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Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort

Anand-Ivell, Ravinder; Heng, Kee; Severn, Katie; Antonio, Leen; Bartfai, Gyorgy; Casanueva, Felipe F.; Huhtaniemi, Ilpo T.; Giwercman, Aleksander; Maggi, Mario; O'Neill, Terence W; Punab, Margus; Rastrelli, Giulia; Slowikowska?Hilczer, Jolanta; Tournoy, Jos; Vanderschueren, Dirk; Wu, Frederick CW; Ivell, Richard


Kee Heng

Leen Antonio

Gyorgy Bartfai

Felipe F. Casanueva

Ilpo T. Huhtaniemi

Aleksander Giwercman

Mario Maggi

Terence W O'Neill

Margus Punab

Giulia Rastrelli

Jolanta Slowikowska?Hilczer

Jos Tournoy

Dirk Vanderschueren

Frederick CW Wu

Richard Ivell


Background: Aging in men is accompanied by a broad range of symptoms, including sexual dysfunction, cognitive and musculoskeletal decline, obesity, type 2 diabetes, cardiovascular disease and hypertension, organ degeneration/failure, and increasing neoplasia, some of which are associated with declining levels of Leydig cell-produced testosterone. High natural biological variance, together with multiple factors that can modulate circulating testosterone concentration, may influence its interpretation and clinical implications. Insulin-like peptide 3 is a biomarker of Leydig cell function that might provide complementary information on testicular health and its downstream outcomes. Objectives: To characterize insulin-like peptide 3 as a biomarker to assess gonadal status in aging men. Methods and materials: A large European multicenter (European Male Aging Study) cohort of community-dwelling men was analyzed to determine how insulin-like peptide 3 relates to a range of hormonal, anthropometric, and lifestyle parameters. Results and discussion: Insulin-like peptide 3 declines cross-sectionally and longitudinally within individuals at approximately 15% per decade from age 40 years, unlike testosterone (1.9% per decade), which is partly compensated by increasing pituitary luteinizing hormone production. Importantly, lower insulin-like peptide 3 in younger men appears to persist with aging. Multiple regression analysis shows that, unlike testosterone, insulin-like peptide 3 is negatively dependent on luteinizing hormone and sex hormone-binding globulin and positively dependent on follicle-stimulating hormone, suggesting a different mechanism of gonadotropic regulation. Circulating insulin-like peptide 3 is negatively associated with increased body mass index or waist circumference and with smoking, and unlike testosterone, it is not affected by weight loss in obese individuals. Geographic variation in mean insulin-like peptide 3 within Europe appears to be largely explained by differences in these parameters. The results allowed the establishment of a European-wide reference range for insulin-like peptide 3 (95% confidence interval) adjusted for increasing age. Conclusion: Insulin-like peptide 3 is a constitutive biomarker of Leydig cell functional capacity and is a robust, reliably measurable peptide not subject to gonadotropin-dependent short-term regulation and within-individual variation in testosterone.


Anand-Ivell, R., Heng, K., Severn, K., Antonio, L., Bartfai, G., Casanueva, F. F., …Ivell, R. (2022). Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort. Andrology, 10(7), 1328-1338.

Journal Article Type Article
Acceptance Date Jun 20, 2022
Online Publication Date Jun 30, 2022
Publication Date 2022-10
Deposit Date Sep 6, 2022
Publicly Available Date Sep 7, 2022
Journal Andrology
Print ISSN 2047-2919
Electronic ISSN 2047-2927
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 10
Issue 7
Pages 1328-1338
Keywords Urology; Endocrinology; Reproductive Medicine; Endocrinology, Diabetes and Metabolism
Public URL
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