quality:corruption
Genetic predisposition

Idiopathic hypogonadotropic hypogonadism (IHH), otherwise known as congenital GnRH deficiency, has a known genetic basis. This heterogenous disease is caused by defects in GnRH secretion from the pituitary or the effect of GnRH on the pituitary. Implicated loci encode proteins necessary for proper GnRH secretion, action, and neuronal development. The variable expressivity of the disorder, likely resulting from epigenetic modifications and/or multiple genetic defects, has led to the hypothesis that mutations involved in IHH cause increased risk for the functional GnRH deficiency observed in FHA patients. Heterozygous mutations at loci implicated in IHH have been shown to be present in patients with FHA at a rate higher than eumenorrheic controls. The genes implicated included the following: FGFR1, which is involved in the specification, fate, migration, and survival of GnRH -secreting neurons, PROKR2 and KAL1, which enable the migration of GnRH -secreting neurons, and GNRHR, which encodes the pituitary receptor activated by GnRH1. Mutations in PROKR2 or FGFR1 may cause mechanistic dysfunction of GnRH pathways by either decreasing the number of GnRH -secreting cells that are able to migrate to the hypothalamus in development, inhibiting maturation of these cells during maturity, or disrupting GnRH secretion in adulthood. FHA patients harboring these mutations have been shown to be able to resume regular menses, further reinforcing that while genetic defects may predispose one to the condition, environmental factors play a pivotal role in disease manifestation. It is possible that heterozygosity at these loci are not sufficient to cause IHH, but decrease the threshold for HPO inhibition due to environmental factors such as weight loss, stress, and excessive exercise. Functionally speaking, carrying these mutations could confer a selective advantage in a famine conditions, and it is not uncommon for the alleles to be inherited from an asymptomatic parents in both heterozygous and homozygous recessive manifestations of IHH.