An understanding of normal physiology helps in using laboratory testing to define the cause of gonadal dysfunction. Pulsatile gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus stimulates the release of gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)).1,2 Leydig cells synthesize and secrete testosterone in response to LH, and testosterone and its metabolites dihydrotestosterone (DHT) and estradiol have feedback effects on LH secretion. The seminiferous tubule compartment comprises about 85% of the mass of the testicular mass and contains Sertoli cells that are responsive to FSH, thereby increasing production of an androgen-binding protein and enabling the testes to concentrate testosterone manifold above the serum levels. Inhibin secreted by Sertoli cells feeds back on GnRH and FSH secretion.4
Circulating testosterone levels demonstrate distinct episodic and diurnal rhythms.1,2 Diurnal patterns show morning peak testosterone levels and nadir levels in the afternoon, which are more evident in younger than older males. Consequently, reference ranges for testosterone measurements are established for morning blood samples on at least two different days.
Pinpointing the cause and extent of hypogonadism makes it possible to tailor successful replacement therapy (Table 3). Primary hypogonadism may be associated with small testes, azoospermia, or oligospermia and elevated FSH but with normal testosterone and LH. Both diminished sperm and testosterone with elevation of LH and FSH also occur. Gynecomastia is observed more often in males and boys with primary than in secondary or tertiary hypogonadism because estradiol production relative to testosterone is excessive in response to FSH stimulation of aromatase of the testes. Secondary and tertiary hypogonadism is more likely than primary hypogonadism to have concurrent reductions of both sperm and testosterone production, and LH and FSH are inappropriately low.
Table 2 lists the disorders with congenital and acquired hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. The causes may be congenital, hereditary, or acquired. The most common cause of primary hypogonadism is Klinefelter's syndrome (1 in 500-1000 males).1,2 Aging,5-7 obesity,8 diabetes,9 and the metabolic syndrome10 are the most common secondary/tertiary causes and affect 20-30% of males with these disorders. Patients with Kallmann's syndrome have a deficiency of GnRH as a hereditary disorder.11
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