Hypogonadotropic hypogonadism (HH) is a condition characterized by isolated gonodal failure occurring in the setting of low gonadotropins and the absence of any anatomic or functional cause. Specifically, there is a deficient secretion of hypothalamic gonadotropic releasing hormone (GNRH). Clinically, HH is characterized by hypogonadism, incomplete puberty, and infertility. Males may show a decreased libido, erectile dysfunction, decreased muscle strength and aggression, while in women, amenorrhea and dyspareunia might be seen. Affected patients do not experience hot flashes. Hypothalamic-pituitary function is normal in most patients, and no abnormality is seen in imaging tests either. The clinical presentation is very similar to that of Kallmann syndrome, except for the lack of anosmia in HH.
In a study of French conscripts, the prevalence of HH was found to be nearly 1 in 10,000. In most cases, the condition is diagnosed in adolescence when patients complain of incomplete or delayed puberty. The levels of various hormones in the serum can be measured by routine blood tests to diagnose the condition. Other evidences supporting a final confirmation include the response of LH to GNRH and MRI scans of the head.
The standard treatment strategy for all affected post-pubertal patients is gonadal steroid replacement therapy, i.e., testosterone for males, either through injections or as slow-releasing skin patches, and estrogen-progestin for females. For patients that suffer from infertility in spite of this strategy, assisted reproductive technologies, such as ovulation induction and in vitro fertilization are available. Other associated conditions, such as osteoporosis, adrenocortical insufficiency, and congenital heart disease, need also to be managed. The prognosis for patients with HH is fairly good. Some who have cardiac or neurologic complications might be expected to have a lower life span. Again, patients who have an adrenocortical manifestation can often die early, if they are not treated properly.
About a third of all cases of HH are familial, while the rest are probably sporadic, or arise from new genetic mutations. Within the familial cases, about 64% are transmitted in an autosomal dominant manner, while about a quarter are autosomal recessive in nature. A small percentage is transmitted in an X-linked manner.
In different families, several different genes and genetic loci have been implicated in the pathogenesis of HH. The most studied of these are the mutations in the GNRHR (Gonadotropin Releasing Hormone Receptor) gene, which result in GNRH (Gonadotropin-releasing hormone) resistance. This G protein coupled receptor, present on the surface of certain cell types, is responsible for mediating the effects of GNRH and ultimately affects the release of LH and FSH. Other genes linked to HH include loss of function mutations in GPR54, another G protein coupled receptor, and its agonist - Kisspeptin-54, Leptin and its receptor, NELF gene that codes for the human nasal embryonic LHRH factor, and the Fibroblast Growth Factor Receptor 1 (FGFR1).
Hypogonadotropic hypogonadism has been shown to be associated with several other abnormal conditions, including Prader-Willi syndrome, Bardet-Bidel syndrome, and CHARGE syndrome. Those patients that show hypogonadism without the presence of any of the above condition are referred to as having hypogonadotropic hypogonadism.