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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; Maggi, Mario; O’Connor, Daryl B.; O’Neill, Terence W.; Punab, Margus; Rastrelli, Giulia; Slowikowska-Hilczer, Jolanta; Tournoy, Jos; Vanderschueren, Dirk; Wu, Frederick C. W.; Anand-Ivell, Ravinder

Authors

Richard Ivell

Kee Heng

Leen Antonio

Gyorgy Bartfai

Felipe F Casanueva

Ilpo T Huhtaniemi

Aleksander Giwercman

Mario Maggi

Daryl B. O’Connor

Terence W. O’Neill

Margus Punab

Giulia Rastrelli

Jolanta Slowikowska-Hilczer

Jos Tournoy

Dirk Vanderschueren

Frederick C. W. Wu



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 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.

Citation

Ivell, R., Heng, K., Severn, K., Antonio, L., Bartfai, G., Casanueva, F. F., …Anand-Ivell, R. (2022). The Leydig cell biomarker INSL3 as a predictor of age-related morbidity: Findings from the EMAS cohort. Frontiers in Endocrinology, 13, Article 1016107. https://doi.org/10.3389/fendo.2022.1016107

Journal Article Type Article
Acceptance Date Oct 24, 2022
Online Publication Date Nov 8, 2022
Publication Date Nov 8, 2022
Deposit Date Nov 29, 2022
Publicly Available Date Dec 2, 2022
Journal Frontiers in Endocrinology
Electronic ISSN 1664-2392
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 13
Article Number 1016107
DOI https://doi.org/10.3389/fendo.2022.1016107
Keywords Endocrinology, Diabetes and Metabolism
Public URL https://nottingham-repository.worktribe.com/output/13454457

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