Male Hypogonadism. Part I: Epidemiology of Hypogonadism

AD Seftel


Int J Impot Res. 2006;18(2):115-120. 

In This Article

Controversies in Diagnosis

Diagnostic issues in hypogonadism will be covered at greater length in part II of this three-part review. The diagnosis of male hypogonadism, particularly PADAM, is fraught with controversy. Frequently debated topics include threshold hormone levels for determining PADAM; whether low T levels in the presence of normal LH levels warrant further workup to detect underlying hypothalamic-pituitary axis disorders; the optimal manner in which to measure these hormone levels, particularly total testosterone (TT); and the ideal hormone fraction to identify patients with hypogonadism: TT, bioavailable testosterone (BT), or free testosterone (FT).

According to the preponderance of literature from the past 30 years based on traditional radioimmunoassay (RIA) methods with or without chromatography, the reference range for TT is 300-1000 ng/dl.[26,27] Another way to determine the threshold for 'low TT' is statistical, that is, 2.5 standard deviations (s.d.'s) below the mean for healthy young men. In a recent study on the clinical utility of GnRH testing in the differential diagnosis of PADAM and secondary hypogonadism, a Swiss group used a threshold TT of <337 ng/dl, which was 2.5 s.d.'s lower than the mean for a group of 13 young healthy controls (mean age=33.9 years): approximately 625 ng/dl.[28]

One argument for using 300 ng/dl as the threshold for diagnosing male hypogonadism is that there is a functional correlation with erectile dysfunction (ED). Studying 162 elderly (mean age=64.1 years) men with ED (mean duration=45.6 months), a Korean group reported that hypogonadism (serum TT <300 ng/dl) was among the strongest independent predictors of a poor response to sildenafil 25-100 mg for 8 weeks. Only poor pretreatment erectile function (International Index of Erectile Function (IIEF) erectile function domain score <17) was a stronger independent prognostic factor (OR=2.2; 95% CI=1.45-7.33).[29]

Another consideration in the diagnosis of male hypogonadism is that measurements of TT may vary during different times of the day or year and from laboratory to laboratory. In a recent study, coefficients of variation between laboratories using the same methods/instruments ranged from 5.1 to 22.7%.[26] The median value of the quality control sample across all laboratories was 297 ng/dl, with results as low as 160 ng/dl (hypogonadal) and as high as 508 ng/dl (eugonadal). Certain manufacturers of automated assay platforms also provide normal male reference ranges that are much lower than the reference TT range of 300-1000 ng/dl cited above, with lower limits ranging from 170 to 200 ng/dl and upper limits ranging from 700 to 800 ng/dl.

Total T levels show marked circadian and circannual variation. Owing to the circadian variation, the Second International Consultation on Erectile Dysfunction of the World Health Organization (WHO)[30] recommended that a blood sample for serum T determination should be obtained between 0800 and 1100, when T levels typically peak in healthy young men. This circadian rhythmicity may be abolished or blunted in men with advancing age[10] or during certain forms of TRT.

The method of choice for determining serum TT levels is liquid chromatography-tandem mass spectrometry (LC-MS-MS). However, this methodology is not available to many hospitals and office practices. A recent study determined that commercially available automated and manual methods are capable of discriminating eugonadal from hypogonadal TT values in the presence of adult male reference ranges established by each laboratory.[26] More than 60% of serum samples from men with TT within the adult male range were within ±20% of values determined by LC-MS-MS. Certain methods (eg DPC Immulite) were biased toward lower values, while others were biased toward higher values (eg Bayer ADVIA Centaur) across a wide range of serum TT concentrations.

The chief problem with the commercially available immunoassays was in determining very low serum TT (<100 ng/dl): in specimens with such low TT values typical of prepubertal males (and females), 56-90% of values generated by commercially available assays fell outside the ±20% window around LC-MS-MS values.[26] As mentioned above, values obtained with the DPC Immulite were systematically lower and those obtained by the Bayer ADVIA Centaur systematically higher than the values provided by LC-MS-MS. Other assays (DPC-RIA and Roche Elecys) exhibited large percent differences in both directions. None of these assays is considered reliable enough to investigate serum TT levels in children and women.[26,31]

A morning T level ≤300 ng/dl should be confirmed by a repeated measurement at the same time of day. However, neither a low TT nor clinical symptoms are sufficient to discriminate PADAM from secondary, hypogonadotropic hypogonadism attributed to hypothalamic-pituitary axis disorders. In a recent study,[28] lack of libido was present in approximately 54% of men with PADAM and 67% of those with secondary hypogonadism; ED in 58 and 53%, respectively; fatigue in 38 and 58%; depressive mood in 25 and 21%; and osteopenia or osteoporosis in 17 and 29%.

According to guidelines from the American Association of Clinical Endocrinologists (AACE), exceedingly low T levels (≤150 ng/dl) warrant pituitary imaging even in the absence of other signs or symptoms.[32] Others use a threshold of <200 ng/dl to trigger magnetic resonance imaging (MRI).[33,34] Some authorities recommend sellar MRI with thyroxine, cortisol, and prolactin assessments when secondary hypogonadism is considered likely.[33]

Based on extensive hormonal evaluation of elderly men with normal and low levels of T, as compared with those with primary and secondary hypogonadism and young, healthy volunteers, a Swiss group[28] recently developed an algorithm for the use of GnRH testing to discriminate secondary, hypogonadotropic hypogonadism from PADAM. First, if repeated serum TT levels are below <337 ng/dl in an elderly man, a GnRH stimulation test should be conducted. A peak LH following GnRH stimulation of >15 mU/l precludes costly imaging studies to rule out secondary (hypogonadotropic) hypogonadism. On the other hand, elderly men who have TT levels below <337 ng/dl in the presence of a blunted LH response to GnRH (<15 IU/l) should undergo MRI to rule out pituitary disease.[28] The most recent WHO guidelines recommend a confirmatory TT if a morning level is below the lower limit of 'the accepted normal values' as well as assessment of LH, FSH, and prolactin.[30]

Compared with men having PADAM, those with secondary hypogonadism were significantly younger (52.5 vs 62.3 years; P<0.05) and had significantly lower levels of basal TT (167 vs 271 ng/dl), as well as significantly lower levels of basal LH and FSH and LH and FSH responses to GnRH administration.[28]

Finally, there is ongoing debate as to which androgenic fraction is the most reliable indicator of hypogonadism. Approximately 50-70% of circulating T is bound tightly to SHBG and is hence physiologically inactive. A further 20-30% is bound loosely to albumin and 1-3% circulates free in the serum. Only these latter two fractions are available to tissues and are thus termed BT. Free testosterone can be calculated[35,36] or measured by equilibrium dialysis. One measure of FT is the free androgen index (FAI=TT/SHBG × 100).[37] Bioavailable T is measured using an ammonium sulphate precipitation method and may also be computed.

According to the most recent WHO guidelines,[30] TT assays may not indicate true androgenic status, particularly in elderly men. The WHO guidelines state that BT and cFT are the most reliable and accessible assays to establish male hypogonadism. Because, for example, serum TT may be normal in patients with primary testicular disorders (eg, Klinefelter syndrome) or increased SHBG, obtaining FT or BT may also be useful.[32] However, the validity and accessibility of a number of diagnostic tests (eg, equilibrium dialysis) and other, dynamic assessments are matters of ongoing debate.

A recent cross-sectional study of a cohort of 1072 men undergoing elective coronary angiography demonstrated that measures of TT were superior to computed FT or BT in the determination of hypogonadism. When TT levels were borderline, in the range of 216-346 ng/dl, estimates of FT proved superior to TT alone.[38]


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