Identification of late-onset hypogonadism in middle-aged and elderly men
Open accessAbstract
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).
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Late-onset hypogonadism is objectively defined as requiring three sexual symptoms in conjunction with total testosterone below 11 nmol/liter and free testosterone below 220 pmol/liter.
“A syndrome of late-onset hypogonadism has since been objectively defined as requiring three sexual symptoms (decreased sexual interest, fewer morning erections and erectile dysfunction) in conjunction with a total testosterone below 11 nmol/liter and free testosterone below 220 pmol/liter [23]”
From Sleep, testosterone and cortisol balance, and ageing men (2022) · cites this paper as [23]
The European Male Aging Study identified age-related increases in symptomatic hypogonadism, with rates of 0.1% among men aged 40-49, 0.6% among 50-59, 3.2% among 60-69, and 5.1% among 70-79.
“The European Male Aging Study (EMAS) also identified age-related increases in symptomatic hypogonadism, with rates of 0.1% among 40–49 year old men rising to 0.6% (50–59), 3.2% (60–69), and 5.1% (70–79).”
From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [4]
The prevalence of symptomatic hypogonadism is poorly defined, with estimates of 2.1-17% in population-based surveys of men aged 30-87 years depending on the criterion used.
“The prevalence of symptomatic hypogonadism remains poorly defined, with estimates ranging from 2.1–17% in population-based surveys of men aged 30–87 years depending upon criterion utilized.”
From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [4]
In EMAS, obesity was associated with a 13-fold increased risk of nonclassical or late-onset hypogonadism, whereas the presence of 2 or more comorbidities increased the risk of LOH risk by only 5.2-fold.
“In EMAS, obesity was associated with a 13-fold increased risk of nonclassical or late-onset hypogonadism (LOH) defined as the syndromic coexistence of sexual dysfunction and low testosterone concentrations, whereas the presence of 2 or more comorbidities increased the risk of LOH risk by only 5.2-fold.35”
From Hypogonadism and male obesity: Focus on unresolved questions (2018) · cites this paper as [35]
Testosterone levels in men with functional hypogonadism are usually only modestly reduced and fluctuate around the lower limit of normal.
“Second, testosterone levels in men with functional hypogonadism are usually only modestly reduced and fluctuate around the lower limit of normal.”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
Even in stringently defined late-onset hypogonadism, 60% had testosterone levels ≥8.0 nmol/L (231 ng/day).
“Even in stringently defined late-onset hypogonadism, 60% had testosterone levels ≥8.0 nmol/L (231 ng/day) (10).”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
Clinical features of androgen deficiency in middle-aged and older men are nonspecific.
“First, the clinical features of androgen deficiency in middle-aged and older men are nonspecific.”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
In other observational studies of middle-aged and older men, symptoms and low testosterone also seldomly occurred together.
“In other observational studies of middle-aged and older men, symptoms and low testosterone also seldomly occurred together (Supplemental Fig. 1) (8–10).”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
Community prevalence estimates of potentially functional hypogonadism in middle-aged and older men vary from 2.1% to 12.3%.
“The community prevalence estimates of potentially functional hypogonadism in middle-aged and older men (also referred to as late-onset, age-related, or adult-onset hypogonadism) vary from 2.1% to 12.3% (8–10)”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
In EMAS, even among men with late-onset hypogonadism defined by stringent syndromic criteria, the association of low testosterone with symptoms was attenuated after adjustment for comorbidities.
“In EMAS, even among men with late-onset hypogonadism defined by stringent syndromic criteria, the association of low testosterone with symptoms was attenuated after adjustment for comorbidities (10).”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
In EMAS, only nine of 32 candidate symptoms of androgen deficiency were associated with testosterone levels, and of these only three sexual symptoms clustered with low testosterone and had a syndromic association.
“In the European Male Aging Study (EMAS) a cross-sectional survey of community-dwelling men, only nine of 32 candidate symptoms of androgen deficiency were associated with testosterone levels, and of these only three sexual symptoms clustered with low testosterone and had a syndromic association (10).”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
In EMAS, obesity increased the prevalence of late-onset hypogonadism by 13-fold and comorbidities by ninefold.
“In EMAS, obesity increased the prevalence of late-onset hypogonadism by 13-fold and comorbidities by ninefold.”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
Late-onset hypogonadism was uncommon in men who were lean (0.4%) or healthy (0.6%) and was relatively rare in men who were both.
“Late-onset hypogonadism was uncommon in men who were lean (0.4%) or healthy (0.6%) and was relatively rare in men who were both (10).”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
Functional hypogonadism is relatively uncommon in healthy men.
“Fourth, functional hypogonadism is relatively uncommon in healthy men.”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
In middle-aged and older men, low testosterone is associated with reduced physical activity and several end-organ deficits such as sarcopenia, reduced bone mass, or the metabolic syndrome.
“In middle-aged and older men, low testosterone is associated with reduced physical activity and several end-organ deficits such as sarcopenia, reduced bone mass, or the metabolic syndrome (10).”
From A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management (2017) · cites this paper as [10]
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- Authors
- Wu, F. C. W., Tajar, A., Beynon, J. M., Pye, S. R., Silman, A. J., Finn, J. D., O'Neill, T. W., Bartfai, G., Casanueva, F. F., Forti, G., Giwercman, A., Han, T. S., Kula, K., Lean, M. E. J., Pendleton, N., Punab, M., Boonen, S., Vanderschueren, D., Labrie, F., & Huhtaniemi, I. T.
- Affiliations
- Manchester Academic Health Science Centre (GB)
- Arthritis Research UK (GB)
- Complejo Hospitalario Universitario de Santiago (ES)
- University of Florence (IT)
- Skåne University Hospital (SE)
- University College London (GB)
- Medical University of Lodz (PL)
- University of Glasgow (GB)
- Salford Royal NHS Foundation Trust (GB)
- Tartu University Hospital (EE)
- KU Leuven (BE)
- Université Laval (CA)
- Imperial College London (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2010-07-08
- Volume
- 363
- Issue
- 2
- Pages
- 123-135
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2096237552
- Cited by
- 1,544
- References
- 41
- Citations by year
- 2026: 68 · 2025: 85 · 2024: 77 · 2023: 81 · 2022: 112 · 2021: 97 · 2020: 98 · 2019: 104 · 2018: 82 · 2017: 111 · 2016: 113 · 2015: 109 · 2014: 115 · 2013: 85 · 2012: 100
- FWCI
- 69.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institute for Health and Care Research
- Goddard Space Flight Center
- Manchester Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Psychiatry and Mental health › Sexual function and dysfunction studies
- Keywords
- andropause, androgen deficiency, older men, middle-aged men, sexual symptoms, erectile dysfunction, low libido, total testosterone, free testosterone, diagnostic criteria, depression, fatigue
- MeSH terms
- Activities of Daily Living, Adult, Aged, Depression, Europe, Fatigue, Health Surveys, Humans, Hypogonadism, Erectile Dysfunction, Libido, Male, Middle Aged, Surveys and Questionnaires, Testosterone, Prevalence, Logistic Models, Age of Onset
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