Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.
Signs and symptoms There is a relatively broad spectrum of clinical signs and symptoms that can occur in, ranging from complete absence of sexual development to partial completion of puberty that does not subsequently progress. Of note, the X-linked form of Kallmann syndrome (KS) form of GnRH insensitivity relating to mutations in the ANOS1 gene has the most consistent severe phenotypic presentation (i.e., prepubertal testes size and complete absence of gonadotropin-releasing hormone [GnRH]-induced luteinizing hormone [LH] pulsations during frequency sampling studies) of all of the genes associated with this condition. GnRH insensitivity can present at any age, but the presenting signs and symptoms are a function of the age-related period of reproductive activity. During the neonatal period, boys with the more severe cases of GnRH insensitivity can present with microphallus and/or cryptorchidism, presumably due to in utero and/or neonatal GnRH deficiency; approximately one-half of boys with microphallus have GnRH insensitivity as the underlying diagnosis. In comparison, newborn girls with GnRH insensitivity have no obvious abnormal reproductive tract findings that might provide clues to the diagnosis. However, in both sexes, other congenital nonreproductive features may be present (e.g., midline facial defects, skeletal abnormalities). During childhood, since the hypothalamic GnRH-pituitary-gonadal axis is quiescent, a diagnosis of GnRH insensitivity can generally be heralded only in the presence of nonreproductive phenotypes (e.g., the lack of sense of smell in some patients [anosmia] or skeletal abnormalities, such as cleft lip/cleft palate, hearing deficits, or syndactyly). At puberty, patients of both sexes can present with a complete form of GnRH insensitivity that is characterized by a failure to initiate sexual maturation (e.g., lack of secondary sexual characteristics, primary amenorrhea in girls, lack of virilization in boys) and failure to establish a pubertal growth spurt. Some patients present with partial forms of GnRH insensitivity and undergo some degree of pubertal development that subsequently ceases. For example, some males with GnRH insensitivity exhibit some testicular growth, while some females can have thelarche and menarche, but hypogonadotropic hypogonadism (HH) is demonstrable soon thereafter. Extremely rarely, a few have completely normal pubertal development and adulthood gonadal function, only to develop HH with prepubertal levels of testosterone but sometimes with normal testicular size as a clue to its acquired status, i.e., developing only after adult testicular development has been complete subsequently in adulthood, leading to infertility and sexual dysfunction. These patients are referred to as having the adult-onset or acquired form of GnRH insensitivity.
Causes Congenital Causes
Genetic Mutations Kallmann syndrome ANOS1 (formerly KAL1), X-linked recessive KS SOX10 (SRY-box 10 gene), autosomal dominant KS with variable penetrance IL17RD, autosomal dominant KS with variable penetrance SEMA3A, autosomal dominant KS with variable penetrance FEZF1, autosomal recessive KS IL17RD, autosomal dominant KS with variable penetrance Digenic and Oligogenic Mutations A heterozygous FGFR1 mutation and heterozygous deletion in the NSMF gene in the anosmic pedigree A compound heterozygous GNRHR mutation and heterozygous FGFR1 mutation in the normosmic pedigree GnRH deficiency associated with mental retardation/obesity Congenital malformations often associated with craniofacial anomalies Laurence-Moon-Biedl syndrome Prader-Willi syndrome Acquired Causes
Benign tumors and cysts Craniopharyngiomas Germinomas, meningiomas, gliomas, astrocytomas Metastatic tumors (breast, lung, prostate) Chronic systemic disease Malnutrition, anorexia nervosa, bulimia Hypothyroidism, hyperprolactinemia, diabetes mellitus, Cushing's disease Post-androgen abuse Infiltrative diseases Hemochromatosis Granulomatous diseases Histiocytosis Head trauma Pituitary apoplexy Drugs - marijuana, opioids, anabolic steroids
Pathophysiology The genetic mechanisms of gonadotropin-releasing hormone (GnRH) insensitivity involve mutations in at least twenty-four genes regulating GnRH neuronal migration, secretion, and activity. So far, the mechanisms underlying gonadotropin deficiency, both in prepubertal and in adulthood onset forms, remain unknown in most of the cases. The lack of endogenous hypothalamic gonadotropin-releasing hormone (GnRH) secretion/action in patients with GnRH insensitivity cannot be proven by direct assay of GnRH in the portal circulation but can be reasonably inferred by two findings:
The lack of any endogenous GnRH-induced luteinizing hormone (LH) pulses during frequent blood sampling Typically, most patients respond to exogenous GnRH when administered in a pulsatile regimen designed to mimic endogenous GnRH secretion (GnRH dose and frequency based upon a previous study of LH secretion in normal men) with robust gonadotropin secretion. This responsiveness demonstrates the intact anatomic and functional integrity of the gonadotrophs and the gonads in these patients.
Diagnosis When suspected on the basis of the clinical presentation or physical findings, the diagnosis of GnRH insensitivity should be confirmed biochemically. The diagnosis requires the following findings:
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