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TESTOSTERONE AND OTHER ANDROGENS

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In men, testosterone is the principal secreted androgen. Leydig cells synthesize the majority of testosterone by the pathways shown in Figure 41–1. In women, testosterone also is the principal androgen and is synthesized in the corpus luteum and the adrenal cortex by similar pathways. The testosterone precursors androstenedione and dehydroepiandrosterone are weak androgens that can be converted peripherally to testosterone.

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Figure 41–1

Pathway of synthesis of testosterone in the Leydig cells of the testes. In Leydig cells, the 11 and 21 hydroxylases (present in adrenal cortex) are absent but CYP17 (17 α-hydroxylase) is present. Thus, androgens and estrogens are synthesized; corticosterone and cortisol are not formed. Bold arrows indicate favored pathways.

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SECRETION AND TRANSPORT OF TESTOSTERONE. Testosterone secretion is greater in men than in women at almost all stages of life, a difference that explains many of the other differences between men and women. In the first trimester in utero, the fetal testes begin to secrete testosterone, the principal factor in male sexual differentiation, probably stimulated by human chorionic gonadotropin (hCG) from the placenta. By the beginning of the second trimester, the serum testosterone concentration is close to that of mid-puberty, ~250 ng/dL (Figure 41–2). Testosterone production then falls by the end of the second trimester, but by birth the value is again ~250 ng/dL, possibly due to stimulation of the fetal Leydig cells by luteinizing hormone (LH) from the fetal pituitary gland. The testosterone value falls again in the first few days after birth, but it rises and peaks again at ~250 ng/dL at 2-3 months after birth and falls to <50 ng/dL by 6 months, where it remains until puberty. During puberty, from ~12 to 17 years of age, the serum testosterone concentration in males increases so that by early adulthood the serum testosterone concentration is 500 ng/dL to 700 ng/dL in men, compared to 30 ng/dL to 50 ng/dL in women. The magnitude of the testosterone concentration in the male is responsible for the pubertal changes that further differentiate men from women. As men age, their serum testosterone concentrations gradually decrease, which may contribute to other effects of aging in men.

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Figure 41–2

Schematic representation of the serum testosterone concentration from early gestation to old age.

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LH, secreted by the pituitary gonadotropes (see Chapter 38), is the principal stimulus of testosterone secretion in men, perhaps potentiated by follicle-stimulating hormone (FSH), also secreted by gonadotropes. The secretion of LH by gonadotropes is positively regulated by hypothalamic gonadotropin-releasing hormone (GnRH); testosterone directly inhibits LH secretion in a negative feedback loop. LH is secreted in pulses, which occur approximately every 2 h and are greater in magnitude in the morning. The pulsatility appears to result from pulsatile secretion of GnRH from the hypothalamus. Testosterone secretion is likewise pulsatile and diurnal, the highest plasma concentrations occurring at ~8 a.m. and the lowest at ~8 p.m. The morning peaks diminish as men age. Sex hormone-binding globulin (SHBG) binds ~40% of circulating testosterone with high affinity, rendering the bound hormone unavailable for biological effects. Albumin binds almost 60% of circulating testosterone with low affinity, leaving ~2% unbound or free. In women, LH stimulates the corpus luteum (formed from the follicle after release of the ovum) to secrete testosterone. Under normal circumstances, however, estradiol and progesterone...

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