Pulsatile Gonadotropin Secretion

Experiments in ovariectomized rhesus monkeys rendered gonadotropin deficient with hypothalamic lesions led to the proposal that an intermittent pattern of GnRH secretion was necessary for normal LH secretion (28). In those animals, GnRH administered in pulses stimulated LH secretion, but GnRH administered continuously was much less effective. The pulsatile nature of LH secretion was subsequently established in all species, including man (29). Accordingly, LH secretion is stimulated when GnRH is administered in pulses to patients who are gonadotropin deficient but not when GnRH is administered continuously (30). An understanding of these physiological principles led to the use of pulsatile GnRH as a treatment to stimulate fertility and to the development of long-acting GnRH analogs that produce a biochemical gonadec-tomy as a treatment for patients with prostate cancer and other androgen-dependent disorders (31).

With current assays, GnRH is undetectable in the peripheral circulation. Therefore, GnRH secretion cannot be studied directly in humans. Instead, changes in circulating LH levels are used as a surrogate marker for GnRH pulse generator activity. LH secretion is determined by the frequency, amplitude, and duration of its secretory pulses. Presumably because of its longer circulating half-life, FSH pulses are less clearly defined in peripheral blood than are LH pulses. FSH pulses are clearly evident in jugular blood (in ewes) where clearance effects are minimized (32).

Cultured pituitary cells that are perifused with GnRH pulses are a powerful model, yielding important information on GnRH actions and other factors that regulate gonadotropin secretion under controlled conditions. Using this experimental approach, shown in Fig. 3, episodes of LH, as well as FSH secretion, are distinct and short lived, with a rapid upstroke and abrupt termination. LH pulse amplitude is directly proportional to the GnRH dose administered, and the median duration of an LH pulse approx 25 min.

In contrast to the regularity of LH pulses produced by a constant dose of GnRH in vitro, Fig. 4 illustrates that LH pulses in the peripheral circulation in man vary in amplitude and that interpulse intervals are inconstant. LH pulses in vivo are also characterized by a less rapid upstroke and a slower decline from the peak than are pulses in vitro. This

Testosterone Secretion

Fig. 3. Secretion of luteinizing hormone (LH) by pituitary cells from adult male primates perifused with pulses of gonadotropin-releasing hormone (GnRH). Pulses of GnRH (2.5 nM) were applied to the cells every 1 hr for 2 min. Fractions of the column effluent were collected every 10 min, and LH was measured in the media by immunoassay. (Data from ref. 56.)

10 20 30 40 50 60 Fraction Number

Fig. 3. Secretion of luteinizing hormone (LH) by pituitary cells from adult male primates perifused with pulses of gonadotropin-releasing hormone (GnRH). Pulses of GnRH (2.5 nM) were applied to the cells every 1 hr for 2 min. Fractions of the column effluent were collected every 10 min, and LH was measured in the media by immunoassay. (Data from ref. 56.)

presumably reflects dilution of secreted hormone by plasma in the general circulation and the influence of LH clearance by the liver and kidney. Whether LH is released in the basal interval between GnRH-initiated secretory episodes has been debated, but this mode of secretion is small and is probably not biologically important.

Hormone pulse detection has been standardized by the development of computer algorithms (33). Using this approach, objective assessment of the frequency and amplitude characteristics of hormone pulses has been possible. LH secretion pulses occur throughout the day and night in normal adult men. However, estimates of the LH frequency (GnRH) pulses in men have varied based on the intensity and duration of the blood sampling protocol, the assay used to measure LH, and the algorithm used to identify pulses. Most investigators have proposed an average frequency of 1 LH pulse every 1-2 h for normal men, but, interestingly, there is a large between-individual variation (34). Because of variability in pulse amplitude and frequency, the distinction between true and artifactual pulses is difficult. One approach is to coanalyze LH and uncombined a-subunit pulses (34), because a-subunit is released into the circulation by GnRH, together with LH and FSH (see Fig. 4). According to this logic, concordant LH and a-subunit fluctuations presumably reflect true GnRH pulsatile signals. There is generally a positive relationship between LH pulse amplitude and the preceding interpulse interval, in part because a longer interval allows for the circulating level to decline to a lower baseline value.

In addition to moment-to-moment pulsatile pattern of LH secretion, there is a diurnal rhythm in circulating LH, as well as testosterone levels, in pubertal boys with increased LH pulsatile amplitude during sleep and increased testosterone levels in the early morning hours (35). Although there is a diurnal variation in plasma testosterone in adults, there is no clear diurnal rhythm for LH in most adult men (36), implying that the diurnal variation in testosterone levels in men is only partly

Diurnal Variation Testosterone

Clock Time

Fig. 4. Circulating luteinizing hormone (LH) and a-subunit levels in a normal adult man. Blood samples were drawn every 10 min for 12 h beginning at 0800 h and measured for LH using Nichols Allegro LH 2-site assay and a specific assay double antibody immunoassay for a-subunit.

Clock Time

Fig. 4. Circulating luteinizing hormone (LH) and a-subunit levels in a normal adult man. Blood samples were drawn every 10 min for 12 h beginning at 0800 h and measured for LH using Nichols Allegro LH 2-site assay and a specific assay double antibody immunoassay for a-subunit.

LH controlled. The diurnal testosterone variation in men is disrupted by fragmented sleep (37), but the mechanism for this alteration has not been established. The diurnal variation in testosterone is blunted in older men (38) and in young men with testicular failure (39).

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