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Regulation of testosterone secretion in men involves a coordinated series of signals between the hypothalamus, pituitary, and testes. Gonadotropin-releasing hormone (GnRH) is secreted in pulses from the hypothalamus approximately every 2 h and stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, which, in turn, act on the testes to stimulate testosterone production and spermatogenesis.1 From a functional standpoint, the testis can be viewed as a 2-compartment structure. LH acts on Leydig cells to stimulate steroidogenesis, causing an increase in both intratesticular and systemic testosterone levels. FSH acts on Sertoli cells and, in the presence of adequate amounts of intratesticular testosterone, stimulates sperm production. Gonadal steroids, in turn, exert a negative feedback effect on the hypothalamus and pituitary to maintain LH and FSH levels within a tight range. There is additional regulation of FSH by a nonsteroidal factor made by Sertoli cells called inhibin B.2 The majority of circulating testosterone is bound to sex hormone–binding globulin (SHBG), albumin, cortisol-binding globulin, and orosomucoid, with only approximately 2% to 4% being unbound or free. Epidemiologic studies suggest that it is the free fraction of testosterone that is biologically active based on the demonstration that it correlates better with symptoms of hypogonadism than total testosterone.3


Pathology at one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis causes hypogonadism, a clinical syndrome characterized by failure of the testes to make physiological concentrations of testosterone, resulting in symptoms and signs of androgen deficiency and/or disruption of spermatogenesis.4 Hypogonadism can be classified in multiple ways: (1) according to the site of the defect in the HPG axis (primary or secondary), (2) time of onset (congenital or acquired), or (3) potential for reversibility (organic or functional).

Defects at the level of the testis cause primary or hypergonadotropic hypogonadism, whereas abnormalities in the hypothalamus and pituitary cause secondary or hypogonadotropic hypogonadism. Both forms of hypogonadism are characterized by low levels of testosterone and impairment of spermatogenesis but are distinguished by gonadotropin levels, which are elevated in primary hypogonadism and low or inappropriately normal in patients with secondary hypogonadism. In addition, some conditions, such as aging, can affect multiple levels of the HPG axis, disrupting secretion of GnRH from the hypothalamus as well as the testosterone response to LH due to a decrease in Leydig cell number.5 In this situation, gonadotropin levels in a given individual are variable, depending on whether primary or secondary hypogonadism predominates. From a clinical standpoint, the classification of hypogonadism by the site of the defect has important therapeutic implications for fertility. In most patients with hypogonadotropic hypogonadism, spermatogenesis can be induced by administration of gonadotropins or pulsatile GnRH. Fertility options for patients with primary gonadal failure were traditionally limited to use of donor sperm or adoption. However, advances in assisted reproductive technologies have made it possible in some ...

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