Gonadotropin-releasing Hormone Neurosecretory System Research Articles

Prostaglandin E 2 release from astrocytes triggers gonadotropin-releasing hormone (GnRH) neuron firing via EP2 receptor activation

Astrocytes in the hypothalamus release prostaglandin E(2) (PGE(2)) in response to cell-cell signaling initiated by neurons and glial cells. Upon release, PGE(2) stimulates the secretion of gonadotropin-releasing hormone (GnRH), the neuropeptide that controls reproduction, from hypothalamic neuroendocrine neurons. Whether this effect on GnRH secretion is accompanied by changes in the firing behavior of these neurons is unknown. Using patch-clamp recording we demonstrate that PGE(2) exerts a dose-dependent postsynaptic excitatory effect on GnRH neurons. These effects are mimicked by an EP2 receptor agonist and attenuated by protein kinase A (PKA) inhibitors. The acute blockade of prostaglandin synthesis by indomethacin (INDO) or the selective inhibition of astrocyte metabolism by fluoroacetate (FA) suppresses the spontaneous firing activity of GnRH neurons in brain slices. Similarly, GnRH neuronal activity is reduced in mice with impaired astrocytic PGE(2) release due to defective erbB signaling in astrocytes. These results indicate that astrocyte-to-neuron communication in the hypothalamus is essential for the activity of GnRH neurons and suggest that PGE(2) acts as a gliotransmitter within the GnRH neurosecretory system.

The Recreational Drug Ecstasy Disrupts the Hypothalamic-Pituitary-Gonadal Reproductive Axis in Adult Male Rats

Reproductive function involves an interaction of three regulatory levels: hypothalamus, pituitary, and gonad. The primary drive upon this system comes from hypothalamic gonadotropin-releasing hormone (GnRH) neurosecretory cells, which receive afferent inputs from other neurotransmitter systems in the central nervous system to result in the proper coordination of reproduction and the environment. Here, we hypothesized that the recreational drug (±)-3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’), which acts through several of the neurotransmitter systems that affect GnRH neurons, suppresses the hypothalamic-pituitary-gonadal reproductive axis of male rats. Adult male Sprague-Dawley rats self-administered saline or MDMA either once (acute) or for 20 days (chronic) and were euthanized 7 days following the last administration. We quantified hypothalamic GnRH mRNA, serum luteinizing hormone concentrations, and serum testosterone levels as indices of hypothalamic, pituitary, and gonadal functions, respectively. The results indicate that the hypothalamic and gonadal levels of the hypothalamic-pituitary-gonadal axis are significantly altered by MDMA, with GnRH mRNA and serum testosterone levels suppressed in rats administered MDMA compared to saline. Furthermore, our finding that hypothalamic GnRH mRNA levels are suppressed in the context of low testosterone concentrations suggests that the central GnRH neurosecretory system may be a primary target of inhibitory regulation by MDMA usage.

Neuroendocrine control of reproductive aging: roles of GnRH neurons

The process of reproductive senescence in many female mammals, including humans, is characterized by a gradual transition from regular reproductive cycles to irregular cycles to eventual acyclicity, and ultimately a loss of fertility. In the present review, the role of the hypothalamic gonadotropin-releasing hormone (GnRH) neurons is considered in this context. GnRH neurons provide the primary driving force upon the other levels of the reproductive axis. With respect to aging, GnRH cells undergo changes in biosynthesis, processing and release of the GnRH decapeptide. GnRH neurons also exhibit morphologic and ultrastructural alterations that appear to underlie these biosynthetic properties. Thus, functional and morphologic changes in the GnRH neurosecretory system may play causal roles in the transition to acyclicity. In addition, GnRH neurons are regulated by numerous inputs from neurotransmitters, neuromodulators and glia. The relationship among GnRH cells and their inputs at the cell body (thereby affecting GnRH biosynthesis) and the neuroterminal (thereby affecting GnRH neurosecretion) is crucial to the function of the GnRH system, with age-related changes in these relationships contributing to the reproductive senescent process. Therefore, the aging hypothalamus is characterized by changes intrinsic to the GnRH cell, as well as its regulatory inputs, which summate to contribute to a loss of reproductive competence in aging females.

Neuronal-glial plasticity in gonadotropin-releasing hormone release in adult female rats: role of the polysialylated form of the neural cell adhesion molecule

The gonadotropin-releasing hormone (GnRH) neurosecretory system undergoes marked structural and functional changes during the ovarian cycle. The aim of this study was to examine the neuroanatomical relationship between GnRH neurons and a polysialylated form of neural cell adhesion molecule (PSA-NCAM), a known marker of neuronal plasticity. Using immunohistofluorescent dual labeling, we determined that axon terminals of GnRH in the median arcuate nucleus (ME-ARC) region of the hypothalamus in the proestrous phase of the estrous cycle were intimately associated with PSA-NCAM. To further examine whether PSA-NCAM expression associated with GnRH neuron terminals varies in conjugation with cyclic changes in ovarian steroid hormone levels, we examined GnRH and PSA-NCAM dual expression in ovariectomized (OVX) and estrogen-progesterone-primed OVX (EBP-OVX) rats. The expression of PSA-NCAM immunoreactivity associated with the GnRH neurons in the proestrous phase and EBP-OVX rats was significantly higher than during the diestrous phase and in OVX rats where GnRH secretion declines. We further examined whether the structural changes in GnRH axon terminals in the ME-ARC region are also associated with glial plasticity. By extension and retraction of the glial processes, the GnRH neuron terminals in the ME-ARC region could undergo dynamic plastic changes that control GnRH release during the proestrous phase. PSA-NCAM expression was also seen on glial cells in the ME-ARC region. The close association between PSA-NCAM on GnRH and glial cells in the ME-ARC region of the hypothalamus in the rat showed dynamic structural changes in GnRH neuron terminals during the estrous cycle. These observations suggested that PSA-NCAM may act as a molecular substrate to promote neuroplastic changes in the GnRH neurosecretory system.

Progesterone Treatment That either Blocks or Augments the Estradiol-Induced Gonadotropin-Releasing Hormone Surge Is Associated with Different Patterns of Hypothalamic Neural Activation

Progesterone can either augment or inhibit the surge of gonadotropin-releasing hormone (GnRH) that drives the preovulatory luteinizing hormone (LH) surge. This study investigated the central mechanisms through which progesterone might achieve these divergent effects by examining the effects of exogenous steroids on the activation of GnRH neurons and non-GnRH-immunopositive cells in the preoptic area/anterior hypothalamus of steroid-treated ovariectomized ewes. Fos expression (an index of cellular activation) was examined during the estradiol-induced GnRH surge in ewes treated with progesterone using regimes that have been reported to either augment (progesterone pretreatment) or inhibit (progesterone treatment at the time of the surge-inducing estradiol increment) the GnRH surge. Control groups received either no progesterone pretreatment or no surge-inducing estradiol increment. Induction of an LH surge was associated with a significant (p < 0.0001) increase in the proportion of activated GnRH neurons, irrespective of whether ewes received progesterone pretreatment. However, the number of non-GnRH-immunopositive cells activated during the surge was significantly (p < 0.0001) increased in ewes that received the progesterone pretreatment. By contrast, the proportion of GnRH neurons and non-GnRH-immunopositive cells that expressed Fos was significantly (p < 0.0001) reduced in ewes in which the surge was inhibited by progesterone compared to ewes in which a surge was stimulated. These data indicate that (1) progesterone pretreatment increases the activation of non-GnRH cells during the estradiol-induced surge, but does not affect the proportion of GnRH neurons activated and (2) when administered concurrently with a surge-inducing estradiol increment, progesterone prevents the activation of GnRH neurons and non-GnRH cells that is normally associated with the estradiol-induced surge. Therefore, progesterone does not appear to augment the GnRH surge by increasing the proportion of GnRH neurons that are activated by estradiol, whereas inhibition of the GnRH surge involves prevention of the activation of GnRH neurons. Thus, the augmentation and inhibition of the GnRH surge by progesterone appear to be regulated via different effects on the GnRH neurosecretory system.

Gonadotropin-Releasing Hormone and NMDA Receptor Gene Expression and Colocalization Change during Puberty in Female Rats

During development, an increase in gonadotropin-releasing hormone (GnRH) release occurs that is critical for the initiation of puberty. This increase is attributable, at least in part, to activation of the GnRH neurosecretory system by inputs from neurotransmitters, such as glutamate, acting via NMDA receptors. We examined changes in GnRH and NMDA-R1 gene expression by RNase protection assay of preoptic area-anterior hypothalamic (POA-AH) dissections of female rats undergoing normal puberty or in which precocious puberty was induced by treatment with the glutamate agonist NMA. GnRH mRNA levels increased significantly throughout normal development; this was accelerated by treatment with NMA. NMDA-R1 mRNA levels increased only between P10 and P20. The acceleration of the elevation in GnRH mRNA levels by NMDA suggests that a stimulation of GnRH gene expression may be a rate-limiting factor for the onset of puberty. This is attributable to a post-transcriptional mechanism because GnRH primary transcript levels, an index of proGnRH gene transcription, were not observed to change during puberty. Alterations in the colocalization of GnRH neurons with the NMDA-R1 subunit during puberty also were assessed immunocytochemically. The percentage of GnRH neurons that double-labeled with NMDA-R1 was 2% in prepubertal rats and 3% in pubertal rats; this increased to 19% in postpubertal rats. Taken together, these studies suggest that an increase in glutamatergic input to GnRH neurons plays a role in the increase in GnRH release and gene expression that occurs at the initiation of puberty.

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

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

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.

Sexual Dimorphism of Gonadotropin-Releasing Hormone (GnRH) Neurons in the Goat Hypothalamus.

A study was conducted to examine if gonadotropin-releasing hormone (GnRH) neurons show sex-related differences in the hypothalamus of the mature goat. The localization of GnRH neurons were made evident immunohistochemically using a monoclonal antibody against GnRH in coronal sections (40μm thick) of the hypothalamic area of male and female goats. The localization of immunoreactive GnRH (GnRH-ir) cell bodies was assessed according to the stereotaxic coordinates of the brain atlas for the Shiba goat, and was compared between the male and the female brains. The morphological characteristics and distribution pattern of GnRH-ir neurons, and the projection pattern of GnRH-ir fibers were similar between the sexes. On the other hand, the number of GnRH-ir neurons showed sexual dimorphism; the estimated total number of GnRH cell bodies in the hypothalamus of the male goat (4, 020 ± 572, Mean ± SEM) was greater (P<0.01) than that for the female (2, 223 ± 284). These results indicate that the goats of both sexes have a similar GnRH neurosecretory system, although the male goat has a greater population of GnRH neurons in the rostral hypothalamus.

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.