Peripheral INSL3 concentrations decline with age in a large population of Australian men

The novel peptide hormone insulin-like peptide 3 (INSL3) is a major secretory product of the Leydig cells of the testis, and in adult men is secreted into the blood, giving rise to circulating concentrations ranging from 0.5 to 2.5 ng/mL. We studied a large randomly recruited cohort of 1183 men from South Australia, comparing serum INSL3 concentrations with age, and a variety of endocrine, cognitive and morphological parameters. While INSL3 concentration declines significantly (p < 0.001) and continuously with age from 1.29 +/- 0.47 ng/mL in young men (age 35-44 years) to 0.79 +/- 0.39 ng/mL in the age group 75-80 years, there is no correlation with testosterone or components of the hypothalamo-pituitary-gonadal (HPG) axis, independent of age, nor with any other parameter measured, including thyroid or prostate status and obesity. For men exhibiting normal follicle stimulating hormone (FSH) and high luteinizing hormone (LH) levels, there was a significant inverse correlation with plasma oestradiol. Unilaterally orchidectomized men had INSL3 values intermediate between intact men and anorchid subjects, and showed inverse correlations (p < 0.001) between INSL3 and FSH or LH concentrations, which were independent of age. Taken together, the data show that INSL3 is an independent measure of Leydig cell function (quality and number), which appears to be independent of acute control via the HPG axis. Its decline with age reflects a decline in the properties of the Leydig cell population only, and emphasizes a gonadal component in the age-related decrease in androgen production.