Hypogonadotropic Hypogonadism: Hormonal Responses to Low Dose Pulsatile Administration of Gonadotropin-Releasing Hormone*

Abstract

Patients with isolated gonadotropin deficiency were studied to determine whether pulsatile low dose gonadotropin-releasing hormone (GnRH) could induce the hormonal changes seen during normal puberty. Four male and two female patients with immature responses to a standard GnRH test (2.5 micrograms/kg) were given GnRH (0.025 micrograms/kg) iv every 2 h for 5 days. FSH responses varied between the sexes, and FSH concentrations in males rose continuously to 17.2 +/- 4.7 mIU/ml on day 5. In the females, FSH peaked at 13.8 and 15.8 mIU/ml on days 3-4 and then declined. The males showed increasing and the females decreasing incremental FSH responses to GnRH. LH concentrations and incremental responses to GnRH rose throughout the study in both sexes. Plasma testosterone rose slightly in the males to 0.7 +/- 0.2 ng/ml (P < 0.05), but in females estradiol increased to follicular range concentrations of 128 and 102 pg/ml. Standard GnRh tests on day 6 revealed maturation of gonadotropin responses in all patients. After termination of pulsatile GnRH, four patients were given single low dose GnRH injections on two to seven occasions over a period of 2-32 days. Initial LH responses were 2- to 14-fold greater than those seen on day 5 of pulsatile GnRH, and decreased over the next 3 weeks. FSH responses showed less initial augmentation and declined more slowly. Low dose pulsatile administration of GnRH to patients with isolated gonadotropin deficiency results in changing patterns of hormone secretion similar to those seen during puberty. Exaggerated pituitary sensitivity to GnRH may be present long after a brief period of GnRH stimulation, and may indicate previous rather than current secretion of GnRH.

Selective inhibition of follicle-stimulating hormone secretion by estradiol. Mechanism for modulation of gonadotropin responses to low dose pulses of gonadotropin-releasing hormone.

“…In an effort to elucidate the nature of these changing responses we have previously administered low doses of GnRH in a pulsatile manner, to mimic the presumed physiological pattern of GnRH secretion, to female patients with absent or greatly reduced endogenous GnRH secretion. Our results (4,5) and those of others (6,7) have shown that the initial response to GnRH is one of predominant FSH secretion that later declines, while LH responses gradually increase. This pattern seen over 5 d of pulsatile GnRH injections is similar to that present during sexual maturation in girls.…”

“…Gonadotropin concentrations are reported as milliInternational Units of the second international reference preparation of human menopausal gonadotropin after conversion from LER 907, which was used as the assay standard. The limit of detectability of the estradiol assay depended upon the volume of plasma available and was 10-15 pg/ml when 2 ml were used, and 20-30 pg/ml when only 1 jections after which FSH rose to a mean of 5.3±0.3 on day 5. In both patients, plasma estradiol remained below assay detectability throughout the study.…”

Application of gonadotropin releasing hormone in hypogonadotropic hypogonadism--diagnostic and therapeutic aspects

“…The changing pattern in patients with a GnRH deficiency and delayed puberty shows that pulsatile GnRH is able to modify the pituitary response to GnRH within several days (8). Evidence for the idea that patients with a GnRH deficiency have a delayed response to GnRH compared with patients with delayed puberty as a result of impaired priming during the fetal and infant period was not found.…”

Pulsatile GnRH administration stimulates the number of pituitary GnRH receptors in seasonally anoestrous ewes

“…It has been suggested that intermittent delivery of GnRH to the pituitary gland is essential for gonadotrophin secretion to be maintained. Exogenous GnRH given in a pulsatile manner every 1\p=n-\2h to GnRH-deficient humans or monkeys can mimic the hormonal changes of puberty and the menstrual cycle Valk et al, 1980;Wildt et al, 1980). McLeod et al (1982a) have also reported that injections of low doses of GnRH every 2 h result in a sustained increase in pulsatile LH secretion in seasonally anoestrous ewes until the onset of a preovulatory LH surge, and that such animals, if primed with progesterone, will eventually ovulate and exhibit normal luteal function.…”