AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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 a 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 KS patients, in contrast to patients with IHH, whose sense of smell is normal.

Pathophysiology

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

Some of the genes involved in the pathogeneses of KS and IHH have been cloned. Mutations of the KAL gene, which encodes a putative neural cell adhesion molecule, have been described in several patients with X-linked KS. In these patients, both 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 recently been described in patients with autosomal dominant KS.

Mutations of the DAX1 gene, which encodes a nuclear transcription factor, lead to X-linked IHH associated with adrenal hypoplasia congenita (AHC). Mutations of genes encoding either leptin or the leptin receptor underlie isolated cases of autosomally transmitted IHH associated with early-onset obesity. Mutations of the GnRH receptor gene leading to GnRH resistance and autosomally transmitted hypogonadotropic hypogonadism have been described.

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 1 patient, isolated bioinactive luteinizing hormone (LH) was present because of a homozygous mutation in the LH beta subunit gene, which led to hypogonadotropic hypogonadism. 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 GPR54, a gene encoding a G protein–coupled receptor, have recently been reported as a cause of hypogonadotropic hypogonadism. The physiologic role of kisspeptin-54, the endogenous neuropeptide agonist for this receptor, is under investigation. In addition, heterozygous missense mutations of the human nasal embryonic LHRH factor (NELF) gene may be associated with hypogonadotropic hypogonadism.

Frequency

International

The prevalence of IHH was approximately 1 in 10,000 men in a study of French conscripts (Fromantin, 1973). A study of Sardinian military recruits reports the prevalence of hypogonadism associated with anosmia (KS) as 1 in 86,000 men (Filippi, 1986). Methodological limitations of case ascertainment by medical record review should be kept in mind when interpreting these findings.

Mortality/Morbidity

• Associated complications affect both quality of life and survival.
• Both patients with KS and those with IHH 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 KS and IHH cases.

Age

• Classic KS and IHH are both congenital disorders.
• Adult-onset or acquired IHH 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.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Because classic Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH) are both congenital disorders, the terms classic and congenital are used interchangeably to refer to KS and IHH.

Patients with classic KS or IHH 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 KS or IHH do not experience hot flashes.

All patients with KS 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).

• Absent or incomplete puberty
  
  
  • Patients with either classic KS or IHH 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 IHH 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 IHH is unclear.
  
  
  
  • Delayed, but otherwise normal, puberty has also been reported in female carriers of DAX1 mutations who have family members with X-linked IHH associated with AHC.
     
• Decreased libido and erectile dysfunction
  
  
  • These symptoms are almost universal in men with either KS or IHH.
  
  
  
  • Androgen replacement improves both libido and erectile function.
     
• Amenorrhea
  
  
  • Primary amenorrhea develops in the vast majority of women with classic KS or IHH.
  
  
  
  • 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 IHH may present with infertility and a history of previously documented fertility.
  
  
  
  • In either KS or IHH, 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
  
  
  • Both male and female patients with KS 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 KS, including female obligate carriers in X-linked KS pedigrees, may have anosmia or hyposmia without hypogonadism and may represent one end of the spectrum of KS.
     
• Fatigue, dyspnea, cyanosis, palpitations, syncope
  
  
  • Patients with KS 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 KS.



• Symptoms of primary adrenocortical insufficiency
  
  
  • This occurs in males with X-linked IHH 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 KS or IHH.

  • Similarly, an arm span greater than height by more than 5 cm is observed only in patients with congenital KS or IHH.

  • 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 congenital KS or IHH. Men with adult-onset IHH may report decreased shaving frequency. In addition, lack of temporal hair recession (male-type baldness) is noted in men with KS or IHH.
• High-pitched voice is present in men with only congenital KS or IHH.
• Lack of breast development is observed in women with congenital KS or IHH. Women with long-standing hypothalamic amenorrhea may experience a decrease in breast size.
• Gynecomastia is observed only rarely in men with classic KS or IHH 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 congenital KS or IHH.
• Axillary and pubic terminal hair may be scantly present in these patients (with the exception of patients with X-linked IHH and AHC) because of circulating adrenal androgens. Males with congenital KS or IHH have a female escutcheon without terminal hair growth along the midline towards the umbilicus.
• Men with congenital KS or IHH 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 IHH are either within the normal range or mildly decreased (10-15 mL).

  • Cryptorchidism is present in a minority of men with classic KS or IHH.

• Males with classic KS or IHH have small penises (<8 cm long in adults). In addition, prostate size is decreased, particularly in men with classic KS or IHH.

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

• All patients with KS 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 KS experience color blindness, as assessed by Ishihara plate testing. In addition, sensorineural hearing loss has been reported in some KS patients.

• Some patients with X-linked KS 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 KS. Short metacarpals and pes cavus also have been reported in a minority of KS patients.

• Cardiovascular findings are present in some patients with KS 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 KS or IHH 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 KS patients.
• Conditions associated with primary adrenocortical insufficiency are present in males with X-linked IHH and AHC. A detailed discussion of these conditions is beyond the scope of this review.
• Early-onset obesity is present in patients with IHH and mutations of either the leptin gene or the leptin receptor gene.

Causes

Classic Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH) are congenital genetic disorders. Approximately one third of KS and IHH cases appear to be inherited. The remaining two thirds of all KS and IHH 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).

• Some of the genes associated with KS and IHH have been identified, including mutations of the KAL gene, which cause X-linked KS. Loss-of-function mutations of the gene encoding FGFR1 have recently been described in patients with autosomal dominant KS.
• • The KAL 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 KAL gene have been reported in about 50% of patients with X-linked KS. 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 KS 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 KAL gene and the steroid sulfatase gene.
     
• Mutations of the DAX1 gene lead to X-linked IHH and AHC.
• • 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 IHH. Limited data suggest that, in these patients, IHH may be acquired postnatally but before the expected onset of puberty. In contrast to patients with KS and most other patients with IHH, these individuals have both 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 IHH without AHC has been reported.
     
• Mutations of either the leptin gene or the leptin receptor gene lead to autosomal recessive IHH and early-onset obesity.
• • Patients with homozygous mutations of the leptin gene present with early onset, severe obesity, and IHH secondary to a hypothalamic defect in GnRH secretion.
  
  
  
  • Patients with homozygous mutations of the leptin receptor also present with early-onset, morbid obesity and IHH. In contrast to patients with KS, as well as the vast majority of IHH 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 IHH. In contrast, mutations of the gene encoding for GnRH itself have not been described in patients with hypogonadotropic hypogonadism.
• • Homozygous or compound heterozygous mutations of the GnRH receptor have been found in approximately 2% of patients with IHH who may present with either complete hypogonadotropic hypogonadism secondary to GnRH resistance or who may have some evidence of pubertal maturation, albeit incomplete.
  
  
  
  • Mutations of the GnRH gene have not been reported in patients with IHH or KS.
     
• Rarely, hypogonadotropic hypogonadism occurs as a result of isolated FSH deficiency due to homozygous mutations in the FSH beta subunit gene.



• In 1 patient, isolated bioinactive LH was present because of a homozygous mutation in the LH beta subunit gene, which led to hypogonadotropic hypogonadism.



• 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 GPR54, a gene encoding a G protein–coupled receptor, have recently been reported as a cause of hypogonadotropic hypogonadism. In addition, heterozygous missense mutations of the NELF gene may be associated with idiopathic hypogonadotropic hypogonadism.



• 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 mi/wk), excessive weight loss, anorexia nervosa, and psychogenic stress.



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

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Börjeson-Forssman-Lehmann syndrome
CHARGE syndrome (coloboma, heart disease, atresia choanae, retarded growth and retarded development and/or CNS anomalies, genital hypoplasia, and ear anomalies and/or deafness)
Constitutional delay in growth and development
Empty sella
Histiocytosis X
Hypophysitis
Isolated FSH deficiency
Isolated LH deficiency
Klinefelter syndrome
Laurence-Moon-Biedl syndrome
Leopard syndrome
Lowe syndrome
Martsolf syndrome
Polycystic ovary syndrome
Prader-Willi syndrome
PROP-1 deficiency
Rothmund-Thomson syndrome
Rud syndrome
Turner syndrome

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Serum electrolytes
• • Serum electrolyte levels are within reference range in patients with classic Kallmann syndrome (KS).
  
  
  
  • Patients with idiopathic hypogonadotropic hypogonadism (IHH) 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 KS and IHH.
  
  
  
  • The serum ferritin level should be measured in suspected adult-onset IHH 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 KS or IHH. 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 KS or IHH 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 KS or IHH but has limited diagnostic value.
  
  
  
  • Serum extraction and 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 Image 2)
• • Serum LH and FSH levels are low-normal or decreased in postpubertal-aged patients with KS or IHH. Gonadotropin levels are inappropriate relative to the serum levels of testosterone or estradiol.
  
  
  
  • These test results are of diagnostic value in postpubertal-age patients because they help differentiate KS or IHH from primary gonadal dysfunction, including Turner syndrome and Klinefelter syndrome.
  
  
  
  • Serum LH and FSH levels cannot reliably distinguish between KS or IHH 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 KS and IHH.
  
  
  
  • Patients with IHH 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 insulinlike growth factor I and serum insulinlike 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 KS.
  
  
  
  • Patients with IHH 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.
     
• Morning serum cortisol and plasma adrenocorticotropic hormone
• • These tests are used to screen for adrenocortical insufficiency in patients with suspected IHH. A morning serum cortisol level that is higher than 18 mcg/dL suggests adequate glucocorticoid secretory reserve.
  
  
  
  • Patients with IHH 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 KS or IHH.
  
  
  
  • 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 KS or IHH before recommending either fertility therapy or contraception.
  
  
  
  • Although patients with classic KS or IHH 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
• • Both patients with KS and those with IHH 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 KS 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 (see Image 1).
  
  
  
  • Patients with IHH 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 KS. 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 KS.



• Bone densitometry by dual-energy x-ray absorptiometry
• • Dual-energy x-ray absorptiometry (DEXA) is recommended for all hypogonadal patients, including those with KS, IHH, or hypothalamic amenorrhea.
  
  
  
  • DEXA 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 KS and IHH.
  
  
  
  • 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 KS or IHH, 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 KS or IHH. 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. 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 KS or IHH, 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 KS or IHH 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 KS and IHH, 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 KS or IHH and individuals with constitutional delay in growth and development.

  • Because it is both 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 KS or IHH.

  • If hCG (3000 U) is administered twice a week for several weeks, patients with KS or IHH 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 IHH secondary to DAX1 gene mutations.

  • It involves the bolus intravenous (ie, 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 IHH who are short compared to others of the same age and who have leptin receptor mutations. In contrast, patients with KS 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, arginine infusion, L-dopa, clonidine, GH-releasing hormone, exercise, and sleep. A detailed discussion of these tests is beyond the scope of this review.

• Audiometry: This should be performed in patients with KS and suspected sensorineural deafness.
• Electroencephalography: This should be conducted as a part of the workup of patients with KS 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 KS and a learning disability to assess intelligence and exclude attention deficit disorder.

Procedures

• Cardiac catheterization: This provides important diagnostic information in patients with KS 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 KS. In a 19-week-old fetus with KS, prematurely arrested olfactory axons and GnRH-expressing neurons were found in the space between the cribriform plate and the meninges, supporting the hypothesis that both GnRH deficiency and anosmia in KS (X-linked form) are secondary to abnormalities of neuronal migration during development.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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 (KS) and idiopathic hypogonadotropic hypogonadism (IHH) 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 KS or IHH do not achieve adequate sperm counts on either GnRH or gonadotropin therapy.
• Patients with KS 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 mg/d) and vitamin D (600-800 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

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Patients with KS or IHH 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) or gonadotropin-based regimens. Clomiphene may also be used in women with hypothalamic amenorrhea.

Drug Category: Androgens

Androgen replacement in males with KS or IHH 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.

Drug Category: Steroid hormones

Estrogen replacement therapy in females with KS or IHH 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.

Drug Name	Ethinyl estradiol (Estinyl)
Description	Induces the synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics.
Adult Dose	10-20 mcg/d PO for 21 d/mo or continuously
Pediatric Dose	Initial dose typically started at 12-13 years: 5-10 mcg/d PO for as long as 6 mo, slowly (in 6-mo intervals) increasing toward adult dose
Contraindications	Breast cancer; endometrial cancer; undiagnosed genital bleeding; pregnancy; active liver disease; venous thromboembolic disease
Interactions	Ethinyl estradiol may reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use of ethinyl estradiol with hydantoins may reduce seizure control
Pregnancy	X - Contraindicated in pregnancy
Precautions	Endometrial hyperplasia and increased risk of endometrial cancer can be prevented by adding a progestin (after occurrence of breakthrough bleeding or as long as 6 mo of estrogen therapy in adolescents); annual mammography is recommended in older women; endometrial biopsy is indicated for persistent, unanticipated vaginal bleeding

Drug Name	Estradiol (Estrace)
Description	Increases synthesis of DNA, RNA, and many proteins in target tissues.
Adult Dose	1-2 mg/d PO for 21 d/mo or continuously
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; breast cancer; endometrial cancer; undiagnosed genital bleeding; pregnancy; active liver disease; venous thromboembolic disease
Interactions	May reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use of ethinyl estradiol with hydantoins may reduce seizure control
Pregnancy	X - Contraindicated in pregnancy
Precautions	Endometrial hyperplasia and increased risk of endometrial cancer can be prevented by adding a progestin; annual mammography recommended in older women; endometrial biopsy indicated for persistent, unanticipated vaginal bleeding; caution in hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease

Drug Name	Transdermal estradiol (Climara, Estraderm, FemPatch, Noven, Vivelle, Vivelle-Dot)
Description	Increases synthesis of DNA, RNA, and many proteins in target tissues.
Adult Dose	1 skin patch (delivering 0.05-0.10 mg/d) is applied once (Climara, FemPatch) or twice (Estraderm, Noven, Vivelle, Vivelle-Dot) per wk
Pediatric Dose	Not established
Contraindications	Breast cancer; endometrial cancer; undiagnosed genital bleeding; pregnancy; active liver disease; venous thromboembolic disease
Interactions	May reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; increase in corticosteroid levels may occur when administered concurrently with estradiol; use of estradiol with hydantoins may reduce seizure control
Pregnancy	X - Contraindicated in pregnancy
Precautions	Endometrial hyperplasia and increased risk of endometrial cancer can be prevented by adding a progestin; annual mammography is recommended in older women; endometrial biopsy is indicated for persistent, unanticipated vaginal bleeding

Drug Category: Progestins

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.

Drug Category: Hypothalamic releasing hormones

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 KS and IHH. Some patients with GnRH receptor mutations may respond to high-dose GnRH therapy.

Drug Category: Gonadotropins

These successfully restore fertility in most patients with KS or IHH. Patients with IHH 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 females, ovulation induction protocols are complex and vary. A detailed discussion of these protocols is beyond the scope of this review.

Drug Name	Human chorionic gonadotropin (Chorex, Pregnyl, Choron)
Description	Stimulates production of gonadal steroid hormones.
Adult Dose	Males: 1000-2000 U IM 3 times per wk Females: Ovulation induction protocols are complex and vary
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; prostate cancer
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Gynecomastia, edema, headache, irritability, depression, and pain at injection sites may occur

Drug Category: Ovulation stimulators

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 KS or IHH.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Admit patient for diagnostic testing and surgery as needed.

Further Outpatient Care

• Follow up to assess effectiveness of prescribed therapies and monitor for adverse reactions to medications.
• Parenteral testosterone therapy is associated with prostate growth (not exceeding that of age-matched men), fluid retention, gynecomastia, sleep apnea exacerbation, and erythrocytosis. A decrease in serum high-density lipoprotein (HDL) cholesterol levels may occur.
• Transdermal testosterone is frequently associated with contact dermatitis at the application site, which may be prevented by application of a topical steroid prior to the use of the patch, as well as adverse effects associated with parenteral testosterone therapy.
• Prostate examination and monitoring for urinary obstructive symptoms, as well as serial determinations of PSA, hematocrit, and serum lipid levels, are important in patients on testosterone replacement therapy.
• Estrogen replacement therapy is associated with edema, nausea, vomiting, and breast tenderness, and it may exacerbate migraines. Cholestatic jaundice, pancreatitis, and hypertriglyceridemia may also occur. Endometrial hyperplasia (and the associated risk of endometrial cancer) is prevented by the concomitant use of a progestin for 12-14 days a month.
• Older women on estrogen replacement therapy are also at a somewhat increased risk for venous thromboembolic disease and may be at a higher risk for breast cancer, although this remains controversial. Annual breast and pelvic examinations, Papanicolaou smears, and mammograms (for older women) are recommended. The effect of estrogen replacement therapy on cardiovascular disease risk in postmenopausal age women is controversial. A thorough discussion of the topic is beyond the scope of this review.

In/Out Patient Meds

• Medications include gonadal steroid replacement (testosterone in males and estrogen-progestin in females) in postpubertal-aged patients.
• Both male and female patients with KS or IHH who desire fertility may choose between pulsatile gonadorelin (GnRH) infusion and gonadotropin therapy. 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, and GIFT, 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

• Congenital heart disease
• • Various cardiac lesions have been reported in a small subset of patients with KS, 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 IHH 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 KS cases.

  • Some patients with KS or IHH 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 KS and IHH, 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

• Both patients with KS and those with IHH can survive for lengthy periods in the absence of associated life-threatening conditions.
• Fertility can be restored in most patients with classic KS and IHH.
• Although KS was previously thought to be a life-long disorder, cases of patients with KS who experienced spontaneous complete recovery of gonadal function have been reported recently.
• 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 KS or IHH.
• Patients should know that, although KS or IHH 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 eMedicine's Men's Health Center and Women's Health Center. Also, see eMedicine's patient education articles Impotence/Erectile Dysfunction and Amenorrhea.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to recognize the presence of an underlying condition, such as hemochromatosis or a pituitary tumor, in patients presenting with hypogonadotropic hypogonadism
• Failure to obtain semen analysis before recommending that a man with KS or IHH does not need to take contraceptive precautions
• Failure to recognize the presence of KS-associated conditions, including osteoporosis, adrenocortical insufficiency, congenital heart disease, or neurologic manifestations
• Failure to implement endocarditis prophylaxis in patients with certain forms of congenital heart disease

Special Concerns

• Prenatal diagnosis of X-linked KS and IHH is possible for family members with a known mutation of the KAL gene or DAX1 gene, respectively, by using molecular genetic and cytogenetic analysis (Southern blot or fluorescence in situ hybridization) of fetal DNA.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  MRI of the brain in patients with KS and 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.)
	View Full Size Image
	eMedicine Zoom View (Interactive!)
Media type:  MRI

Media file 2:  This is a frequently sampled serum luteinizing hormone (LH) profile in a male patient with KS in comparison with a healthy individual. It shows lack of LH pulsatility in the former.
	View Full Size Image
	eMedicine Zoom View (Interactive!)
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Clement K, Vaisse C, Lahlou N, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. Mar 26 1998;392(6674):398-401. [Medline].
• Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. Dec 2005;90(12):6609-15. [Medline].
• Dode C, Levilliers J, Dupont JM, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. Apr 2003;33(4):463-5. [Medline].
• Filippi G. Klinefelter's syndrome in Sardinia. Clinical report of 265 hypogonadic males detected at the time of military check-up. Clin Genet. 1986;30(4):276-284. [Medline].
• Fromantin M, Gineste J, Didier A, Rouvier J. Impuberism and hypogonadism at induction into military service. Statistical study. Probl Actuels Endocrinol Nutr. May 3 1973;16:179-99. [Medline].
• Gottsch ML, Cunningham MJ, Smith JT, et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. Sep 2004;145(9):4073-7. [Medline].
• Hoffman AR, Crowley WF Jr. Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med. Nov 11 1982;307(20):1237-41. [Medline].
• Iovane A, Aumas C, de Roux N. New insights in the genetics of isolated hypogonadotropic hypogonadism. Eur J Endocrinol. Nov 2004;151 Suppl 3:U83-8. [Medline].
• Layman LC. The molecular basis of human hypogonadotropic hypogonadism. Mol Genet Metab. Oct 1999;68(2):191-9. [Medline].
• Merke DP, Tajima T, Baron J, Cutler GB Jr. Hypogonadotropic hypogonadism in a female caused by an X-linked recessive mutation in the DAX1 gene. N Engl J Med. 1999;340(16):1248-52. [Medline].
• Miura K, Acierno JS, Seminara SB. Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). J Hum Genet. 2004;49(5):265-8. [Medline].
• Nachtigall LB, Boepple PA, Pralong FP, Crowley WF Jr. Adult-onset idiopathic hypogonadotropic hypogonadism--a treatable form of male infertility. N Engl J Med. Feb 6 1997;336(6):410-5. [Medline].
• Pitteloud N, Acierno JS Jr, Meysing AU, Dwyer AA, Hayes FJ, Crowley WF Jr. Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab. Mar 2005;90(3):1317-22. [Medline].
• Pralong FP, Gomez F, Castillo E, et al. Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab. Oct 1999;84(10):3811-6. [Medline].
• Quinton R, Cheow HK, Tymms DJ, Bouloux PM, Wu FC, Jacobs HS. Kallmann's syndrome: is it always for life?. Clin Endocrinol (Oxf). Apr 1999;50(4):481-5. [Medline].
• Quinton R, Duke VM, de Zoysa PA, et al. The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis [published erratum appears in J Clin Endocrinol Metab 1996 Oct;81(10):3614]. J Clin Endocrinol Metab. Aug 1996;81(8):3010-7. [Medline].
• Rugarli EI, Ballabio A. Kallmann syndrome. From genetics to neurobiology. JAMA. Dec 8 1993;270(22):2713-6. [Medline].
• Seminara SB, Achermann JC, Genel M, et al. X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females. J Clin Endocrinol Metab. Dec 1999;84(12):4501-9. [Medline].
• Seminara SB, Hayes FJ, Crowley WF Jr. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations. Endocr Rev. Oct 1998;19(5):521-39. [Medline].
• Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. Oct 23 2003;349(17):1614-27. [Medline].
• Silveira LF, MacColl GS, Bouloux PM. Hypogonadotropic hypogonadism. Semin Reprod Med. Nov 2002;20(4):327-38. [Medline].
• Waldstreicher J, Seminara SB, Jameson JL, et al. The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J Clin Endocrinol Metab. Dec 1996;81(12):4388-95. [Medline].

Article Last Updated: Jun 1, 2006