INSL3: an informative testis biomarker for assessing the HPG axis in men

The male hypothalamo–pituitary–gonadal (HPG) axis is an integrated endocrine system linking hypothalamic GnRH secretion, pituitary gonadotropins (LH and FSH), Leydig cell steroidogenesis, Sertoli cell function, and spermatogenesis. While conventional parameters such as testosterone or LH may be subject to high biological variance due to their pulsatile mode of secretion and multiple stress-related or environmental influences, the Leydig-cell-secreted peptide insulin-like peptide 3 (INSL3) offers a robust and constitutive alternative reflecting Leydig cell number, differentiation status, and long-term functional capacity. This narrative review considers INSL3 across the male life course in relation to other components of the HPG axis, including in fetal development, minipuberty, pubertal development, and male aging. It shows how measuring INSL3 offers important granularity in understanding issues such as the effects of environmental endocrine disruption, childhood, and lifestyle influences on pubertal development as well as on adult Leydig cell capacity, hypogonadism, and age-related morbidity. The presented evidence suggests that INSL3 will prove to be a useful biomarker for the HPG axis in adult life, though the reference range in healthy adults is quite large for yet unknown reasons; associations with BMI as well as early childhood and adolescent influences are described. While INSL3 reflects the GnRH–LH–testosterone arm of the HPG axis and is normally not directly linked to the spermatogenic compartment and male fertility, some studies do suggest a supportive relationship which merits further research. Similarly, other functions of INSL3 in men also remain underexplored.