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Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.

Bookshelf ID: NBK1278PMID: 20301455

Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency Overview

Synonyms: Isolated Hypogonadotropic Hypogonadism, Idiopathic Hypogonadotropic Hypogonadism. Includes: GNRHR-Related Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency, KISS1R-Related Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency, TACR3-Related Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency

J Carl Pallais, MD, MPH, Margaret Au, MBE, MS, CGC, Nelly Pitteloud, MD, Stephanie Seminara, MD, and William F Crowley, Jr, MD.

Author Information
J Carl Pallais, MD, MPH
Instructor, Harvard Medical School
Endocrine Unit
Massachusetts General Hospital
Boston, Massachusetts
Margaret Au, MBE, MS, CGC
Reproductive Endocrine Unit
Massachusetts General Hospital
Boston, Massachusetts
Nelly Pitteloud, MD
Assistant Professor of Medicine, Harvard Medical School
Reproductive Endocrine Unit
Massachusetts General Hospital
Boston, Massachusetts
Stephanie Seminara, MD
Associate Professor of Medicine, Harvard Medical School
Reproductive Endocrine Unit
Massachusetts General Hospital
Boston, Massachusetts
William F Crowley, Jr, MD
Professor of Medicine, Chief of the Reproductive Endocrine Unit
Massachusetts General Hospital
Boston, Massachusetts

Initial Posting: May 23, 2007; Last Update: October 14, 2010.

Summary

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Disease characteristics. Isolated GnRH deficiency (IGD), the subject of this GeneReview, is caused by impaired gonadotropin release in the setting of otherwise normal anterior pituitary anatomy and function and in the absence of secondary causes of hypogonadotropic hypogonadism (HH). IGD, also known as idiopathic or isolated hypogonadotropic hypogonadism (IHH), is a small but important subset of HH that is broadly defined as inappropriately low serum concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the setting of hypogonadism. IGD can first be apparent in infancy, adolescence, or adulthood. Infant boys with congenital (i.e., present at birth) IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt. Approximately 60% of individuals with IGD have an impaired sense of smell.

Causes. IGD is caused by complete or partial absence of GnRH-mediated release of LH and FSH. In the presence of anosmia (inability to smell), IGD is called Kallmann syndrome (KS) (~60% of all IGD); in the presence of a normal sense of smell it is called normosmic IGD (nIGD) (~40% of all IGD). Causative mutations in several genes have been found in individuals with either Kallmann syndrome or nIGD.

Genetic counseling. IGD is frequently simplex (i.e., a single occurrence in a family) (~60%) and may not have an inherited basis. Approximately 30% of IGD is familial and can be inherited in an autosomal dominant, autosomal recessive, X-linked recessive, or digenic manner depending on the gene involved.

Management. Treatment of manifestations: to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (testosterone or human chorionic gonadotropin [hCG] injections in males; estrogen and progestin in females); to stimulate spermatogenesis or folliculogenesis, either combined gonadotropin therapy (hCG and human menopausal gonadotropins [hMG] or recombinant FSH [rFSH]) or pulsatile GnRH therapy. Consider in vitro fertilization if spermatogenesis is achieved but infertility persists; treatment for decreased bone mass as needed.

Definition of Isolated GnRH Deficiency

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Isolated GnRH deficiency (IGD) is caused by selective impairments of the hypothalamic-pituitary axis resulting in inappropriately low gonadotropin secretion with otherwise normal pituitary function.

Normal physiology. Typically, episodic stimulation of LH and FSH secretion from the pituitary by gonadotropin-releasing hormone (GnRH) represents the initial neuroendocrine step in the reproductive cascade. Its commanding role in this biologic hierarchy allows GnRH to control pulsatile gonadotropin secretion, modulate gonadal steroid feedback, and ultimately determine the initiation or suppression of pubertal development and fertility across the life cycle [Hoffman & Crowley 1982, Crowley et al 1985].

Under normal conditions, the hypothalamic-pituitary-gonadal (HPG) axis undergoes a series of dynamic changes from fetal life to adulthood. The HPG axis begins its activity in late gestation, remains active throughout the first several months of infancy, and then becomes remarkably dampened during the years of the childhood "quiescence" [Waldhauser et al 1981]. At puberty, unknown biologic triggers re-ignite GnRH secretion, resulting in full sexual maturation. Therefore, the controls of the reproductive axis are in dynamic flux, turning on and turning off in response to as-yet-unknown biologic signals at various time points in the reproductive life cycle.

Hypogonadotropic hypogonadism. HH is characterized by inappropriately low serum concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the setting of hypogonadism. Hypogonadotropic hypogonadism is most frequently acquired and caused by a number of pathologic processes but it can also occur as part of various congenital syndromes.

Isolated GnRH deficiency. IGD is a relatively rare but important subset of HH caused by impaired gonadotropin release in the setting of normal pituitary anatomy and function and in the absence of secondary causes of HH.

Terminology. The terminology of HH has evolved with the increased understanding of reproductive physiology. Initially, the term “hypogonadism” was used to refer to individuals with impaired sexual development based on a combination of findings from both clinical history (e.g., amenorrhea, hot flashes, erectile dysfunction) and physical examination (e.g., small testes, vaginal pallor). With greater understanding of the HPG axis and the introduction of urinary gonadotropin measurements, the terms “hypergonadotropic” hypogonadism was used to identify those with a primary gonadal defect and “hypogonadotropic” hypogonadism identified those with a central (i.e., pituitary or hypothalamic) defect. Once anatomic (and later functional) causes of central hypogonadism were identified, “idiopathic” or “isolated” HH (IHH) was then used to indicate those in which secondary causes of HH had been excluded.

Subsequently the ability to measure the effect of exogenous GnRH administration demonstrated that the vast majority of individuals with “idiopathic” HH had a functional deficiency of GnRH resulting from a defect in GnRH biosynthesis, secretion, and/or action in an otherwise normal anterior pituitary (hence “isolated GnRH deficiency”). Aside from hypothalamic hypogonadism, individuals with isolated GnRH deficiency (IGD) have normal pituitary function tests and their hypogonadism typically responds to a physiologic regimen of exogenous GnRH [Hoffman & Crowley 1982].

At this point, “isolated GnRH deficiency” (IGD) is the better term for what was previously called idiopathic HH. IGD more properly reflects the current understanding of the clinical entity. The ensuing use of molecular genetic testing has identified mutations in candidate genes that explain some, but not all, of the causes of IGD.

Clinical Manifestations

The clinical manifestations of IGD depend on the stage of development at which the deficiency in the reproductive axis first occurred (infancy, adolescence, or adulthood). Although most cases of IGD are identified at puberty, suggestive clinical features may be present in infancy. Rarely, individuals have normal sexual maturation and develop IGD in adulthood.

Infancy. The signs of gonadotropin deficiency in a male (micropenis and cryptorchidism) may be present at birth but typically the significance of these findings is not recognized until puberty. Cryptorchidism and micropenis (stretched penile length <1.9 cm in a full term male infant) can be a manifestation of an early impairment in the reproductive axis in boys, especially when associated with abnormally low serum concentrations of gonadotropins and testosterone in the first months of life [Grumbach 2005].

Adolescence. At puberty, most individuals with IGD have abnormal sexual maturation, usually with incomplete development of secondary sexual characteristics. However, the degree to which sexual maturation is affected can vary (see Fertile eunuch variant).

The impaired sexual development can result in adult males with prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth and deepening of the voice), and decreased muscle mass. Females can have little or no breast development and primary amenorrhea. Since adrenal maturation proceeds normally, the low levels of androgens produced in the adrenal glands may be sufficient for normal onset of pubic hair growth (adrenarche) in both sexes.

Because of the failure of growth plates in the bone to fuse in the absence of sex hormones, most individuals with impaired pubertal development typically have a eunuchoid body habitus (i.e., arm span exceeds height by ≥5 cm). Although skeletal maturation is delayed, the rate of linear growth is usually normal (save for the absence of a distinct pubertal growth spurt) [Van Dop et al 1987].

Adulthood. Although the majority of individuals with IGD "present" during adolescence, some individuals have normal sexual maturation but develop IGD well into their adult years [Nachtigall et al 1997]. Adult males with IGD with normal virilization and, in some situations, proven paternity have biochemical parameters very similar to those of males with the congenital form, including low serum concentration of testosterone, apulsatile LH secretion, and responsiveness to a regimen of physiologic doses of exogenous GnRH [Nachtigall et al 1997].

Fertile eunuch variant. The severity of IGD varies; in some individuals, some degree of pubertal development can occur. At one extreme of this spectrum of abnormal pubertal development is the "fertile eunuch" variant of this syndrome. This term is used to describe males who exhibit clinical evidence of hypogonadism associated with low serum concentration of testosterone but show some evidence of partial pubertal development with normal or near-normal testicular volumes, often sperm present in their ejaculate, and/or normal levels of the seminiferous tubular secretory protein, inhibin B.

Analyses of the pulsatile pattern of gonadotropins in individuals with IGD have demonstrated a rather broad spectrum of abnormal developmental patterns varying from completely absent GnRH-induced LH pulses to sleep-entrained GnRH release that is indistinguishable from that of early puberty [Spratt et al 1987, Nachtigall et al 1997, Raivio et al 2007]. This level of GnRH activity is sufficient for spermatogenesis with the potential to achieve fertility with little or no treatment [Smals et al 1978].

Reversal. Reversal of IGD, defined as restoration of normal serum testosterone concentrations after cessation of even brief treatment with sex steroid, gonadotropin, or GnRH, occurs in about 10% of men with either Kallmann syndrome or normosmic IGD (nIGD) [Raivio et al 2007]. This post-treatment “awakening” of the hypothalamic-pituitary-gonadal axis suggests the presence of hypothalamic GnRH neurons that do not function during adolescence and possibly require environmental stimuli to initiate normal activity.

Anosmia. In addition to the reproductive defect, approximately two thirds of individuals with IGD have an impaired sense of smell (anosmia/hyposmia) [Bianco & Kaiser 2009]. The presence or absence of olfactory defects determines whether an individual with IGD is classified as having Kallmann Syndrome (IGD and anosmia) or normosmic IGD (nIGD) (see Kallmann Syndrome).

Establishing the Diagnosis

The diagnosis of IGD is established by the presence of both suggestive clinical findings and laboratory findings consistent with hypogonadotropic hypogonadism, and the absence of secondary causes of hypothalamic hypogonadism (see Differential Diagnosis) (Figure 1).

Figure 1

Figure

Figure 1. Testing algorithm to establish the diagnosis of isolated GnRH deficiency

Clinical Findings

Hypogonadism. Individuals with IGD typically have clinical evidence of arrested sexual maturation or hypogonadism. These findings include absence of secondary sexual characteristics, diminished libido, infertility, amenorrhea in women, and erectile dysfunction in men. Physical examination should include analysis of Tanner staging (see Table 1) to determine severity and onset of hypogonadism.

  • In IGD, men typically have Tanner stage I-II genitalia whereas women typically have Tanner stage I breasts. Both men and women typically have Tanner stage II-III pubic hair (since pubic hair is controlled in part by adrenal androgens).

  • Normal adult testicular volume is 15-20 mL. Men with IGD often have subnormal testicular volumes (<12 mL) and may present with prepubertal testicular volumes (<4 mL).

  • If the IGD occurred in adulthood after normal sexual maturation (rare for IGD but common for acquired hypogonadotropic hypogonadism), secondary sexual characteristics may be fully developed.

Table 1. Tanner Staging of Puberty

Tanner Stage
IIIIIIIVV
Pubic hair NoneSparse hair that is long and slightly pigmentedDarker, coarser, curly hairAdult hair covering pubisLaterally distributed adult-type hair
Male genitalia Childhood appearance of testes, scrotum, and penis (testicular volume <4 mL)Enlargement of testes and penis; reddish discoloration of scrotumContinued growth of testes and elongation of penisContinued growth of testes, widening of the penis with growth of the glans penis; scrotal darkeningMature adult genitalia (testicular volume >15 mL)
Female breast developmentPapillae elevated, no breast budBreast bud with slightly elevated papillaeBreast and areola confluent and elevatedAreola and papillae project above breastMature (breast and areola confluent, papillae project)

Anosmia (Figure 2). Approximately two thirds of individuals with IGD have anosmia/hyposmia (Kallmann syndrome, KS) and one third have normosmic IGD (nIHH) [Bianco & Kaiser 2009].

Figure 2

Figure

Figure 2. Genes associated with isolated GnRH deficiency by sense of smell and mode of inheritance

Notes:

* ≤ 5th percentile for age and gender using the University of Pennsylvania smell identification test (UPSIT)

** (more...)

Sense of smell can be evaluated by history and by formal diagnostic smell tests, such as the University of Pennsylvania smell identification test (UPSIT) [Doty 2007]. This "scratch and sniff" test evaluates an individual's ability to identify 40 microencapsulated odorants and can be easily performed in most clinical settings. Identification of anosmia, hyposmia, or normosmia is based on the individual’s score, age at testing, and gender.

  • In general, individuals with IGD scoring at or below the 5th percentile (typically either hyposmic or anosmic) receive a diagnosis of Kallmann syndrome.

  • Individuals scoring above the 5th percentile (could be hyposmic or normosmic) are considered to have normosmic IGD.

Laboratory Findings

IGD is characterized by low or normal serum concentration of LH and FSH in the setting of low circulating concentrations of sex steroids (total testosterone [T] <100 ng/dL; estradiol [E2] <50 pg/mL).

Absence of Secondary Causes of Hypogonadotropic Hypogonadism

When clinical and laboratory findings are suggestive, further evaluation is required to distinguish IGD from HH caused by secondary disease processes or as part of other congenital syndromes (Figure 1; Table 2). IGD is a small subset of hypogonadotropic hypogonadism characterized by otherwise normal anterior pituitary anatomy and function. As acquired causes of hypogonadotropic hypogonadism are significantly more common than IGD, it is important to exclude secondary processes that disturb the hypothalamic-pituitary axis prior to making the diagnosis of IGD (see Differential Diagnosis).

Additional laboratory and radiologic evaluation may be required to exclude secondary causes of HH. These include measurement of serum concentration of other pituitary hormones, serum iron studies, and hypothalamic/pituitary imaging.

Differential Diagnosis of Isolated GnRH Deficiency

Primary hypogonadism. Although the clinical manifestations of IGD are similar to those of primary hypogonadism (i.e., defect in gonadal function), disorders causing primary hypogonadism (e.g., anorchism, partial androgen resistance, infections) are typically associated with elevated serum concentrations of gonadotropins.

Secondary causes of hypogonadotropic hypogonadism. Multiple disease processes ranging from systemic diseases to brain and pituitary tumors can result in impaired gonadotropin secretion. These conditions can be relatively common and frequently give rise to defects in other pituitary hormones.

Acquired and syndromic causes of HH that need to be excluded prior to making the diagnosis of IGD include the following:

  • CNS or pituitary tumors

  • Pituitary apoplexy

  • Brain/pituitary radiation

  • Head trauma

  • Drugs: GnRH agonists/antagonists, glucocorticoids, narcotics, chemotherapy

  • Functional deficiency resulting from chronic systemic illness, eating disorders, malnutrition, hypothyroidism, hyperprolactinemia, diabetes mellitus, Cushing's disease

  • Syndromes such as CHARGE syndrome, Prader-Willi syndrome, combined pituitary hormone deficiency, Bardet-Biedl syndrome, and leptin deficiency / resistance syndromes can be associated with other significant clinical findings and/or other pituitary hormone defects. See Table 2.

  • Systemic diseases such as hemochromatosis (see HFE-Associated Hereditary Hemochromatosis), sarcoidosis, and histiocytosis

Table 2. Syndromes Associated with Hypogonadotropic Hypogonadism

SyndromeGenetic MechanismPhenotypeReferenceGenetic Test Availability
Prader-Willi syndromeLoss of paternal 15q11.2Hypotonia in infancy, developmental delay, cryptorchidism/micropenis in males, abnormal satiety, intellectual disabilityCassidy & Schwartz [2009]Clinical
Image testing.jpg
Combined pituitary hormone deficiencyPROP1 mutationVarious degrees of hypopituitarismPhillips et al [2005] Clinical
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HESX1 mutation Cohen & Radovick [2002]Clinical
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LHX3 mutationClinical
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Obesity syndromesPCSK1 (PC1) mutationMorbid obesity, hypocortisolism, hypoinsulinemiaJackson et al [1997], Jackson et al [2003] Clinical
Image testing.jpg
LEP mutationMorbid obesityStrobel et al [1998]Clinical
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LEPR mutationClément et al [1998]Clinical
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Bardet-Biedl syndromeMutation of one of 12 genes 1Developmental delay, visual impairment, post-axial polydactyly, obesity, renal impairmentWaters & Beales [2010]Testing available for most of the 12 genes involved 1
CHARGE syndromeCHD7 mutationColoboma, heart defect, choanal atresia, growth retardation, ear abnormalitiesLalani et al [2009], Pinto et al [2005]Clinical
Image testing.jpg
HemochromatosisHFE mutationsCirrhosis, diabetes, cardiomyopathy, arthritis, skin hyperpigmentationKowdley et al [2006]Clinical
Image testing.jpg

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The 12 genes associated with BBS: BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, MKKS/BBS6, BBS7, TTC8/BBS8, B1/BBS9, BBS10, TRIM32/BBS11, BBS12

Additional clinical, laboratory, and radiologic evaluations may be required to exclude syndromic and secondary causes of hypogonadotropic hypogonadism. Careful evaluation should include physical examination for other systemic findings, family history, measurement of serum concentration of other pituitary hormones, serum iron studies, and hypothalamic/pituitary imaging.

Despite thorough evaluations, IGD can sometimes remain difficult to distinguish from other causes of decreased gonadotropin secretion.

Infancy. Although males with IGD may have cryptorchidism and/or microphallus at birth, these are not specific for IGD. Numerous disorders can give rise to these genital defects, ranging from isolated findings to congenital syndromes such as Prader-Willi syndrome or abnormal pituitary development (see PROP1-Related Combined Pituitary Hormone Deficiency). This is particularly true for cryptorchidism, the most common birth defect of the male genitalia.

Adolescence. Perhaps the most difficult distinction to make is between IHH and constitutional delay of puberty (CDP). Time is a critical factor in distinguishing between these two conditions. In CDP, spontaneous and otherwise normal puberty eventually occurs whereas in IGD spontaneous sexual maturation does not occur at any time. Evidence suggests that CDP and IGD are not discrete clinical entities but rather are part of a phenotypic spectrum. In families with IGD, delayed puberty occurs at a much higher frequency in otherwise "normal" family members than in the general population, suggesting that CDP may represent a milder clinical variant of the IGD phenotype [Waldstreicher et al 1996, Pitteloud et al 2006a].

Although the distinction between CDP and IGD cannot be reliably made at any age, age 18 years has traditionally been used to diagnose IGD in the absence of clinical features associated with IGD or Kallmann syndrome (e.g., anosmia, synkinesia). However, the recent description of IGD "reversals" occurring in persons in their 20s or beyond raises the possibility that such individuals may have a severe form of CDP.

No clinically available tests can differentiate CDP from IGD. Data analyses have verified that the mean serum concentrations of LH and sex hormones after GnRH or hCG (human chorionic gonadotropin) stimulation vary significantly between individuals with CDP and those with IGD. Nevertheless, the clinical utility of measuring serum LH and sex hormone concentrations after stimulation with GnRH and hCG is limited by the significant variation in individual LH and sex hormone serum concentrations, resulting in considerable overlap between groups [Degros et al 2003].

Combining a 19-day hCG test with a conventional GnRH test may improve differentiation [Segal et al 2009]. Additionally, a peak-to-basal ratio of free alpha subunit (FAS) after the administration of GnRH may help distinguish between CDP and IGD. A peak-to-basal ratio of FAS after the administration of GnRH distinguishes one group from the other with a sensitivity and specificity in the 95% range and an overlap rate of 10% [Mainieri & Elnecave 2003]. However, given the relatively small number of individuals studied and limited follow-up, prospective validation is required to determine the true diagnostic reliability.

Prevalence

Estimates of the overall incidence of IGD vary from approximately 1:86,000 to 1:10,000 [Seminara et al 1998]. The true prevalence of IGD is difficult to determine as no study has performed careful reproductive phenotyping in large unselected populations.

In the authors' cohort of 250 individuals with IGD, males predominate, with a male-to-female ratio of nearly 4:1 [Seminara et al 1998].

Causes of Isolated GnRH Deficiency

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Identification of specific genes causing isolated GnRH deficiency (IGD) has been complicated by the following:

  • Disease rarity

  • Small families as a result of reproductive defect

  • Delayed onset of the reproductive phenotype (i.e., late adolescence)

  • Incomplete penetrance (i.e., clinical manifestations absent in individuals with a known genetic defect)

  • Variable expressivity (i.e., different clinical phenotypes among individuals who have the identical gene defect; variable expressivity can occur in both the GnRH deficiency phenotype and the associated clinical findings)

  • Similar reproductive phenotype resulting from numerous mutations in various genes (overlapping phenotypes make it difficult to pool affected individuals to determine the genetic cause)

Despite these challenges, studies of families with IGD have resulted in the discovery of specific genes causing autosomal dominant, autosomal recessive, and X-linked forms of IGD (see Table 3 and Table 4). Additionally, digenic cases of normosmic IGD (nIGD) and Kallmann syndrome have been reported with affected individuals harboring two or more mutations in genes known to contribute to GnRH deficiency [Pitteloud et al 2007a, Canto et al 2009, Sykiotis et al 2010].

The genetic causes of Kallmann syndrome and nIGD are summarized in Table 3 and Table 4. Some genes (FGFR1, FGF8, PROKR2, PROK2, CHD7) have been associated with both anosmic and normosmic IGD.

Table 3. Causes of Kallmann Syndrome (IGD with Anosmia)

Inheritance% of Kallmann SyndromeGenetic MechanismAdditional FindingsReferenceGenetic Test Availability
Chromosomal RareDeletion Xp22.3 →pterShort stature, chondrodysplasia punctata, intellectual disability, steroid sulfatase deficiency, ichthyosisBallabio et al [1989]Clinical
Image testing.jpg
Autosomal dominant 10%FGFR1 mutation 1Cleft lip/palate, dental agenesis, brachydactyly, syndactyly, corpus callosum agenesis 1Dodé et al [2003], Pitteloud et al [2006b] Clinical
Image testing.jpg
5%PROKR2 mutation 1Obesity, pectus excavatum, seizures, synkinesia, high-arched palate, pes planus, hyperlaxity of digits, hearing loss 1Dodé et al [2006], Pitteloud et al [2007b], Abreu et al [2008], Cole et al [2008]Clinical
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<5%PROK2 mutation 1Clinical
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5%-10%CHD7 mutation 1, 2High-arched or cleft palate, dental agenesis, auricular dysplasia, deafness, coloboma, short stature 1, 2Kim et al [2008], Jongmans et al [2009]Clinical
Image testing.jpg
<5%FGF8 mutation 1Cleft lip/palate, hyperlaxity of the digits, hearing loss, ocular hypertelorism, camptodactyly 1Falardeau et al [2008], Trarbach et al [2010]Research only
X-linked 5%-10%KAL1 mutation/deletionSynkinesia 3, unilateral renal agenesis, sensorineural hearing loss, high-arched palate, cryptorchidism and/or microphallus at birthGeorgopoulos et al [1997], Oliveira et al [2001] Clinical
Image testing.jpg
Unknown 60%-75%Bianco & Kaiser [2009]

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Also associated with normosmic IGD in some cases

2. Can be associated with the broader phenotype of CHARGE syndrome (see Table 2)

3. Mirror movement of digits

Table 4. Causes of Normosmic Isolated GnRH Deficiency (nIGD)

Inheritance% of Normosmic IGDGenetic MechanismPhenotypeReferenceGenetic Test Availability
Autosomal dominant <5%FGFR1 mutation 1Cleft lip/palate, dental agenesis, brachydactyly 1Pitteloud et al [2006b], Trarbach et al [2006] Clinical
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<5%PROK2 mutation 1Isolated GnRH deficiency 1Dodé et al [2006], Abreu et al [2008], Cole et al [2008] Clinical
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<5%PROKR2 mutation 1Obesity, pectus excavatum, seizures, synkinesia, high-arched palate, pes planus, hyperlaxity of digits, hearing loss 1Abreu et al [2008], Cole et al [2008]Clinical
Image testing.jpg
5%-10%CHD7 mutation 1High-arched or cleft palate, dental agenesis, auricular dysplasia, deafness, coloboma, short stature 1Kim et al [2008]Clinical
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<5%FGF8 mutation 1Cleft lip/palate, hearing loss 1Trarbach et al [2010]Research only
Autosomal recessive 5%-40%GNRHR mutationIsolated abnormality in GnRH secretion or responsede Roux et al [1997], Cerrato et al [2006], Bédécarrats & Kaiser [2007] Clinical
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2%-5% KISS1R mutationde Roux et al [2003], Seminara et al [2003], Semple et al [2005] Clinical
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<5%TACR3 mutationTopaloglu et al [2009], Guran et al [2009], Gianetti et al [2010]Clinical
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<5%TAC3 mutation Topaloglu et al [2009]Research only
<5%GNRH1 mutationBouligand et al [2009], Chan et al [2009]Research only
X-linked UnknownDAX1 mutation/deletionX-linked adrenal hypoplasia congenitaVilain [2009]Clinical
Image testing.jpg
Unknown ~50% Bianco & Kaiser [2009]

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Also associated with Kallmann syndrome in some cases

Evaluation Strategy

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Once other causes of hypogonadism are excluded (see Differential Diagnosis) and the diagnosis of isolated GnRH deficiency (IGD) has been established in an individual, the following approach can be used to determine the specific cause of IGD to aid in discussions of prognosis and genetic counseling.

Family history. A three-generation family history should include questions regarding consanguinity and findings in the proband and relatives including: pubertal development, anosmia, craniofacial abnormalities (cleft lip/palate/missing teeth), hearing loss, synkinesia of the digits, microphallus and cryptorchidism, and morbid obesity. If other individuals with IGD or these associated findings are identified in the family, the mode of inheritance may become apparent. In the majority of individuals, however, no such family history is present.

Past medical history is appropriate to determine whether cryptorchidism and/or microphallus were present at birth.

Physical examination to determine the degree of GnRH deficiency and the presence of associated signs and symptoms can direct attention to nIGD or Kallmann syndrome.

Molecular genetic testing is clinically available for some disorders (see Table 3 and Table 4: Genetic Test Availability).

Genetic Counseling

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Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

Mode of Inheritance

Isolated GnRH deficiency (IGD) is more frequently simplex (i.e., a single occurrence in a family) (~2/3) and the cause may be unknown. Approximately one third of IGD has an identifiable cause: chromosomal deletion or autosomal dominant, autosomal recessive, X-linked, or digenic inheritance.

If a family history of IGD is present or if a genetic cause is identified through physical examination and/or molecular genetic testing (see Table 3 and Table 4), the mode of inheritance may be clear.

If a proband has an inherited or de novo chromosome abnormality or a mutation in a specific gene causing IGD, genetic counseling is indicated.

Empiric Risks to Family Members

Specific issues. If it is not possible to determine the mode of inheritance, the individual with IGD should be counseled that IGD may have a genetic cause, and that his/her offspring may be at risk of inheriting the mutation.

Variable expressivity and incomplete penetrance of IGD-causing genetic mutations have been documented, particularly in genes in which the inheritance pattern of mutations is described as “autosomal dominant” (see Table 3 and Table 4). Thus, the phenotypically normal sib of a proband could have a mutation that could be expressed in his/her offspring. Digenicity may account for the variable expressivity or incomplete penetrance in families.

Unfortunately, limited knowledge of the genes involved and the absence of clinical tests to identify mutations means that in most instances of IGD it is not possible to provide accurate information on the risk to the offspring or sibs of the proband.

Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See Image testing.jpg for a list of laboratories offering DNA banking.

Management

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Evaluations Following Initial Diagnosis of Isolated GnRH Deficiency

To establish the extent of disease and needs of an individual diagnosed with isolated GnRH deficiency (IGD), the following evaluations are recommended:

In addition to assessing the degree of hypogonadism/GnRH deficiency, potential deterioration in bone health that may have resulted from periods of low-circulating sex hormones needs to be addressed. Depending on the timing of puberty, duration of GnRH deficiency, and other osteoporotic risk factors (e.g., glucocorticoid excess, smoking), one should consider obtaining a bone mineral density study (see Treatment of Manifestations: Bone Mineral Density).

Treatment of Manifestations

Treatment options for the hypogonadism of IGD include sex steroids, gonadotropins, and pulsatile GnRH administration. Choice of therapy is determined by the goal(s) of treatment, i.e., to induce and maintain secondary sex characteristics and/or to bring about fertility.

Sex Steroid Replacement

As the majority of individuals with IGD have not progressed through puberty, one of the initial challenges in treating these individuals is the initiation of the process of sexual maturation. When fertility is not immediately desired, replacement with gonadal steroids is the most practical option. Initial therapy should be started at low doses and gradually increased with the development of secondary characteristics.

For males with IGD

  • Testosterone replacement. In boys or men with prepubertal features, normal virilization can be effectively achieved with testosterone replacement.

    • Occasionally, low dose testosterone is given in early infancy to young boys with micropenis when IGD is first identified [Bin-Abbas et al 1999].

    • Boys do not generally need to be treated until the time of puberty. Usual starting doses are 25-50 mg of a long-acting testosterone ester given intramuscularly every two weeks.

    • The doses can be gradually increased by 25-50 mg every two to three months until full virilization is achieved.

    • Once adult doses (~200 mg/2 weeks) are reached, further adjustments are based on serum testosterone levels.

    • Transdermal methods of testosterone administration can also be used; they have the added benefit of offering a more favorable pharmacokinetic profile.

    • Therapy should be continued indefinitely to ensure normal sexual function and maintenance of proper muscle, bone, and red blood cell mass.

  • Human chorionic gonadotropin (hCG) injections can also be used to normalize serum concentration of testosterone and induce development of secondary sexual characteristics. Treatment with hCG is usually initiated at 1,000 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentrations. Although treatment with hCG can also promote testicular growth, this treatment must be weighed against the increased risk of developing gynecomastia that occurs as a result of the stimulation of estrogen production from the testes by hCG. To some extent this side effect can be minimized by gradually reducing the dose of hCG to the minimum required to sustain a serum testosterone concentration in the >300 ng/dL range. Ultimately, the determination of which formulation to choose is based on the preference of the individual being treated.

For females with IGD. Initial treatment for congenital IGD should consist of unopposed estrogen replacement via one of several modes of treatment to allow optimal breast development. After a period of approximately six months, when breast development has been optimized, a progestin should be added for endometrial protection.

Many formulations of estrogens and progestins are available and these can be given in either cyclical or continuous fashion. Preference of the individual plays an important role in choosing the right treatment plan, although low estrogen formulations should be considered in individuals with clotting abnormalities (see Factor V Leiden Thrombophilia and Prothrombin Thrombophilia).

Fertility Induction

For males with IGD. Although androgen administration helps maintain normal sexual function, gonadotropins are usually required to realize the fertility potential in males with IGD.

  • Gonadotropin therapy. Traditionally, a combination of gonadotropins (hCG and human menopausal gonadotropins [hMG] or recombinant FSH [rFSH]) is utilized to stimulate spermatogenesis. Treatment with hCG is usually initiated at 1,000 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentration. FSH is added to the regimen at doses ranging from 37.5 to 75 IU as either hMG or recombinant formulation. Depending on the initial testicular volume, some males with IHH can produce sufficient sperm to achieve conception with hCG treatment alone [Burris et al 1988]. However, if after six to nine months, semen analysis reveals persistent azoospermia or marked oligospermia, FSH is added to the regimen at doses ranging from 37.5 to 75 IU as either hMG or recombinant formulation. Liu et al [2009] have also noted that previous treatment with gonadotropins may result in a shortened period of subsequent gonadotropin treatment initiation to spermatogenesis.

    Testicular volume must be tracked, as it is one of the primary determinants of successful spermatogenesis. In fact, sperm are rarely seen in the semen analysis until testicular volume reaches 8 mL [Whitcomb & Crowley 1990]. In individuals without a history of cryptorchidism, sperm function is usually normal and conception can occur even with relatively low sperm counts.

  • Pulsatile GnRH stimulation. An alternative method for induction of spermatogenesis is pulsatile GnRH. As the primary defect of IGD is typically localized to the hypothalamus, the pituitary responds appropriately to physiologic doses of GnRH. GnRH therapy usually fails if a pituitary defect exists, making gonadotropin therapy the treatment of choice in such cases.

    Subcutaneous administration of GnRH in a pulsatile manner through a portable pump that delivers a GnRH bolus every two hours is an efficient way of inducing testicular growth and spermatogenesis [Pitteloud et al 2002]. Although gonadotropin therapy or pulsatile GnRH stimulation can induce spermatogenesis in approximately 90%-95% of men with IGD, some men have a better response to pulsatile GnRH stimulation than to gonadotropin therapy. However, pulsatile GnRH therapy is not currently approved by the Food and Drug Administration for the treatment of infertility in men and thus is available for treatment of infertility in men only at specialized research centers.

  • In vitro fertilization. Successful spermatogenesis can be obtained in most males with IGD through pulsatile GnRH therapy or combined gonadotropin therapy. Men with IGD usually do not have a defect in sperm function; thus, low sperm numbers can often result in conception. However, if infertility remains a problem despite successful spermatogenesis, in vitro fertilization is increasingly an option.

For females with IGD

  • Pulsatile GnRH stimulation is also an approved therapy for folliculogenesis in women with IGD. Intravenous administration of GnRH at various frequencies throughout the menstrual cycle closely mimics normal cycle dynamics with the resulting ovulation of a single follicle [Santoro et al 1986]. This therapy offers a clear advantage over the traditional treatment with exogenous gonadotropins, which involves higher rates of both multiple gestation and ovarian hyperstimulation syndrome. For either approach, however, the rate of conception is approximately 30% per ovulatory cycle [Martin et al 1990].

Bone Mineral Density

Specific treatment for decreased bone mass should be considered depending on the degree of bone mineralization. (See Evaluations Following Initial Diagnosis of IGD.)

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Resources

Go to:

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.

References

Go to:

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Chapter Notes

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Revision History

  • 14 October 2010 (me) Comprehensive update posted live

  • 23 May 2007 (me) Review posted to live Web site

  • 1 June 2006 (jcp) Original submission

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