Testosterone Physiology
Testosterone is an anabolic steroid synthesized primarily by the Leydig cells in the testes in males, the ovaries in females, and adrenal glands in both sexes. It is synthesized from cholesterol, with androstenedione, androstenediol, dehydroepiandrosterone (DHEA), progesterone, and pregnenolone acting as some of the intermediate substrates.
Secretion Rhythm
Testosterone production is regulated by hormonal secretions from the hypothalamus and the pituitary gland in the brain. The process begins as the hypothalamus secretes gonadotropin-releasing hormone (GnRH) in generative pulses. In response to these steady intermittent bursts of GnRH, the pituitary gland releases luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which act directly on the testes.
FSH activates the Sertoli cells that produce sperm (spermatogenesis). LH stimulates the Leydig cells to secrete testosterone in a daily rhythm characterized by peak levels in the morning and low levels in the evening. Once it reaches high levels, testosterone production generates negative loop feedback to the hypothalamus to downregulate LH release and diminish further testosterone production. In this way, testosterone inhibits its own secretion.
Like most hormonal-control feedback mechanisms, this is a closed-loop system, which also operates in the opposite direction to guard against deficiencies. The healthy functioning of this feedback loop ensures a steady secretion of gonadotropins, resulting in relatively constant levels of testosterone secretion by the testes.
Aging
During puberty, male testosterone levels increase approximately 10 to 20 times, triggering the development of mature male genitalia and secondary hair patterns, sperm production, accelerated musculoskeletal development, and behavioral changes.
Barring specific factors that may trigger hypogonadism, such as illness, lifestyle, or environment (see section on “Hypogonadism”), the decline of testosterone production due to aging often begins in a man’s forties. At age 50, it is estimated that at least half of all males have bioavailable testosterone levels that are lower than that found in healthy young men. The primary cause of this decline is chronic deterioration of Leydig cells in the testes; a 20-old man has approximately 700 million Leydig cells bu by age 80 that number will be reduced to about 200 million.1 This age-related drop in testosterone is more pronounced in patients with chronic illnesses, such as rheumatoid arthritis or those at risk of frailty or wasting conditions. In men of advanced age (over 70), dramatic drops in testosterone levels often occur in conjunction with a decline in circulating IGF-1 levels.2
Age-induced testosterone decline and other sex hormone alterations are associated with a gradual weakening of the male hypothalamic-pituitary-gonadal axis. Bioavailable testosterone is the portion of testosterone unbound to proteins in the blood. This unbound testosterone is freely available to impact target tissues and organs throughout the body. As testosterone levels fall, concomitant elevations in sex hormone binding globulin (SHBG) further reduce the amount of bioavailable testosterone in the body. Both the pulse secretion and bioactivity of luteinizing hormone also decrease. Aging Leydig cells will often show reduced sensitivity to stimulation by human chorionic gonadotropin hormone. In men of advanced age, increases in follicle stimulating hormone are also observed. However, one study found that 70% of men over age 50 with low bioavailable testosterone levels displayed low LH levels, suggesting that secondary hypogonadism can develop as a result of diminished HPA-axis responsiveness, which occurs with a gradual decline in testicular function.3
