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The Leydig cell biomarker INSL3 as a predictor of age-related morbidity : Findings from the EMAS cohort

Ivell, Richard ; Heng, Kee ; Severn, Katie ; Antonio, Leen ; Bartfai, Gyorgy ; Casanueva, Felipe F. ; Huhtaniemi, Ilpo T. ; Giwercman, Aleksander LU ; Maggi, Mario and O’Connor, Daryl B. , et al. (2022) In Frontiers in Endocrinology 13.
Abstract

Background: Insulin-like peptide 3 (INSL3) is a constitutive hormone secreted in men by the mature Leydig cells of the testes. It is an accurate biomarker for Leydig cell functional capacity, reflecting their total cell number and differentiation status. Objectives: To determine the ability of INSL3 to predict hypogonadism and age-related morbidity using the EMAS cohort of older community-dwelling men. Materials & methods: Circulating INSL3 was assessed in the EMAS cohort and its cross-sectional and longitudinal relationships to hypogonadism, here defined by testosterone (T) <10.5nmol/l, and a range of age-related morbidities determined by correlation and regression analysis. Results & discussion: While INSL3 is an accurate... (More)

Background: Insulin-like peptide 3 (INSL3) is a constitutive hormone secreted in men by the mature Leydig cells of the testes. It is an accurate biomarker for Leydig cell functional capacity, reflecting their total cell number and differentiation status. Objectives: To determine the ability of INSL3 to predict hypogonadism and age-related morbidity using the EMAS cohort of older community-dwelling men. Materials & methods: Circulating INSL3 was assessed in the EMAS cohort and its cross-sectional and longitudinal relationships to hypogonadism, here defined by testosterone (T) <10.5nmol/l, and a range of age-related morbidities determined by correlation and regression analysis. Results & discussion: While INSL3 is an accurate measure of primary hypogonadism, secondary and compensated hypogonadism also indicate reduced levels of INSL3, implying that testicular hypogonadism does not improve even when LH levels are increased, and that ageing-related hypogonadism may combine both primary and secondary features. Unadjusted, serum INSL3, like calculated free testosterone (cFT), LH, or the T/LH ratio reflects hypogonadal status and is associated with reduced sexual function, bone mineral density, and physical activity, as well as increased occurrence of hypertension, cardiovascular disease, cancer, and diabetes. Using multiple regression analysis to adjust for a range of hormonal, anthropometric, and lifestyle factors, this relationship is lost for all morbidities, except for reduced bone mineral density, implying that INSL3 and/or its specific receptor, RXFP2, may be causally involved in promoting healthy bone metabolism. Elevated INSL3 also associates with hypertension and cardiovascular disease. When unadjusted, INSL3 in phase 1 of the EMAS study was assessed for its association with morbidity in phase 2 (mean 4.3 years later); INSL3 significantly predicts 7 out of 9 morbidity categories, behaving as well as cFT in this regard. In contrast, total T was predictive in only 3 of the 9 categories. Conclusion: Together with its low within-individual variance, these findings suggest that assessing INSL3 in men could offer important insight into the later development of disease in the elderly.

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publication status
published
subject
keywords
bone mineral density, cardiovascular disease, frailty, hypertension, hypogonadism, sexual function
in
Frontiers in Endocrinology
volume
13
article number
1016107
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85142214198
  • pmid:36425465
ISSN
1664-2392
DOI
10.3389/fendo.2022.1016107
language
English
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yes
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66796cc7-0509-40ca-85bc-27496d4758a5
date added to LUP
2022-12-30 13:38:45
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2024-07-08 07:33:39
@article{66796cc7-0509-40ca-85bc-27496d4758a5,
  abstract     = {{<p>Background: Insulin-like peptide 3 (INSL3) is a constitutive hormone secreted in men by the mature Leydig cells of the testes. It is an accurate biomarker for Leydig cell functional capacity, reflecting their total cell number and differentiation status. Objectives: To determine the ability of INSL3 to predict hypogonadism and age-related morbidity using the EMAS cohort of older community-dwelling men. Materials &amp; methods: Circulating INSL3 was assessed in the EMAS cohort and its cross-sectional and longitudinal relationships to hypogonadism, here defined by testosterone (T) &lt;10.5nmol/l, and a range of age-related morbidities determined by correlation and regression analysis. Results &amp; discussion: While INSL3 is an accurate measure of primary hypogonadism, secondary and compensated hypogonadism also indicate reduced levels of INSL3, implying that testicular hypogonadism does not improve even when LH levels are increased, and that ageing-related hypogonadism may combine both primary and secondary features. Unadjusted, serum INSL3, like calculated free testosterone (cFT), LH, or the T/LH ratio reflects hypogonadal status and is associated with reduced sexual function, bone mineral density, and physical activity, as well as increased occurrence of hypertension, cardiovascular disease, cancer, and diabetes. Using multiple regression analysis to adjust for a range of hormonal, anthropometric, and lifestyle factors, this relationship is lost for all morbidities, except for reduced bone mineral density, implying that INSL3 and/or its specific receptor, RXFP2, may be causally involved in promoting healthy bone metabolism. Elevated INSL3 also associates with hypertension and cardiovascular disease. When unadjusted, INSL3 in phase 1 of the EMAS study was assessed for its association with morbidity in phase 2 (mean 4.3 years later); INSL3 significantly predicts 7 out of 9 morbidity categories, behaving as well as cFT in this regard. In contrast, total T was predictive in only 3 of the 9 categories. Conclusion: Together with its low within-individual variance, these findings suggest that assessing INSL3 in men could offer important insight into the later development of disease in the elderly.</p>}},
  author       = {{Ivell, Richard 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’Connor, Daryl B. 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 Anand-Ivell, Ravinder}},
  issn         = {{1664-2392}},
  keywords     = {{bone mineral density; cardiovascular disease; frailty; hypertension; hypogonadism; sexual function}},
  language     = {{eng}},
  month        = {{11}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Endocrinology}},
  title        = {{The Leydig cell biomarker INSL3 as a predictor of age-related morbidity : Findings from the EMAS cohort}},
  url          = {{http://dx.doi.org/10.3389/fendo.2022.1016107}},
  doi          = {{10.3389/fendo.2022.1016107}},
  volume       = {{13}},
  year         = {{2022}},
}