Vaishali Popat, MD, MPH; Chief Editor: Bryan D Cowan, MD

Gonadotropin-releasing hormone (GnRH) is a neurohormone central to initiation of the reproductive hormone cascade. Pulsatile secretion of GnRH from the hypothalamus is key in establishing and maintaining normal gonadal function. Failure of this release results in isolated GnRH deficiency that can be distinguished by partial or complete lack of GnRH–induced luteinizing hormone (LH) pulses, normalization with pulsatile GnRH replacement therapy, and otherwise normal hypothalamic-pituitary neuroanatomy and neurophysiology.

Clinicians and scientists have long been intrigued by the findings of olfactory disturbances and concomitant reproductive dysfunction. In 1856, Spanish pathologist Maestre de San Juan noted the association between the failure of testicular development and the absence of the olfactory bulbs. However, the syndrome comprising complete GnRH deficiency and lack of olfactory senses is named Kallmann syndrome (KS) after the American geneticist Kallmann.

In 1944, Kallmann, Schoenfeld, and Barrera were the first to identify a genetic basis to this disorder.[1] In 1954, de Morsier connected the syndrome of hypogonadism and anosmia with the abnormal development of the anterior portion of the brain.[2] KS is a rare disorder that occurs in both sexes. In contrast to KS, GnRH deficiency leading to hypogonadotropic hypogonadism with an intact sense of smell is termed idiopathic hypogonadotropic hypogonadism (IHH). IHH results from dysfunction of GnRH neurons that have developed and migrated properly, whereas KS is caused by defective migration of GnRH neurons to their proper position in the hypothalamus during fetal development.

Pathophysiology

Gonadotropin-releasing hormone neurons

A fundamental understanding of the anatomy, biochemistry, ontogeny, and physiology of GnRH neurons aids in understanding the pathophysiology, diagnosis, and treatment of KS and idiopathic hypogonadotropic hypogonadism (IHH).

Gonadotropin-releasing hormone and gonadotropin-releasing hormone receptors

The decapeptide GnRH is derived from posttranslation processing of a tripartite 92–amino acid (AA) pre-pro-GnRH. The first 23 AA is a signal peptide and the last 56 AA is known as GnRH–associated protein (GAP). GnRH is encoded from a single gene located on the short arm of chromosome 8. Serum levels of GnRH are difficult to obtain due to its short half-life (2-4 min) and complete confinement to the hypophyseal-portal blood supply. Due to the small structure and ease of mutation of GnRH, chemists have created several clinically useful GnRH analogs. GnRH binds with high affinity to cell surface LH and follicle stimulating hormone (FSH) receptors located on the pituitary gonadotrophs. These 7-transmembrane, cell surface G protein-coupled receptors activate phospholipase C (PLC).

PLC leads to the activation of several second messenger molecules, the most important being diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP3). In turn, DG activates protein kinase C and causes IP3 -stimulated release of calcium ions from intracellular pools. The result is the synthesis and release of FSH and LH from the pituitary gonadotrophs. The released gonadotropins stimulate the gonads to produce steroid hormones, and in the testes, to produce sperm or in the ovaries, to release oocytes. Mutated GnRH receptors (GnRH-R), as predicted by the biochemistry, could result in the clinical manifestations of isolated gonadotropin deficiency. Many factors interact to regulate the synthesis and secretion of GnRH, and to regulate the translation of GnRH receptors; the review of this regulation is beyond the scope of this article.

Ontogeny and function

During fetal development, the migration of GnRH neurons follows a precise path from the olfactory placode to the preoptic area of the hypothalamus in mammals. The olfactory placode is composed of thickened ectoderm that is lateral to the head of the developing embryo and invaginates to form simple olfactory pits on either side of the nasal septum. The lateral epithelium of the olfactory pits gives rise to the olfactory nerves. The medial portion develops into the site of initial GnRH appearance and the terminal nerves. The terminal nerves, ganglionated cranial nerves for which the exact function is unknown, enter the forebrain and serve as a highway for the GnRH neuronal migration. In humans, GnRH neuron migration begins in the 6th week of embryonic development.

Migrating GnRH neurons do not contain neurosecretory vesicles until they reach the area of the arcuate nucleus in the hypothalamus. For this reason, neurons that do not reach the forebrain are unable to secrete GnRH. GnRH neurons have been identified in the fetal hypothalamus at 9 weeks' gestation and are connected to the pituitary portal system by 16 weeks' gestation. At 10 weeks' gestation, gonadotropes are detectable in the pituitary, and by the 12th week, FSH and LH are measurable in the bloodstream. Fetal peripheral blood levels of gonadotropins peak during the second trimester of pregnancy and decrease by term as the negative feedback mechanism develops.

LH pulsatility, which can be measured in the bloodstream, is determined by the precise frequency and amplitude of pulsatile GnRH release; thus, serum LH is used as a marker of GnRH pulsatility.[3]

GnRH is secreted during the neonatal period, resulting in pulsatile LH and FSH secretion, which decreases by age 6 months in boys and by age 1-2 years in girls until puberty. Before the initiation of puberty, GnRH is still secreted in a pulsatile fashion but at reduced amplitude and frequency. The hypothalamic pulse generator, the master regulator of GnRH secretion, is likely suppressed by a mechanism that inhibits GnRH release but not its synthesis.

This theory has been demonstrated in primates, in which GnRH messenger RNA (mRNA) and proteins are abundant in the hypothalamus during an equivalent developmental stage.

The pubertal period is characterized by a predominantly nocturnal increase in both the amplitude and frequency of GnRH–induced LH pulses. Sex steroids are secreted from the gonads in response to this nocturnal increase in gonadotropins. Gonadotropins continue to be secreted in a pulsatile fashion, under the control of pulsatile GnRH release, during adulthood. The mechanism that awakens the pubertal surge of more robust GnRH secretion is not completely understood. Metabolic cues, steroid hormones, neurosteroids, growth factors, and neurotransmitter systems have been implicated, including glutamate, gamma-aminobutyric acid, neuropeptide Y (NPY), opioids, leptin, kisspeptin, and estradiol.[4]

Most studies in males have shown LH pulses to occur every 2 hours; in females, LH (and thus GnRH) pulse frequency varies throughout the menstrual cycle. In the early follicular phase, LH pulse frequency is every 90 minutes and increases to every 60 minutes by the late follicular phase. The LH "surge" that triggers ovulation occurs due to a "switch" from negative to positive feedback of estrogen at the pituitary, leading to a brief burst of pulsatile LH release, which stimulates ovulation.[5] Following ovulation, LH pulse frequency decreases, with frequency ranging from every 4-8 hours during the luteal phase.

Studying gonadotropin-releasing hormone secretion

Studying GnRH physiology in humans and animal models has been challenging. GnRH itself is almost entirely confined to the portal blood supply of the pituitary, thus direct sampling in humans is not feasible, and difficult if not impossible in animal models. Measurements of GnRH in the periphery are inaccurate because of its rapid 2-minute to 4-minute half-life. Much of the information known about GnRH has come from animal studies.

Belchetz and coworkers in the 1970s demonstrated in rhesus monkeys that pulsatile release of GnRH is required for maintaining gonadotrope function.[6] The researchers were able to differentiate between episodic and continuous stimulation by GnRH causing maintenance and desensitization, respectively, of the gonadotrope response.

Another model developed to study GnRH neuron function is immortalized GnRH cell lines. Interestingly, implantation of these cells into the hypothalami of female GnRH–deficient mice restores normal estrus (equivalent of menstrual) cycles. Immortalized GnRH cell lines in culture have provided an important in vitro tool for studying reproductive neuroendocrine function. In vivo studies of GnRH neuron function have also been possible since development of transgenic mouse models in which GnRH neurons are labeled with green fluorescent protein (GnRH-GFP mouse).[7] This model allows GnRH neurons to be visualized in vivo in hypothalamic sections. Studies from this model are elucidating the complex physiology of GnRH neurons, including neuronal firing patterns, neuronal inputs, migratory patterns, and intracellular signaling systems.

Human studies have been limited to frequent sampling studies in healthy and diseased models, the use of pharmacological probes, and genetic studies. As in animals, LH has long been used as a marker of GnRH pulse activity in humans. Most recently, the glycoprotein free alpha subunit (FAS) has been used as a marker due to its correlation with LH. FAS is useful in tracking GnRH because of its 12-minute to 15-minute half-life. In addition to LH and FAS, an estimate of endogenous GnRH can be obtained using GnRH antagonists as probes. Administering a GnRH antagonist induces a GnRH receptor blockade so that the amount of GnRH present is inversely proportional to the amount of LH inhibitor.

Epidemiology

Frequency

United States

The incidence of KS in the United States is 1 case per 10,000 men and 1 case per 50,000 women. The incidence of normosmic IHH is also rare and is estimated to be around 1 case in 70,000 to 1 case in 100,000 individuals.

International

By examining military records, the incidence of KS has been estimated to be between 1 case per 86,000 in Sardinia and 1 case in 10,000 in France.[8]

Mortality/Morbidity

These patients are not known to have an increased mortality rate; however, prolonged deficiency in gonadal hormones contributes to increased morbidity and may contribute to the aging process.

Race

Race is not a factor in incidence.

Sex

In a referral population at Massachusetts General Hospital over a 20-year period, the male-to-female ratio was 3.9 to 1.[9]

A spectrum of GnRH deficiency, with various secretory patterns ranging from complete lack of LH pulsatility to diminished pulse amplitude similar to early puberty, occurs in both men and women, contributing to the clinical heterogeneity of the disorder. This suggests that multiple genetic determinants may control the expression of GnRH secretion.

Age

The disease comes to attention when the patient fails to begin puberty and does not develop secondary sexual characteristics.