Hypogonadism pathophysiology: Difference between revisions

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* 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>
* 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>
* 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 gene
!Comments
|-
|-
! rowspan="5" |Kalman Syndrome
| rowspan="5" |Kalman 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
|SOX 10
!
|
* 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 funciton is to encode the semaphorin 3A.
* Semaphorin 3A is important for the GnRH neurons migration.
* Defect in 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="4" |Idiopathic hypogonadotrophic hypogonadism (IHH) (Normal smelling sensation - normosmia)
|KISS1R
|KISS1R
!
|
|
|
|-
|-
!
|KISS
|KISS
!
|
|
|
|-
|-
!
|GNRH1
|GNRH1
!
|
|
|
|-
|-
!
|TAC3
|TAC3
!
|
|
|
|-
|-
!
| rowspan="5" |Mixed anosmic and nosmic IHH
!FGFR1
|FGFR1
!
|
|
|
|-
|-
!
|FGF8
!FGF8
|
!
|
|
|-
|-
!
|PROK2
!PROK2  
PROKR2
PROKR2
!
|
|
|
|-
|-
!
|CHD7
!CHD7
|
!
|
|
|-
|-
!
|NSMF
!NSMF
|
!
|
|
|}
|}


Revision as of 20:01, 20 July 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

Pathophysiology

Pathogenesis

Hypogonadism in males

  • 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).
    • GnRH stimulates the pituitary gland which by its role secretes the gonadal hormones the Follicle Stimulating Hormone (FSH) and the Luteinizing Hormone (LH).
    • 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.
  • 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.[1]
  • 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.[2]
  • It has been proved that GnRH deficiency is associated with most cases of idiopathic hypogonadotrophic hypogonadism in males.

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.[3]
  • In this table number of genes with the associated diseases causing hypogonadism are enlisted:
Associated disease Genes Mutation Associated features with the gene Comments
Kalman syndrome (With loss of smelling sense - Anosmia) ANOS 1[4]
  • 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.[5]
SOX 10
  • Autosomal dominant
  • Deafness[6]
  • Iris pigmentation
SEMA3A
  • Loss of function mutations
  • SEMA3A gene's funciton is to encode the semaphorin 3A.
  • Semaphorin 3A is important for the GnRH neurons migration.
  • Defect in SEMA3A gene will end up with GnRH deficiency.[7]
IL17RD
  • Autosomal dominant
  • Deafness
FEZF1
  • Autosomal recessive
  • Loss of function mutations
Idiopathic hypogonadotrophic hypogonadism (IHH) (Normal smelling sensation - normosmia) KISS1R
KISS
GNRH1
TAC3
Mixed anosmic and nosmic IHH FGFR1
FGF8
PROK2

PROKR2

CHD7
NSMF

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.

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