Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism 

Updated: Aug 07, 2018
Author: Nicholas A Tritos, MD, DSc, MMSc, FACP, FACE; Chief Editor: George T Griffing, MD 

Overview

Background

Classic Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH) are rare genetic conditions that encompass the spectrum of isolated hypogonadotropic hypogonadism. Most patients have gonadotropin-releasing hormone (GnRH) deficiency, as suggested by their response to pulsatile GnRH therapy. Hypothalamic-pituitary function is otherwise normal in most patients, and hypothalamic-pituitary imaging reveals no space-occupying lesions. By definition, either anosmia (lack of sense of smell) or severe hyposmia is present in patients with Kallmann syndrome, in contrast to patients with idiopathic hypogonadotropic hypogonadism, whose sense of smell is normal.

Pathophysiology

Deficient hypothalamic GnRH secretion underlies the markedly abnormal gonadotropin secretion patterns in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. The result is hypogonadism; infertility; and absent, incomplete, or partial pubertal maturation.

Some of the genes involved in the pathogenesis of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism have been identified. However, the genes involved remain unidentified in over 50% of patients.[1]  These conditions can be transmitted as autosomal dominant, autosomal recessive or X linked traits. Of note, oligogenic inheritance has been well-described.

Mutations of the KAL1 gene, which encodes a putative neural cell adhesion molecule (anosmin), have been described in several patients with X-linked Kallmann syndrome. In these patients, GnRH deficiency and anosmia are believed to be secondary to abnormalities of neuronal migration during development.

Loss-of-function mutations of the gene encoding fibroblast growth factor receptor 1 (FGFR1) have been described in patients with autosomal dominant Kallmann syndrome.[2, 3] Heterozygous loss-of-function mutations of the gene encoding FGFR1 have also been described in individuals with idiopathic hypogonadotropic hypogonadism, normal smell sense, and normal MRI of the olfactory system.[4]  Of note, anosmin may enhance fibroblast growth factor signaling through the fibroblast growth factor receptor 1.

Mutations of the gene encoding fibroblast growth factor 8 have been found in a small minority of patients with autosomal dominant Kallmann syndrome.[3] In addition, mutations of the gene encoding chromodomain-helicase DNA-binding protein 7 (CHD7) have been found in some patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism, some of whom have features of the CHARGE syndrome (characterized by delayed growth and development, congenital cardiac defects, dysmorphic ears, hearing loss, coloboma of the eyes).

Loss-of-function mutations of critical components of the prokineticin pathway have been implicated in the pathogenesis of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism.[5, 6] Specifically, homozygous mutations of prokineticin 2 were found in 2 brothers with Kallmann syndrome and in their sister, who had idiopathic hypogonadotropic hypogonadism.[7] Homozygous, heterozygous or compound heterozygous mutations of the prokineticin receptor 2 have also been associated with Kallmann syndrome.[8] Digenic inheritance has been suggested in an individual carrying heterozygous mutations of prokineticin receptor 2 and KAL1.[8, 9]

Mutations of the DAX1 gene, which encodes a nuclear transcription factor, lead to X-linked idiopathic hypogonadotropic hypogonadism associated with adrenal hypoplasia congenita (AHC).[10] Mutations of genes encoding either leptin or the leptin receptor underlie isolated cases of autosomally transmitted idiopathic hypogonadotropic hypogonadism associated with early-onset obesity.[11] Several loss-of-function mutations of the GnRH receptor gene leading to GnRH resistance and autosomally transmitted hypogonadotropic hypogonadism have been described.[12] In addition, autosomal recessive mutations of the GnRH gene may underlie hypogonadotropic hypogonadism.

Rarely, hypogonadotropic hypogonadism occurs as a result of isolated follicle-stimulating hormone (FSH) deficiency due to homozygous mutations in the FSH beta subunit gene. In one patient, isolated bioinactive luteinizing hormone (LH) was present as a result of a homozygous mutation in the LH beta subunit gene, which prevented binding of LH to its receptor. This patient presented with hypogonadotropic hypogonadism, despite high levels of immunoreactive serum LH. A second patient had a different homozygous mutation in the LH beta subunit gene that prevented LH heterodimerization and secretion. He presented with hypogonadotropic hypogonadism and undetectable serum LH.

In another patient, a mutation in the prohormone convertase gene (PC1) led to hypogonadotropic hypogonadism, in addition to extreme obesity, hypocortisolemia, and deficient conversion of proinsulin to insulin.

Homozygous mutations in KISS1R (kisspeptin 1 receptor gene, also known as GPR54), a gene encoding a G protein–coupled receptor, which binds kisspeptin 1, have been reported as a cause of hypogonadotropic hypogonadism.[13] Inactivating mutations of the gene encoding kisspeptin 1 may also underlie hypogonadotropic hypogonadism.[14] Kisspeptin 1 and its receptor have an important role in the regulation of GnRH and the onset of puberty.[15, 16]

Homozygous mutations in the genes encoding neurokinin B (TAC3) or its receptor (TACR3) have also been described in some patients with autosomal recessive idiopathic hypogonadotropic hypogonadism. Interestingly, reversal of hypogonadism during adult life has been described in patients with these mutations.

Heterozygous missense mutations of the NSMF (NMDA receptor synaptonuclear signaling and neuronal migration factor, also known as NELF) gene have been associated with Kallmann syndrome.[17] Mutations of additional genes have been implicated in the pathogenesis of Kallmann syndrome and/or hypogonadotropic hypogonadism, including the following genes: WDR11, FGF17, IL17RD, DUSP6, SPRY4, FLRT3, AXL, SOX10,SEMA3A, and HS6ST11.[3, 18, 19, 20, 21, 22, 23]

A study by Turan et al that described the phenotype and prevalence of CCDC141 mutations in idiopathic hypogonadotropic hypogonadism/Kallmann syndrome confirmed that inactivating CCDC141 variants cause normosmic idiopathic hypogonadotropic hypogonadism but not Kallmann syndrome.[24]

Epidemiology

Frequency

International

The prevalence of idiopathic hypogonadotropic hypogonadism was approximately 1 in 10,000 men in a study of French conscripts.[25] A study of Sardinian military recruits reports the prevalence of hypogonadism associated with anosmia (Kallmann syndrome) as 1 in 86,000 men.[26] Methodological limitations of case ascertainment by medical record review should be kept in mind when interpreting these findings.

Mortality/Morbidity

Associated complications affect the patient's quality of life and his/her survival.

  • Patients with Kallmann syndrome and those with idiopathic hypogonadotropic hypogonadism survive long term if they do not have associated conditions such as congenital heart disease or neurologic manifestations.

  • Adrenocortical insufficiency is fatal unless recognized and treated. Thyroid function must also be assessed. In patients who do not receive adequate gonadal steroid replacement, hypogonadal osteoporosis may develop insidiously.

Sex

The male-to-female ratio ranges from 4:1 to 5:1.

The male-to-female ratio is approximately 2.5:1 among strictly familial Kallmann syndrome and idiopathic hypogonadotropic hypogonadism cases.

Age

Classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism are both congenital disorders.

Adult-onset or acquired idiopathic hypogonadotropic hypogonadism has recently been described in men aged 30-50 years.

Hypothalamic amenorrhea represents an acquired form of GnRH deficiency that occurs predominantly among young women and may be associated with excessive exercise, extreme weight loss, or psychogenic stress. This may occur particularly in patients with anorexia nervosa.

 

Presentation

History

Because classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism are both congenital disorders, the terms classic and congenital are used interchangeably to refer to Kallmann syndrome and idiopathic hypogonadotropic hypogonadism.[27]

Patients with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism may not experience puberty or may experience incomplete puberty and have symptoms associated with hypogonadism. For men, these symptoms include decreased libido, erectile dysfunction, decreased muscle strength, and diminished aggressiveness and drive. For women, symptoms include amenorrhea and dyspareunia. Notably, patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism do not experience hot flashes.

All patients with Kallmann syndrome have either anosmia or severe hyposmia and may exhibit symptoms of associated conditions including those of congenital heart disease (eg, fatigue, dyspnea, cyanosis, palpitations, syncope) or neurologic manifestations (eg, color blindness, hearing deficit, epilepsy, paraplegia).[28]

Absent or incomplete puberty

Some male patients may present with microphallus and cryptorchidism during the neonatal period. Patients with either classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism report no pubertal maturation; however, occasionally, individuals have a history of partial progression through puberty. These male patients were previously labeled fertile eunuchs.

Family members of patients with idiopathic hypogonadotropic hypogonadism may have a history of delayed, although otherwise normal, puberty. This occurs in 12-15% of family members, versus 1% in the general population. Whether these individuals actually represent one end of the spectrum of idiopathic hypogonadotropic hypogonadism is unclear.

Delayed, but otherwise normal, puberty has also been reported in female carriers of DAX1 mutations who have family members with X-linked idiopathic hypogonadotropic hypogonadism associated with AHC.

Decreased libido and erectile dysfunction

These symptoms are almost universal in men with either Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Androgen replacement improves libido and erectile function.

Amenorrhea

Primary amenorrhea develops in the vast majority of women with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Women with hypothalamic amenorrhea present with secondary amenorrhea, typically precipitated by excessive exercise, weight loss, or psychological stress.

Dyspareunia

This may occur in women because of decreased vaginal lubrication.

Infertility

Almost all untreated patients are infertile.

Individuals with adult-onset idiopathic hypogonadotropic hypogonadism may present with infertility and a history of previously documented fertility.

In either Kallmann syndrome or idiopathic hypogonadotropic hypogonadism, restoring fertility is possible in patients who generally respond to treatment with pulsatile GnRH or gonadotropins.

Decreased muscle strength and diminished aggressiveness and drive (in men)

These symptoms are ameliorated significantly by androgen replacement.

Cautioning patients' families about possible behavioral changes in response to such therapy is helpful.

Osteoporosis

All hypogonadal patients are at high risk of osteoporosis if untreated.

Although asymptomatic, patients have a greater fracture risk.

Androgen or estrogen replacement therapy may prevent or ameliorate osteoporosis in men or women, respectively.

Anosmia or hyposmia

Male and female patients with Kallmann syndrome have either an absent or severely impaired sense of smell.

Patients may not be aware of the deficit and must be specifically tested.

Family members of patients with Kallmann syndrome, including female obligate carriers in X-linked Kallmann syndrome pedigrees, may have anosmia or hyposmia without hypogonadism and may represent one end of the spectrum of Kallmann syndrome.

Fatigue, dyspnea, cyanosis, palpitations, syncope

Patients with Kallmann syndrome may have any of these symptoms as manifestations of congenital heart disease such as atrial septal defect (ASD), ventricular septal defect (VSD), Ebstein anomaly, transposition of the great vessels, right aortic arch, atrioventricular block, right bundle-branch block, and Wolff-Parkinson-White (WPW) syndrome.

A detailed discussion of these conditions is beyond the scope of this review.

Color blindness, sensorineural deafness, paraplegia, or epilepsy

These occur in a minority of patients with Kallmann syndrome.

Skeletal abnormalities

Patients with mutations interfering with FGF signaling may have cleft lip, cleft palate or syndactyly.

Symptoms of primary adrenocortical insufficiency

This occurs in males with X-linked idiopathic hypogonadotropic hypogonadism and AHC.

These patients typically present in infancy or childhood with adrenal crisis.

A detailed discussion of these symptoms is beyond the scope of this review.

Physical

Physical findings associated with hypogonadism include eunuchoidal skeletal proportions.

A low ratio, less than 1:1 in adults, of the upper body segment (crown to pubis) to the lower body segment (pubis to heels) is present only in patients with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Similarly, an arm span greater than height by more than 5 cm is observed only in patients with congenital Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Height for age is normal in these patients, distinguishing them during adolescence from individuals with constitutional delay in growth and development because adolescents in the latter group tend to be short for chronological age.

Absence of terminal facial hair and decreased body hair is observed in men with Kallmann syndrome or who have congenital idiopathic hypogonadotropic hypogonadism. Men with adult-onset idiopathic hypogonadotropic hypogonadism may report decreased shaving frequency. In addition, lack of temporal hair recession (male-type baldness) is noted in men with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

High-pitched voice is present only in men with Kallmann syndrome or congenital idiopathic hypogonadotropic hypogonadism.

Lack of breast development is observed in women with Kallmann syndrome or congenital idiopathic hypogonadotropic hypogonadism. Women with long-standing hypothalamic amenorrhea may experience a decrease in breast size.

Gynecomastia is observed only rarely in men with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism at the time of diagnosis, but it may occur as an adverse effect of androgen replacement therapy in these patients.

Muscle mass is decreased, muscle strength is diminished, and fat is distributed over the hips and chest, particularly in men with Kallmann syndrome or congenital idiopathic hypogonadotropic hypogonadism.

Axillary and pubic terminal hair may be scantly present in these patients (with the exception of patients with X-linked idiopathic hypogonadotropic hypogonadism and AHC) because of circulating adrenal androgens. Males with Kallmann syndrome or congenital idiopathic hypogonadotropic hypogonadism lack terminal hair growth along the midline towards the umbilicus.

Men with Kallmann syndrome or congenital idiopathic hypogonadotropic hypogonadism have prepubertal testes (< 4 mL) and lack scrotal pigmentation. Some patients (previously known as fertile eunuchs) experience some testicular growth in association with partial GnRH deficiency. Testicular volumes in patients with adult-onset idiopathic hypogonadotropic hypogonadism are either within the normal range or mildly decreased (10-15 mL). Cryptorchidism is present in a minority of men with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Males with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism have small penises (< 8 cm long in adults). In addition, prostate size is decreased, particularly in men with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

In women, the vaginal mucosa has a deep red color because of the lack of squamous epithelial differentiation.

All patients with Kallmann syndrome by definition have anosmia or severe hyposmia. Formal smell testing can be carried out by administering the Smell Identification Test (SIT, Sensonics, Haddon Heights, NJ), which is a standardized, multiple choice test that includes 40 scratch-and-sniff panels, each with 4 possible answers. Alternatively, the sense of smell can be evaluated by using serial dilutions of multiple odorants such as dimethyl sulfide, menthone, acetic acid, exaltolide, amyl acetate, cineole, and pm-carbinol (Olfacto Laboratories, El Cerrito, Calif), according to the protocol of Rosen and Rogol.

A small percentage of patients with Kallmann syndrome experience color blindness, as assessed by Ishihara plate testing. In addition, sensorineural hearing loss has been reported in some Kallmann syndrome patients.

Some patients with X-linked Kallmann syndrome and a contiguous gene syndrome may have ichthyosis.

Cleft lip, cleft palate, or high (arched) palate has been reported in 6-22% of patients with Kallmann syndrome. Short metacarpals and pes cavus also have been reported in a minority of Kallmann syndrome patients.

Cardiovascular findings are present in some patients with Kallmann syndrome who have congenital heart disease (including ASD, VSD, Ebstein anomaly, transposition of the great vessels, right aortic arch, atrioventricular block, right bundle-branch block, and WPW syndrome). A detailed discussion of these findings is beyond the scope of this review.

Neuropsychiatric findings that exist in a minority of patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism include abnormal eye movements (including gaze-evoked horizontal nystagmus, abnormal pursuit, and saccades), synkinesia (mirror movements of the opposite upper extremity), paraplegia, cerebellar ataxia, and learning disability (secondary to mental retardation). Synkinesia has been reported only in X-linked Kallmann syndrome patients.

Conditions associated with primary adrenocortical insufficiency are present in males with X-linked idiopathic hypogonadotropic hypogonadism and AHC. A detailed discussion of these conditions is beyond the scope of this review.

Early-onset obesity is present in patients with idiopathic hypogonadotropic hypogonadism and mutations of either the leptin gene or the leptin receptor gene.

Causes

Classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism are congenital genetic disorders.[29, 30] Approximately one third of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism cases appear to be inherited. The remaining two thirds of all Kallmann syndrome and idiopathic hypogonadotropic hypogonadism cases appear to be sporadic and may represent new mutations. Genetic transmission appears to be autosomal dominant (approximately 64% of families), autosomal recessive (about 25% of families), or X-linked (about 11% of families). Oligogenic inheritance is also well-described.

Some of the genes associated with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism have been identified, including mutations of the KAL1 gene, which cause X-linked Kallmann syndrome. The KAL1 gene (present on band Xp22.3) encodes anosmin-1, a putative neural cell adhesion molecule that is essential for the migration of olfactory neuron axons toward the olfactory bulb and the establishment of synaptic connections between these axons and the mitral cells present in the olfactory bulb. The GnRH synthesizing neurons originate in the olfactory placode (outside the brain) and migrate along the olfactory neuron axons to their final location in the brain in a process that is also critically dependent on the presence of anosmin-1.

Several mutations of the KAL1 gene have been reported in about 50% of patients with X-linked Kallmann syndrome. In these patients, lack of anosmin-1 leads to disruption of the olfactory pathway, causing anosmia and absence of GnRH neuronal migration, resulting in GnRH deficiency (hypothalamic secretory defect only) and hypogonadotropic hypogonadism.

Some patients presenting with X-linked Kallmann syndrome and ichthyosis have a contiguous gene syndrome secondary to large interstitial deletions of Xp22.3 that include at least part of the coding regions of the KAL1 gene and the steroid sulfatase gene.

Loss-of-function mutations of the gene encoding FGFR1 have been described in patients with autosomal dominant Kallmann syndrome. In addition, mutations of the gene encoding fibroblast growth factor 8 have been found in a small minority of patients with autosomal dominant Kallmann syndrome. Furthermore, mutations of the gene encoding chromodomain-helicase DNA-binding protein 7 have been found in some patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Loss-of-function mutations of critical components of the prokineticin pathway have been implicated in the pathogenesis of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism.[5, 6] Specifically, homozygous mutations of prokineticin 2 were found in 2 brothers with Kallmann syndrome and in their sister, who had idiopathic hypogonadotropic hypogonadism.[7] Homozygous, heterozygous, or compound heterozygous mutations of the prokineticin receptor 2 have also been associated with Kallmann syndrome.[8] Digenic inheritance has been suggested in an individual carrying heterozygous mutations of prokineticin receptor 2 and KAL1.[8, 9]

Mutations of the DAX1 gene lead to X-linked idiopathic hypogonadotropic hypogonadism and AHC.[31] The DAX1 gene (present on band Xp21) encodes a putative orphan receptor (without known ligand) that belongs to the steroid hormone receptor superfamily and is believed to be a transcription factor with a critical function in the development of the hypothalamic-pituitary-gonadal axis and the adrenal cortex. Males with mutations in the DAX1 gene present with AHC (primary adrenocortical insufficiency in infancy or childhood) and idiopathic hypogonadotropic hypogonadism. Limited data suggest that, in these patients, idiopathic hypogonadotropic hypogonadism may be acquired postnatally but before the expected onset of puberty. In contrast to patients with Kallmann syndrome and most other patients with idiopathic hypogonadotropic hypogonadism, these individuals have hypothalamic and pituitary gonadotroph secretory defects and may also have intrinsic defects in spermatogenesis. One case involving a female patient with a homozygous DAX1 mutation and idiopathic hypogonadotropic hypogonadism without AHC has been reported.

Mutations of either the leptin gene or the leptin receptor gene lead to autosomal recessive idiopathic hypogonadotropic hypogonadism and early-onset obesity.[11]  Patients with homozygous mutations of the leptin gene present with early onset, severe obesity, and idiopathic hypogonadotropic hypogonadism secondary to a hypothalamic defect in GnRH secretion.

Patients with homozygous mutations of the leptin receptor also present with early-onset, morbid obesity and idiopathic hypogonadotropic hypogonadism. In contrast to patients with Kallmann syndrome, as well as the vast majority of idiopathic hypogonadotropic hypogonadism cases, reported patients with leptin receptor mutations have central hypothyroidism as well as decreased growth hormone (GH) secretion, presumably on the basis of hypothalamic dysfunction.

Mutations of the GnRH receptor gene cause GnRH resistance and autosomal recessive idiopathic hypogonadotropic hypogonadism. In addition, mutations of the gene encoding for GnRH itself have been described in patients with hypogonadotropic hypogonadism.[3]  

Homozygous or compound heterozygous mutations of the GnRH receptor have been found in approximately 40% of autosomal recessive and 15% of sporadic cases of patients with idiopathic hypogonadotropic hypogonadism, who may present with either complete hypogonadotropic hypogonadism secondary to GnRH resistance or who may have some evidence of pubertal maturation, albeit incomplete.[32]

Rarely, hypogonadotropic hypogonadism occurs as a result of isolated FSH deficiency due to homozygous mutations in the FSH beta subunit gene. In one patient, isolated bioinactive LH was present because of a homozygous mutation in the LH beta subunit gene, which led to the secretion of LH with reduced binding affinity to its receptor, causing hypogonadotropic hypogonadism. A second patient was found to have a different homozygous mutation in the LH beta subunit gene; the mutation prevented LH heterodimerization and secretion.

In another patient, a mutation in PC1 led to hypogonadotropic hypogonadism, in addition to extreme obesity, hypocortisolemia, and deficient conversion of proinsulin to insulin.

Homozygous mutations in KISS1R (kisspeptin 1 receptor gene, also known as GPR54), a gene encoding a G protein–coupled receptor which binds kisspeptin 1, have been reported as a cause of hypogonadotropic hypogonadism. In addition, mutations of the gene encoding kisspeptin 1 may underlie the presence of hypogonadotropic hypogonadism. Kisspeptin 1 and its receptor have an important role in the regulation of GnRH and the onset of puberty.[13] Also of note, heterozygous missense mutations of the NSMF (NMDA receptor synaptonuclear signaling and neuronal migration factor, also known as NELF) gene have been associated with Kallmann syndrome.

Homozygous mutations in the genes encoding neurokinin B (TAC3) or its receptor (TACR3) have also been described in some patients with autosomal recessive idiopathic hypogonadotropic hypogonadism. Interestingly, reversal of hypogonadism during adult life has been described in patients with these mutations.

Mutations of many additional genes have been implicated in the pathogenesis of Kallmann syndrome and/or hypogonadotropic hypogonadism, including the following genes: WDR11, FGF17, IL17RD, DUSP6, SPRY4, FLRT3, AXL, SOX10,SEMA3A, and HS6ST11.[3]

Although no risk factors can be identified in a large subset of patients with hypothalamic amenorrhea, the condition is associated with strenuous exercise (eg, running >20 min/wk), excessive weight loss, anorexia nervosa, and psychogenic stress. Recent data indicate that mutations in some of the genes associated with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism are also implicated in the pathogenesis of hypothalamic amenorrhea in some patients.[33]

The cause of adult-onset idiopathic hypogonadotropic hypogonadism in males is unknown. Notably, strenuous exercise, excessive weight loss, an eating disorder, or psychogenic stress is absent.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Serum electrolytes

Serum electrolyte levels are within reference range in patients with classic Kallmann syndrome.

Patients with idiopathic hypogonadotropic hypogonadism secondary to DAX1 gene mutations typically present with early-onset adrenocortical insufficiency and may have hyponatremia and hyperkalemia before specific treatment is begun.

Serum ferritin

Serum ferritin levels are within reference range in all patients with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism.

The serum ferritin level should be measured in suspected adult-onset idiopathic hypogonadotropic hypogonadism cases to rule out hemochromatosis, an important cause of acquired hypogonadotropic hypogonadism.

Serum or urine beta-human chorionic gonadotropin level (pregnancy test)

This test should be performed for all patients with secondary amenorrhea, including suspected hypothalamic amenorrhea, to rule out pregnancy.

Serum (total or free) testosterone

Serum (total or free) testosterone is always decreased in postpubertal-aged males with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. These patients usually have very low total serum testosterone levels (< 100 ng/dL in adults). Measuring the serum free testosterone level rather than the total testosterone level has no advantage in the diagnosis of Kallmann syndrome or idiopathic hypogonadotropic hypogonadism except in very obese individuals. Obesity decreases the sex hormone–binding globulin (SHBG) level and therefore decreases the total testosterone level.

The serum testosterone level is not increased in females with hypothalamic amenorrhea, but it should be measured to exclude hyperandrogenic disorders, such as polycystic ovary syndrome.

Serum estradiol

The serum estradiol level is decreased in postpubertal-aged females with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism but has limited diagnostic value.

Serum extraction by chromatography should be performed prior to estradiol assay in order to improve the precision and sensitivity of the assay in suspected cases of estrogen deficiency.

Serum luteinizing hormone and follicle-stimulating hormone

See the image below.

This is a frequently sampled serum luteinizing hor This is a frequently sampled serum luteinizing hormone (LH) profile in a male patient with Kallmann syndrome (KS) in comparison with a healthy individual. It shows lack of LH pulsatility in the former.

Serum LH and FSH levels are low-normal or decreased in postpubertal-aged patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. Gonadotropin levels are inappropriate relative to the serum levels of testosterone or estradiol.

These test results are of diagnostic value in postpubertal-aged patients because they help differentiate Kallmann syndrome or idiopathic hypogonadotropic hypogonadism from primary gonadal dysfunction, including Turner syndrome and Klinefelter syndrome.

Serum LH and FSH levels cannot reliably distinguish between Kallmann syndrome or idiopathic hypogonadotropic hypogonadism patients and individuals with constitutional delay in growth and development.

Serum thyroid-stimulating hormone and serum free thyroxine (or free thyroxine index)

These tests are used to screen for secondary hypothyroidism.

Serum thyroid-stimulating hormone (TSH) and free thyroxine levels are within reference range in patients with classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism.

Patients with idiopathic hypogonadotropic hypogonadism and severe obesity secondary to mutations of the leptin receptor gene may have secondary hypothyroidism, including a normal or low TSH level and a low serum free thyroxine level.

Serum insulin-like growth factor I and serum insulin-like growth factor binding protein 3

These tests are used to screen for GH deficiency in childhood but have poor diagnostic sensitivity in adults.

These test results are within reference range in patients with classic Kallmann syndrome.

Patients with idiopathic hypogonadotropic hypogonadism and severe obesity secondary to mutations of the leptin receptor gene may have decreased GH secretion, including low insulinlike growth factor I (IGF I) and insulinlike growth factor binding protein 3 (IGFBP 3) levels.

Early morning serum cortisol and plasma adrenocorticotropic hormone

These tests are used to screen for adrenocortical insufficiency in patients with suspected idiopathic hypogonadotropic hypogonadism. A morning serum cortisol level that is higher than 18 mcg/dL suggests adequate glucocorticoid secretory reserve.

Patients with idiopathic hypogonadotropic hypogonadism secondary to DAX1 gene mutations typically present with early-onset primary adrenocortical insufficiency, including a low morning serum cortisol level and high plasma adrenocorticotropic hormone (ACTH) levels.

Serum prolactin

Serum prolactin levels are normal in patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

This level should be measured in order to exclude hyperprolactinemic conditions, such as infiltrative hypothalamic disorders (including sarcoidosis and histiocytosis X) and prolactin-secreting pituitary tumors.

Semen analysis

Semen analysis should be conducted in male patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism before recommending either fertility therapy or contraception.

Although patients with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism have azoospermia or severe oligozoospermia, spontaneous recovery of gonadal axis function is possible.

Patients with the fertile eunuch variant may have apparently normal spermatogenesis despite low serum testosterone and LH levels.

Semen analysis is an important monitoring tool during any fertility therapy.

Imaging Studies

Magnetic resonance imaging of the brain

Patients with Kallmann syndrome and those with idiopathic hypogonadotropic hypogonadism have a structurally normal hypothalamus and pituitary gland. MRI helps exclude hypothalamic or pituitary lesions in patients with hypogonadism and low or normal serum gonadotropin levels.

Approximately 75% of patients with Kallmann syndrome have abnormal olfactory systems on MRI, including complete agenesis of olfactory bulbs and sulci, shallow olfactory sulci, or medial orientation of the olfactory sulci (opening into the interhemispheric fissures, as shown below).[34]

MRI of the brain in patients with Kallmann syndrom MRI of the brain in patients with Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH). Panel A is a coronal T1-weighted image of a male with KS showing (abnormal) medially oriented olfactory sulci (black arrows) and normal appearing olfactory bulbs (white arrows). Panel B is an axial T1-weighted image of the same male with KS showing the presence of olfactory sulci (white arrows). Panel C is a coronal T1-weighted image of a female with IHH showing normal olfactory bulbs (large arrows) and sulci (small arrows). Panel D is a coronal T1-weighted image of a female with KS showing lack of olfactory bulbs with shallow olfactory sulci (arrows). (Images reproduced from Quinton R, et al: The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab 1996; 81: 3010-3017, with permission from the Endocrine Society).

Patients with idiopathic hypogonadotropic hypogonadism have normal olfactory systems on MRI.

Transthoracic echocardiogram

This test is helpful in screening for congenital heart disease, which is present in a small subset of patients with Kallmann syndrome. These abnormalities include ASD, VSD, Ebstein anomaly, transposition of the great vessels, and right aortic arch. A discussion of the pertinent echocardiographic findings is beyond the scope of this review.

Ultrasound examination of the kidneys

This test is helpful in excluding unilateral renal agenesis, which affects a small proportion of patients with Kallmann syndrome.

Bone densitometry by dual-energy radiographic absorptiometry (DXA)

DXA is recommended for all hypogonadal patients, including those with Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, or hypothalamic amenorrhea.

DXA is important in order to detect the presence of osteopenia or osteoporosis and to monitor the response of the skeleton to gonadal steroid replacement therapy.

Bone age

Estimate epiphyseal maturation (ie, bone age) by obtaining a radiograph of the left hand and wrist and comparing epiphyseal growth with standards (according to the method of Greulich and Pyle or the Tanner-Westinghouse method).

Delayed epiphyseal maturation is nonspecific and is present in individuals with untreated congenital hypogonadism, including classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism.

Bone age should be monitored in adolescents on gonadal steroid replacement in order to avoid excessive advance of epiphyseal maturation, which would compromise adult height.

Other Tests

Maturation index

Collecting epithelial cells from the upper third of the vagina with a spatula or cotton swab and evaluating a fixed smear by the Papanicolaou method provides an index of estrogen activity. Superficial mature cells represent at least 30% of all cells in women with normal menstrual cycles.

Although very sensitive (even more so than some serum estradiol assays), the method is subject to artifacts during processing and requires expertise in interpretation, thus limiting its use to experienced laboratories and its indications to the assessment of the adequacy of estrogen replacement in hypogonadal women.

Progestin-induced withdrawal bleeding

Administration of medroxyprogesterone (10 mg/d for 5 d) leads to secretory transformation of endometrium previously exposed to estrogen. Withdrawal bleeding (within a wk after finishing the 5-d course) indicates the presence of estrogen-primed endometrium.

Women with amenorrhea, including some women with hypothalamic amenorrhea, who experience withdrawal bleeding in this test have maintained some degree of estrogen secretion.

Women with a profound lack of estrogen, including patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism, are unlikely to respond.

Progestin-estrogen–induced withdrawal bleeding

Administration of estrogen such as conjugated estrogens (1.25-2.5 mg/d for 25-30 d) with medroxyprogesterone (10 mg/d for the last 10 d) is followed by withdrawal bleeding within 10 days after finishing the 1-month course in most women with amenorrhea secondary to hypogonadism, including Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. Lack of withdrawal bleeding in this test suggests the presence of abnormal endometrium (including uterine synechiae) or outflow obstruction.

Gonadotropin-releasing hormone stimulation test

This test is performed by measuring the serum LH and FSH level responses to the intravenous or subcutaneous administration of 100 mcg of GnRH (no longer commercially available in the US). Venous blood samples are obtained before GnRH (baseline) and at 15, 30, 45, and 60 minutes after GnRH administration.

Most patients with hypothalamic hypogonadism, including Kallmann syndrome or idiopathic hypogonadotropic hypogonadism, have a diminished gonadotropin response in this test (normal adult response is a 2- to 5-fold increase in LH levels and a smaller increase in FSH levels). Unfortunately, similar findings may also be observed in individuals with pituitary disease (eg, tumors). Some patients may have delayed or normal response.

Pulsatile administration of GnRH to patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism for a week usually restores subsequent pituitary responsiveness to GnRH.

Frequent serum sampling for luteinizing hormone levels

Measurement of serum LH levels at 10- to 20-minute intervals provides an indirect index of GnRH secretion in humans.

Pulse analysis indicates the absence of LH pulsations in the majority of patients with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism, though some may have LH pulses of low frequency or amplitude.

The presence of LH pulsations exclusively during sleep has been noted in some patients with a history of partial progression through puberty or in men with fertile eunuch syndrome.

In rare patients, immunoreactive (albeit biologically inactive) LH pulses may be present.

This test may differentiate between patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism and individuals with constitutional delay in growth and development.

Because it is time-consuming and resource-intensive, this test is largely restricted to research settings.

Human chorionic gonadotropin stimulation test (males only)

This test is performed by measuring serum testosterone before a single intramuscular injection of 3000 U of hCG and daily for 5 days after injection.

Healthy adults have a doubling of serum testosterone over baseline in response to hCG administration, and prepubertal boys normally show an increase to more than 200 ng/dL.

Serum testosterone levels do not increase acutely (after a single dose of hCG) in patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

If hCG (3000 U) is administered twice a week for several weeks, patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism show a progressive increase in serum testosterone levels by 6 weeks.

This test is of limited diagnostic value.

Short cosyntropin (Cortrosyn) stimulation test

This test is used to confirm the diagnosis of primary adrenocortical insufficiency that typically occurs in children with AHC and subsequent development of idiopathic hypogonadotropic hypogonadism secondary to DAX1 gene mutations.

It involves the bolus intravenous or intramuscular administration of the ACTH analog cosyntropin (Cortrosyn, 250 mcg) and serum collection 1 hour after cosyntropin administration for cortisol assay.

A normal adrenal response in a nonstressed individual is indicated by a peak serum cortisol level of more than 20 mcg/dL (1 h after cosyntropin).

Evaluation of growth hormone secretion

Evaluation is indicated in patients with suspected GH deficiency, including patients with idiopathic hypogonadotropic hypogonadism who are short compared to others of the same age and who have leptin receptor mutations. In contrast, patients with Kallmann syndrome have normal height compared to others of the same age.

Several provocative tests can be performed to evaluate GH secretion in patients who are short compared to others of the same age with a low IGF I or IGFBP 3 serum level. These tests involve the administration of stimuli for GH secretion, including insulin-induced hypoglycemia, glucagon, and arginine infusion alone or in combination with GH-releasing hormone. A detailed discussion of these tests is beyond the scope of this review.

Audiometry

This should be performed in patients with Kallmann syndrome and suspected sensorineural deafness.

Electroencephalography

This should be conducted as a part of the workup of patients with Kallmann syndrome and seizures. A detailed discussion of electroencephalography (EEG) findings in these patients is beyond the scope of this review.

Psychometric testing

This should be performed in patients with Kallmann syndrome and a learning disability to assess intelligence and exclude attention deficit disorder.

Procedures

Cardiac catheterization: This provides important diagnostic information in patients with Kallmann syndrome and suspected congenital heart disease. A detailed discussion of pertinent findings is beyond the scope of this review.

Histologic Findings

The hypothalamus and the pituitary gland are grossly normal. Absence of olfactory bulbs and abnormal (shallow, absent, or medially oriented) olfactory sulci are frequent findings in patients with Kallmann syndrome. In a 19-week-old fetus with Kallmann syndrome, prematurely arrested olfactory axons and GnRH-expressing neurons were found in the space between the cribriform plate and the meninges, supporting the hypothesis that GnRH deficiency and anosmia in Kallmann syndrome (X-linked form) are secondary to abnormalities of neuronal migration during development.

 

Treatment

Medical Care

Evaluation and therapy can usually be implemented on an outpatient basis. Inpatient evaluation and treatment may be necessary for patients with congenital heart disease or acute adrenocortical insufficiency.

All postpubertal-age patients with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism are candidates for gonadal steroid replacement therapy in the absence of specific contraindications. Additional therapies to restore fertility can be implemented on request.

Behavioral modification and psychological counseling may benefit individuals with hypothalamic amenorrhea. Such approaches should be offered before estrogen replacement therapy.

Medical therapies are used to treat associated conditions, including osteoporosis, adrenocortical insufficiency, congenital heart disease, and neurologic disorders.

Surgical Care

Assisted reproductive technologies, including in vitro fertilization (IVF), zygote intrafallopian transfer (ZIFT), and gamete intrafallopian transfer (GIFT), have been used successfully when male patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism do not achieve adequate sperm counts on either GnRH or gonadotropin therapy.

Patients with Kallmann syndrome and congenital heart disease may need corrective surgery. A detailed description of the pertinent procedures is beyond the scope of this review.

Patients with cleft lip or palate also need surgical correction.

Consultations

Adult or pediatric specialists should be consulted, depending on the patient's age.

Consultations include the following:

  • Endocrinologist and reproductive endocrinologist

  • Cardiologist

  • Cardiothoracic surgeon and pediatric surgeon

  • Neurologist and psychiatrist

  • Otolaryngologist

  • Dermatologist

Diet

No dietary restrictions are required in the absence of congenital heart disease. Salt restriction (adult Na+ intake < 2 g/d) is advised for patients with congestive heart failure.

All patients must ensure an adequate calcium (1200-1500 mg/d) and vitamin D (800-1000 U/d) intake, especially if they are osteopenic. Dietary supplements may be necessary for patients to achieve these goals.

Activity

Routine activity restrictions are not necessary; however, patients with osteoporosis need to avoid high-impact sports and situations conducive to falls.

Activity restrictions are also appropriate in patients with certain forms of congenital heart disease or seizures.

 

Medication

Medication Summary

Patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism who do not desire fertility should have gonadal steroid replacement therapy, including testosterone in males and estrogen-progestin in females, unless contraindicated. Fertility options include either GnRH (gonadorelin [no longer commercially available in the US]) or gonadotropin-based regimens. Clomiphene may also be used in women with hypothalamic amenorrhea.

Androgens

Class Summary

Androgen replacement in males with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism restores libido, erectile function, and well-being. In addition, androgen replacement promotes the development of secondary sex characteristics (eg, facial, axillary, and pubic hair) and increases muscle strength. A short course of androgens in infancy leads to penile growth in infants with micropenis. Androgen replacement also improves bone density and may prevent osteoporosis. Either parenteral or transdermal testosterone is the drug of choice for androgen replacement. Orally administered alkylated androgens should be avoided because of the risk of serious hepatic toxicity, including peliosis hepatitis, cholestasis, and hepatocellular carcinoma.

Testosterone (Aveed, Depo-Testosterone, Delatestryl, Testopel)

Promotes and maintains secondary sex characteristics in males who are androgen deficient. Several testosterone salts (eg, enanthate, cypionate, undecanoate) are available in a long-acting oil-based preparations.

Testosterone transdermal (Androderm, AndroGel, Testim, Axiron, Fortesta)

Androgenic anabolic steroid indicated for testosterone replacement. Several preparations are available as topical gels or transdermal patches. Patches are changed daily. Testosterone is a schedule III controlled substance.

Testosterone intranasal (Natesto)

Testosterone promotes growth and development of male sex organs and maintains secondary sex characteristics in androgen-deficient males. Indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone (congenital or acquired) including primary hypogonadism and hypogonadotropic hypogonadism.

Steroid hormones

Class Summary

Estrogen replacement therapy in females with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism promotes the development of secondary sex characteristics, including breast development and menstrual function, and it may prevent osteoporosis. Oral contraceptives may be used as replacement therapy in young women. A thorough discussion of estrogen replacement therapy in older (postmenopausal women) is beyond the scope of this review.

Conjugated estrogens (Premarin)

Induces the synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics.

Ethinyl estradiol (Estinyl)

Induces the synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics.

Estradiol (Estrace)

Increases synthesis of DNA, RNA, and many proteins in target tissues.

Transdermal estradiol (Climara, Estraderm, FemPatch, Noven, Vivelle, Vivelle-Dot)

Increases synthesis of DNA, RNA, and many proteins in target tissues.

Progestins

Class Summary

Medroxyprogesterone is usually administered to female patients on estrogen replacement therapy for 12-14 d/mo. Induces secretory changes in endometrium and leads to withdrawal bleeding, which is essential for prevention of estrogen-induced endometrial hyperplasia. Patients on combination oral contraceptives already receive a progestin and do not need additional medroxyprogesterone therapy.

Medroxyprogesterone (Provera)

Stops endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. Typically does not stop acute bleeding episode but produces a normal bleeding episode following withdrawal.

Hypothalamic releasing hormones

Class Summary

Pulsatile administration of gonadorelin (GnRH) by subcutaneous (SC) or preferably intravenous (IV) infusion restores pituitary-gonadal axis function and fertility in the majority of people with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. Some patients with GnRH receptor mutations may respond to high-dose GnRH therapy. Gonadorelin is no longer commercially available in the US.

Gonadorelin (GnRH, Factrel, Lutrepulse)

Stimulates pituitary release of LH.

Gonadotropins

Class Summary

These successfully restore fertility in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. Patients with idiopathic hypogonadotropic hypogonadism and AHC may have an intrinsic defect in spermatogenesis and may not respond to gonadotropin therapy. In men, hCG should be used alone for as long as 1 year and may be effective alone in patients with partial gonadotropin deficiency. Having verified that androgen levels are normal on hCG therapy, FSH should be added to the regimen after that period. In addition, induction of puberty with FSH and LH after a period of FSH priming has been proposed in boys.[35] In females, ovulation induction protocols are complex and vary. A detailed discussion of these protocols is beyond the scope of this review.

Follicle-stimulating hormone (Fertinex, Follistim)

Stimulates gonadal steroid production. Either recombinant or human purified hormone may be used.

Human chorionic gonadotropin (Chorex, Pregnyl, Profasi, Novarel)

Stimulates production of gonadal steroid hormones.

Ovulation stimulators

Class Summary

Clomiphene acts as an antiestrogen to decrease negative estrogen feedback on hypothalamus. In addition, clomiphene may have effects on the pituitary gland and ovaries and can induce ovulation in women with hypothalamic amenorrhea. Clomiphene is not likely to be effective in patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Clomiphene citrate (Clomid, Milophene, Serophene)

Stimulates release of pituitary gonadotropins.

 

Follow-up

Further Outpatient Care

Medications include gonadal steroid replacement (testosterone in males and estrogen-progestin in females) in postpubertal-aged patients.

Male and female patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism who desire fertility may choose between pulsatile gonadorelin (GnRH) infusion and gonadotropin therapy (the former is no longer available in the US). Clomiphene may be helpful in women with hypothalamic amenorrhea and should be tried first in this patient population after correction of the precipitating factors, if possible. Assisted reproductive technologies, including IVF, ZIFT, GIFT, and intracytoplasmic sperm injection (ICSI), have been used successfully when male patients do not achieve adequate sperm counts on GnRH or gonadotropin therapy.

Patients with primary adrenocortical insufficiency need glucocorticoid and mineralocorticoid replacement therapy.

Antiepileptic medications are needed in patients with seizures.

Patients with congenital heart disease may need pharmacologic therapy as well. Details of these therapies are beyond the scope of this review.

Patients with ichthyosis are treated with alpha-hydroxy acids, such as glycolic acid or lactic acid.

Further Inpatient Care

Admit patient for diagnostic testing and surgery as needed.

Inpatient & Outpatient Medications

Medications include gonadal steroid replacement (testosterone in males and estrogen-progestin in females) in postpubertal-aged patients.

Male and female patients with KS or IHH who desire fertility may choose between pulsatile gonadorelin (GnRH) infusion and gonadotropin therapy (the former is no longer available in the US). Clomiphene may be helpful in women with hypothalamic amenorrhea and should be tried first in this patient population after correction of the precipitating factors, if possible. Assisted reproductive technologies, including IVF, ZIFT, GIFT, and ICSI have been used successfully when male patients do not achieve adequate sperm counts on GnRH or gonadotropin therapy.

Patients with primary adrenocortical insufficiency need glucocorticoid and mineralocorticoid replacement therapy.

Antiepileptic medications are needed in patients with seizures.

Patients with congenital heart disease may need pharmacologic therapy as well. Details of these therapies are beyond the scope of this review.

Patients with ichthyosis are treated with alpha-hydroxy acids, such as glycolic acid or lactic acid.

Transfer

Transfer may be indicated for specific diagnostic testing or surgery.

Deterrence/Prevention

Patients at risk of osteoporosis should avoid high-impact sports and situations conducive to falls.

Patients with certain forms of congenital heart disease should avoid strenuous exercise.

Patients with recent seizures must refrain from certain activities and sports (such as diving) that would put them at risk if another seizure were to occur during participation.

Complications

Complications include the following:

  • Congenital heart disease: Various cardiac lesions have been reported in a small subset of patients with Kallmann syndrome, including the following: ASD, atrioventricular block, Ebstein anomaly, right aortic arch, right bundle-branch block and WPW syndrome, transposition of the great vessels, and VSD. Early diagnosis and management of these conditions is important in order to minimize patient mortality and morbidity.

  • Primary adrenocortical insufficiency: Male patients with X-linked idiopathic hypogonadotropic hypogonadism and AHC usually present in infancy or childhood with adrenal insufficiency. This is fatal unless diagnosed and treated appropriately.

  • Neurologic manifestations: Anosmia or hyposmia occurs in all Kallmann syndrome cases. Some patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism exhibit a variable neurologic symptomatology, including the following: cerebellar ataxia, gaze abnormalities, impaired vision, mental retardation, seizures, sensorineural deafness, spastic paraplegia, and synkinesia (mirror movements).

  • Osteoporosis: Patients with hypogonadism, including all individuals with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism, are at increased risk for osteoporosis. Osteoporosis may be prevented or treated by adequate gonadal steroid replacement. Additional therapies for osteoporosis, including diet and exercise, bisphosphonates, and calcitonin, may be needed.

  • Short metacarpals and pes cavus

  • Ichthyosis

  • Cleft lip or palate

Prognosis

Patients with Kallmann syndrome and those with idiopathic hypogonadotropic hypogonadism can survive for lengthy periods in the absence of associated life-threatening conditions.

Fertility can be restored in most patients with classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism.

Although Kallmann syndrome and idiopathic hypogonadotropic hypogonadism were previously thought to be lifelong disorders, cases of patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism who experienced spontaneous complete recovery of gonadal function have been reported.[36]

Women with hypothalamic amenorrhea may also experience complete recovery of gonadal function, particularly if precipitating factors are corrected.

Some patients with congenital heart disease or neurologic manifestations may experience a limited lifespan.

Adrenocortical insufficiency is fatal unless recognized and treated; however, patients who are treated adequately should have long-term survival.

Osteoporosis increases the risk of fracture, which may compromise patient survival and quality of life.

Patient Education

Patients should be made aware of the risks and benefits of gonadal steroid replacement therapy.

Patients should know that current therapies permit fertility in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Patients should know that, although Kallmann syndrome or idiopathic hypogonadotropic hypogonadism are usually life-long conditions, spontaneous recovery of gonadal function is possible in some individuals.

Patients with adrenocortical insufficiency should be familiar with sick day rules.

Activity restrictions should be discussed in patients with osteoporosis, congenital heart disease, or seizures.

For excellent patient education resources, visit eMedicineHealth's Men's Health Center and Women's Health Center. Also, see eMedicineHealth's patient education articles Impotence/Erectile Dysfunction and Amenorrhea.