Pattern Of Gonadotropin-releasing Hormone Secretion Research Articles

Hypothalamic kisspeptin neurons as potential mediators of estradiol negative and positive feedback

Gonadal steroid feedback regulates the brain’s patterned secretion of gonadotropin-releasing hormone (GnRH). Negative feedback, which occurs in males and during the majority of the female cycle, modulates the amplitude and frequency of GnRH pulses. Positive feedback occurs in females when high estradiol induces a surge pattern of GnRH release. These two forms of feedback and their corresponding patterns of GnRH secretion are thought to be mediated by kisspeptin-expressing neurons in two hypothalamic areas: the arcuate nucleus and the anteroventral periventricular area. In this review, we present evidence for this theory and remaining questions to be addressed.

Gonadotropin-releasing hormone (GnRH) surge generator in female rats

Publisher Summary In rats, gonadotropin-releasing hormone (GnRH) expressing neurons, which control luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretions from the anterior pituitary, are mainly located in the preoptic area (POA), but some GnRH-I neurons are also found in the mediobasal hypothalamus (MBH) in rats. One of most remarkable characteristics of GnRH neurons is that they do not originate from the hypothalamus but from the olfactory placode and migrate toward the hypothalamus during developmental stages. Another interesting characteristic is their secretion patterns. Secretion of LH, which is assumed to reflect GnRH secretion from the hypothalamus into the portal vein, shows two remarkably different patterns. The chapter has hypothesized two patterns of GnRH secretion that are controlled by different neural mechanisms: (1) the GnRH pulse generator, previously known as the tonic center, and (2) the GnRH surge generator, previously known as the phasic or the cyclic center. This chapter focuses on the putative GnRH surge generator of female rats.

Gonadotropin Pulsations across Development

Initiation and maintenance of the reproductive axis in the human is contingent upon the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. In man, tracking endogenous GnRH secretion relies on frequent peripheral sampling of three glycoprotein products of the gonadotrope, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and free α-subunit (FAS). FAS is superior to LH as a surrogate marker of GnRH secretory dynamics in those circumstances where GnRH secretion is rapid or where the pituitary LH response is low. The pattern of GnRH secretion is constantly changing across development; from high levels during the neonatal period, through a period of quiescence in mid-childhood, followed by sleep-entrained reactivation of the reproductive axis at the onset of puberty, ultimately culminating in the adult pattern of pulsatile secretion which in the male is approximately every 2 h and in the female varies with the stage of the menstrual cycle. This episodic mode of secretion allows differential impact of feedback mechanisms on the GnRH neurons and facilitates the maintenance of the reproductive axis during periods of stress by allowing frequency and amplitude modulations.

Does estradiol induce the preovulatory gonadotropin-releasing hormone (GnRH) surge in the ewe by inducing a progressive change in the mode of operation of the GnRH neurosecretory system.

Estradiol profoundly influences GnRH secretion during the follicular phase of the estrous cycle of the sheep. Estradiol not only regulates the frequency and amplitude of GnRH pulses, but also produces qualitative changes in its pattern of release and induces a sustained GnRH surge during which discrete pulses are not readily evident. In this study, we tested the hypothesis that qualitative changes in GnRH secretion are an integral part of an estradiol-induced change in the mode of operation of the GnRH neurosecretory system that leads to generation of the GnRH surge. This was achieved by the measurement of GnRH in samples of pituitary portal blood collected at 1-min intervals for an 11-h period encompassing the pre- and early surge periods in an artificial follicular phase model. In each of the seven ewes studied, a highly characteristic alteration in the moment to moment pattern of GnRH was observed. This consisted of a progressive change from a strictly episodic pattern of GnRH release to one containing both episodic and nonepisodic components and, after amplification of both components, a period of extremely high values during which individual episodic increases were no longer readily recognizable. Preliminary mathematical modeling of the data suggested that these patterns could be produced by a change in GnRH from a predominantly low to a mixture of low and high amplitude inputs. Similar changes in minute to minute patterns of GnRH secretion were observed during the natural follicular phase. These findings are consistent with the hypothesis that estradiol induces the GnRH surge by altering the mode of neurosecretion, rather than by merely causing quantitative changes in the episodic pattern of release.

Estradiol induces both qualitative and quantitative changes in the pattern of gonadotropin-releasing hormone secretion during the presurge period in the ewe

Estradiol induces both qualitative and quantitative changes in the pattern of gonadotropin-releasing hormone secretion during the presurge period in the ewe

Estradiol induces both qualitative and quantitative changes in the pattern of gonadotropin-releasing hormone secretion during the presurge period in the ewe.

The follicular phase rise in circulating estradiol causes a suppression of GnRH pulse amplitude and an increase in pulse frequency before stimulation of the preovulatory GnRH surge in the ewe. Studies in which samples were collected at 10-min intervals were found unsuitable to determine whether GnRH secretion is exclusively pulsatile at this time or whether estradiol induces additional qualitative changes in the pattern of GnRH secretion that, combined with the quantitative changes, result in generation of the surge. To address these issues, GnRH was measured in pituitary portal blood and LH in peripheral blood collected at 1- and 10-min intervals, respectively, in ewes receiving no estradiol (n = 5), a luteal phase level of circulating estradiol (n = 5), or a peak follicular phase concentration of estradiol (n = 5). The results provide evidence that, in a dose-dependent manner, estradiol induces the secretion of significant amounts of GnRH between pulses and alters the shape of GnRH pulses by reducing the slope of the rising and falling phases of each pulse. These findings lead to the conclusion that during the presurge period in the ewe, estradiol induces qualitative change in the pattern of GnRH release in addition to stimulating GnRH pulse frequency and reducing pulse amplitude.

Variable patterns of gonadotropin-releasing hormone secretion during the estrogen-induced luteinizing hormone surge in ovariectomized ewes.

There have been a number of studies of GnRH secretion into the hypophysial portal blood at the time of the estrogen-induced LH surge, but the exact pattern of secretion at the onset of the positive feedback event remains a point of some dispute. In the present study, GnRH concentrations in portal plasma and jugular venous LH concentrations were measured in samples taken at 2.5-min intervals from five ovariectomized control ewes and seven ovariectomized ewes that were treated with 50 micrograms estradiol benzoate (im) to cause a LH surge. The frequency of GnRH pulses was calculated using a modification of previous criteria because of the frequent sampling. It was found that GnRH pulse frequency increased during the LH surge, being greatest during the "leading edge" of the surge. Perhaps more importantly, the data show that variable patterns of GnRH secretion occur at the start of the LH surge and during the surge, suggesting that no single pattern can be identified as an initiation signal of the positive feedback event. These data are consistent with other results that have been obtained in this laboratory in cyclic animals.

Variable patterns of gonadotropin-releasing hormone secretion during the estrogen-induced luteinizing hormone surge in ovariectomized ewes

There have been a number of studies of GnRH secretion into the hypophysial portal blood at the time of the estrogen-induced LH surge, but the exact pattern of secretion at the onset of the positive feedback event remains a point of some dispute. In the present study, GnRH concentrations in portal plasma and jugular venous LH concentrations were measured in samples taken at 2.5-min intervals from five ovariectomized control ewes and seven ovariectomized ewes that were treated with 50 micrograms estradiol benzoate (im) to cause a LH surge. The frequency of GnRH pulses was calculated using a modification of previous criteria because of the frequent sampling. It was found that GnRH pulse frequency increased during the LH surge, being greatest during the "leading edge" of the surge. Perhaps more importantly, the data show that variable patterns of GnRH secretion occur at the start of the LH surge and during the surge, suggesting that no single pattern can be identified as an initiation signal of the positive feedback event. These data are consistent with other results that have been obtained in this laboratory in cyclic animals.

The neuroendocrine signal for ovulation

The central nervous system plays a crucial role in determining if and when ovulation occurs. This neural regulation of fertility is achieved, in large measure, by means of the secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus. This report addresses changes in the secretion of GnRH into hypophyseal portal blood, and the regulation of these changes, leading up to ovulation in the domestic sheep. During the estrous cycle, the process of ovulation is heralded by a large preovulatory surge in the secretion of luteinizing hormone (LH). Recent studies have provided strong evidence that this LH discharge is induced by an unambiguous surge in the secretion of GnRH into hypophyseal portal blood. This surge of GnRH is massive and sustained, and is triggered by the increase in circulating estradiol secreted from the developing preovulatory ovarian follicles. Although the mechanism by which the increment in estradiol activates the GnRH neuronal network remains to be determined, this process involves a switch in the pattern of GnRH secretion. At the time of this switch, a pattern of GnRH release that is strictly episodic at other times of the estrous cycle gives way to a surge that sustains a continuous elevation of GnRH in portal blood for many hours. This switch in the operation of the GnRH neurosecretory system, and the resultant massive release of GnRH, constitutes the neuroendocrine signal for ovulation.

The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations.

Several lines of evidence indicate that hypothalamic-pituitary-gonadal activity varies among men with idiopathic hypogonadotropic hypogonadism (IHH). To test the hypothesis that a spectrum of abnormalities of GnRH secretion underlies the syndrome of IHH, we characterized the patterns of GnRH-induced gonadotropin secretion during periods of frequent sampling in 50 consecutive men with IHH and contrasted them with those in 20 normal men. The largest group of IHH patients (n = 42) had no detectable LH or FSH pulsations and could be categorized into 2 subsets according to the presence or absence of evidence of spontaneous puberty. The most severely affected subset (n = 32), who recalled no history of puberty, had testes with a mean volume of 3.3 +/- 0.5 (+/- SEM) ml, with a prepubertal appearance on biopsy, and often were anosmic (n = 17). The second subset of apulsatile IHH men (n = 10) had histories of partial or complete spontaneous sexual development with subsequent isolated loss of sexual function, testes with a mean volume of 13.3 +/- 1.9 ml (P less than 0.01 compared to the first subset), a pubertal or adult appearance of the testes on biopsy, and an intact sense of smell. In a second group of IHH patients (n = 3), LH was secreted predominantly in a nighttime pattern similar to that of normal children during early puberty. These men were aged 18-24 yr, had a mean testicular volume of 10.5 +/- 2.3 ml, pubertal changes on testicular biopsy, and an intact sense of smell. A third group of IHH men (n = 4) had LH pulses of abnormally low amplitude. Only one patient in this group had a history of spontaneous sexual development. The mean testicular volume of these patients was 5.6 +/- 1.9 ml, and the testes appeared prepubertal (n = 3) or pubertal (n = 1) on biopsy. In addition to these groups, another patient had apparent LH pulsations and nearly normal amplitude, but the LH was bioinactive and appeared to consist chiefly of alpha-subunit. Testing of other anterior pituitary hormone functions did not distinguish IHH men from normal men. However, those IHH patients with some evidence of endogenous GnRH secretion had higher basal and stimulated serum PRL levels than IHH men without such evidence (P less than 0.05), suggesting an influence of GnRH on PRL secretion.