Insulin-Like Factor 3 and the HPG Axis in the Male

Richard Ivell,Ravinder Anand-Ivell,Kee Heng

doi:10.3389/fendo.2014.00006

Abstract

The hypothalamic–pituitary–gonadal (HPG) axis comprises pulsatile GnRH from the hypothalamus impacting on the anterior pituitary to induce expression and release of both LH and FSH into the circulation. These in turn stimulate receptors on testicular Leydig and Sertoli cells, respectively, to promote steroidogenesis and spermatogenesis. Both Leydig and Sertoli cells exhibit negative feedback to the pituitary and/or hypothalamus via their products testosterone and inhibin B, respectively, thereby allowing tight regulation of the HPG axis. In particular, LH exerts both acute control on Leydig cells by influencing steroidogenic enzyme activity, as well as chronic control by impacting on Leydig cell differentiation and gene expression. Insulin-like peptide 3 (INSL3) represents an additional and different endpoint of the HPG axis. This Leydig cell hormone interacts with specific receptors, called RXFP2, on Leydig cells themselves to modulate steroidogenesis, and on male germ cells, probably to synergize with androgen-dependent Sertoli cell products to support spermatogenesis. Unlike testosterone, INSL3 is not acutely regulated by the HPG axis, but is a constitutive product of Leydig cells, which reflects their number and/or differentiation status and their ability therefore to produce various factors including steroids, together this is referred to as Leydig cell functional capacity. Because INSL3 is not subject to the acute episodic fluctuations inherent in the HPG axis itself, it serves as an excellent marker for Leydig cell differentiation and functional capacity, as in puberty, or in monitoring the treatment of hypogonadal patients, and at the same time buffering the HPG output.

Highlights

Insulin-like factor 3 (INSL3) is a member of the peptide hormone family, which includes insulin, IGF1 and IGF2, and relaxin, besides a small number of less well-known peptides [1, 2]
There may be other sites of local synthesis in some peripheral tissues, but these do not contribute to the circulating levels of the hormone, which are exclusively derived from the testes, and could only have local autocrine or paracrine effects
INSL3 production appears to follow the anatomical differentiation of Leydig cells consequent upon the massive pubertal LH pulsatility, and peaks at around day 40 in the rat, subsequently declines to stabilize at a lower circulating concentration as the HPG axis attains its stable adult configuration, with the maximal testosterone output and negative feedback

Summary

Introduction

Insulin-like factor 3 (INSL3) is a member of the peptide hormone family, which includes insulin, IGF1 and IGF2, and relaxin, besides a small number of less well-known peptides [1, 2]. Adult-type Leydig cells differentiate during puberty in an LH-dependent manner, dependent both on the increasing production and pulse frequency of pituitary LH, as well as on the expression of full-length functional LH receptors by the immature Leydig cells.

Results

Conclusion