Isolated hypogonadotropic hypogonadism


Isolated hypogonadotropic hypogonadism, also called idiopathic or congenital hypogonadotropic hypogonadism, as well as isolated or congenital gonadotropin-releasing hormone deficiency, is a condition which results in a small subset of cases of hypogonadotropic hypogonadism due to deficiency in or insensitivity to gonadotropin-releasing hormone where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.

Presentation

Congenital hypogonadotropic hypogonadism presents as hypogonadism, e.g., reduced or absent puberty, low libido, infertility, etc. due to an impaired release of the gonadotropins, follicle-stimulating hormone and luteinizing hormone, and a resultant lack of sex steroid and peptides production by the gonads.
In Kallmann syndrome, a variable non-reproductive phenotype occurs with anosmia including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis.

Causes

IHH is divided into two syndromes: IHH with olfactory alterations or anosmia, Kallmann syndrome and IHH with normal smell.
Kallmann syndrome is responsible for approximately 50% of all cases of the condition. It is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, and WDR11 , genes which are related to defects in neuronal migration.
Gene defects associated with IHH and normal smell include PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11, as in KS, but in addition
also mutations in KISS1R, TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB. GnRH insensitivity is the second most common cause of IHH, responsible for up to 20% of cases.
A minority of less than 5-10% is due to inactivating mutations in genes which positively regulate GnRH secretion such as,CHD7, KISS1R, and TACR3.
The causes of about 25% of all IHH cases are still unknown.

Genetics

See Genetics of GnRH deficiency conditions

Diagnosis

Treatment