Male Hypogonadism. Part II: Etiology, Pathophysiology, and Diagnosis

A. Seftel


Int J Impot Res. 2006;18(3):223-228. 

In This Article


In addition to recognizing presenting symptoms, conducting appropriate laboratory testing is central to diagnosing male hypogonadism.[3] According to the Second International Consultation on Erectile Dysfunction of the World Health Organization (WHO),[43] a blood sample for serum T determination should be obtained between 0800 and 1100 hours, when T levels typically peak in healthy young men. This circadian rhythmicity may be abolished or blunted in men with advancing age[44] or during certain forms of TRT.

A morning T level ≤300 ng/dl should be confirmed and if there is a need to differentiate primary from secondary hypogonadism, levels of LH and FSH should be evaluated.[43] According to the guidelines of 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.[2] Some authorities recommend sellar magnetic resonance imaging with thyroxine, cortisol, and prolactin assessments when secondary hypogonadism is considered likely.[45] According to Australian consensus guidelines:[46]

  • primary (hypergonadotropic) hypogonadism is indicated by serum T<231 ng/dl with LH>1.5 times the upper limit of normal (1.5 × ULN);

  • secondary (hypogonadotropic) hypogonadism is indicated by T<231 ng/dl without LH elevations;

  • Leydig-cell failure is indicated by T=231-432 ng/dl with LH>1.5 × ULN; and

  • androgen resistance is indicated by T>864 ng/dl with LH>1.5 × ULN.

Total T assays may not indicate true androgenic status, particularly in elderly men. According to the most recent WHO guidelines,[43] BT (normal range=92-420 ng/dl) and FT (normal=5-21 ng/dl) are the most reliable assays to establish male hypogonadism. As serum T may be normal in patients with primary testicular disorders (e.g. Klinefelter syndrome) or increased SHBG, obtaining FT or BT may also be useful.[2] However, the validity and accessibility of a number of diagnostic tests (e.g. equilibrium dialysis) and other, dynamic assessments are matters of ongoing debate.

Recent data from the Massachusetts Male Ageing Study (MMAS) provide perspectives on normal androgen ranges.[47] In the MMAS, the threshold for abnormally low total T as established by the 2.5th percentile was 251 ng/dl for healthy men aged 40-49 years, 216 ng/dl for ages 50-59, 196 ng/dl for ages 60-69, and 156 ng/dl for ages 70-79. Corresponding 2.5th-percentile values for FT were 5.3, 4.2, 3.7, and 2.2 ng/dl, while corresponding values for BT were 99.7, 79.8, 69.7, and 41.8 ng/dl.

In the MMAS, the mean FT in men aged 40-49 years was 14.3 ng/dl, with a range of 3.7 ng/dl (mean-2 standard deviations (s.d.)), to 24.9 ng/dl (mean+2 s.d.). The mean FT in men aged 70-79 was 7.6 ng/dl (0.8-14.4 ng/dl). The mean BT in men aged 40-49 years was 270.9 ng/dl (69.2-469.7 ng/dl) and the mean BT in men aged 70-79 was 144.1 ng/dl (14.4-270.9 ng/dl).[47]

As with ED, signs and symptoms of hypogonadism often go unreported to physicians. Therefore, it is important to maintain a proactive dialogue with the patient about possible symptoms such as low libido, ED, impaired concentration, and fatigue to uncover hypogonadism. It is also often important to inquire about increased fatigue during TRT because this may be a manifestation of treatment-related sleep apnea.