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Cited by 69Hormonal and reproductive studiesHypothalamic control of reproductive hormonesAdrenal Hormones and Disorders

Symptomatic androgen deficiency develops only when both total and free testosterone decline in obese men who may have incident biochemical secondary hypogonadism: Prospective results from the EMAS

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Rastrelli, Giulia, O'Neill, Terence W., Ahern, Tomas, Bártfai, György, Casanueva, Felipe F., Forti, Gianni, Keevil, Brian, Giwercman, Aleksander +12 more·2018·Clinical Endocrinology
DOI 10.1111/cen.13756
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Abstract

Summary: Objective: Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex hormone–binding globulin (SHBG) is altered. Low total testosterone (TT) is commonly encountered in obesity where SHBG is typically decreased. We aimed to assess the contribution of FT in improving the diagnosis of symptomatic secondary hypogonadism (SH), identified initially by low total testosterone (TT), and then further differentiated by normal FT (LNSH) or low FT (LLSH). Design: Prospective observational study with a median follow‐up of 4.3 years. Patients: Three thousand three hundred sixty‐nine community‐dwelling men aged 40‐79 years from eight European centres. Measurements: Subjects were categorized according to baseline and follow‐up biochemical status into persistent eugonadal (referent group; n = 1880), incident LNSH (eugonadism to LNSH; n = 101) and incident LLSH (eugonadism to LLSH; n = 38). Predictors and clinical features associated with the transition from eugonadism to LNSH or LLSH were assessed. Results: The cumulative incidence of LNSH and LLSH over 4.3 years was 4.9% and 1.9%, respectively. Baseline obesity predicted both LNSH and LLSH, but the former occurred more frequently in younger men. LLSH, but not LNSH, was associated with new/worsened sexual symptoms, including low desire [OR = 2.67 (1.27‐5.60)], erectile dysfunction [OR = 4.53 (2.05‐10.01)] and infrequent morning erections [OR = 3.40 (1.48‐7.84)]. Conclusions: These longitudinal data demonstrate the importance of FT in the diagnosis of hypogonadism in obese men with low TT and SHBG. The concurrent fall in TT and FT identifies the minority (27.3%) of men with hypogonadal symptoms, which were not present in the majority developing low TT with normal FT.

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  • Longitudinal analysis of EMAS confirmed that only 27.3% of men with low total T truly have low free T and develop clinical symptoms, while 72.7% have low total T but normal free T and no sexual symptoms.

    “Only a small portion of men (27.3%) with low total T truly have low free T and develop the accompanying clinical symptoms of hypogonadism. This in contrast to the larger portion of men (72.7%) that develop an apparent biochemical hypogonadism. While this latter proportion of men have low total T values, their free T was in fact in normal range, exempting them from experiencing sexual symptoms [251”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [251]

    The Discussion reports that, among men developing apparent biochemical secondary hypogonadism, 27.3% had low total and free testosterone and 72.7% had low total but normal free testosterone. The Symptoms sections report more frequent sexual symptoms in the former group and no difference from persistently eugonadal men in the latter. The claim overstates these group-level findings: it implies that every man in the 27.3% developed symptoms and that every man in the 72.7% was free of them; the percentages also describe incident secondary hypogonadism, not all men with low total testosterone. (LLM, conf=0.87)

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Authors
Rastrelli, G., O'Neill, T. W., Ahern, T., Bártfai, G., Casanueva, F. F., Forti, G., Keevil, B., Giwercman, A., Han, T. S., Slowikowska‐Hilczer, J., Lean, M. E. J., Pendleton, N., Punab, M., Antonio, L., Tournoy, J., Vanderschueren, D., Maggi, M., Huhtaniemi, I. T., Wu, F. C. W., & the EMAS study group
Affiliations
  • University of Florence (IT)
  • Division of Musculoskeletal and Dermatological Sciences Faculty of Biology, Medicine and Health Arthritis Research UK Centre for Epidemiology Manchester Academic Health Science Centre University of Manchester and NIHR Manchester Musculoskeletal Biomedical Research Centre Manchester University NHS Foundation Trust Manchester UK
  • Andrology Research Unit Division of Endocrinology, Diabetes & Gastroenterology Domain of Cardiovascular, Metabolic and Nutritional Sciences School of Medical Sciences Faculty of Biology, Medicine and Health Manchester Academic Health Science Centre The University of Manchester Manchester UK
  • University of Szeged (HU)
  • Universidade de Santiago de Compostela (ES)
  • Wythenshawe Hospital (GB)
  • Lund University (SE)
  • Royal Holloway University of London (GB)
  • Department of Andrology and Reproductive Endocrinology Medical University of Lodz Lodz Poland
  • University of Glasgow (GB)
  • Manchester Academic Health Science Centre (GB)
  • Tartu University Hospital (EE)
  • KU Leuven (BE)
  • Imperial College London (GB)
Corresponding author
Rastrelli, Giulia
ORCID
Venue
Clinical Endocrinology
Publisher
Wiley
Published
2018-07-23
Volume
89
Issue
4
Pages
459-469
ISSN
  • 0300-0664 (ISSN-L)
  • 1365-2265
DOI
10.1111/cen.13756
OpenAlex
W2807449881
Cited by
69
References
13
Citations by year
2026: 2 · 2025: 12 · 2024: 8 · 2023: 6 · 2022: 12 · 2021: 11 · 2020: 7 · 2019: 6 · 2018: 4
FWCI
5.57
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Clinical Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • Lirias (submittedVersion, other-oa)
  • Florence Research (University of Florence) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
  • Arthritis Research UK
  • National Institute for Health Research
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 › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
secondary hypogonadism, free testosterone, total testosterone, sex hormone-binding globulin, obesity, androgen deficiency, erectile dysfunction, low libido, morning erections, hypogonadism diagnosis, men
MeSH terms
Adult, Aged, Humans, Hypogonadism, Hypothyroidism, Male, Middle Aged, Obesity, Prospective Studies, Testosterone, Logistic Models, Observational Studies as Topic

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