The hypothalamus, the part of the brain that sits above the pituitary and controls it, governs several endocrine axes at once, so its disorders can disturb more than one hormone system. Beyond hormone release it regulates temperature, the sleep-awake cycle, appetite, the autonomic system, behaviour and memory, which is why hypothalamic disease often produces features outside endocrinology as well.
Among its endocrine effects, several act on gonadotropin-releasing hormone (GnRH), the hypothalamic hormone that drives the pituitary’s release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). When GnRH is deficient, LH and FSH fall and the gonads are under-stimulated, a state called hypogonadotropic hypogonadism. Four examples show how the same end result can arise from different mechanisms.
Kallmann syndrome combines deficient GnRH production with anosmia or hyposmia. The link between the two is developmental: GnRH-producing neurons begin in the olfactory placode and migrate into the hypothalamus along olfactory pathways, and the X-linked ANOS1 (KAL1) gene product, anosmin-1, is needed for that migration; it was the first gene linked to the syndrome. When migration fails, both the olfactory bulbs and the hypothalamic GnRH supply are affected, so a reduced sense of smell accompanies the hypogonadism. The same syndrome can also result from many other genes, inherited in autosomal or X-linked patterns or occurring sporadically, and it may include colour blindness, optic atrophy, nerve deafness, cleft palate, renal abnormalities, cryptorchidism and neurological findings such as mirror movements. The endocrine picture is the same in both sexes — low LH, FSH and sex steroids — but it presents differently: boys show delayed puberty and a micropenis, while girls show primary amenorrhoea and failure of secondary sexual development.
Bardet-Biedl syndrome is caused by mutations in several genes that affect the function of the basal body and cilia, so the phenotype varies between patients. Its usual features are intellectual disability, renal failure, obesity, hexadactyly, brachydactyly and childhood retinal degeneration that leaves most patients blind by 30 years of age. GnRH deficiency is part of the syndrome, present in about 75% of male and 50% of female patients.
Leptin and leptin receptor mutations show the same pathway from a different direction. Leptin signals the hypothalamus about the body’s energy stores, and when that signal is lost the result is hyperphagia and obesity together with central hypogonadism: reduced GnRH production lowers LH and FSH.
Prader-Willi syndrome also causes hypogonadotropic hypogonadism as part of its hypothalamic picture.
These conditions are congenital or genetic in origin. Damage to a previously normal hypothalamus or pituitary later in life, from tumours, trauma, vascular events and other insults, raises a different set of causes.