Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men

Published at www.nejm.org June 16, 2010 (10.1056/NEJMoa0911101)
Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men

Frederick C.W. Wu, M.D., Abdelouahid Tajar, Ph.D., Jennifer M. Beynon, M.B., Stephen R. Pye, M.Phil., Alan J. Silman, M.D., Joseph D. Finn, B.Sc., Terence W. O'Neill, M.D., Gyorgy Bartfai, M.D., Felipe F. Casanueva, M.D., Ph.D., Gianni Forti, M.D., Aleksander Giwercman, M.D., Ph.D., Thang S. Han, M.D., Ph.D., Krzysztof Kula, M.D., Ph.D., Michael E.J. Lean, M.D., Neil Pendleton, M.D., Margus Punab, M.D., Ph.D., Steven Boonen, M.D., Ph.D., Dirk Vanderschueren, M.D., Ph.D., Fernand Labrie, M.D., Ph.D., Ilpo T. Huhtaniemi, M.D., Ph.D., for the EMAS Group


ABSTRACT

Background The association between aging-related testosterone deficiency and late-onset hypogonadism in men remains a controversial concept. We sought 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.

Methods We surveyed a random population sample of 3369 men between the ages of 40 and 79 years at eight European centers. Using questionnaires, we collected data with regard to the subjects' general, sexual, physical, and psychological health. Levels of total testosterone were measured in morning blood samples by mass spectrometry, and free testosterone levels were calculated with the use of Vermeulen's formula. Data were randomly split into separate training and validation sets for confirmatory analyses.

Results In the training set, symptoms of poor morning erection, low sexual desire, erectile dysfunction, inability to perform vigorous activity, depression, and fatigue were significantly related to the testosterone level. Increased probabilities of the three sexual symptoms and limited physical vigor were discernible with decreased testosterone levels (ranges, 8.0 to 13.0 nmol per liter [2.3 to 3.7 ng per milliliter] for total testosterone and 160 to 280 pmol per liter [46 to 81 pg per milliliter] for free testosterone). However, only the three sexual symptoms had a syndromic association with decreased testosterone levels. An inverse relationship between an increasing number of sexual symptoms and a decreasing testosterone level was observed. These relationships were independently confirmed in the validation set, in which the strengths of the association between symptoms and low testosterone levels determined the minimum criteria necessary to identify late-onset hypogonadism.

Conclusions Late-onset hypogonadism can be defined by the presence of at least three sexual symptoms associated with a total testosterone level of less than 11 nmol per liter (3.2 ng per milliliter) and a free testosterone level of less than 220 pmol per liter (64 pg per milliliter).


The clinical importance of an age-related reduction in the testosterone level1,2,3 remains controversial.4,5 Because of the uncertainty regarding the nature of testosterone deficiency in aging men,6,7,8,9 recent guidelines have suggested that so-called late-onset hypogonadism be regarded as a clinical and biochemical state with advancing age, characterized by particular symptoms and a low level of serum testosterone.10,11 However, few data on hypogonadism in aging men are available4,8,12 because of the lack of evidence regarding the exact criteria for identifying testosterone deficiency in older men who do not have pathological hypogonadism.6,13 Although a familiar array of symptoms typify severe testosterone deficiency (total testosterone level, <6 to 8 nmol per liter [1.7 to 2.3 ng per milliliter]) in younger patients, symptoms in aging men are nonspecific and are mimicked by other prevalent disorders. The testosterone level below which symptoms of androgen deficiency emerge and adverse health outcomes ensue in older men remains unclear, and the use of arbitrary thresholds is not appropriate.11
We conducted a study in a general population of middle-aged and elderly men in order to characterize the clinical symptoms associated with a low testosterone level, to identify the thresholds of testosterone below which such symptoms become increasingly prevalent, and to define essential criteria for the syndrome of late-onset hypogonadism on the basis of the presence of symptoms associated with a low testosterone level.14

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