Insulin-like peptide 3 (INSL3) as an indicator of leydig cell insufficiency (LCI) in Middle-aged and older men with hypogonadism: reference range and threshold

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

Abstract

Insulin-like peptide 3 (INSL3) is a circulating biomarker for Leydig cell functional capacity in men, also indicating Leydig Cell Insufficiency (LCI) and potential primary hypogonadism. Using results from large cohort studies we explore sources of biological and technical variance, and establish a reference range for adult men. It is constitutively secreted with little within-individual variation and reflects testicular capacity to produce testosterone. The main INSL3 assays available indicate good concordance with low technical variance; there is no effect of ethnicity. INSL3 declines with age from 35 years at about 15% per decade. Like low calculated free testosterone, and to a lesser extent low total testosterone, reduced INSL3 is significantly associated with increasing age-related morbidity, including lower overall sexual function, reflecting LCI. Consequently, low INSL3 (≤0.4 ng/ml; ca. <2 SD from the population mean) might serve as an additional biochemical marker in the assessment of functional hypogonadism (late-onset hypogonadism, LOH) where testosterone is in the borderline low range. Excluding individuals with low LCI (INSL3 ≤ 0.4 ng/ml) leads to an age-independent (> 35 years) reference range (serum) for INSL3 in the eugonadal population of 0.4 − 2.3 ng/ml, with low INSL3 prospectively identifying individuals at risk of increased future morbidity.

Citation

Anand-Ivell, R., Heng, K., Antonio, L., Bartfai, G., Casanueva, F. F., Maggi, M., O’Neill, T. W., Punab, M., Rastrelli, G., Slowikowska-Hilczer, J., Tournoy, J., Vanderschueren, D., Wu, F. C., Huhtaniemi, I. T., & Ivell, R. (2024). Insulin-like peptide 3 (INSL3) as an indicator of leydig cell insufficiency (LCI) in Middle-aged and older men with hypogonadism: reference range and threshold. Aging Male, 27(1), Article 2346322. https://doi.org/10.1080/13685538.2024.2346322

• Journal Article Type: Review
• Acceptance Date: Apr 17, 2024
• Online Publication Date: Apr 26, 2024
• Publication Date: 2024
• Deposit Date: Apr 27, 2024
• Publicly Available Date: Apr 30, 2024
• Journal: Aging Male
• Print ISSN: 1368-5538
• Electronic ISSN: 1473-0790
• Publisher: Taylor and Francis
• Peer Reviewed: Peer Reviewed
• Volume: 27
• Issue: 1
• Article Number: 2346322
• DOI: https://doi.org/10.1080/13685538.2024.2346322
• Keywords: Leydig Cells, INSL3, Male, Reference Values, hypogonadism, Aged, Middle Aged, Hypogonadism - blood, Humans, Proteins - analysis, Testosterone - blood, leydig cell, Insulins - blood, Insulin - blood, HPG axis, Biomarkers - blood, Adult
• Public URL: https://nottingham-repository.worktribe.com/output/34154903
• Publisher URL: https://www.tandfonline.com/doi/full/10.1080/13685538.2024.2346322
• Additional Information: Peer Review Statement: The publishing and review policy for this title is described in its Aims & Scope.; Aim & Scope: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=itam20; Received: 2024-02-16; Accepted: 2024-04-17; Published: 2024-04-26