Age-related testosterone decline is due to waning of both testicular and hypothalamic-pituitary function

References

• Wu FC, Tajar A, Pye SR, et al. 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 2008;93:2737–45
   PubMed Web of Science ®Google Scholar
• Feldman HA, Longcope C, Derby CA, et al. 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 2002;87:589–98
   PubMed Web of Science ®Google Scholar
• Morley JE, Kaiser FE, Perry HM, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997;46:410–13
   PubMed Web of Science ®Google Scholar
• Harman SM, Metter EJ, Tobin JD, et al. Baltimore longitudinal study of aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001;86:724–31
   PubMed Web of Science ®Google Scholar
• Dabaja AA, Bryson CF, Schlegel PN, Paduch DA. The effect of hypogonadism and testosterone-enhancing therapy on alkaline phosphatase and bone mineral density. BJU Int 2015;115:480–5
   PubMed Web of Science ®Google Scholar
• Ramasamy R, Wilken N, Scovell JM, et al. Hypogonadal symptoms are associated with different serum testosterone thresholds in middle-aged and elderly men. Urology 2014;84:1378–82
   PubMed Web of Science ®Google Scholar
• Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363:123–35
   PubMed Web of Science ®Google Scholar
• Lackner JE, Rucklinger E, Schatzl G, et al. Are there symptom-specific testosterone thresholds in aging men? BJU Int 2011;108:1310–15
   PubMed Web of Science ®Google Scholar
• Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab 2006;91:4335–43
   PubMed Web of Science ®Google Scholar
• Scovell JM, Ramasamy R, Wilken N, et al. Hypogonadal symptoms in young men are associated with a serum total testosterone threshold of 400 ng/dL. BJU Int 2015 . [Epub ahead of print]. doi: 10.1111/bju.12970
   PubMed Web of Science ®Google Scholar
• Bhasin S, Cunningham GR, Hayes FJ, et al. Endocrine Society Task Force. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536–59
   PubMed Web of Science ®Google Scholar
• Tajar A, Forti G, O'Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab 2010;95:1810–18
   PubMed Web of Science ®Google Scholar
• Scott HM, Mason JI, Sharpe RM. Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds. Endocr Rev 2009;30:883–925
   PubMed Web of Science ®Google Scholar
• Rubens R, Dhont M, Vermeulen A. Further studies on Leydig cell function in old age. J Clin Endocrinol Metab 1974;39:40–5
   PubMed Web of Science ®Google Scholar
• Chen H, Hardy MP, Huhtaniemi I, Zirkin BR. Age-related decreased Leydig cell testosterone production in the brown Norway rat. J Androl 1994;15:551–7
   PubMed Web of Science ®Google Scholar
• Neaves WB, Johnson L, Porter JC, et al. Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. J Clin Endocrinol Metab 1984;59:756–63
   PubMed Web of Science ®Google Scholar
• Sasano N, Ichijo S. Vascular patterns of the human testis with special reference to its senile changes. Tohoku J Exp Med 1969;99:269–80
   PubMed Web of Science ®Google Scholar
• Takizawa T, Hatakeyama S. Age-associated changes in microvasculature of human adult testis. Acta Pathol Jpn 1978;28:541–54
   PubMedGoogle Scholar
• Regadera J, Nistal M, Paniagua R. Testis, epididymis, and spermatic cord in elderly men. Correlation of angiographic and histologic studies with systemic arteriosclerosis. Arch Pathol Lab Med 1985;109:663–7
   PubMed Web of Science ®Google Scholar
• Beattie MC, Adekola L, Papadopoulos V, et al. Leydig cell aging and hypogonadism. Exp Gerontol 2015. [Epub ahead of print]. doi: 10.1016/j.exger.2015.02.014
   PubMed Web of Science ®Google Scholar
• Araujo AB, Wittert GA. Endocrinology of the aging male. Best Pract Res Clin Endocrinol Metab 2011;25:303–19
   PubMed Web of Science ®Google Scholar
• Takahashi PY, Liu PY, Roebuck PD, et al. Graded inhibition of pulsatile luteinizing hormone secretion by a selective gonadotropin-releasing hormone (GnRH)-receptor antagonist in healthy men: evidence that age attenuates hypothalamic GnRH outflow. J Clin Endocrinol Metab 2005;90:2768–74
   PubMed Web of Science ®Google Scholar
• Gruenewald DA, Naai MA, Marck BT, Matsumoto AM. Age-related decrease in hypothalmic gonadotropin-releasing hormone (GnRH) gene expression, but not pituitary responsiveness to GnRH, in the male brown Norway rat. J Andrology 2000;21:72–84
   PubMed Web of Science ®Google Scholar
• Urban RJ, Veldhuis JD, Blizzard RM, Dufau ML. Attenuated release of biologically active luteinizing hormone in healthy aging men. J Clin Invest 1988;81:1020–9
   PubMed Web of Science ®Google Scholar
• Veldhuis JD, Urban RJ, Lizarralde G, et al. Attenuation of luteinizing-hormone secretory burst amplitude as a proximate basis for the hypoandrogenism of healthy aging in men. J Clin Endocrinol Metab 1992;75:52–8
   Web of Science ®Google Scholar
• Kaler LW, Critchlow V. Anterior-pituitary luteinizing-hormone secretion during continuous perifusion in aging male-rats. Mech Ageing Dev 1984;25:103–15
   PubMed Web of Science ®Google Scholar
• Winters SJ, Sherins RJ, Troen P. The gonadotropin-suppressive activity of androgen is increased in elderly men. Metab Clin Exp 1984;33:1052–9
   PubMed Web of Science ®Google Scholar
• Molnar CS, Vida B, Sipos MT, et al. Morphological evidence for enhanced kisspeptin and neurokinin B signaling in the infundibular nucleus of the aging man. Endocrinology 2012;153:5428–39
   PubMed Web of Science ®Google Scholar
• Darby E, Anawalt BD. Male hypogonadism: an update on diagnosis and treatment. Treat Endocrinol 2005;4:293–309
   PubMedGoogle Scholar
• Sartorius G, Spasevska S, Idan A, et al. Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the healthy man study. Clin Endocrinol (Oxf) 2012;77:755–63
   PubMed Web of Science ®Google Scholar
• Camacho EM, Huhtaniemi IT, O'Neill TW, et al. 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 2013;168:445–55
   PubMed Web of Science ®Google Scholar
• European Association of Urology. Guidelines on male hypogonadism. March 2015. Available from: http://uroweb.org
   Google Scholar
• Lunenfeld B, Mskhalaya G, Zitzmann M, et al. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. Aging Male 2015;18:5–15
   PubMed Web of Science ®Google Scholar
• Administration USFaD. Advisory committee industry briefing document: testosterone replacement therapy. Available from: http://FDA.gov [last accessed 17 Sep 2014]
   Google Scholar
• US Food and Drug Administration. Testosterone products: drug safety communication - FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke. Available from: http://FDA.gov [last accessed 3 March 2015]
   Google Scholar
• Perls T, Handelsman DJ. Disease mongering of age-associated declines in testosterone and growth hormone levels. J Am Geriatr Soc 2015;63:809--11
   PubMed Web of Science ®Google Scholar
• Snyder PJ, Ellenberg SS, Cunningham GR, et al. The testosterone trials: seven coordinated trials of testosterone treatment in elderly men. Clin Trials 2014;11:362–75
   PubMed Web of Science ®Google Scholar