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

Abstract

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.

Peripheral insulin-like factor 3 concentrations are reduced in men with type 2 diabetes mellitus: effect of glycemic control and visceral adiposity on Leydig cell function

“…In the present study, INSL3 was successfully detected in the serum of both diabetic patients and controls by the EIA assay giving results similar to previous data obtained by the INSL3 time-resolved fluorescence immunoassay (TRFIA) (16,17). Nonetheless, serum INSL3 levels did not show a significant correlation with both testosterone and LH levels in diabetic patients and controls.…”

“…Nonetheless, serum INSL3 levels did not show a significant correlation with both testosterone and LH levels in diabetic patients and controls. This lack of correlation might be related to the low degree of the Leydig cell function impairment, as a significant correlation between serum INSL3 and testosterone or LH levels has not been reported also in a large cohort of healthy men (17). Indeed, we cannot exclude that it might depend on the small size of our series.…”

“…Indeed, the present findings firstly suggest the existence of subtle alterations at gonadal level also in diabetic patients with normal testosterone values, regardless of the presence of symptoms of androgen deficiency. The global impairment of Leydig cell function in T2DM is confirmed by the finding of reduced circulating levels of INSL3, a novel peptide hormone mainly derived from Leydig cells (15,16,25,26), which have been indicated as an absolute measure of either quality or number of the Leydig cells, independently from gonadotropin stimulation (16,17,(27)(28)(29)(30). The higher LH levels in diabetic patients than in controls, though in the normal range, might suggest that when few or poor-quality Leydig cells are present, more LH is required to achieve normal circulating testosterone levels.…”

“…Previous reports investigated INSL3 concentrations in adult normal subjects and in men with different testicular disorders, showing a lower amount in subjects with testicular damage (15,16) and a decrease in its concentration with aging in normal men (17). INSL3 measurement, as a parameter of the HPG axis impairment, has not been reported in T2DM up to now.…”

Structural Validation and Homology Modeling of Differentially Expressed Proteins in Rattus Norvergicus Induced by Bisphenol a and Probiotic Treatement.

“…In humans, circulating INSL3 increases through puberty, to reach a maximum in early adulthood, and subsequently appears to decline to significantly lower plasma levels in aging men [16,17]. Recently, it has been suggested [18] that androgens and phthalates at high concentration may modulate Insl3 gene expression in cultured Leydig cells.…”