At a Glance
Any patient with delayed puberty characterized by absence of secondary sexual characteristics at 13 years of age for girls and 14 years of age for boys is a candidate for investigation of hypogonadism. In children younger than the age of puberty, any signs of abnormal external genitalia may prompt testing.
Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins with otherwise normal pituitary function. When associated with anosmia or hyposmia, this hypogonadotropism is named Kallmann syndrome (KS), whereas isolated hypogonadotropic hypogonadism (HH) with a normal sense of smell is called normosmic IHH (nIHH).
KS can be sporadic or familial and affects both males and females. The incidence of KS is approximately 1 in 8,000–10,000 males and 1 in 40,000–50,000 females. Familial cases display different modes of inheritance: X-linked, autosomal dominant (AD), and autosomal recessive (AR).
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In addition to hypogonadotropic hypogonadism and anosmia/hyposmia, KS may have a variety of associated anomalies. They include microphallus (up to 65%), cryptorchidism (up to 73%), hearing loss (~30%), renal agenesis, synkinesis (the involuntary movement of one hand when the other is moved or mirror movement), cleft lip with or without palate (13–14%), dental agenesis, musculoskeletal anomalies, oculomotor anomalies, and heart defects.
The presence of these associated anomalies is important to recognize, as hypogonadotropic hypogonadism may be difficult to diagnose before puberty. Recognition of these anomalies in infancy or early childhood is important in making the diagnosis. Early diagnosis will be critical for appropriate patient care and better counseling for future pregnancy planning of the family.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
HH is the disorder of hypothalamic-pituitary-gonad axis. HH is caused by decreased release or function of gonadotropin-releasing hormone (GnRH), which results in decreased gonadotropin production in the pituitary, including follicle stimulating hormone (FSH) and luteinizing hormone (LH). As a result, the production of sex steroids (testosterone or estradiol) is decreased, in turn, causing lack or delay of secondary sexual maturation.
Total testosterone for males and estradiol for females along with gonadotropins FSH and LH should be tested to confirm the clinical suspicion of HH. Patients usually have low levels of corresponding sex steroids, as well as low FSH and LH for sex and age. If all three hormone levels are low, no further tests are necessary, except for the purpose of genetic counseling in which case molecular analysis to identify gene mutations may be indicated.
If levels of sex steroids, FSH, or LH are not clearly decreased, further studies based on family history to identify gene mutations may help determine the etiology of the patient’s clinical symptoms.(Table 1)
Table 1.
| Testosterone or Estradiol | FSH | LH |
| Decreased | Decreased | Decreased |
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
If the patient takes or abuses androgenic steroids, the serum testosterone level will be normal or high. In this situation, whether the low FSH and LH levels are due to negative feedback of high testosterone or low GnRH cannot be determined. Detailed clinical history of medication is critical in the evaluation. Similarly, taking exogenous estrogenic compounds may also increase the level of estradiol and prevent the correct diagnosis.
Reference ranges vary with age and sexual developmental stages of the child. Using age and tanner-stage specific reference ranges is very important. Testosterone levels are low at birth, rise within weeks, and remain at normal male pubertal levels for about 2 months before declining to the low, barely detectable childhood levels. Testosterone has a diurnal variation, with peak serum levels at 4:00–8:00 AM and minimum levels at 4:00–8:00 PM. Estradiol levels in newborns are elevated at birth but fall into prepubertal levels within 2 weeks. Errors in diagnosis could occur without using the appropriate reference ranges.
What Lab Results Are Absolutely Confirmatory?
Currently, there are six genes (KAL1, FGFR1, PROK2, PROKR2, FGF8, and CHD7) found to be associated with KS. Finding the mutation in one of those genes confirms the diagnosis. However, only 30% of patients with clinical diagnosis of KS have one of those mutations.
To know which genes to test for, a patient’s history is necessary, so one would not simply test all six genes. KAL1 gene is responsible for X-linked KS. FGFR1, also known as KAL2, transmits in an autosomal dominant fashion. Some mutations are associated with certain abnormalities. For example, clefting has been found to be associated with FGFR1, FGF8, and CHD7, but not with KAL1, PROK2, or PROKR2. So, for KS patients with clefting, it is reasonable to first test FGFR1, FGF8, and CHD7.
Both GNRH1 (preprohormone of GnRH) and GNRHR (GnRH receptor) defects produce autosomal recessive (AR) isolated nIHH without developmental defects such as hyposmia. GNRHR mutations have been suggested in some reports to account for 40–50% of familial AR nIHH.
Although genotyping is absolutely confirmatory, it is complex and insensitive for both KS and nIHH.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
Usually, decreased total testosterone, FSH, and LH are adequate for working up patients of HH. Measurement of free testosterone may be useful for obese patients. In human circulation, testosterones are bond by sex hormone binding globulin (SHBG; 65%), and albumin (30%). Only 1–4% of testosterones are free in the plasma. Testosterone is weakly bound to serum albumin and dissociates easily. The combination of free testosterone and albumin-bound testosterone is termed bioavailable testosterone.
Obese patients have lower levels of SHBG, which makes the total testosterone level appear low but without significant effect on the level of functional free testosterone. Measurement of free or bioavailable testosterone and SHBG are useful to make the correct interpretation of low total testosterone. Other situations that may decrease the SHBG include hypothyroidism, androgen use, nephritic syndrome, Cushing’s disease, and acromegaly. Hyperthyroidism, hepatic cirrhosis, and estrogen use may increase the level of SHBG. Free or bioavailable testosterone should be used in those situations.
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
The testosterone assay is most commonly performed using immunoassay, but immunoassay has lower sensitivity, which may not detect low level of testosterone. Immunoassay is also prone to interference by patients’ endogenous compounds, especially in young children. Variation among different immunoassays is high, which prevents standardization of the testosterone test.
Liquid chromatography tandem mass spectrometry (LC-MS/MS) has become the most accurate method of steroid measurement. Although the variation is still relatively high, the specificity and sensitivity of steroid measurement is significantly improved. Currently, LC-MS/MS methodology requires expensive instruments and experienced technologists and is only used in large medical centers or reference laboratories. If there is discrepancy between a test result and clinical suspicion, LC-MS/MS may be used to confirm the testosterone level. In addition, the lack of specificity in the immunoassay is more critical in the newborn and early infant periods. In our hospital, all the testosterone levels on patients less than 1 month of age are performed using LC-MS/MS.
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