Hypogonadism pathophysiology

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

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.
• 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.
• 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.
• 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	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.
	SOX 10	Autosomal dominant	Deafness 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.
	IL17RD	Autosomal dominant	Deafness
	FEZF1	Autosomal recessive Loss of function mutations
Idiopathic hypogonadotrophic hypogonadism (IHH) (Normal smelling sensation - normosmia)	KISS1R	Gain of function mutations		KISS1R is important for GnRH secretion and puberty process.
	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 of pre-pro GnRH encoding.
	TAC3	Autosomal recessive	Microcephallus Cryptorchidism	Mutation in the pituitary - hypothalamic pathway signaling.
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.
	FGF8	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.

●PROK2 and PROKR2, autosomal recessive IHH and heterozygous mutations with putative dominant inheritance with variable penetrance – Mutations in PROK2 and PROKR2 (encoding the ligand, prokineticin 2, and its cognate receptor, prokineticin 2 receptor, respectively) have been associated with both KS and normosmic IHH. The unusual feature of these mutations is that while homozygous mutations do occur, they are seen in only approximately 10 percent of patients, 90 percent of the mutations in this ligand or receptor being heterozygous, a genetic puzzle since the animal model of this syndrome is autosomal recessive in nature [58,59]. However, given the increasing evidence of oligogenic inheritance in this condition, this finding implies other as-yet-to-be-described genes may well be mutated in these patients. PROK2 is known to function as a chemo-attractant for the types of neural progenitor cells that ultimately populate the olfactory bulb and assist in its dynamic function during life. It has been hypothesized that this olfactory developmental role of PROK2 is the major determinant of its role in GnRH neuronal ontogeny [58,59].