Deficiency in insulin‐like growth factors signalling in mouse Leydig cells increase conversion of testosterone to estradiol because of feminization

Abstract

Aim A growing body of evidence pointed correlation between insulin‐resistance, testosterone level and infertility, but there is scarce information about mechanisms. The aim of this study was to identify the possible mechanism linking the insulin‐resistance with testosterone‐producing‐Leydig‐cells functionality. Methods We applied in vivo and in vitro approaches. The in vivo model of functional genomics is represented by INSR/IGF1R‐deficient‐testosterone‐producing Leydig cells obtained from the prepubertal (P21) and adult (P80) male mice with insulin + IGF1‐receptors deletion in steroidogenic cells (Insr/Igf1r‐DKO). The in vitro model of INSR/IGF1R‐deficient‐cell was mimicked by blockade of insulin/IGF1‐receptors on the primary culture of P21 and P80 Leydig cells. Results Leydig‐cell‐specific‐insulin‐resistance induce the development of estrogenic characteristics of progenitor Leydig cells in prepubertal mice and mature Leydig cells in adult mice, followed with a dramatic reduction of androgen phenotype. Level of androgens in serum, testes and Leydig cells decrease as a consequence of the dramatic reduction of steroidogenic capacity and activity as well as all functional markers of Leydig cell. Oppositely, the markers for female‐steroidogenic‐cell differentiation and function increase. The physiological significances are the higher level of testosterone‐to‐estradiol‐conversion in double‐knock‐out‐mice of both ages and few spermatozoa in adults. Intriguingly, the transcription of pro‐male sexual differentiation markers Sry/Sox9 increased in P21‐Leydig‐cells, questioning the current view about the antagonistic genetic programs underlying gonadal sex determination. Conclusion The results provide new molecular mechanisms leading to the development of the female phenotype in Leydig cells from Insr/Igf1r‐DKO mice and could help to better understand the correlation between insulin resistance, testosterone and male (in)fertility.

The Insulin/Insulin‐like Growth Factor signalling connects metabolism with sexual differentiation

“…In conclusion, the results published by Radovic Pletikosic and colleagues 2 suggest that sexual differentiation might involve a direct effect of obesity‐related factors on the testis, and in particular on Leydig cells, through a modification of the expression of sex‐determination factors, even in adult animals . In light of these observations, sexual differentiation is likely more plastic than generally assumed and links the influence of environmental factors, metabolic fitness and health conditions to male physiology, metabolism and reproductive capacity (Figure 1).…”

“…Correspondingly, the Insulin/Insulin‐like Growth Factor (IGF) pathway has been described as a key player of sexual development and reproduction 1 . In this issue, Radovic Pletikosic and colleagues demonstrated that Insulin/IGF signalling exerts its action through the regulation of steroidogenesis in Leydig cells 2 .…”

Growing Up Under Constant Light: A Challenge to the Endocrine Function of the Leydig Cells

“…As for Trypan blue exclusion test, cell viability was greater than 95%. The controls to validate this purification method’s comprehensiveness were challenges of purified cells (although few of them) from the inter-layers with hCG ( 20 ). Briefly, the cells from the inter-layers (few of them) were collected following the described procedures and incubated with/without (10 ng/ml), but androgen production was not detected.…”

Open research data – Expectations and limitations

“…Some authors consider this and have no limitations on which requests will be answered. 11 Only a few articles stating that primary data are available. 12 These examples highlight the limitations of open data, as every request needs to be answered equally.…”