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.

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

Journal: The aging male : the official journal of the International Society for the Study of the Aging Male 2024;27(1):2346322

PMID: 38676285

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.

Address: School of Biosciences, University of Nottingham, Sutton Bonington, UK.; Department of Chronic Diseases and Metabolism, Laboratory of Clinical and Experimental Endocrinology, Leuven, KU, Belgium.; Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium.; Department of Obstetrics, Gynaecology and Andrology, Albert Szent-Gyorgy Medical University, Szeged, Hungary.; Department of Medicine, Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago (IDIS), CIBER de Fisiopatología Obesidad y Nutricion (CB06/03), Instituto Salud Carlos III, Santiago de Compostela, Spain.; Endocrinology and Andrology Unit, "Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.; Centre for Epidemiology Versus Arthritis, The University of Manchester & NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, UK.; Andrology Clinic, Tartu University Hospital, and Institute of Clinical Medicine, and Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.; Department of Andrology and Reproductive Endocrinology, Medical University of Łódź, Łódź, Poland.; Department of Geriatrics, University Hospitals Leuven, and Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.; Department of Endocrinology, Manchester University NHS Foundation Trust, Manchester, UK.; Institute of Reproductive and Developmental, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Campus, London, UK.; School of Biosciences, University of Nottingham, Sutton Bonington, UK.; School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, UK.
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