Testosterone

Secretion and Metabolism

Testosterone is the principal androgen secreted by the mature testis. The normal young man produces about 7 mg each day, of which less than 5% is derived from adrenal secretions. This amount decreases somewhat with age, so that by the seventh decade and beyond testosterone production may have decreased to 4 mg per day; however, in the absence of illness or injury, men do not experience a sharp drop in testosterone production akin to the abrupt cessation of estrogen production in the postmenopausal woman. As with the other steroid hormones, testosterone in blood is largely bound to plasma protein, with only about 2 to 3% present as free hormone. About 50% is bound to albumin and about 45% to sex-hormone-binding globulin (SHBG), which is also called testosterone-estradiol-binding globulin (TeBG). This glycoprotein binds both estrogen and testosterone, but its single binding site has a higher affinity for testosterone. Its concentration in plasma is decreased by androgens. Consequently, SHBG is more than twice as abundant in the circulation of women than men. In addition to its functions as a carrier protein, SHBG may also act as an enhancer of hormone action. Persuasive evidence has been amassed to indicate that SHBG binds to specific receptors on cell membranes and increases the formation of cAMP when its steroid binding site is occupied. The nature of the receptor has not been characterized, nor has the physiological importance of this action been established. Although testosterone decreases expression of SHBG in hepatocytes, both testosterone and FSH increase transcription of the same gene in Sertoli cells, where its protein product was given the name androgen-binding protein (ABP) before its identity with SHBG was known. ABP is secreted into the lumens of seminiferous tubules.

Testosterone that is not bound to plasma proteins diffuses out of capillaries and enters nontarget as well as target cells. In some respects, testosterone can be considered to be a prohormone, because it is converted in extratesticular tissues to other biologically active steroids. Testosterone may be reduced to the more potent androgen, 5a-dihydrotestosterone, in the liver in a reaction catalyzed by the enzyme 5a-reductase type I and returned to the blood. This enzyme is a component of the steroid hormone degradative pathway and also reduces 21-carbon adrenal steroids. Testosterone is also reduced to dihydrotestosterone in the cytoplasm of its target cells mainly through the catalytic activity of 5a-reductase type II, whose abundance in these cells is increased by the actions of testosterone. Dihydrotestosterone is only about 5% as abundant in blood as testosterone and is derived primarily from extratesticular metabolism. Some testosterone is also metabolized to estradiol (Fig. 7) in both androgen target and nontarget tissues. A variety of cells, including some in brain, breast, and adipose tissue, can convert testosterone and androstenedione to estra-diol and estrone, which produce cellular effects that are different from, and sometimes opposite to, those of testosterone. The concentration of estrogens in blood of normal men is similar to that of women in the early follicular phase of the menstrual cycle (see Chapter 46). About two-thirds of these estrogens are formed from androgen outside of the testis. Although less than 1% of the peripheral pool of testosterone is converted to estrogens, it is important to recognize that estradiol produces its biological effects at concentrations that are far below those required for androgens to produce their effects. In other tissues, including liver, reduction catalyzed by 5^-reductase destroys androgenic potency. The liver is the principal site of degradation of testosterone and releases water-soluble sulfate or glucuronide conjugates into blood for excretion in the urine.

Mechanism of Action

Like other steroid hormones, testosterone penetrates the target cells whose growth and function it stimulates. Androgen target cells generally convert testosterone to 5a-dihydrotestosterone before it binds to the androgen receptor. The androgen receptor is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily (see Chapter 2). It binds both testosterone and dihydrotestosterone, but the dihydro- form dissociates from the receptor much more slowly than testosterone and therefore is the predominant androgen associated with DNA. It is likely that the higher affinity of dihydro-testosterone for the androgen receptor accounts for its greater biological potency compared to testosterone. Upon binding testosterone or dihydrotestosterone, the liganded receptor complex binds to androgen response elements in specific target genes and, along with a cell-specific array of transcription factors and coactivators,

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