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Multidisciplinary Insights Into the Assessment, Diagnosis, and Management of Hypogonadism

Diagnostic tests

Accurate measurement of testosterone levels is essential to diagnose hypogonadism; however, this too is fraught with challenges. The methods to measure total testosterone include immunoassays, immunometric assays, and, most recentl , mass spectrometry.26 Recognizing the difficulties in measuring testosterone, the Endocrine Society established a task force to review the issues.

Wang and colleagues demonstrated a wide variation in testosterone measurements, both between laboratories and between assays.27 Values as low as 160 ng/dL and as high as 508 ng/dL were reported on the same sample. This illustrates how variability complicates making an accurate diagnosis.

To address this issue, the Centers for Disease Control and Boston University are collaborating to standardize testosterone assays across laboratories. Their goal is to develop recommendations for defining androgen deficiency, potentially using a risk-type profile similar to that of the Framingham Heart Disease study, rather than discrete cutoff values.28,29

Another issue with diagnosing testosterone deficiency is the lack of reliable reference ranges, the statistical distribution of hormone concentrations in a healthy population. Such reference ranges are typically generated from small samples, not population-based samples. However, vigorously established reference ranges are not available for most hormones, not just testosterone.

Total testosterone Bioavailable testosterone Free testosterone

Sum of protein-bound and free testosterone in circulation22 Free testosterone plus testosterone loosely bound to albumin22 The 0.5%-3.0% of testosterone not bound to albumin or SHBG22

Total testosterone is the most widely available and least expensive assay.23 Free testosterone is that not bound to SHBG or albumin and amounts to only 0.5% to 3.0% of total testosterone.22 Although this is a more accurate assessment of hypogonadism, the direct or analog free testosterone assay is inaccurate. Equilibrium dialysis is a much more dependable measure, but very few laboratories are capable of performing this complicated assay.

Calculating the free testosterone index, total testosterone divided by SHBG, also is unreliable for individual patients.23,24 Bioavailable testosterone (ie, not bound to SHBG) may be the most reliable test, indicating how much testosterone is available to target tissues, but this test is expensive and not widely available.23 Calculations of free testosterone or bioavailable testosterone using the mass action equation provide useful and reliable estimates.

The free and bioavailable testosterone calculator is available from the International Society for the Study of the Aging Male’s Web site at http://issam.ch/freetesto.htm30

When should clinicians measure free testosterone levels? Free testosterone should be measured for men with conditions that will markedly alter their SHBG levels, such as obesity, chronic inflammatory disease (eg, HIV), hyperthyroidism, or liver disease and for older men who have higher SHBG with borderline free testosterone (200-350 ng/dL).22

In men found to be testosterone deficient, measurement of LH and follicle-stimulating hormone (FSH) levels can help determine whether the defect is at the testicular level (ie, primary) or at the hypothalamic-pituitary site (ie, secondary).22 Table 3 illustrates the laboratory and other studies that can be used to further evaluate for hypogonadism.24 Additional workups for men with hypogonadism include measuring serum levels of prolactin, ferritin, iron-binding capacity, prostate-specific antigen (PSA) and digital rectal examination (DRE),1 dual-energy x-ray absorptiometry (DEXA) scan to determine bone mineral density (BMD), and brain magnetic resonance imaging. Karyotyping should be conducted for men with undiagnosed primary testicular disease to rule out Klinefelter syndrome.22

current data, they can more accurately diagnose and appropriately treat their male patients who have testosterone deficiency.

Key messages

  • Measure testosterone levels in men with signs and symptoms of hypogonadism

  • Measure total testosterone levels by a reliable assa , preferably in the morning, and confirm low values with repeat measurement

  • Use the normative ranges specific to the assay

  • Use ancillary clinical and laboratory data to corroborate the diagnosis

Table 3. Further Evaluation of Hypogonadism Based on American Association of Clinical Endocrinologists Guidelines24

Laboratory Studies Testosterone

Gonadotropins Luteinizing hormone Follicle-stimulating hormone

Other Studies Bone densitometry Pituitary imaging Genetic studies

In summar , there are many challenges to diagnosing hypogonadism. However, if clinicians are aware of the limitations and abreast of

Testicular biopsy, scrotal exploration


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