Evaluation of Congenital Hypogonadotropic Hypogonadism

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Hypogonadism is defined as a defect in one of the two major functions of the testes (i.e., production of T and spermatogenesis). Hypogonadism can reflect either a primary testicular defect (hypergonadotropic hypogonadism) or a disorder of the pituitary or hypothalamus (secondary or hypogonadotropic hypogonadism). Serum LH and FSH concentrations distinguish primary from secondary hypogonadotropic hypogonadism.

Primary hypogonadism is diagnosed in the presence of low serum T levels, oligospermia, or azoospermia, and elevated serum gonadotropin levels. In contrast, secondary hypogonadism is defined by a low T level and a reduced sperm count in the setting of low or inappropriately normal serum LH and FSH concentrations.

Given the diurnal rhythm of T secretion in normal men, T should be measured in a morning blood sample. If the initial level is low, repeat measurements should be performed. In secondary hypogonadism, the serum LH response to a single bolus of exogenous GnRH cannot determine if the defect is localized to the pituitary or hypothalamus, because a subnormal response may occur in both settings. Indeed, patients with complete GnRH deficiency are likely to have had no prior exposure to endogenous GnRH, and in this setting, repeated GnRH administration is needed to prime the gonadotropes and induce a gonadotropin response. Although not often used clinically, a pretreatment inhibin-B level may be a useful predictor of therapeutic outcome for men with CHH who desire to conceive (31). Finally, although frequent blood sampling to characterize the pulsatile pattern of LH secretion may help refine the diagnosis in a research study, it is not practical in the clinical setting.

A semen analysis should be obtained in patients with congenital hypogonatropic hypogonadism who can produce an ejaculate and should include an assessment of the volume, sperm count, motility, and morphology. The World Health Organization (WHO) criteria for normal semen analysis parameters are a volume greater than 2 mL, a sperm count of >20 million/mL or more of ejaculate with motility 50% or greater, and normal morphology in 30% or greater. Because of the variability in sperm counts, it is worthwhile to obtain a second semen specimen if the first sample is abnormal.

Finally, in the case of secondary hypogonadism, it is critical to assess other pituitary functions (see Chapter 8), including a prolactin level, to ensure that the defect is isolated to the hypothalamic-pituitary-gonadal axis. A ferritin level should be measured to exclude hemochromatosis. Patients with hypogonadotropic hypogonadism typically undergo adrenarche at a normal age and should, therefore, have normal adult male dehydroepiandrosterone levels. Radiographic evaluation should include a bone age determination, MRI of the pituitary and hypothalamic area, and a DEXA scan to assess BMD.

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