Hypogonadism pathophysiology: Difference between revisions

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Revision as of 14:50, 5 September 2017

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 effect of different factors and diseases on the pituitary-hypothalamic-gonadal pathway. 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. Estrogen also helps in the process of ovulation. Deficiency of GnRH leads to decrease of testosterone levels and eventually causing hypogonadism. Genetic mutations have a big role as well in the development of hypogonadism. There are more than 25 gene mutations participate in the pathogenesis of hypogonadism. These genes like genes responsible for Kallmann syndrome as ANOS 1, SOX10, SEMA3A, IL17RD and FEZF1. Other genes include KISS, GNRNH, and PROK.

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 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 inhibits the production of FSH and LH from the pituitary.
Testosterone deficiency can occur when different acquired or congenital disease affects the organs responsible for its secretion. So, pathogenesis of the hypogonadism in males depends on the underlying cause.^[1]
GnRH deficiency has the main role in hypogonadism pathogenesis in males as it leads to decrease production of the gonadal hormone and deficiency of testosterone eventually.^[2]
It has been proved that GnRH deficiency is associated with most cases of idiopathic hypogonadotropic hypogonadism in males.

Genetic

Genetic mutations have a big 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
Kallman 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]
	SOX10	Autosomal dominant	Deafness^[6] Iris pigmentation
	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	Autosomal dominant	Deafness
	FEZF1	Autosomal recessive Loss of function mutations
Idiopathic hypogonadotropic hypogonadism (IHH) (normal smelling sensation - normosmia)	KISS1R	Gain of function mutations		KISS1R is important for GnRH secretion and puberty process.^[8]
	KISS1	Autosomal recessive Loss of functions mutations
	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	Autosomal recessive		GNRH1 is responsible for pre-pro GnRH encoding.^[9]
	TAC3	Autosomal recessive	Microcephalus Cryptorchidism	Mutation in the pituitary - hypothalamic pathway signaling.^[10]
Mixed anosmic and nosmic IHH	FGFR1	Autosomal dominant Loss of function mutations	Hereditary spherocytosis. Cleft palate Unilateral deafness	It has an organizational function with ANOS1. Products of ANOS1 act like a co receptor for FGFR1.^[11]
	FGF8^[12]	Autosomal dominant	Deafness Cleft lip and palate Osteoporosis
	PROK2 PROKR2	Autosomal recessive		It has a role in the development of olfactory bulb and GnRH neurons migration.^[13]

References

↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.

Template:WH Template:WS

[pmid22247861-1] 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.

[pmid3098771-2] 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.

[pmid26194704-3] 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.

[pmid1922361-4] 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.

[pmid2687610-5] 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.

[pmid23643381-6] 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.

[pmid21059704-7] 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.

[pmid18272894-8] 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.

[pmid19535795-9] 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.

[pmid20332248-10] 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.

[pmid15548653-11] 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.

[pmid18596921-12] 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.

[pmid18559922-13] 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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@@ Line 4: / Line 4: @@
 ==Overview==
-Hypogonadism pathophysiology depends mainly on the effect of different factors and [[diseases]] on the [[Pituitary gland|pituitary]]-[[hypothalamic]]-[[gonadal]] pathway. [[Testosterone]] is secreted in response to stimulation signals 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. [[Estrogen]] also helps in the process of [[ovulation]]. Deficiency of [[GnRH]] leads to decrease of [[testosterone]] levels and eventually causing hypogonadism. [[Genetic mutations]] have a big role as well in the development of hypogonadism. There are more than 25 [[Gene mutation|gene mutations]] participate in the pathogenesis of hypogonadism. These genes like genes responsible for [[Kallmann syndrome]] as ANOS 1, [[SOX10]], [[SEMA3A]], IL17RD and FEZF1. Other [[genes]] include KISS, GNRNH, and PROK.
+Hypogonadism pathophysiology depends mainly on the effect of different factors and [[diseases]] on the [[Pituitary gland|pituitary]]-[[hypothalamic]]-[[gonadal]] pathway. [[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. [[Estrogen]] also helps in the process of [[ovulation]]. Deficiency of [[GnRH]] leads to decrease of [[testosterone]] levels and eventually causing hypogonadism. [[Genetic mutations]] have a big role as well in the development of hypogonadism. There are more than 25 [[Gene mutation|gene mutations]] participate in the pathogenesis of hypogonadism. These genes like genes responsible for [[Kallmann syndrome]] as ANOS 1, [[SOX10]], [[SEMA3A]], IL17RD and FEZF1. Other [[genes]] include KISS, GNRNH, and PROK.
 ==Pathophysiology==
@@ Line 12: / Line 12: @@
 ==== 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 (biology)|signals]] from the [[brain]] cortex to the [[hypothalamus]]. The [[hypothalamus]] by its role secrets the [[Gonadotropin-releasing hormone|gonadotropin releasing hormones (GnRH)]].
+** Testosterone is secreted in response to stimulation from the [[brain]] 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 [[Gonadotropin|gonadal 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.
 ** 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]] affects 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 the 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 decrease production 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>
-* It has been proved that GnRH deficiency is associated with most cases of idiopathic hypogonadotropic hypogonadism in males.
+* It has been proved that [[GnRH]] deficiency is associated with most cases of idiopathic hypogonadotropic hypogonadism in males.
 === Genetic ===
-* [[Genetic mutations]] have a big role in the 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 big 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:
 {| class="wikitable"
 !Associated disease
 !Genes
 !Mutation
 !Associated features with the mutated gene
 !Comments
 |-
-| rowspan="5" |Kalman syndrome (With loss of smelling sense - Anosmia)
+| rowspan="5" |Kallman 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>
 |
@@ Line 72: / Line 72: @@
 |
 |-
-| rowspan="5" |Idiopathic hypogonadotropic hypogonadism (IHH) (Normal smelling sensation - normosmia)
+| rowspan="5" |Idiopathic hypogonadotropic hypogonadism (IHH) (normal smelling sensation - normosmia)
 |KISS1R
 |