Effects of decreasing the frequency of gonadotropin-releasing hormone stimulation on gonadotropin secretion in gonadotropin-releasing hormone-deficient men and perifused rat pituitary cells.

Abstract

The effects of decreasing the frequency of pulsatile gonadotropin-releasing hormone (GnRH) stimulation on pituitary responsiveness were studied in (a) men with isolated GnRH deficiency who had achieved normal sex steroid levels during prior long-term pulsatile GnRH replacement and (b) perifused dispersed pituitary cells from male rats in the absence of sex steroids. In three groups of four GnRH-deficient men, the frequency of GnRH stimulation was decreased at weekly intervals from (a) every 2-34 h (group I), (b) every 2-8 h without testosterone replacement (group II), or (c) every 2-8 h with testosterone replacement (group III). In three groups of three columns of perifused dispersed pituitary cells, pulses of GnRH were administered every 2, 4, or 8 h.In groups I and II, mean area under the luteinizing hormone (LH) curve increased (P < 0.025) and serum testosterone levels fell (P < 0.035) as the frequency of GnRH stimulation was decreased. In group III, the area under the LH curve also increased (P < 0.01) although serum testosterone levels were constant, thereby demonstrating that the increase in pituitary responsiveness to slow frequencies of GnRH stimulation occurs independently of changes in the sex steroid hormonal milieu. The area under the LH curve also increased in the perifused dispersed rat pituitary cells when the frequency of GnRH administration was decreased to every 8 h (P < 0.05), thus demonstrating that the enhanced pituitary responsiveness to slow frequencies of GnRH stimulation is maintained even in the complete absence of gonadal steroids.Nadir LH levels fell in all three groups (P < 0.01) as the frequency of GnRH stimulation was decreased. In contrast, mean peak LH levels, the rate of LH rise, and the rate of endogenous LH decay were constant as the frequency ofGnRH stimulation was decreased. Finally, as the GnRH interpulse interval increased, mean LH levels fell, and mean follicle-stimulating hormone levels were stable or fell.

Interplay between Dose and Frequency of GnRH Administration in Determining Pituitary Gonadotropin Responsiveness

“…When comparing the responses of individual study participants, considerable variance in LH amplitudes was noted both within and across the different frequencies of the study similar to the individual variances we have encountered previously [11,12,13]. This variability may well reflect individual genetic variations in causes of this syndrome.…”

“…As previously demonstrated, the administration of GnRH at 8-hour intervals is insufficient to sustain LH and consequently testosterone levels within the normal range [13]. Hence, subjects participating in the 8-hour arm of the study (IPI = 8 h) received a 100-mg intramuscular dose of testosterone enathate prior to the first intravenous transition dose.…”

“…Maintaining a fixed dose of GnRH but increasing the frequency of pulsatile administration can destabilize and ultimately desensitize pituitary gonadotropin secretion [12] while decreasing the frequency of GnRH stimulation produces an increase in pituitary responsiveness to GnRH [13]. These findings demonstrate that the frequency of exogenous GnRH administration, independent of its dosage, is a critical determinant of the gonadotrope’s secretion of LH and FSH in the human.…”

The Functional Significance of FSH in Spermatogenesis and the Control of Its Secretion in Male Primates

“…7). Additional slowing of the frequency of GnRH stimulation in similar patients to 1 pulse every 8 h also failed to enhance FSH secretion (189). In one other study of men with idiopathic hypogonadotropic hypogonadism, however, circulating FSH levels during GnRH stimulation at 1 pulse every 90 min was greater than that at the faster frequency (190).…”

Male hypogonadism

“…1). In general, the effects of GnRH on FSHb transcription are limited, confirming the need of further mechanisms involved in FSHb mRNA expression [11] ( Fig. 1).…”