Ontogeny of Gonadotropin Releasing Hormone Secretion

The pattern of gonadotropin-releasing hormone (GnRH) induced gonadotropin secretion in the human changes dynamically with sexual development (see Fig. 1). Therefore, understanding the ontogeny of GnRH secretion is essential for assessing normal sexual maturation and pathologic states, such as congenital hypogonadotropic hypogonadism.

GnRH neurons originate in the olfactory placode and migrate along the olfactory tract through the cribriform plate to the forebrain to reach their final destination, the arcuate nucleus of the hypothalamus. GnRH neurons have been observed in the human hypothalamus by the ninth week of gestation, and by 12-14 wk, gonadotropins are first detectable in the fetal circulation (1). Their biosynthesis is at least partially dependent on GnRH, as evidenced by the ability of GnRH to induce luteinizing hormone (LH) synthesis and secretion in fetal human pituitary cell cultures (2). Anencephalic fetuses, which lack a hypothalamus, secrete glycoprotein hormone a-subunit but do not produce LH-P or follicle-stimulating hormone (FSH)-P subunits, demonstrating the complete dependence of the dimeric gonadotropins on GnRH (1).

During the neonatal period, increased pulsatile GnRH secretion induces a rise in gonadotropin secretion that, in turn, initiates gonadal hormone production (3). During

From: Male Hypogonadism: Basic, Clinical, and Therapeutic Principles Edited by: S. J. Winters © Humana Press Inc., Totowa, NJ

INFANCY

CHILDHOOD GnRH (LH)

PUBERTY

ADULT

Fig. 1. Schematic drawing of the activity of the hypothalamic-pituitary-gonadal axis across the life cycle. During the neonatal window, pulsatile gonadotropin-releasing hormone (GnRH) stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, which induce adult levels of testosterone, estradiol, and inhibin B. Childhood is marked by a low-amplitude LH secretion and low testosterone levels. Pubertal reactivation of the hypothalamic-pituitary-gonadal axis subsequently triggers the onset of sexual maturation, initially in a sleep-entrained pattern.

Fig. 1. Schematic drawing of the activity of the hypothalamic-pituitary-gonadal axis across the life cycle. During the neonatal window, pulsatile gonadotropin-releasing hormone (GnRH) stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, which induce adult levels of testosterone, estradiol, and inhibin B. Childhood is marked by a low-amplitude LH secretion and low testosterone levels. Pubertal reactivation of the hypothalamic-pituitary-gonadal axis subsequently triggers the onset of sexual maturation, initially in a sleep-entrained pattern.

childhood, the hypothalamic-pituitary axis is not completely quiescent, because the pulsatile release of gonadotropins has been shown in prepubertal boys using ultrasensitive LH assays (4), as discussed more thoroughly in Chapter 4. The onset of puberty is marked by sleep-entrained reactivation of the reproductive axis, characterized by a striking increase in the amplitude of LH pulses, with less change in frequency, resulting in stimulation of the target gonad (5,6). As puberty progresses, gonadotropin secretion occurs during both the day and the night, promoting the development of secondary sexual characteristics and the pubertal changes in body composition. During adulthood, gonadotropins are secreted in pulsatile fashion, with one pulse approximately every 2 h in adult men (see Fig. 2). There is considerable variability among individuals in both the frequency and the amplitude of LH pulses, as well as in the ensuing testosterone (T) levels. Indeed, in 15% of normal men, long interpulse intervals between LH secretory pulses were observed during a 12-h period of frequent blood sampling (every 10 min), resulting in a transient decrease in serum T levels to as low as 3.5 nmol/L (see Fig. 3) (7).

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