Hypogonadism pathophysiology: Difference between revisions

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==Overview==
==Overview==
Hypogonadism pathophysiology depends mainly on the deficiency of the [[Testosterone|testosterone hormone]]. [[Testosterone]] is secreted in response to stimulation from the [[brain]] to the [[hypothalamus]] which secretes the [[Gonadotropin-releasing hormone|gonadotropin releasing hormones (GnRH)]]. [[GnRH]] is responsible for secretion of [[FSH]] and [[LH]]. In males, LH stimulates the [[leydig cells]] in the [[Testicle|testes]] which produce [[testosterone]] by converting the [[cholesterol]] to testosterone. In females, [[FSH]] and [[LH]] stimulate secretion of [[estrogen]] which helps in [[Follicle|follicles]] maturation. Also, [[estrogen]] is involved in the [[ovulation]] process. [[GnRH]] deficiency may lead to decrease of [[testosterone]] levels and eventually causing hypogonadism. [[Genetic mutations]] have a major role in the development of hypogonadism as well as other factors. There are more than 25 [[Gene mutation|gene mutations]] participate in the pathogenesis of hypogonadism. Genes that are responsible for [[Kallmann syndrome]] include ANOS 1, [[SOX10]], [[SEMA3A]], IL17RD and FEZF1. Other influencing [[genes]] are KISS, GNRNH, and PROK. 
==Pathophysiology==
==Pathophysiology==


Line 9: Line 11:


==== Hypogonadism in males ====
==== Hypogonadism in males ====
* The hypogonadism pathogenesis in males depends mainly on the testosterone deficiency. Testosterone secretion occurs as the following:
* The hypogonadism pathogenesis in males depends mainly on the [[testosterone]] deficiency. [[Testosterone]] secretion occurs as the following:
** Testosterone is secreted in response to stimulation signals from the brain cortex to the hypothalamus. The hypothalamus by its role secrets the gonadotropin releasing hormones (GnRH).  
** Testosterone is secreted in response to stimulation from the [[cerebral cortex]] to the [[hypothalamus]]. The [[hypothalamus]] by its role secrets the [[Gonadotropin-releasing hormone|gonadotropin releasing hormones (GnRH)]].  
** GnRH stimulates the pituitary gland which by its role secretes the gonadal hormones the Follicle Stimulating Hormone (FSH) and the Luteinizing Hormone (LH).  
** [[GnRH]] stimulates the [[pituitary gland]] which by its role secretes the [[Gonadotropins|gonadotropin hormones]] the [[Follicle Stimulating Hormone|Follicle Stimulating Hormone (FSH)]] and the [[Luteinizing hormone|Luteinizing Hormone (LH)]].  
** In males, LH stimulates the leydig cells in the testes which produce testosterone by converting the cholesterol to testosterone.  
** In males, [[LH]] stimulates the [[Leydig cells]] in the [[testes]] which produce [[testosterone]] by converting the [[cholesterol]] to testosterone.  
** Production of testosterone from the testes gives negative feed back to the pituitary. This feedback inhibit the production of FSH and LH from the pituitary.
** Production of [[testosterone]] from the [[testes]] gives negative feed back to the [[Pituitary gland|pituitary]]. This feedback inhibits the production of [[FSH]] and [[LH]] from the [[pituitary]].
* Testosterone deficiency can occur when different acquired or congenital disease affect the organs responsible for its secretion. So, pathogenesis of the hypogonadism in males depends on the underlying cause.<ref name="pmid22247861">{{cite journal| author=Kumar P, Kumar N, Thakur DS, Patidar A| title=Male hypogonadism: Symptoms and treatment. | journal=J Adv Pharm Technol Res | year= 2010 | volume= 1 | issue= 3 | pages= 297-301 | pmid=22247861 | doi=10.4103/0110-5558.72420 | pmc=3255409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22247861  }}</ref>  
* [[Testosterone]] deficiency can occur when different [[acquired]] or [[congenital disease|congenital]] factors affect the [[organs]] responsible for its secretion. So, pathogenesis of the hypogonadism in males depends on the underlying cause.<ref name="pmid22247861">{{cite journal| author=Kumar P, Kumar N, Thakur DS, Patidar A| title=Male hypogonadism: Symptoms and treatment. | journal=J Adv Pharm Technol Res | year= 2010 | volume= 1 | issue= 3 | pages= 297-301 | pmid=22247861 | doi=10.4103/0110-5558.72420 | pmc=3255409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22247861  }}</ref>  
* GnRH deficiency has a main role in hypogonadism pathogenesis in males as it leads to decrease of the gonadal hormone and deficiency of testosterone eventually.<ref name="pmid3098771">{{cite journal| author=Spratt DI, Carr DB, Merriam GR, Scully RE, Rao PN, Crowley WF| title=The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations. | journal=J Clin Endocrinol Metab | year= 1987 | volume= 64 | issue= 2 | pages= 283-91 | pmid=3098771 | doi=10.1210/jcem-64-2-283 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3098771  }}</ref>  
* [[GnRH]] deficiency has the main role in hypogonadism pathogenesis in males as it leads to decreased production of the [[Gonadotropins|gonadotropin hormones]] and [[testosterone]] deficiency eventually.<ref name="pmid3098771">{{cite journal| author=Spratt DI, Carr DB, Merriam GR, Scully RE, Rao PN, Crowley WF| title=The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations. | journal=J Clin Endocrinol Metab | year= 1987 | volume= 64 | issue= 2 | pages= 283-91 | pmid=3098771 | doi=10.1210/jcem-64-2-283 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3098771  }}</ref>  
* It has been proved that GnRH deficiency is associated with most cases of idiopathic hypogonadotrophic hypogonadism in males.  
* It has been proved that [[GnRH]] deficiency is associated with most cases of idiopathic hypogonadotropic hypogonadism in males.  


==== Genetic ====
=== Genetic ===
* Gentic mutations have a big role in development of the hypogonadism especially congenital hypogonadotropic hypogonadism. There are more than 25 genes participate in the pathogenesis of hypogonadism.<ref name="pmid26194704">{{cite journal| author=Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L et al.| title=Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. | journal=Nat Rev Endocrinol | year= 2015 | volume= 11 | issue= 9 | pages= 547-64 | pmid=26194704 | doi=10.1038/nrendo.2015.112 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26194704  }}</ref>
* [[Genetic mutations]] have a role in the development of the hypogonadism especially [[congenital]] hypogonadotropic hypogonadism. There are more than 25 [[genes]] responsible for the pathogenesis of hypogonadism.<ref name="pmid26194704">{{cite journal| author=Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L et al.| title=Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. | journal=Nat Rev Endocrinol | year= 2015 | volume= 11 | issue= 9 | pages= 547-64 | pmid=26194704 | doi=10.1038/nrendo.2015.112 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26194704  }}</ref>
* In this table number of genes with the associated diseases causing hypogonadism are enlisted:  
* In this table number of genes with the associated diseases causing hypogonadism are enlisted:
{| class="wikitable"
{| class="wikitable"
!Associated disease
!Associated disease
!'''Genes'''
!Genes  
!Mutation
!Mutation
!Associated features with the mutated gene
!Comments
|-
|-
! rowspan="5" |Kalman Syndrome
| rowspan="5" |[[Kallmann syndrome]] (with loss of smelling sense - anosmia)
|ANOS 1<ref name="pmid1922361">{{cite journal| author=Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R et al.| title=A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. | journal=Nature | year= 1991 | volume= 353 | issue= 6344 | pages= 529-36 | pmid=1922361 | doi=10.1038/353529a0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1922361  }}</ref>  
|ANOS 1<ref name="pmid1922361">{{cite journal| author=Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R et al.| title=A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. | journal=Nature | year= 1991 | volume= 353 | issue= 6344 | pages= 529-36 | pmid=1922361 | doi=10.1038/353529a0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1922361  }}</ref>
!gene deletions or point mutations.
|
* X - linked recessive
* [[Gene deletion]] or [[point mutations]]
|
* [[Anosmia]]
* [[Renal agenesis]]
|
* [[GnRH]] deficiency results from impairment of migration of the hormonal [[neurons]] to the [[hypothalamus]] in the [[embryological]] development.<ref name="pmid2687610">{{cite journal| author=Schwanzel-Fukuda M, Bick D, Pfaff DW| title=Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. | journal=Brain Res Mol Brain Res | year= 1989 | volume= 6 | issue= 4 | pages= 311-26 | pmid=2687610 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2687610  }}</ref>
|-
|-
|SOX 10
|[[SOX10]]
!
|
* [[Autosomal dominant]]
|
* [[Deafness]]<ref name="pmid23643381">{{cite journal| author=Pingault V, Bodereau V, Baral V, Marcos S, Watanabe Y, Chaoui A et al.| title=Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. | journal=Am J Hum Genet | year= 2013 | volume= 92 | issue= 5 | pages= 707-24 | pmid=23643381 | doi=10.1016/j.ajhg.2013.03.024 | pmc=3644631 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23643381  }}</ref>
* [[Iris]] [[pigmentation]]
|
|-
|-
|SEMA3A
|[[SEMA3A]]
!
|
* Loss of function mutations
|
|
* SEMA3A gene's function is to encode the [[semaphorin]] 3A. 
* Semaphorin 3A is important for the [[GnRH]] neurons migration.
* A defect in [[SEMA3A|SEMA3A gene]] will end up with GnRH deficiency.<ref name="pmid21059704">{{cite journal| author=Cariboni A, Davidson K, Rakic S, Maggi R, Parnavelas JG, Ruhrberg C| title=Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism. | journal=Hum Mol Genet | year= 2011 | volume= 20 | issue= 2 | pages= 336-44 | pmid=21059704 | doi=10.1093/hmg/ddq468 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21059704  }}</ref>
|-
|-
|IL17RD
|IL17RD
!
|
* [[Autosomal dominant]]
|
* [[Deafness]]
|
|-
|-
|FEZF1
|FEZF1
!
|
* [[Autosomal recessive]]
* Loss of function mutations
|
|
|-
|-
!
| rowspan="5" |Idiopathic hypogonadotropic hypogonadism (IHH) (normal smelling sensation - normosmia)
|KISS1R
|KISS1R
!
|
* Gain of function mutations
|
|
* KISS1R is important for [[GnRH]] secretion and [[puberty]] process.<ref name="pmid18272894">{{cite journal| author=Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S et al.| title=A GPR54-activating mutation in a patient with central precocious puberty. | journal=N Engl J Med | year= 2008 | volume= 358 | issue= 7 | pages= 709-15 | pmid=18272894 | doi=10.1056/NEJMoa073443 | pmc=2859966 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18272894  }}</ref>
|-
|KISS1
|
* [[Autosomal recessive]]
* Loss of functions mutations
|
|
|-
|-
!
|GNRHR
|KISS
|
!
* Loss of function mutations
|
|
* Patients with hypogonadism due to GNRHR mutations usually do not respond properly to the [[GnRH|exogenous GnRH]].
* On big doses of GnRH, [[ovulation]] may be initiated in some patients.
|-
|-
!
|GNRH1
|GNRH1
!
|
* [[Autosomal recessive]]
|
|
* GNRH1 is responsible for pre-pro GnRH encoding.<ref name="pmid19535795">{{cite journal| author=Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P et al.| title=Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. | journal=N Engl J Med | year= 2009 | volume= 360 | issue= 26 | pages= 2742-8 | pmid=19535795 | doi=10.1056/NEJMoa0900136 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19535795  }}</ref>
|-
|-
!
|TAC3
|TAC3
!
|
* [[Autosomal recessive]]
|
* [[Microcephalus]]
* [[Cryptorchidism]]
|
* Mutation in the [[Pituitary gland|pituitary]] - [[Hypothalamus|hypothalamic]] pathway signaling.<ref name="pmid20332248">{{cite journal| author=Gianetti E, Tusset C, Noel SD, Au MG, Dwyer AA, Hughes VA et al.| title=TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. | journal=J Clin Endocrinol Metab | year= 2010 | volume= 95 | issue= 6 | pages= 2857-67 | pmid=20332248 | doi=10.1210/jc.2009-2320 | pmc=2902066 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20332248  }}</ref>
|-
|-
!
| rowspan="3" |Mixed anosmic and nosmic IHH
!FGFR1
|FGFR1
!
|
* [[Autosomal dominant]]
* Loss of function mutations
|
* [[Hereditary spherocytosis]].
* [[Cleft palate]]
* [[Deafness|Unilateral deafness]]
|
* FGFR1 gene has an organizational function with ANOS1.
* Products of ANOS1 act like a co receptor for FGFR1.<ref name="pmid15548653">{{cite journal| author=González-Martínez D, Kim SH, Hu Y, Guimond S, Schofield J, Winyard P et al.| title=Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism. | journal=J Neurosci | year= 2004 | volume= 24 | issue= 46 | pages= 10384-92 | pmid=15548653 | doi=10.1523/JNEUROSCI.3400-04.2004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15548653  }}</ref>
|-
|-
!
|[[FGF8]]<ref name="pmid18596921">{{cite journal| author=Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y et al.| title=Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. | journal=J Clin Invest | year= 2008 | volume= 118 | issue= 8 | pages= 2822-31 | pmid=18596921 | doi=10.1172/JCI34538 | pmc=2441855 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18596921  }}</ref>
!FGF8
|
!
* [[Autosomal dominant]]
|
* [[Deafness]]
* [[Cleft lip and palate]]
* [[Osteoporosis]]
|
|-
|-
!
|PROK2
!PROK2  
PROKR2
PROKR2
!
|
|-
* [[Autosomal recessive]]
!
|
!CHD7
|
!
* PROK2 and PROKR2 has a role in the development of [[olfactory bulb]] and [[GnRH]] neurons migration.<ref name="pmid18559922">{{cite journal| author=Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D et al.| title=Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. | journal=J Clin Endocrinol Metab | year= 2008 | volume= 93 | issue= 9 | pages= 3551-9 | pmid=18559922 | doi=10.1210/jc.2007-2654 | pmc=2567850 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18559922  }}</ref>
|-
!
!NSMF
!
|}
|}


Latest revision as of 16:36, 3 October 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Overview

Hypogonadism pathophysiology depends mainly on the deficiency of the testosterone hormone. Testosterone is secreted in response to stimulation from the brain to the hypothalamus which secretes the gonadotropin releasing hormones (GnRH). GnRH is responsible for secretion of FSH and LH. In males, LH stimulates the leydig cells in the testes which produce testosterone by converting the cholesterol to testosterone. In females, FSH and LH stimulate secretion of estrogen which helps in follicles maturation. Also, estrogen is involved in the ovulation process. GnRH deficiency may lead to decrease of testosterone levels and eventually causing hypogonadism. Genetic mutations have a major role in the development of hypogonadism as well as other factors. There are more than 25 gene mutations participate in the pathogenesis of hypogonadism. Genes that are responsible for Kallmann syndrome include ANOS 1, SOX10, SEMA3A, IL17RD and FEZF1. Other influencing genes are KISS, GNRNH, and PROK.

Pathophysiology

Pathogenesis

Hypogonadism in males

Genetic

  • Genetic mutations have a role in the development of the hypogonadism especially congenital hypogonadotropic hypogonadism. There are more than 25 genes responsible for the pathogenesis of hypogonadism.[3]
  • In this table number of genes with the associated diseases causing hypogonadism are enlisted:
Associated disease Genes Mutation Associated features with the mutated gene Comments
Kallmann syndrome (with loss of smelling sense - anosmia) ANOS 1[4]
SOX10
SEMA3A
  • Loss of function mutations
  • SEMA3A gene's function is to encode the semaphorin 3A.
  • Semaphorin 3A is important for the GnRH neurons migration.
  • A defect in SEMA3A gene will end up with GnRH deficiency.[7]
IL17RD
FEZF1
Idiopathic hypogonadotropic hypogonadism (IHH) (normal smelling sensation - normosmia) KISS1R
  • Gain of function mutations
KISS1
GNRHR
  • Loss of function mutations
  • Patients with hypogonadism due to GNRHR mutations usually do not respond properly to the exogenous GnRH.
  • On big doses of GnRH, ovulation may be initiated in some patients.
GNRH1
  • GNRH1 is responsible for pre-pro GnRH encoding.[9]
TAC3
Mixed anosmic and nosmic IHH FGFR1
  • FGFR1 gene has an organizational function with ANOS1.
  • Products of ANOS1 act like a co receptor for FGFR1.[11]
FGF8[12]
PROK2

PROKR2

References

  1. ↑ Kumar P, Kumar N, Thakur DS, Patidar A (2010). "Male hypogonadism: Symptoms and treatment". J Adv Pharm Technol Res. 1 (3): 297–301. doi:10.4103/0110-5558.72420. PMC 3255409. PMID 22247861.
  2. ↑ Spratt DI, Carr DB, Merriam GR, Scully RE, Rao PN, Crowley WF (1987). "The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations". J Clin Endocrinol Metab. 64 (2): 283–91. doi:10.1210/jcem-64-2-283. PMID 3098771.
  3. ↑ Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L; et al. (2015). "Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment". Nat Rev Endocrinol. 11 (9): 547–64. doi:10.1038/nrendo.2015.112. PMID 26194704.
  4. ↑ Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R; et al. (1991). "A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules". Nature. 353 (6344): 529–36. doi:10.1038/353529a0. PMID 1922361.
  5. ↑ Schwanzel-Fukuda M, Bick D, Pfaff DW (1989). "Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome". Brain Res Mol Brain Res. 6 (4): 311–26. PMID 2687610.
  6. ↑ Pingault V, Bodereau V, Baral V, Marcos S, Watanabe Y, Chaoui A; et al. (2013). "Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness". Am J Hum Genet. 92 (5): 707–24. doi:10.1016/j.ajhg.2013.03.024. PMC 3644631. PMID 23643381.
  7. ↑ Cariboni A, Davidson K, Rakic S, Maggi R, Parnavelas JG, Ruhrberg C (2011). "Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism". Hum Mol Genet. 20 (2): 336–44. doi:10.1093/hmg/ddq468. PMID 21059704.
  8. ↑ Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S; et al. (2008). "A GPR54-activating mutation in a patient with central precocious puberty". N Engl J Med. 358 (7): 709–15. doi:10.1056/NEJMoa073443. PMC 2859966. PMID 18272894.
  9. ↑ Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P; et al. (2009). "Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation". N Engl J Med. 360 (26): 2742–8. doi:10.1056/NEJMoa0900136. PMID 19535795.
  10. ↑ Gianetti E, Tusset C, Noel SD, Au MG, Dwyer AA, Hughes VA; et al. (2010). "TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood". J Clin Endocrinol Metab. 95 (6): 2857–67. doi:10.1210/jc.2009-2320. PMC 2902066. PMID 20332248.
  11. ↑ González-Martínez D, Kim SH, Hu Y, Guimond S, Schofield J, Winyard P; et al. (2004). "Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism". J Neurosci. 24 (46): 10384–92. doi:10.1523/JNEUROSCI.3400-04.2004. PMID 15548653.
  12. ↑ Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y; et al. (2008). "Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice". J Clin Invest. 118 (8): 2822–31. doi:10.1172/JCI34538. PMC 2441855. PMID 18596921.
  13. ↑ Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D; et al. (2008). "Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum". J Clin Endocrinol Metab. 93 (9): 3551–9. doi:10.1210/jc.2007-2654. PMC 2567850. PMID 18559922.

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