Abstract
Purpose
To better understand the effects of aging, metabolic syndrome, diurnal variation, and seasonal variation on serum testosterone levels in the context of current guideline statements on testosterone deficiency.
Methods
This cross-sectional study utilized the United Kingdom Biobank. Physical examination, anthropomorphic measurements, and laboratory evaluation were performed at the time of enrollment from 2006 to 2010. The primary outcomes were the effect of age, the presence of metabolic syndrome, the time of day, and the month of the year on serum testosterone levels.
Results
Among 197,883 included men, the 5th, 25th, 50th, 75th and 95th percentile testosterone levels in men without metabolic syndrome were significantly higher than those in men with metabolic syndrome at every decade of life (p < 0.001). The average testosterone level within each group (men without metabolic syndrome vs. men with) was clinically similar across decade of life (12.43 in 40’s 12.29 in 50’s 12.24 in 60’s vs. 10.69 in 40’s 10.56 in 50’s 10.63 in 60’s respectively). Average testosterone levels decreased with blood draws later in the day ranging from 10.91 to 12.74 nmol/L (p < 0.01). Similarly, there was seasonal variation in serum testosterone ranging from 11.86 to 12.18 nmol/L (p < 0.01).
Conclusions
We found significant variation in serum testosterone according to the presence of metabolic syndrome and time of laboratory draw, but not according to age. These data challenge the prior dogma of age-related hypogonadism and favor an individualized approach towards serum testosterone measurement and interpretation. However, further studies are needed to correlate these population-based data with individuals’ hypogonadal symptoms.
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References
Mulhall JP, Trost LW, Brannigan RE et al (2018) Evaluation and management of testosterone deficiency: AUA guideline. J Urol 200:423–432. https://doi.org/10.1016/j.juro.2018.03.115
Harman SM, Metter EJ, Tobin JD et al (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore longitudinal study of aging. J Clin Endocrinol Metab 86:724–731. https://doi.org/10.1210/jcem.86.2.7219
Liu PY, Beilin J, Meier C et al (2007) Age-related changes in serum testosterone and sex hormone binding globulin in Australian men: longitudinal analyses of two geographically separate regional cohorts. J Clin Endocrinol Metab 92:3599–3603. https://doi.org/10.1210/jc.2007-0862
Wu FCW, Tajar A, Pye SR et al (2008) Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 93:2737–2745. https://doi.org/10.1210/jc.2007-1972
Lokeshwar SD, Patel P, Fantus RJ et al (2021) Decline in serum testosterone levels among adolescent and young adult men in the USA. Eur Urol Focus 7:886–889. https://doi.org/10.1016/j.euf.2020.02.006
Mulligan T, Frick MF, Zuraw QC et al (2006) Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 60:762–769. https://doi.org/10.1111/j.1742-1241.2006.00992.x
Snyder PJ, Bhasin S, Cunningham GR et al (2016) Effects of testosterone treatment in older men. N Engl J Med 374:611–624. https://doi.org/10.1056/NEJMoa1506119
Salter CA, Mulhall JP (2019) Guideline of guidelines: testosterone therapy for testosterone deficiency. BJU Int 124:722–729. https://doi.org/10.1111/bju.14899
Behre HM, Tammela TLJ, Arver S et al (2012) A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. Aging Male 15:198–207. https://doi.org/10.3109/13685538.2012.699562
Grabner M, Bodhani A, Khandelwal N et al (2017) Clinical characteristics, health care utilization and costs among men with primary or secondary hypogonadism in a US commercially insured population. J Sex Med 14:88–97. https://doi.org/10.1016/j.jsxm.2016.10.012
Smith RP, Coward RM, Kovac JR, Lipshultz LI (2013) The evidence for seasonal variations of testosterone in men. Maturitas 74:208–212. https://doi.org/10.1016/j.maturitas.2012.12.003
Shlykova N, Davidson E, Krakowsky Y et al (2020) Absent diurnal variation in serum testosterone in young men with testosterone deficiency. J Urol 203:817–823. https://doi.org/10.1097/JU.0000000000000630
Svartberg J, Jorde R, Sundsfjord J et al (2003) Seasonal variation of testosterone and waist to hip ratio in men: the Tromsø study. J Clin Endocrinol Metab 88:3099–3104. https://doi.org/10.1210/jc.2002-021878
Wang C, Catlin DH, Demers LM et al (2004) Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 89:534–543. https://doi.org/10.1210/jc.2003-031287
Travison TG, Vesper HW, Orwoll E et al (2017) Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe. J Clin Endocrinol Metab 102:1161–1173. https://doi.org/10.1210/jc.2016-2935
Sudlow C, Gallacher J, Allen N et al (2015) UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med 12:e1001779. https://doi.org/10.1371/journal.pmed.1001779
Huang PL (2009) A comprehensive definition for metabolic syndrome. Dis Model Mech 2:231–237. https://doi.org/10.1242/dmm.001180
Martins AD, Majzoub A, Agawal A (2019) Metabolic syndrome and male fertility. World J Mens Health 37:113–127. https://doi.org/10.5534/wjmh.180055
Kim J-W, Oh M-M, Yoon C-Y et al (2013) The effect of diet-induced insulin resistance on DNA methylation of the androgen receptor promoter in the penile cavernosal smooth muscle of mice. Asian J Androl 15:487–491. https://doi.org/10.1038/aja.2013.26
Camacho EM, Huhtaniemi IT, O’Neill TW et al (2013) Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol 168:445–455. https://doi.org/10.1530/EJE-12-0890
Corona G, Monami M, Rastrelli G et al (2011) Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med 8:272–283. https://doi.org/10.1111/j.1743-6109.2010.01991.x
Corona G, Monami M, Rastrelli G et al (2011) Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int J Androl 34:528–540. https://doi.org/10.1111/j.1365-2605.2010.01117.x
Hirode G, Wong RJ (2020) Trends in the prevalence of metabolic syndrome in the United States, 2011–2016. JAMA 323:2526–2528. https://doi.org/10.1001/jama.2020.4501
Albertsson-Wikland K, Rosberg S, Lannering B et al (1997) Twenty-four-hour profiles of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol levels: a semilongitudinal study throughout puberty in healthy boys. J Clin Endocrinol Metab 82:541–549. https://doi.org/10.1210/jcem.82.2.3778
Brambilla DJ, Matsumoto AM, Araujo AB, McKinlay JB (2009) The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men. J Clin Endocrinol Metab 94:907–913. https://doi.org/10.1210/jc.2008-1902
Plymate SR, Tenover JS, Bremner WJ (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 10:366–371. https://doi.org/10.1002/j.1939-4640.1989.tb00120.x
Crawford ED, Barqawi AB, O’Donnell C, Morgentaler A (2007) The association of time of day and serum testosterone concentration in a large screening population. BJU Int 100:509–513. https://doi.org/10.1111/j.1464-410X.2007.07022.x
Andersson A-M, Carlsen E, Petersen JH, Skakkebaek NE (2003) Variation in levels of serum inhibin B, testosterone, estradiol, luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin in monthly samples from healthy men during a 17-month period: possible effects of seasons. J Clin Endocrinol Metab 88:932–937. https://doi.org/10.1210/jc.2002-020838
Moskovic DJ, Eisenberg ML, Lipshultz LI (2012) Seasonal fluctuations in testosterone-estrogen ratio in men from the Southwest United States. J Androl 33:1298–1304. https://doi.org/10.2164/jandrol.112.016386
Tancredi A, Reginster J-Y, Luyckx F, Legros J-J (2005) No major month to month variation in free testosterone levels in aging males. minor impact on the biological diagnosis of “andropause.” Psychoneuroendocrinology 30:638–646. https://doi.org/10.1016/j.psyneuen.2005.02.002
Brambilla DJ, O’Donnell AB, Matsumoto AM, McKinlay JB (2007) Lack of seasonal variation in serum sex hormone levels in middle-aged to older men in the Boston area. J Clin Endocrinol Metab 92:4224–4229. https://doi.org/10.1210/jc.2007-1303
Lee JH, Lee SW (2021) Monthly variations in serum testosterone levels: results from testosterone screening of 8367 middle-aged men. J Urol 205:1438–1443. https://doi.org/10.1097/JU.0000000000001546
Valdés S, Maldonado-Araque C, Lago-Sampedro A et al (2017) Reference values for TSH may be inadequate to define hypothyroidism in persons with morbid obesity: Di@bet.es study. Obesity 25:788–793. https://doi.org/10.1002/oby.21796
Addo OY, Yu EX, Williams AM et al (2021) Evaluation of hemoglobin cutoff levels to define anemia among healthy individuals. JAMA Netw Open 4:e2119123. https://doi.org/10.1001/jamanetworkopen.2021.19123
World Health Organization (2010) WHO laboratory manual for the examination and procession of human Semen. WHO, Geneva
Brambilla DJ, O’Donnell AB, Matsumoto AM, McKinlay JB (2007) Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men. Clin Endocrinol (Oxf) 67:853–862. https://doi.org/10.1111/j.1365-2265.2007.02976.x
Rosner W, Auchus RJ, Azziz R et al (2007) Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 92:405–413. https://doi.org/10.1210/jc.2006-1864
Keevil BG, Adaway J (2019) Assessment of free testosterone concentration. J Steroid Biochem Mol Biol 190:207–211. https://doi.org/10.1016/j.jsbmb.2019.04.008
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RJF—conceptualization, investigation, methodology, writing, reviewing. DRG—investigation, writing, reviewing. CC—data curation, software, formal analysis, methodology, reviewing. BTH—conceptualization, supervision, reviewing. JX—conceptualization, supervision, reviewing. JW—data curation, software, reviewing. JES—conceptualization, investigation, methodology, reviewing. AKN—investigation, methodology, reviewing. REB—conceptualization, investigation, methodology, reviewing. JAH—conceptualization, investigation, methodology, writing, reviewing.
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Dr. Brannigan is a former member of the American Urological Association guideline panel on Testosterone Deficiency.
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Fantus, R.J., Greenberg, D.R., Chang, C. et al. Novel reference range values for serum testosterone: a cross-sectional study of 200,000 males. J Endocrinol Invest (2024). https://doi.org/10.1007/s40618-024-02319-0
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DOI: https://doi.org/10.1007/s40618-024-02319-0