Evidence-based criteria identifying late-onset hypogonadism defined

June 2011

Identification of late-onset hypogonadism in middle-aged and elderly men. Wu FC, Tajar A, Beynon JM, et al. N Engl J Med 2010;363(2):123-135.

This was a systematic investigation of a random population sample of 3369 middle-aged and elderly men (aged 40–79 years) to establish evidence-based criteria for identifying late-onset hypogonadism in the general population on the basis of an association between symptoms and a low testosterone level. The men surveyed were participating in the European Male Aging Study (EMAS) at eight European centers. Data were collected on the men’s general, sexual, physical, and psychological health, and total testosterone levels were measured in morning blood samples and free testosterone levels were calculated. Data were randomly split into separate training and validation sets for confirmatory analyses.

A total of 32 items were considered as possible candidates for symptoms of androgen deficiency on the basis of previous recommendations and studies; all items were then screened statistically and those that were significantly associated with total or free testosterone levels were selected for independent validation and further divided into symptomatic and asymptomatic categories. The findings were published in the New England Journal of Medicine.1


Nine symptoms were confirmed to be significantly related to total or free testosterone level1

  • Three sexual symptoms: 
    1. decreased frequency of morning erection
    2. low sexual desire (decreased frequency of sexual thoughts), and
    3. erectile dysfunction
  • Three physical symptoms: 
    1. inability to engage in vigorous activity
    2. inability to walk more than 1 km
    3. inability to bend, kneel or stoop
  • Three psychological symptoms: 
    1. loss of energy
    2. sadness
    3. fatigue
  • The probability of symptoms increased with decreased levels of testosterone and the presence of the three sexual symptoms correlated most closely with low testosterone levels1
  • More than 25% of men with normal testosterone levels had similar sexual symptoms1
  • Total testosterone levels <317 ng/dL (11 nmol/L) and free testosterone levels <64 pg/mL (220 pmol/L) and the presence of the three sexual symptoms were identified as diagnostic criteria for late−onset hypogonadism.1

What is known

Diagnostic criteria for treatable late-onset hypogonadism in current guidelines are based on the presence of a variety of symptoms and signs suggestive of testosterone deficiency in combination with a low serum testosterone level.2,3 However, evidence-based data regarding the exact criteria for identifying testosterone deficiency in older men have been lacking, as their symptoms may be non-specific and/or mimicked by other underlying comorbidities. Consequently, the threshold testosterone level below which the symptoms of androgen deficiency become apparent, and adverse health outcomes develop, in older men has been unclear and an arbitrary testosterone level confirming the diagnosis of hypogonadism in all patients has not been supported by the available evidence.2

This systematic investigation of a large, random population sample of aging men by University of Manchester researchers, working with colleagues at Imperial College London, UCL (University College London) and other European partners, sought to establish evidence-based criteria for identifying late-onset hypogonadism in the general population.

What this study adds

This study verified the symptoms significantly associated with late-onset hypogonadism. The study provides evidence-based criteria that the presence of a cluster of three sexual symptoms, together with low testosterone levels, can be regarded as necessary to establish a diagnosis of late-onset hypogonadism, although other non-sexual symptoms may also be present.

The findings should provide new guidance to physicians prescribing testosterone therapy, and are, according to Dr William Bremner in an accompanying editorial,4 “a valuable addition to earlier research, as well as to society guidelines, which have also proposed the combination of symptoms and low testosterone levels to establish the diagnosis of late-onset hypogonadism”. The study suggests that sexual symptoms rather than non-specific physical and psychological symptoms should be used to accurately identify patients with late-onset hypogonadism. The research also identified the thresholds of testosterone below which certain symptoms become increasingly prevalent. Documented levels of testosterone below these thresholds are necessary to confirm the diagnosis of hypogonadism in symptomatic older men. Although the practice of using total testosterone as the primary biochemical criterion for the diagnosis of late-onset hypogonadism was supported by the study, the researchers consider that applying a threshold of 220 pmol/L for free testosterone may be useful in patients with multiple symptoms and a borderline level of total testosterone (8−11 nmol/L).

The lead author of the study, Professor Fred Wu from The University of Manchester’s School of Biomedicine, commented on the university’s website (http://www.manchester.ac.uk) that “…the long list of nonspecific symptoms that have a potential association with testosterone deficiency makes it difficult to establish a clear diagnosis of late-onset hypogonadism… It is therefore important to specify the presence of all three sexual symptoms of the nine testosterone-related symptoms we identified, together with low testosterone, in order to increase the probability of correctly diagnosing late-onset hypogonadism.”


  • Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363(2):123-135. Return to content
  • Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006;91(6):1995-2010. Return to content
  • Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 2009;55(1):121-130. Return to content
  • Bremner WJ. Testosterone deficiency and replacement in older men. N Engl J Med 2010;363(2):189-191. Return to content