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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. LU ; Giwercman, Aleksander LU ; Maggi, Mario and O'Neill, Terence W. , et al. (2022) In Andrology 10(7). p.1328-1338
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aging male, HPG axis, hypogonadism, INSL3, Leydig cell, testosterone
in
Andrology
volume
10
issue
7
pages
1328 - 1338
publisher
Wiley-Blackwell
external identifiers
  • pmid:35770372
  • scopus:85133654363
ISSN
2047-2919
DOI
10.1111/andr.13220
language
English
LU publication?
yes
id
d877689c-6363-43b4-b2f0-9a0a8d3038e2
date added to LUP
2022-10-04 11:41:32
date last changed
2024-04-18 10:55:23
@article{d877689c-6363-43b4-b2f0-9a0a8d3038e2,
  abstract     = {{<p>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.</p>}},
  author       = {{Anand-Ivell, Ravinder and Heng, Kee and Severn, Katie and Antonio, Leen and Bartfai, Gyorgy and Casanueva, Felipe F. and Huhtaniemi, Ilpo T. and Giwercman, Aleksander and Maggi, Mario and O'Neill, Terence W. and Punab, Margus and Rastrelli, Giulia and Slowikowska-Hilczer, Jolanta and Tournoy, Jos and Vanderschueren, Dirk and Wu, Frederick C.W. and Ivell, Richard}},
  issn         = {{2047-2919}},
  keywords     = {{aging male; HPG axis; hypogonadism; INSL3; Leydig cell; testosterone}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{1328--1338}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Andrology}},
  title        = {{Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort}},
  url          = {{http://dx.doi.org/10.1111/andr.13220}},
  doi          = {{10.1111/andr.13220}},
  volume       = {{10}},
  year         = {{2022}},
}