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

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]

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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

Template:WH Template:WS