Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism Workup

Updated: Oct 10, 2016
  • Author: Nicholas A Tritos, MD, DSc, MMSc, FACP, FACE; Chief Editor: George T Griffing, MD  more...
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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.

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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). [33]

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.

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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.

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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.

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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.

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