Hypogonadism pathophysiology

	Hypogonadism Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Hypogonadism from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
X ray
CT
MRI
Echocardiography or Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Hypogonadism pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hypogonadism pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hypogonadism pathophysiology
CDC on Hypogonadism pathophysiology
Hypogonadism pathophysiology in the news
Blogs on Hypogonadism pathophysiology
Directions to Hospitals Treating Hypogonadism
Risk calculators and risk factors for Hypogonadism pathophysiology

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

Overview[edit | edit source]

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[edit | edit source]

Pathogenesis[edit | edit source]

Hypogonadism in males[edit | edit source]

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 cerebral 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 gonadotropin 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 factors affect 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 decreased production of the gonadotropin hormones and testosterone deficiency eventually.^[2]
It has been proved that GnRH deficiency is associated with most cases of idiopathic hypogonadotropic hypogonadism in males.

Genetic[edit | edit source]

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]	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	FGFR1 gene 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		PROK2 and PROKR2 has a role in the development of olfactory bulb and GnRH neurons migration.^[13]

References[edit | edit source]

↑ 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.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]