Biology of insulin-like factor 3 in human reproduction

Abstract

BACKGROUND Insulin-like factor 3 (INSL3) is a neohormone that has evolved to address specific mammalian traits, in particular, the first phase of testicular descent towards the scrotum during mid-gestation. METHODS A thorough literature search was made in PubMed using the terms INSL3, as well as the older synonyms RLF and Ley-IL. RESULTS INSL3 is a major secretory product of the testicular Leydig cells in the fetus and in adult men, and in rodent models, reduction in fetal INSL3 expression is an early marker of the testicular dysgenesis syndrome. In women, it is produced in lower amounts by ovarian theca and luteal cells, and circulating levels are increased in women with polycystic ovarian syndrome. During pregnancy, there is evidence for an interaction regulating the feto-placental unit. The presence of INSL3 in amniocentesis samples taken at 12-14 weeks gestation is absolutely specific for male gender, and levels are predictive of subsequent pre-eclampsia and/or birthweight. INSL3 is also involved in adult traits, such as spermatogenesis and bone metabolism. In adult men, INSL3 is constitutively expressed and secreted into the bloodstream at a constant level, reflecting the number and/or functional capacity of the Leydig cells. In complete contrast, testosterone is highly variable within individuals, is acutely responsive to fluctuations in the hypothalamic-pituitary-gonadal axis and appears to have marginal diagnostic value. INSL3 declines consistently with age in adult men. CONCLUSIONS INSL3 promises to become an important new diagnostic tool to characterize those men with late-onset hypogonadism and to add clinical diagnostic value at amniocentesis.

Expression of Type II Chorionic Gonadotropin Genes Supports a Role in the Male Reproductive System

“…This peptide would contain the same propeptide cleavage sites and a peptide amidation site common to many secretory peptide hormones. Peptide hormones have numerous and varied roles in spermatogenesis (9,15,28). Thus, our findings raise the possibility that type II CG␤ genes generate other peptides, in addition to the known hCG␤, that function in the male reproductive tract.…”

Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult-type Leydig cell development in male offspring

“…Unlike testosterone, whose enzymatic production is acutely regulated by feedback from the pituitary, INSL3 is constitutively expressed. 26 Circulating testosterone, therefore, does not reveal such an overshoot effect, but once a maximum is attained, the testosterone level is held more or less constant by acute feedback regulation from the HPG axis. Following the overshoot at around day 40, circulating INSL3 production, and presumably Leydig cell activity, relaxes to yield stable and considerably lower adult levels by about days 60-90, when Leydig cell differentiation status has become regularized at a lower level as a consequence of chronic HPG control.…”

“…Additionally, we have assessed the secretion into the circulation of the Leydig cell peptide hormone INSL3, which we have shown is expressed constitutively, and accurately reflects the numbers and/or differentiation status of Leydig cells in humans and other species. 26 Total circulating testosterone was also measured, as was circulating LH. Both parameters were assessed only for single time points per day (from 9:00 a.m. to 11:00 a.m.), and therefore being pulsatile hormones, such measures are of statistical value only for the sample population, where the T/LH ratio should reflect the average capacity of Leydig cells for steroidogenesis.…”

“…26 Analysis of circulating INSL3 (Figure 4) showed that up to PND40 (i.e., during puberty), values for INSL3 tended to be higher in the DBP-and DES-treated groups compared to controls, though subsequent to this time, particularly the DEStreated group indicated lower circulating INSL3 compared to the control group. Besides the increased total INSL3 production (area under the curve) evident for the DBP treated group, there is also a clear shift in the median for each treatment group (Figure 4), with this parameter being at PND42 for the controls, PND38 for the DBPtreated group and PND37 for the DES-treated group.…”

Regulation of the reproductive cycle and early pregnancy by relaxin family peptides

“…Because INSL3 is produced largely by growing antral follicles, circulating levels are influenced by the number of such follicles in the ovary. Thus circulating INSL3 is significantly elevated in women with diagnosed PCOS (polycystic ovarian syndrome) (Havelock et al, 2005;Gambineri et al, 2007;, and is reduced in women with low ovarian reserve (Anand- Ivell et al, 2013), or who are peri-or post-menopausal (Ivell and Anand-Ivell, 2009). We are currently following up such studies to determine whether INSL3 can become an important new clinical parameter to assess follicle growth and development in women of reproductive age.…”