Gonadotropin-releasing hormone insensitivity

Gonadotropin-releasing hormone insensitivity
Gonadotropin-releasing hormone insensitivity
Other names	GnRH insensitivity
Specialty	Endocrinology

Last updated November 08, 2023

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.^{[ citation needed ]}

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.^[1]^[2]

GnRH insensitivity can present at any age, but the presenting signs and symptoms are a function of the age-related period of reproductive activity.^{[ citation needed ]}

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).^{[ citation needed ]}

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).^{[ citation needed ]}

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.^{[ citation needed ]}

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.^[3] 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.^{[ citation needed ]}

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)^[4] with robust gonadotropin secretion. This responsiveness demonstrates the intact anatomic and functional integrity of the gonadotrophs and the gonads in these patients.^{[ citation needed ]}

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:^{[ citation needed ]}

The demonstration of prepubertal serum concentrations of sex steroid hormones (serum testosterone less than 100 ng/dL [3.5 nmol/L] in males or serum estradiol less than 20 pg/mL [73 pmol/L] in females).
Inappropriately low or normal serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations (usually less than 4 to 5 international units/L) rather than the high concentrations expected with primary gonadal failure.
Otherwise normal anterior pituitary function.
Normal appearance of the hypothalamus and pituitary region on magnetic resonance imaging (MRI); when seeking this diagnosis, it is useful to request fine (1 mm) cuts through the olfactory bulb region of the MRI to define subtle abnormalities of the olfactory system that may signal which genetic tests to request first.
Differential diagnosis — For patients fulfilling the above laboratory criteria, the main (and most difficult) differential diagnosis is with constitutional delay of growth and puberty (CDGP).
A definitive diagnosis of GnRH insensitivity in the absence of a family history or prior genetic testing is difficult to make until the patient reaches at least 18 years of age, unless other suggestive features are present (i.e., prior microphallus and/or cryptorchism, anosmia, renal agenesis, skeletal defects, etc.). CDGP is far more common than GnRH insensitivity, affecting approximately 3 percent of adolescents while the incidence of the Kallmann syndrome (KS) form of GnRH insensitivity is 1:48,000 with a clear difference between males (1:30,000) and females (1:125,000).^[5]
No single test can reliably distinguish between GnRH insensitivity and CDGP until more widespread genetic testing becomes available, and therefore, one has to rely on an array of clinical clues as well as on the natural evolution over time. However, certain features may indicate a higher likelihood of GnRH insensitivity rather than CDGP:
A family history of gonadotropin-releasing hormone (GnRH) deficiency, anosmia, and/or the presence of one or several associated congenital abnormalities suggests congenital nonreproductive abnormalities (e.g., cleft lip/palate, syndactyly) suggest KS form of GnRH deficiency.
A history of "stalled" puberty rather than total absence of development, a family history of delayed puberty, or early evidence of breast or testicular development are useful indicators that puberty is likely to occur spontaneously (i.e., CDGP).
The presence of pubic hair suggests GnRH insensitivity because normal adrenarche still occurs; in comparison, both adrenarche and gonadarche are delayed in CDGP, and therefore, pubic hair is usually absent.
In females, functional hypogonadotropic hypogonadism (FHH) (or functional hypothalamic amenorrhea) is part of the differential diagnosis for GnRH insensitivity. The presence of predisposing factors like excessive exercise, weight loss, or psychological stress point towards the diagnosis of FHH rather than GnRH insensitivity.
When GnRH deficiency presents after puberty,^[3] other causes of secondary hypogonadism (particularly tumors of the hypothalamic-pituitary axis) must be eliminated, as GnRH insensitivity is really a diagnosis of exclusion. These include:
Tumors of the hypothalamic-pituitary region that occasionally can be suspected by the presence of other neurologic symptoms (headaches, visual disturbances) or the demonstration of other defects or excess in anterior pituitary hormone secretion on initial biochemical screening. However, enlarging mass lesions in either the pituitary or the central nervous system decrease the secretion of corticotropin (ACTH) or thyroid-stimulating hormone (TSH) less than that of gonadotropins or growth hormone.
Similarly, hemochromatosis should be eliminated by appropriate testing of serum iron, total iron binding capacity, and ferritin levels.

Approach to genetic testing — When the diagnosis of GnRH insensitivity is suspected, it is suggested that referral to a clinical geneticist for further evaluation and possible genetic testing be done. As many of the genes causing GnRH insensitivity have pleotropic physiologic functions, genetic testing can aid assessment of both reproductive and nonreproductive clinical features. In addition, ascertaining the specific inheritance modes can aid genetic screening within the family to predict recurrence risk in siblings, family members or offspring of GnRH insensitivity patients. However, genetic testing in GnRH insensitivity is challenging, given the genetic and allelic heterogeneity, as well as complex oligogenic inheritance patterns. However, in the presence of either clear Mendelian inheritance patterns or specific phenotypic cues, targeted genetic testing or multigene panel testing may be performed. However, if such testing is done, variant interpretation and genetic counseling should be performed in conjunction with a clinical genetics service. Alternatively, several research units have special interests in the genetics of GnRH insensitivity, and clinicians can consider referring these patients to such specialized centers. Genetic testing is now commercially available through several Clinical Laboratory Improvement Amendments (CLIA) laboratories in the United States (GeneDx, Athena Diagnostics, Fulgent Diagnostics).^{[ citation needed ]}

Treatment

The choice of therapy for GnRH insensitivity depends upon the patient's age and desire to achieve one or more of the following goals:^{[ citation needed ]}

Induction of puberty and/or maintenance of sexual maturation
Induction or restoration of fertility

Puberty induction and sexual maturation

Girls and women — Exogenous estrogens are used to start secondary sexual development in prepubertal girls and to build and sustain normal bone and muscle mass. Initiation of treatment are based upon the patient's bone age, current height percentiles, psychosexual needs, and predicted adult height. The shorter the predicted adult height, the later puberty should be induced. Inappropriate use of estrogens may result in rapid osseous maturation with resulting short stature and irregular menstrual bleeding.^{[ citation needed ]}

Initiation of puberty can begin with any type or route of exogenous estrogen, oral or transdermal. Initiation of puberty with transdermal 17-beta estradiol, starting with low doses of approximately 0.08 to 0.12 mcg estradiol per kg/day body weight, is successful and commonly prescribed by pediatricians.^[6] The dose is then gradually increased over several years. Initial therapy consist of unopposed estrogen alone to maximize breast growth, achieve appropriate skeletal maturation, and to induce uterine and endometrial proliferation. A progestin eventually needs to be added to prevent endometrial hyperplasia, but adding it prematurely or administering combinations of estrogens and progestins (e.g., birth control pills) before completion of breast development should be avoided because it is likely to reduce ultimate breast size.^{[ citation needed ]}

Once pubertal induction is completed, estrogen and progestin therapy are continued indefinitely. Doses and principles of therapy are similar to those for women with primary ovarian insufficiency.

Boys and men — In boys, puberty can be induced with testosterone, exogenous gonadotropins, or pulsatile gonadotropin-releasing hormone (GnRH) therapy. The latter two options also induce spermatogenesis, which is not necessary for this age group. Testosterone therapy is suggested for pubertal induction in boys. The goals of therapy are to:^{[ citation needed ]}

Induce virilization
Promote optimal skeletal maturation (with bone age monitoring)
Maximize adult height
Promote psychosexual development
Build and sustain normal bone and muscle mass

Oral testosterone preparations should not be used, because of hepatic toxicity. The choices for testosterone replacement include intramuscular injections of long-acting testosterone preparations or topical gels/solutions/patches. Serum testosterone levels should be monitored and dose adjusted.

Whichever form of testosterone replacement is chosen, providing psychological support is important because the patient will have a variety of new and often confusing symptoms, much like an adolescent undergoing puberty but more difficult because it will likely be at a later age. Testosterone therapy should be initiated at a low dose and gradually increased to an adult dose over a few years.^{[ citation needed ]}

Once pubertal induction is completed, testosterone therapy is continued indefinitely.^{[ citation needed ]}

Prognosis

The prognosis is generally good, with the outcome for fertility depending on the severity of the sex hormone deficiency and the age of initiation of treatment. Rare cases of complete resolution have been described but the pathophysiology of the disease in these patients is not understood.^{[ citation needed ]}

Epidemiology

Gonadotropin-releasing hormone (GnRH) insensitivity affects both sexes but has a significant male preponderance. A population-based, epidemiological study from Finland showed a minimal prevalence estimate of the Kallman syndrome (KS) form of Gonadotropin-releasing hormone (GnRH) insensitivity to be 1:48,000 with a clear difference between males (1:30,000) and females (1:125,000).^[5]

Research

The research of GnRH deficiency has been long studied over the past five decades. The classic studies from the 1970s identified that pulsatile release of GnRH from the hypothalamus is a prerequisite for physiologic gonadotrope function. Further theses studies demonstrated that the absence, decreased frequency, or decreased amplitude of pulsatile GnRH release results in the clinical syndrome of hypogonadotropic hypogonadism (HH).^{[ citation needed ]}

Current research primarily aims to define the physiology of GnRH, as it is critical to understanding the clinical heterogeneity of GnRH insufficiency and its comparison to other conditions resulting in hypogonadotropic hypogonadism (HH). Some overall goals of current research have focused on investigating:^{[ citation needed ]}

The neuroendocrine control of reproduction and specifically the physiology and pathophysiology of GnRH secretion and action in humans
Efficacy of genetic counseling and patient management
The psychopathology, sexuality, and personality characteristics in patients with GnRH deficiency under hormonal replacement therapy

Related Research Articles

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormonal signs that puberty has begun. In the United States, girls are considered to have delayed puberty if they lack breast development by age 13 or have not started menstruating by age 15. Boys are considered to have delayed puberty if they lack enlargement of the testicles by age 14. Delayed puberty affects about 2% of adolescents.

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

Pubarche refers to the first appearance of pubic hair at puberty and also it marks the beginning of puberty. It is one of the physical changes of puberty and can occur independently of complete puberty. The early stage of sexual maturation, also known as adrenarche, is marked by characteristics including the development of pubic hair, axillary hair, adult apocrine body odor, acne, and increased oiliness of hair and skin. The Encyclopedia of Child and Adolescent Health corresponds SMR2 with pubarche, defining it as the development of pubic hair that occurs at a mean age of 11.6 years in females and 12.6 years in males. It further describes that pubarche's physical manifestation is vellus hair over the labia or the base of the penis. See Table 1 for the entirety of the sexual maturity rating description.

Gonadarche refers to the earliest gonadal changes of puberty. In response to pituitary gonadotropins, the ovaries in females and the testes in males begin to grow and increase the production of the sex steroids, especially estradiol and testosterone. The ovary and testis have receptors, follicle cells and leydig cells, respectively, where gonadotropins bind to stimulate the maturation of the gonads and secretion of estrogen and testosterone. Certain disorders can result in changes to timing or nature of these processes.

Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other forms of hypogonadotropic hypogonadism, Kallmann syndrome has the additional symptom of a total lack of sense of smell (anosmia) or a reduced sense of smell. If left untreated, people will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably are infertile and are at increased risk of developing osteoporosis. A range of other physical symptoms affecting the face, hands and skeletal system can also occur.

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subset of cases of hypogonadotropic hypogonadism (HH) due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH) where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.

<span class="mw-page-title-main">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

Functional hypothalamic amenorrhea (FHA) is a form of amenorrhea and chronic anovulation and is one of the most common types of secondary amenorrhea. It is classified as hypogonadotropic hypogonadism. It was previously known as "juvenile hypothalamosis syndrome," prior to the discovery that sexually mature females are equally affected. FHA has multiple risk factors, with links to stress-related, weight-related, and exercise-related factors. FHA is caused by stress-induced suppression of the hypothalamic-pituitary-ovarian (HPO) axis, which results in inhibition of gonadotropin-releasing hormone (GnRH) secretion, and gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Severe and potentially prolonged hypoestrogenism is perhaps the most dangerous hormonal pathology associated with the disease, because consequences of this disturbance can influence bone health, cardiovascular health, mental health, and metabolic functioning in both the short and long-term. Because many of the symptoms overlap with those of organic hypothalamic, pituitary, or gonadal disease and therefore must be ruled out, FHA is a diagnosis of exclusion; "functional" is used to indicate a behavioral cause, in which no anatomical or organic disease is identified, and is reversible with correction of the underlying cause. Diagnostic workup includes a detailed history and physical, laboratory studies, such as a pregnancy test, and serum levels of FSH and LH, prolactin, and thyroid-stimulating hormone (TSH), and imaging. Additional tests may be indicated in order to distinguish FHA from organic hypothalamic or pituitary disorders. Patients present with a broad range of symptoms related to severe hypoestrogenism as well as hypercortisolemia, low serum insulin levels, low serum insulin-like growth factor 1 (IGF-1), and low total triiodothyronine (T3). Treatment is primarily managing the primary cause of the FHA with behavioral modifications. While hormonal-based therapies are potential treatment to restore menses, weight gain and behavioral modifications can have an even more potent impact on reversing neuroendocrine abnormalities, preventing further bone loss, and re-establishing menses, making this the recommended line of treatment. If this fails to work, secondary treatment is aimed at treating the effects of hypoestrogenism, hypercortisolism, and hypothyroidism.

A micropenis is an unusually small penis. A common criterion is a dorsal penile length of at least 2.5 standard deviations smaller than the mean human penis size. A micropenis is stretched penile length less than 2.5 cm in term infants, 2.6 cm in one-year-old, 3.5 cm in five year old, 3.8 cm in ten year old, and 9.3 cm in adults. The condition is usually recognized shortly after birth. The term is most often used medically when the rest of the penis, scrotum, and perineum are without ambiguity, such as hypospadias. A microphallus describes a medical term where other sections of genitallia are different, such as hypospadias or cryptorchidism. Micropenis incidence is about 1.5 in 10,000 male newborns in North America.

Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testes in a male. In response to the signals, the gonads produce hormones that stimulate libido and the growth, function, and transformation of the brain, bones, muscle, blood, skin, hair, breasts, and sex organs. Physical growth—height and weight—accelerates in the first half of puberty and is completed when an adult body has been developed. Before puberty, the external sex organs, known as primary sexual characteristics, are sex characteristics that distinguish males and females. Puberty leads to sexual dimorphism through the development of the secondary sex characteristics, which further distinguish the sexes.

Aromatase excess syndrome is a rarely diagnosed genetic and endocrine syndrome which is characterized by an overexpression of aromatase, the enzyme responsible for the biosynthesis of the estrogen sex hormones from the androgens, in turn resulting in excessive levels of circulating estrogens and, accordingly, symptoms of hyperestrogenism. It affects both sexes, manifesting itself in males as marked or complete phenotypical feminization and in females as hyperfeminization.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

Leydig cell hypoplasia (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 genetic males. It is characterized by an inability of the body to respond to luteinizing hormone (LH), a gonadotropin which is normally responsible for signaling Leydig cells of the testicles to produce testosterone and other androgen sex hormones. The condition manifests itself as pseudohermaphroditism, hypergonadotropic hypogonadism, reduced or absent puberty, and infertility.

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

Androgen deficiency is a medical condition characterized by insufficient androgenic activity in the body. Androgen deficiency most commonly affects women, and is also called Female androgen insufficiency syndrome (FAIS), although it can happen in both sexes. Androgenic activity is mediated by androgens, and is dependent on various factors including androgen receptor abundance, sensitivity and function. Androgen deficiency is associated with lack of energy and motivation, depression, lack of desire (libido), and in more severe cases changes in secondary sex characteristics.

The fertile eunuch syndrome or Pasqualini syndrome is a cause of hypogonadotropic hypogonadism caused by a luteinizing hormone deficiency. It is characterized by hypogonadism with spermatogenesis. Pasqualini and Bur published the first case of eunuchoidism with preserved spermatogenesis in 1950 in la Revista de la Asociación Médica Argentina. The hypoandrogenism with spermatogenesis syndrome included:

To date, at least 25 different genes have been implicated in causing gonadotropin-releasing hormone (GnRH) deficiency conditions such as Kallmann syndrome (KS) or other forms of congenital hypogonadotropic hypogonadism (CHH) through a disruption in the production or activity of GnRH. These genes involved cover all forms of inheritance, and no one gene defect has been shown to be common to all cases, which makes genetic testing and inheritance prediction difficult.

References

↑ Pitteloud, Nelly; Hayes, Frances J.; Boepple, Paul A.; DeCruz, Suzzunne; Seminara, Stephanie B.; MacLaughlin, David T.; Crowley, William F. (January 2002). "The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism". The Journal of Clinical Endocrinology and Metabolism. 87 (1): 152–160. doi: 10.1210/jcem.87.1.8131 . ISSN 0021-972X. PMID 11788640.
↑ Quinton, R.; Duke, V. M.; Robertson, A.; Kirk, J. M.; Matfin, G.; de Zoysa, P. A.; Azcona, C.; MacColl, G. S.; Jacobs, H. S.; Conway, G. S.; Besser, M. (August 2001). "Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization". Clinical Endocrinology. 55 (2): 163–174. doi:10.1046/j.1365-2265.2001.01277.x. ISSN 0300-0664. PMID 11531922. S2CID 10368223.
1 2 Nachtigall, L. B.; Boepple, P. A.; Pralong, F. P.; Crowley, W. F. (1997-02-06). "Adult-onset idiopathic hypogonadotropic hypogonadism--a treatable form of male infertility". The New England Journal of Medicine. 336 (6): 410–415. doi: 10.1056/NEJM199702063360604 . ISSN 0028-4793. PMID 9010147.
↑ Marques, P.; et al. (2000). Physiology of GNRH and Gonadotropin Secretion. PMID 25905297.{{cite book}}: |website= ignored (help)
1 2 Laitinen, Eeva-Maria; Vaaralahti, Kirsi; Tommiska, Johanna; Eklund, Elina; Tervaniemi, Mari; Valanne, Leena; Raivio, Taneli (2011-06-17). "Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland". Orphanet Journal of Rare Diseases. 6: 41. doi: 10.1186/1750-1172-6-41 . ISSN 1750-1172. PMC 3143089 . PMID 21682876.
↑ Ankarberg-Lindgren, C.; Elfving, M.; Wikland, K. A.; Norjavaara, E. (July 2001). "Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls". The Journal of Clinical Endocrinology and Metabolism. 86 (7): 3039–3044. doi: 10.1210/jcem.86.7.7667 . ISSN 0021-972X. PMID 11443165.

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[1] Pitteloud, Nelly; Hayes, Frances J.; Boepple, Paul A.; DeCruz, Suzzunne; Seminara, Stephanie B.; MacLaughlin, David T.; Crowley, William F. (January 2002). "The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism". The Journal of Clinical Endocrinology and Metabolism. 87 (1): 152–160. doi: 10.1210/jcem.87.1.8131 . ISSN 0021-972X. PMID 11788640.

[2] Quinton, R.; Duke, V. M.; Robertson, A.; Kirk, J. M.; Matfin, G.; de Zoysa, P. A.; Azcona, C.; MacColl, G. S.; Jacobs, H. S.; Conway, G. S.; Besser, M. (August 2001). "Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization". Clinical Endocrinology. 55 (2): 163–174. doi:10.1046/j.1365-2265.2001.01277.x. ISSN 0300-0664. PMID 11531922. S2CID 10368223.

[:0-3] 1 2 Nachtigall, L. B.; Boepple, P. A.; Pralong, F. P.; Crowley, W. F. (1997-02-06). "Adult-onset idiopathic hypogonadotropic hypogonadism--a treatable form of male infertility". The New England Journal of Medicine. 336 (6): 410–415. doi: 10.1056/NEJM199702063360604 . ISSN 0028-4793. PMID 9010147.

[4] Marques, P.; et al. (2000). Physiology of GNRH and Gonadotropin Secretion. PMID 25905297.{{cite book}}: |website= ignored (help)

[:1-5] 1 2 Laitinen, Eeva-Maria; Vaaralahti, Kirsi; Tommiska, Johanna; Eklund, Elina; Tervaniemi, Mari; Valanne, Leena; Raivio, Taneli (2011-06-17). "Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland". Orphanet Journal of Rare Diseases. 6: 41. doi: 10.1186/1750-1172-6-41 . ISSN 1750-1172. PMC 3143089 . PMID 21682876.

[6] Ankarberg-Lindgren, C.; Elfving, M.; Wikland, K. A.; Norjavaara, E. (July 2001). "Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls". The Journal of Clinical Endocrinology and Metabolism. 86 (7): 3039–3044. doi: 10.1210/jcem.86.7.7667 . ISSN 0021-972X. PMID 11443165.

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