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Male sexual development and function depend on a complex feedback circuit involving the hypothalamus, pituitary, and testes. Male sexual dysfunction can be secondary to hypogonadism or numerous other disorders.
Physiology
The hypothalamus produces gonadotropin-releasing hormone (GnRH), which is released in a pulsatile fashion q 60 to 120 min. The anterior pituitary responds to each pulse of GnRH by producing a corresponding pulse of luteinizing hormone (LH) and, to a lesser degree, follicle-stimulating hormone (FSH). Continuous stimulation by GnRH (as might occur therapeutically) suppresses pituitary release of LH and FSH.
The Leydig cells of the testes respond to LH by producing between 5 and 10 mg of testosterone daily. Testosterone levels are highest in early morning, except in older men, who may lose circadian variation.
Testosterone is synthesized from cholesterol through several intermediate compounds, including dehydroepiandrosterone (DHEA) and androstenedione. Circulating testosterone is mostly protein-bound, about 40% to sex hormone–binding globulin (SHBG) and 58% to albumin. Because testosterone is avidly bound to SHBG, only albumin-bound testosterone (which is less avidly bound) and the 1 to 2% that constitute free testosterone are bioavailable.
In target tissues, about 4 to 8% of testosterone is converted to a more potent metabolite, dihydrotestosterone (DHT), by the enzyme 5 α-reductase. DHT has important trophic effects in the prostate and mediates androgenic alopecia. In adults, spermatogenesis requires adequate intratesticular testosterone, but the role of DHT in spermatogenesis is controversial.
Testosterone and DHT have metabolic effects, including increasing protein anabolism and nitrogen retention, increasing bone density and muscle mass, and modulating the immune system. Testosterone undergoes conversion to estradiol ; estrogen mediates much of the effect of testosterone on organs such as bone and the brain.
Testosterone, DHT, and estradiol provide negative feedback on the hypothalamic-pituitary axis. In males, estradiol is the main inhibitor of LH production, whereas both estradiol and inhibin B, a peptide produced by Sertoli cells of the testes, inhibit production of FSH. In the presence of testosterone, FSH stimulates the Sertoli cells and induces spermatogenesis. In spermatogenesis, each germinal cell (spermatogonium), located adjacent to the Sertoli cells, undergoes differentiation into 16 primary spermatocytes, each of which generates 4 spermatids. Each spermatid matures into a spermatozoon. Spermatogenesis takes 72 to 74 days and yields about 100 million new spermatozoa each day. Upon maturation, spermatozoa are released into the rete testis, where they migrate to the epididymis and eventually to the vas deferens. Migration requires an additional 14 days. Before ejaculation, spermatozoa are mixed with secretions from the seminal vesicles, prostate, and bulbourethral glands.
Sexual
Differentiation, Adrenarche, and Puberty
In the embryo, the presence of a Y chromosome triggers development and growth of the testes, which begin secreting testosterone and a müllerian-duct inhibitor by about 7 wk of gestation. Testosterone virilizes the wolffian duct (which develops into the epididymis, vas deferens, and seminal vesicles). DHT promotes development of the remainder of the male genitals. Testosterone levels peak in the 2nd trimester and fall to almost zero by birth. Testosterone production rises briefly during the first 6 mo of life, the function of which is unclear. Thereafter, testosterone levels remain low until puberty.
LH and FSH are elevated at birth but fall to low levels within a few months, remaining low or undetectable throughout the prepubertal years. Through an unknown mechanism, blood levels of the adrenal androgens DHEA and DHEA sulfate begin to increase several years before puberty. Their conversion to testosterone in small amounts initiates pubic and axillary hair growth (adrenarche).
The mechanisms that initiate puberty are unclear, although early in puberty the hypothalamus becomes less sensitive to the inhibitory effects of sex hormones. This increases secretion of LH and FSH, stimulating testosterone production. Secretion of LH and FSH increases initially only during sleep; later, secretion increases throughout the 24-h period. The increased testosterone levels in boys cause pubertal changes, the first of which are growth of the testes (> 2.5 cm on the long axis, > 3 to 4 mL in volume) and thinning of scrotal skin. Later, penile length, muscle mass, and bone density increase; the voice deepens; and pubic and axillary hair becomes denser and thicker (see Fig. 1: Male Reproductive Endocrinology: Puberty—when male sexual characteristics develop. ).
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Fig. 1
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Puberty—when male sexual characteristics develop.
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Bars indicate normal ranges. No mean is available for change in habitus.
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Effects
of Aging
Both hypothalamic secretion of GnRH and the response of Leydig cells to FSH and LH diminish with aging. Beginning at about age 30, a man's serum total testosterone level declines by 1%/yr. Men aged 70 to 80 tend to have serum testosterone levels that are about ½ to 2⁄3 of those of men in their 20s. In addition, SHBG levels increase with aging, causing an even greater decline in serum free and bioavailable testosterone. FSH and LH levels tend to be normal or high-normal. These age-related changes are sometimes referred to as the andropause, although there are no abrupt changes in hormone levels as occur in the menopause. The decline in testosterone may contribute to age-related muscle loss, osteopenia, loss of libido, and cognitive decline. Testosterone supplementation for men with low-normal levels of testosterone is controversial. Some experts recommend a trial of testosterone supplementation in older men with symptoms or signs of hypogonadism and whose serum testosterone levels are below the lower limit of normal for men aged 20 to 40 yr. No data favor any of the testosterone preparations specifically for use in older men.
Last full review/revision June 2007 by Bradley D. Anawalt, MD
Content last modified June 2007
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