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It controls the production of luteinising hormone and follicle stimulating hormone from the pituitary gland. Alternative names for gonadotrophin-releasing hormone GnRH; gonadotropin-releasing hormone; luliberin; luteinising-hormone-releasing hormone; LHRH; luteinizing-hormone-releasing hormone What is gonadotrophin-releasing hormone?
How is gonadotrophin-releasing hormone controlled? What happens if I have too much gonadotrophin-releasing hormone?
What happens if I have too little gonadotrophin-releasing hormone? Last reviewed: Feb Prev. Glucose-dependent insulinotropic peptide. Cancer Disparities. Cancer Causes and Prevention. Risk Factors. Cancer Prevention Overview. Cancer Screening Overview. Screening Tests. Diagnosis and Staging. Questions to Ask about Your Diagnosis.
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Furthermore, research in this field is demonstrating that mutations in a single gene may not be reproducibly correlated with normal or abnormal smell, blurring the line between those with IHH and Kallmann syndrome.
While GnRH neurons can be found scattered throughout the hypothalamus, those whose cell processes extend to the pituitary portal system congregate in the medial preoptic nucleus of the adult hypothalamus. These cells secrete GnRH into the pituitary portal system which lies over the pituitary infundibulum.
This portal system is fed by the superior hypophyseal arteries, drained by the superior hypophyseal veins and is characterized by a complex web of portal capillary loops. Inactivating mutations in an increasing number of genes have been demonstrated to cause idiopathic hypogonadotropic hypogonadism or Kallmann syndrome in humans. A few of the best characterized of these genes are described below. As a whole, the mutations in this group result in migratory arrest of the GnRH neuronal precursors before they reach their correct position within the arcuate nucleus.
As a result, secreted GnRH does not reach the pituitary and is unable to stimulate gonadotropin secretion. There are six known forms of Kallmann syndrome which are distinguished primarily by the genetic mutation associated with them.
Located on the X chromosome, the KAL1 gene encodes anosmin-1, a secreted extracellular adhesion protein. Anosmin-1 directs migration of the GnRH neurons to the arcuate nucleus and olfactory neurons to the olfactory bulb during fetal development. Therefore, mutations in this protein result in both reproductive and olfactory deficits. These patients commonly have associated midline facial defects such as cleft palate and renal agenesis, and also may demonstrate neurologic abnormalities such as synkinesia mirror movements of the hands , cerebellar dysfunction, or deafness.
Olfactory testing can be done easily in the office with strong odorants such as ground coffee. Interestingly, many of these patients are unaware of their deficit. Mutations in the fibroblast growth factor receptor-1 FGFR1 gene have also been associated with normosmic IHH or Kallmann syndrome, as well as associated cleft palate and dental agenesis. Interestingly, mutations in the gene which encodes fibroblast growth factor 8 FGF8 have recently been shown to cause hypogonadotropic hypogonadism, suggesting that FGF8 is an essential ligand for FGFR1 signaling, at least in terms of the development of a normal GnRH system.
Furthermore, FGFR1 expression co-localizes with anosmin, suggesting a functional link between these two proteins. 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. This research provides the promise of new clinical applications for GnRH analogues including improved cancer treatment.
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