observation was highlighted by Corona and colleagues who performed a meta-analysis of the effects of T supplementation on erectile function and noted improvements in men with lower baseline T levels and no benefits for treatment of eugonadal men.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [132] Corona, 2014, Testosterone supplementation and sexual function: A meta-analysis study, J Sex Med source
Not checked in the free run.
May combine two claims.
InterpretationcitationFindings suggest reduced responsiveness of the hypothalamic-pituitary-gonadal axis in elderly males, which must be accounted for when comparing studies of men of differing ages.
“Findings suggested reduced responsiveness of the hypothalamic-pituitary-gonadal axis in elderly males, an effect, which must be accounted for in comparing studies of men with differing ages.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [128] Tenover, 1991, The effects of normal aging on the response of the pituitary-gonadal axis to chronic clomiphene administration in men, J Androl source
Not checked in the free run.
May combine two claims.
PremisecitationAn observational series of 1031 male veterans with hypogonadism found a significant association between low testosterone and overall mortality, and testosterone supplementation was associated with improved survival.
“A commonly cited observational series involved 1031 male veterans with hypogonadism receiving T supplementation compared against those not receiving treatment.123 Results demonstrated a significant association between low T and overall mortality, while those who received T supplementation were shown to have improved survival.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [123] Shores, 2012, Testosterone treatment and mortality in men with low testosterone levels, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe population studied significantly impacts outcomes, including study setting, participant age and comorbidities, biochemical definition of hypogonadism, and use of specific populations.
“The population studied has a significant impact on outcomes, including the study setting, participant age and comorbidities, biochemical definition of hypogonadism, and the use of specific populations.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationObesity, diabetes mellitus, metabolic syndrome, depression, and other comorbid conditions have marked effects on testosterone levels and on the impact of supplementation.
“Obesity, DM, MetS, depression and other comorbid conditions have marked effects on T levels and impact of supplementation.40”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Ferrini, 1998, Sex hormones and age: A cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men, Am J Epidemiol source
Not checked in the free run.
May combine two claims.
PremisecitationIn Vigen et al., groupings were not matched for age or testosterone levels.
“Additionally, groupings were not matched for age or T levels.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [129] Vigen, 2013, Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels, JAMA source
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenThe date of record sampling is relevant because most laboratories assessing testosterone before 2005 likely used enzyme immunoassay or radioimmunoassay rather than mass spectrometry.
“Similarly, the date of record sampling is relevant, particularly given that the majority of laboratories assessing T prior to 2005 would have likely used EIA or RIA rather than MS.”
Quote in the paperNot a substantial claim- Rests on an assumption: Most laboratories assessing testosterone before 2005 used enzyme immunoassay or radioimmunoassay rather than mass spectrometry.
May combine two claims.
PremisecitationSome randomized controlled trials show modest improvements in questionnaire scales after testosterone administration, while others fail to find consistent associations.
“Although select RCTs have demonstrated modest improvements in scales following T administration, others have failed to identify consistent associations.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [119] Emmelot-Vonk, 2011, Low testosterone concentrations and the symptoms of testosterone deficiency according to the Androgen Deficiency in Ageing Males (ADAM) and Ageing Males' Symptoms rating scale (AMS) questionnaires, Clin Endocrinol source
Not checked in the free run.
- cites [121] Ho, 2012, A randomized, double-blind, placebo-controlled trial on the effect of long-acting testosterone treatment as assessed by the Aging Male Symptoms scale, BJU Int source
Not checked in the free run.
May combine two claims.
PremisecitationAvailable hypogonadism questionnaires correlate with aging and diabetes mellitus, but their associations with total and free testosterone are variable.
“Available questionnaires demonstrate correlations with aging and DM with variable associations noted with TT and fT levels.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [115] Morley, 2006, Comparison of screening questionnaires for the diagnosis of hypogonadism, Maturitas source
Not checked in the free run.
- cites [118] Spetz, 2007, Testosterone correlated to symptoms of partial androgen deficiency in aging men (PADAM) in an elderly Swedish population, Menopause source
Not checked in the free run.
- cites [119] Emmelot-Vonk, 2011, Low testosterone concentrations and the symptoms of testosterone deficiency according to the Androgen Deficiency in Ageing Males (ADAM) and Ageing Males' Symptoms rating scale (AMS) questionnaires, Clin Endocrinol source
Not checked in the free run.
May combine two claims.
PremisecitationThe MMAS and ANDROTEST questionnaires have better specificity (53-65%) but lower sensitivity (60-71%).
“The MMAS and ANDROTEST questionnaires exhibit improved specificity (53–65%), with loss of overall sensitivity (60–71%).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [111] Smith, 2000, Construction and field validation of a self-administered screener for testosterone deficiency (hypogonadism) in ageing men, Clin Endocrinol source
Not checked in the free run.
- cites [114] Corona, 2006, ANDROTEST: A structured interview for the screening of hypogonadism in patients with sexual dysfunction, J Sex Med source
Not checked in the free run.
- cites [115] Morley, 2006, Comparison of screening questionnaires for the diagnosis of hypogonadism, Maturitas source
Not checked in the free run.
May combine two claims.
InterpretationreasoningStudies using lower testosterone values for inclusion criteria are more likely to demonstrate improved outcomes with testosterone supplementation, while those including men with higher baseline testosterone may falsely conclude no effect of therapy.
“Given these findings, studies utilizing lower T values for inclusion criteria are more likely to demonstrate improved outcomes with T supplementation, while those including men with higher baseline T may falsely conclude no effect of therapy.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationOverall variability was only minimally influenced by the calculated free testosterone algorithm used (14%), while different total testosterone and SHBG assays accounted for 82% and 4% of observed variance, respectively.
“Of interest, overall variability was only minimally influenced by the calculated fT algorithm utilized (14% of variability), while the different TT and SHBG assays accounted for 82% and 4% of observed variance, respectively.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [107] Morris, 2004, A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men, Eur J Endocrinol source
Not checked in the free run.
May combine two claims.
PremisecitationDifferent testosterone thresholds may exist for different symptoms including libido, erectile function, muscle anabolism, bone turnover, and adipogenesis, and supplementation beyond a set threshold likely has declining efficacy for that variable.
“As different T thresholds may exist for different symptoms including libido, erectile function, muscle anabolism, bone turnover, and adipogenesis, supplementation beyond a set threshold likely has declining efficacy for that variable.130, 131”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [130] Finkelstein, 2013, Gonadal steroids and body composition, strength, and sexual function in men, N Engl J Med source
Not checked in the free run.
- cites [131] Snyder, 1999, Effect of testosterone treatment on bone mineral density in men over 65 years of age, J Clin Endocrinol Metab
Not checked in the free run.
May combine two claims.
PremisecitationHeinemann and colleagues found significant similarities and compatibility among the AMS, ADAM, and MMAS instruments, with no scale superior.
“In comparing the AMS, ADAM, and MMAS questionnaires, Heinemann and colleagues noted significant similarities and compatibility among instruments, with no one scale demonstrating superiority.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [120] Heinemann, 2004, Can results of the Aging Males' Symptoms (AMS) scale predict those of screening scales for androgen deficiency?, Aging Male source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningComparisons between treatment and control groups must be appropriately matched to reduce errors in data interpretation.
“Additionally, comparisons between treatment and control groups must be appropriately matched to reduce errors in data interpretation.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationPotential beneficial and harmful effects of testosterone supplementation are time-dependent and may not be observed in trials of insufficient duration.
“Potential beneficial and harmful effects of T supplementation are time-dependent and may not be observed in trials of insufficient duration.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningMany hypogonadism publications are performed in specialized populations, and their outcomes are not necessarily generalizable to other populations.
“Many hypogonadism publications are performed in specialized populations, with outcomes reported specifically for that cohort. Outcomes are not necessarily generalizable to other populations, and caution should be observed in extrapolating findings.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Interpretationnone givenConclusions may only be based on outcomes presented and are limited by the statistical power of the study design.
“Conclusions may only be based on outcomes presented and are limited by the statistical power of the study design.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Interpretationnone givenRetrospective and uncontrolled prospective studies are unable to establish causative relationships and are of lesser value than randomized controlled trials and meta-analyses of randomized controlled trials.
“From an evidence-based perspective, retrospective and uncontrolled prospective studies are unable to establish causative relationships and are of lesser value than RCTs and meta-analyses of RCTs.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningThe methodology for adverse event reporting is an important aspect of study design and may impact the rate of adverse events identified.
“The methodology for AE reporting is an important aspect of study design and may impact the rate of AEs identified.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationA comparative analysis between paper-based journal meta-analyses and Cochrane reviews demonstrated significant heterogeneity in the quality of published systematic reviews, with relatively poor adherence to sound methodological principles in the majority of non-Cochrane reviews.
“A comparative analysis between paper-based journal meta-analyses and the more rigorous Cochrane reviews demonstrated significant heterogeneity in the quality of published systematic reviews with relatively poor adherence to sound methodological principles with the majority of non-Cochrane reviews.140”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [140] Jadad, 1998, Methodology and reports of systematic reviews and meta-analyses: A comparison of Cochrane reviews with articles published in paper-based journals, JAMA source
Not checked in the free run.
May combine two claims.
PremisecitationCommon testosterone therapies normalize total testosterone to eugonadal levels in approximately 75-85% of men, indicating a 15-25% rate of suboptimal response.
“Common T therapies result in normalization of TT to eugonadal levels in approximately 75–85% of men, indicating a 15–25% rate of suboptimal response.138, 139”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [138] Kaufman, 2011, Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men, J Sex Med source
Not checked in the free run.
- cites [139] Mazer, 2005, Comparison of the steady-state pharmacokinetics, metabolism, and variability of a transdermal testosterone patch versus a transdermal testosterone gel in hypogonadal men, J Sex Med source
Not checked in the free run.
May combine two claims.
InterpretationcitationInsufficiently powered studies that conclude safety of testosterone supplementation in men with prostate cancer are at risk of type-II errors and are not statistically supportable.
“As such, insufficiently powered studies which conclude safety of T supplementation in men with prostate cancer are at risk of committing type-II errors and are not statistically supportable.143, 144”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [143] Kaplan, 2013, Use of testosterone replacement therapy in the United States and its effect on subsequent prostate cancer outcomes, Urology source
Not checked in the free run.
- cites [144] Pastuszak, 2013, Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy, J Urol source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.
InterpretationreasoningThese studies highlight limitations of indirect markers and suggest a need to rely on objective measures that can definitively address the research question.
“These studies highlight limitations of indirect markers and suggest a need for reliance on objective measures which are able to definitively address the research question.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenThe role of free testosterone over total testosterone remains poorly defined, with no consensus available on hormonal thresholds for hypogonadism.
“The role for fT over TT remains poorly defined, with no consensus available as to hormonal thresholds for hypogonadism.”
Quote in the paperNot a substantial claim- Rests on an assumption: No consensus exists on hormonal thresholds for hypogonadism.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenResults from trials using different testosterone supplementation medications should not be used interchangeably, particularly in regard to specific outcomes.
“Results from trials using different T supplementation medications should not be used interchangeably, particularly in regards to specific outcomes.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationA 3-month anastrozole study showed no significant change in markers of bone resorption, while a subsequent 12-month study showed direct radiologic evidence of bone mineral density loss despite unchanged markers of bone resorption.
“Although one publication of men undergoing anastrozole therapy over a 3-month period demonstrated no significant change in markers of bone resorption, a subsequent 12-month study demonstrated direct radiologic evidence of bone mineral density loss despite unchanged markers of bone resorption.125, 126”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [125] Leder, 2005, Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men, Osteoporos Int source
Not checked in the free run.
- cites [126] Burnett-Bowie, 2009, Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels, J Clin Endocrinol Metab source
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenVariability in testosterone levels depends on several factors including advancing age, cultural or geographic location, lifestyle choices such as exercise and obesity, and comorbid conditions.
“Variability in T levels is dependent on several factors including advancing age, cultural/geographic location, life-style choices (exercise, obesity), and comorbid conditions, among others.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenStudies evaluating multiple factors are at increased risk of type-I errors, while those with inadequate power are more likely to report type-II errors.
“Studies evaluating multiple factors are at an increased risk of performing type-I errors, while those with inadequate power are more likely to report type-II errors.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenStudies relying on unsolicited self-reports or physician reporting likely under-represent the true rate of symptoms compared with patient-completed questionnaires.
“Studies relying on unsolicited self-reports or physician reporting likely under-represent the true rate of symptoms when compared to patient-completed questionnaires.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
Interpretationnone givenStatistical power is one of the most significant aspects of study design.
“One of the most significant aspects of study design is statistical power.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe overall impact of varying formulations on hypogonadal symptoms and adverse events is poorly described, with limited data showing higher rates of erythrocytosis among therapies achieving higher peak testosterone levels.
“The overall impact of the varying formulations on hypogonadal symptoms and AEs is poorly described, with limited data demonstrating higher rates of erythrocytosis noted among therapies achieving higher peak T levels.136, 137”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [136] Ip, 2010, Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets, Eur J Endocrinol source
Not checked in the free run.
- cites [137] Vorkas, 2012, Testosterone replacement therapy and polycythemia in HIV-infected patients, AIDS source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenThe coefficient of determination (R2) does not imply a causative relationship between variables.
“As with OR, R2 does not imply a causative relationship between variables.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenTestosterone levels vary in a diurnal manner and within individuals over time.
“Levels also vary in a diurnal manner and within individuals over time.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningMeta-analyses including varying study designs are more likely to highlight erroneous findings, while highly restrictive meta-analyses may exclude a large portion of available data and risk failing to identify significant outcomes.
“Meta-analyses including varying study designs are more likely to highlight erroneous findings, while highly restrictive meta-analyses may exclude a large portion of available data and thus are at risk of failing to identify significant outcomes.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenAccurate assessment of testosterone remains an ongoing challenge, with mass spectrometry and equilibrium dialysis representing the gold-standard techniques for total and free testosterone, respectively.
“Accurate assessment of T remains an ongoing challenge, with MS and equilibrium dialysis representing the gold-standard techniques for TT and fT, respectively.”
Quote in the paperNot a substantial claim- Rests on an assumption: Mass spectrometry and equilibrium dialysis are the gold-standard techniques for total and free testosterone, respectively.
May combine two claims.
InterpretationreasoningBecause there is no universally accepted standard for conducting meta-analyses, there is significant heterogeneity in the quality and reliability of their findings.
“Given the lack of a universally accepted standard for conducting meta-analyses, there is significant heterogeneity in the quality and reliability of findings.”
Quote in the paperSubstantial claim- Rests on an assumption: There is no universally accepted standard for conducting meta-analyses.
May combine two claims.
PremisecitationRosen and colleagues noted that clinically significant changes in IIEF scores varied by baseline erectile function status: men with mild erectile dysfunction reported a clinically relevant improvement with a two-point IIEF increase, while those with severe erectile dysfunction required a seven-point improvement.
“As an example, Rosen and colleagues noted that clinically significant changes in IIEF scores varied depending on baseline erectile function status.141 Men with mild ED would report a clinically relevant improvement if the IIEF score increased by two points, while those with severe ED required a seven point improvement to note equally significant changes.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [141] Rosen, 2011, Minimal clinically important differences in the erectile function domain of the International Index of Erectile Function scale, Eur Urol source
Not checked in the free run.
May combine two claims.
InterpretationreasoningWider confidence intervals suggest greater variability and reduced likelihood that the reported odds ratio represents the true value, making outcomes with wide confidence intervals less reliable than those with narrower intervals.
“Wider confidence intervals suggest greater variability with reduced likelihood that the OR reported represents the true value. As such, outcomes with wide CIs are less reliable compared to those with narrower intervals.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone givenUse of hypogonadism-specific questionnaires for screening is not routinely performed, and their utility in the management of hypogonadism is of debatable clinical value.
“The use of hypogonadism-specific questionnaires for screening is not routinely performed, with their utility in the management of hypogonadism of debatable clinical value.”
Quote in the paperNot a substantial claim- Rests on an assumption: Hypogonadism-specific questionnaires are not routinely used for screening.
May combine two claims.
InterpretationreasoningStudy design and methodology contribute significantly to the quality of evidence presented and may directly impact reported outcomes.
“Study design and methodology contribute significantly to the quality of evidence presented and may directly impact reported outcomes.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningUse of hypogonadism questionnaires as study endpoints is of questionable clinical utility and validity and should not be relied upon in lieu of objective laboratory, physiologic, or radiologic testing.
“The use of hypogonadism questionnaires as study endpoints is of questionable clinical utility and validity and should not be relied upon in lieu of objective laboratory, physiologic, or radiologic testing.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationThe type of assay used for testosterone assessment should be reported, with greater variability among non-mass-spectrometry total testosterone samples, particularly at lower levels, and systematic overestimation from non-empirically calculated free testosterone measurements.
“The type of assay utilized for T assessment should be reported, with greater variability noted among non-MS TT samples (particularly at lower levels) and systematic overestimation resulting from non-empirically calculated fT measurements.107”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [107] Morris, 2004, A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men, Eur J Endocrinol source
Not checked in the free run.
Classified as probably not a substantial claim.
Interpretationnone givenStatistical power determines a study's ability to detect significant differences based on anticipated deviations in a measured variable.
“A measure of statistical power determines the ability of the study to detect significant differences based on anticipated deviations in a measured variable.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The natural history of prostate cancer development, progression, and recurrence is extended enough that long-duration trials are needed to assess testosterone supplementation effects.
“Duration of therapy is also significant in regards to trials evaluating T supplementation and prostate cancer, particularly given the extended natural history of prostate cancer development, progression, and recurrence.”
The paper relies on this without support.
Most laboratories assessing testosterone before 2005 used enzyme immunoassay or radioimmunoassay rather than mass spectrometry.
“Similarly, the date of record sampling is relevant, particularly given that the majority of laboratories assessing T prior to 2005 would have likely used EIA or RIA rather than MS.”
The paper relies on this without support.
Participant age is a common confounder in the hypogonadism literature.
“Participant age is a common confounder in the hypogonadism literature and must be controlled in observational or retrospective studies of hypogonadism-associated conditions.”
The paper relies on this without support.
Testosterone supplementation in elderly males may exhibit a physiologically blunted effect.
“In addition to the potentially confounding effect of age on associated conditions, T supplementation in elderly males may exhibit a physiologically blunted effect.”
The paper relies on this without support.
Use of selective estrogen receptor modulators may result in reduced efficacy in elderly compared with younger males.
“Similarly, the use of alternative T therapies, such as selective estrogen receptor modulators (SERMs) may result in reduced efficacy in elderly compared to younger males.”
The paper relies on this without support.
There is no universally accepted standard for conducting meta-analyses.
“Given the lack of a universally accepted standard for conducting meta-analyses, there is significant heterogeneity in the quality and reliability of findings.”
The paper relies on this without support.
Mass spectrometry and equilibrium dialysis are the gold-standard techniques for total and free testosterone, respectively.
“Accurate assessment of T remains an ongoing challenge, with MS and equilibrium dialysis representing the gold-standard techniques for TT and fT, respectively.”
The paper relies on this without support.
No consensus exists on hormonal thresholds for hypogonadism.
“The role for fT over TT remains poorly defined, with no consensus available as to hormonal thresholds for hypogonadism.”
The paper relies on this without support.
Hypogonadism-specific questionnaires are not routinely used for screening.
“The use of hypogonadism-specific questionnaires for screening is not routinely performed, with their utility in the management of hypogonadism of debatable clinical value.”
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?
Screening questionnaires are not an appropriate tool to identify candidates for testosterone therapy.
“Screening questionnaires are not an appropriate tool to identify candidates for testosterone therapy andshould not be used at the expense of a full patient evaluation and laboratory testosterone measurement.”
From Evaluation and Management of Testosterone Deficiency: AUA Guideline (2018) · cites this paper as [4]
Specificities and sensitivities vary greatly among available questionnaires, making them ill-suited for screening or as a surrogate for testosterone laboratory testing.
“Specificities and sensitivities vary greatly amongst available questionnaires making them illsuited for screening or for use as a surrogate for testosterone laboratory testing.”
From Evaluation and Management of Testosterone Deficiency: AUA Guideline (2018) · cites this paper as [4]
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.
Total testosterone conversion conflicts with another threshold
MinorThe paper pairs 235 ng/dl with 10.5 nmol/L, but elsewhere pairs the higher value of 300 ng/dl with the lower value of 10.4 nmol/L. The two conversions cannot both be correct.
“TT 235 ng/dl (10.5 nmol/L), fT 98 pg/ml (220 pmol/L).”
“<300 ng/dl [10.4 nmol/L]”
Free testosterone conversion reverses the ordering of values
MinorThe paper pairs 98 pg/ml with 220 pmol/L, but elsewhere pairs the lower value of 70 pg/ml with the higher value of 242.7 pmol/L. One of these conversions is wrong.
“fT 98 pg/ml (220 pmol/L)”
“70 pg/ml (242.7 pmol/L)”
ANDROTEST publication year conflicts with its cited reference
MinorThe text dates ANDROTEST to 2009, while its cited reference lists publication in 2006.
“The ANDROTEST (2009) has also been published”
“114. Corona G Mannucci E Petrone L ANDROTEST: a structured interview for the screening of hypogonadism in patients with sexual dysfunction The journal of sexual medicine 2006 3 706 15”
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Flagged first, then by citations
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Cited by
Sorted by citations
Evaluation and Management of Testosterone Deficiency: AUA Guideline
Mulhall, J. P., Trost, L. W., Brannigan, R. E., Kurtz, E. G., Redmon, J. B., Chiles, K. A., Lightner, D. J., Miner, M. M., Murad, M. H., Nelson, C. J., et al. (2018) · Journal of Urology · doi:10.1016/j.juro.2018.03.115 · Cited by 766 · see citing works
Self-citationHUNTER, S. K., S. ANGADI, S., BHARGAVA, A., HARPER, J., HIRSCHBERG, A. L., D. LEVINE, B., L. MOREAU, K., J. NOKOFF, N., STACHENFELD, N. S., & BERMON, S. (2023) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000003300 · Cited by 241 · see citing works
European Society of Endocrinology Clinical Practice Guideline: Endocrine work-up in obesity
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Hunter, S. K., Angadi, S. S., Bhargava, A., Harper, J., Hirschberg, A. L., Levine, B. D., Moreau, K. L., Nokoff, N. J., Stachenfeld, N. S., & Bermon, S. (2023) · Translational Journal of the American College of Sports Medicine · doi:10.1249/tjx.0000000000000236 · Cited by 43 · see citing works
- Authors
- Trost, L. W., & Mulhall, J. P.
- Affiliations
- Mayo Clinic (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Mulhall, John P.
- Venue
- The Journal of Sexual Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-07-01
- Volume
- 13
- Issue
- 7
- Pages
- 1029-1046
- ISSN
- 1743-6095 (ISSN-L)
- 1743-6109
- PMC
- PMC5516925
- OpenAlex
- W2404570186
- Cited by
- 98
- References
- 140
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 9 · 2023: 10 · 2022: 16 · 2021: 19 · 2020: 12 · 2019: 8 · 2018: 4 · 2017: 2 · 2016: 2
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Journal of Sexual Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- 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
- testosterone measurement, male hypogonadism, mass spectrometry, equilibrium dialysis, circadian rhythm, research design, critical appraisal
- MeSH terms
- Humans, Hypogonadism, Male, Prospective Studies, Surveys and Questionnaires, Reference Values, Research Design, Retrospective Studies, 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 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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