In , we discovered GnIH in the quail hypothalamus. Subsequently, GnIH orthologues were identified in other vertebrate species from fish to humans. As in birds, mammalian and fish GnIH orthologues inhibit gonadotrophin release, indicating a conserved role for this neuropeptide in the control of the hypothalamic-pituitary-gonadal axis across species. GPR54 is also expressed in pituitary cells, but whether gonadotrophs are targets for kisspeptin remains unresolved.
The journey of GnRH begins in the medial olfactory placode. From here, it travels along the olfactory bulb to reach the hypothalamus. GnRH is then secreted, in a pulsatile fashion, into the hypophyseal portal circulation where it reaches its primary destination, the anterior pituitary. Here it binds the gonadotropin-releasing hormone receptor GnRHR , which is a G-protein coupled receptor, on the pituitary gonadotrophic cells.
GnRH secretion occurs from the median eminence into the fenestrated capillaries of portal circulation and then is carried to the anterior pituitary. In humans, estimates of the number of GnRH neurons range between to The co-location of GnRH neurons with other central regulators allows the GnRH network to be influenced by a range of neuroendocrine and metabolic inputs.
Its seven transmembrane domains describe this receptor class. These receptors, when bound by an activating subunit, undergo conformation change and activate intracellular pathways leading to modulation of genes within a target cell, via phosphorylation events.
Activation of the receptors leads to the creation of receptor clusters. These receptor clusters can be shuttled to the surface of the cell or degraded in lysosomes after they become internalized.
A short intracellular carboxy-terminal tail characterizes this particular receptor. This structure helps to prevent desensitization and slow internalization of the receptor. The Gq protein cleaves a molecule called phosphatidylinositolbisphosphate PIP. IP3 stimulated the endoplasmic reticulum to release calcium into the cytosol.
Once these pathways are activated, they lead to the biosynthesis and secretion of gonadotropin. The embryonic development of GnRH neurons closely ties to the olfactory system.
Neurons that release GnRH use vomeronasal and olfactory axons as a scaffold to migrate along. GnRH neuronal development takes place between the 5th and 16th embryonic weeks EW. By the middle of the 6th EW, these neurons begin to migrate near the terminal nerve, where they enter the forebrain. By the 9th EW, these neurons will reach the hypothalamus. Between weeks 13 and 16 of gestation is when migration is considered complete.
The levels of GnRH gradually increase and reach a peak level at the mid gestational age, after which they gradually fall toward the end of the gestational period due to the negative feedback effect of circulating placental steroids. At birth development of GnRH neurons is complete, but the functional maturation of synaptic connectivity is attained later in life, especially at puberty. After birth, these levels remain elevated for two years in girls while for six months in boys. This temporary pause in GnRH release ends at puberty, and recent studies have shown that Kisspeptin neurons are responsible for activation of hypothalamic-gonadotropic axis activation causing the GnRH release at puberty.
Initially, at puberty, GnRH is released in low-frequency pulses during the night, but after the maturation of synaptic connections, it matches the adult pattern. In males, the GnRH pulses occur after 2 hours, while in a female, it changes according to the phases of the menstrual cycle. It is clear that the episodic release of GnRH is a general phenomenon.
Also, fluctuation in the amplitude and frequency of GnRH bursts plays a vital role in initiating hormonal charges that ultimately regulate the menstrual cycle. The frequency of GnRH bursts is decreased by testosterone and progesterone and increased by estrogens. At the end of the menstrual cycle, when progesterone and estrogen secretion decreases, the frequency increases. The sensitivity of gonadotropes increases significantly during the midcycle LH surge; this is due to the exposure to pulses of GnRH at a specific frequency, which describes a critical self-priming effect of GnRH that produces a maximum LH response.
GnRH release changes during the perimenopausal period. As the number of follicles recruited during each menstrual cycle decreases near menopause, so does the amount of estrogen produced, resulting in the reduced negative feedback of estrogen on GnRH release leading to an increase in GnRH release frequency every 55 mins and amplitude. The neurons that produce GnRH are in the hypothalamus, specifically in the infundibular nucleus. Once secreted, GnRH acts on the anterior pituitary where follicle-stimulating hormone FSH and luteinizing hormone LH are secreted and modulate sex steroid production from the gonads.
These receptors have a hydrophilic extracellular domain, intracellular domain, and finally, a hydrophilic transmembrane domain. Genotyping in humans as well as the evaluation of transgenic mouse models suggest that mutations in the PROK2 gene or in the PROKR2 gene are inherited in an autosomal recessive manner.
Nevertheless, affected patients have been identified in whom only a single copy of one of these genes is mutated, suggesting that they have mutations in an alternate gene and are, in fact, compound heterozygotes. The key role of the KiSS-1 receptor in the regulation of the onset of puberty was demonstrated by the development of precocious puberty in a patient with a gain-of-function mutation in this receptor which blunts the rate of receptor desensitization. Patients with severe obesity and hypogonadotropic hypogonadism have been found to harbor mutations in the genes which encode leptin or its receptor.
Mutations in both NKB and its receptor have been identified in patients with hypogonadotropic hypogonadism. Interestingly, NKB is co-expressed with kisspeptin in the arcuate nucleus and may, therefore, play a role in the control of GnRH secretion in coordination with the kisspeptin—kisspeptin receptor system.
The phenotype of these patients ranges from complete absence of sexual maturation to delayed puberty. Inheritance is autosomal recessive with most patients having compound heterozygous mutations.
Recent work in this area has focused on the development of pharmacologic chaperones which can rescue dysfunctional GnRH receptor function through normalization of GnRH receptor folding in the endoplasmic reticulum, thereby restoring ligand binding and intracellular signaling.
The reproductive system is comprised of a complex network of hormones in which GnRH plays a central role. Over the past four decades, great strides have been made in our understanding of GnRH action in both physiologic and pathologic states. Investigators are beginning to unravel the factors required for GnRH neuronal migration and to understand the mechanisms by which pulsatile GnRH secretion initiates puberty and maintains normal adult reproductive function.
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By using the website or clicking OK we will assume you are happy to receive all cookies from us. Search Join Us. Navigation Top This chapter was last updated: February Lisa M. Requirement for pulsatile GnRH secretion In an elegant series of experiments, Ernst Knobil and colleagues demonstrated that pulsatile GnRH is required to achieve sustained gonadotropin secretion.
In the female, GnRH pulse characteristics vary depending on the time of the menstrual cycle with more frequent but lower amplitude pulses during the follicular phase.
High frequency pulses of approximately every 60—90 min favor LH secretion in the follicular phase, while low frequency pulses of every min favor FSH secretion in the late luteal phase.
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