Insulin-Like Peptides in Male Reproductive Biology

Insulin-like peptides, most notably insulin-like peptide 3 (INSL3), constitute a small family of peptide hormones that exert critical roles across male reproductive development and function. Synthesised principally by Leydig cells in the fetal and adult testis, INSL3 binds to the G-protein-coupled receptor RXFP2 to mediate the first phase of testicular descent via gubernacular thickening and to support Leydig cell differentiation and spermatogenesis. Beyond its classical endocrine action, INSL3 also acts in autocrine and paracrine modes within the testicular microenvironment, influencing germ cell survival and steroidogenesis. In the adult male, circulating INSL3 serves as a constitutive biomarker of Leydig cell capacity, distinguished from the more dynamically regulated testosterone axis, and exhibits broader anabolic effects on bone and muscle. Dysregulation of INSL3 signalling is implicated in cryptorchidism, hypogonadism and age-related declines in reproductive health. Comparative analyses across vertebrate species highlight the evolutionary conservation of ligand–receptor interactions and suggest emerging applications of INSL3 measurement in clinical diagnostics, animal breeding programmes and evaluation of environmental endocrine disruptors.

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Insulin-Like Peptides in Male Reproductive Biology publication trend

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Technical terms

Insulin-like peptide 3 (INSL3): A small peptide hormone produced by Leydig cells, essential for testicular descent and a biomarker of Leydig cell function.

RXFP2: A G-protein-coupled receptor for INSL3 located on gubernacular and testicular cells.

Leydig cells: Testicular cells that synthesise testosterone and insulin-like peptides, including INSL3.

Gubernaculum: The ligament that guides the fetal testis from the abdomen into the scrotum under INSL3 control.

Autocrine/paracrine signalling: Local modes of hormone action affecting the secreting cell itself (autocrine) or neighbouring cells (paracrine).

Biomarker: A measurable indicator of physiological or pathological state, here reflecting Leydig cell capacity and testicular health.

References

1. Expression of Insl3 Protein in Adult Danio rerio. International Journal of Molecular Sciences (2024).
2. INSL3/Leydig Insulin-like Peptide Activates the LGR8 Receptor Important in Testis Descent*. Journal of Biological Chemistry (2002).
3. Profiling Insulin Like Factor 3 (INSL3) Signaling in Human Osteoblasts. PLOS ONE (2011).
4. Protective Role of Testicular Hormone INSL3 From Atrophy and Weakness in Skeletal Muscle. Frontiers in Endocrinology (2018).
5. Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort. Andrology (2022).
6. Insulin-Like Peptide 3 (INSL3) Serum Concentration During Human Male Fetal Life. Frontiers in Endocrinology (2019).