Insulin 3-like hormone and its role in epididymo-testicular descent

Abstract

Purpose: The role of insulin 3-like (Insl3) hormone signaling in the testicular descent process has been demonstrated. The purpose of the present study was to evaluate epididymal development in Insl3-deficient mice. Materials and Methods: Heterozygous and homozygous Insl3 mutants of a mixed CD1 X 129/Sv genetic background were generated by breeding Insl3 -/-females with Insl3 +/-males, and their genotypes were determined by polymerase chain reaction. On the first postnatal day, newborn males were sacrificed, embedded in paraffin, and cut in 4 µm sections. Sections were stained with hematoxylin/eosin and immunoreacted with anti-α actin antibody.Results: An analysis of stained sections indicated an arrest in the development of the epididymis in all homozygous mice. The cauda and corpus of the epididymis were undersized. Compared to the heterozygous epididymis, the homozygous epididymis had fewer peritubular layers and dwarfish musculature. We confirmed this with immunostaining with monoclonal antibodies against α-smooth muscle actin. Conclusion: Defective development of the smooth musculature in the epididymis of Insl3 homozygous mutant mice, combined with its high intraabdominal undescended position, supports previous observations regarding the importance of intact epididymis morphology and function for descent of the epididymo-testicular unit.

Absent or Non Descent of the Testis

“…By the 10th week, Leydig cells produce androgens and insulin-like factor 3 (INSL3). Androgens are important for differentiation of various parts of the Wolffian duct and both androgens and INSL3 are required for testicular descent (Hadziselimovic & Adham, 2007;Hutson & Beasley, 1988) Development of the male external genitalia,including the scrotum, occurs between weeks 10 and 15 of gestation and results from the conversion of testosterone to dihydrotestosterone by the enzyme 5 alpha reductase type 2 in the primordia of these tissues. The development of the scrotum allows for the ultimate descent of the testis from the abdomen.…”

“…In humans, androgen insensitivity syndrome owing to null mutations of AR resulted in the female phenotypes (Hadziselimovic & Herzog, 2001;Wensing, 1988). Furthermore, when females were exposed to excessive androgens by testis transplantation during fetal development, the WD persisted, signifying the role of androgen in WD development (Hadziselimovic & Adham, 2007;Rajfer & Walsh, 1977).…”

“…Under androgen stimulation the gubernaculum pulls the epididymis and facilitates its descent, indirectly guiding the testis into the scrotum. (Hadziselimovic, 2001(Hadziselimovic, , 2007 In addition, the epidermal growth factor plays an active role at the level of the placenta to enhance gonadotropin release, which stimulates the fetal testis to secrete factors involved in descent such as descendin, an androgen-independent growth factor involved in gubernacular development. (Hadziselimovic & Adham, 2007) Other mediators of descent include calcitonin gene-related peptide (CGRP).…”

“…(Hutson & Beasley, 1988;Shenker et al 2006) Both (MIF) and testosterone act locally as paracrine hormone. Failing of the testis to secrete the MIF hormone will lead to ipsilateral persistent of mullerian tissues and abnormality of the paracrine function of testosterone is responsible for epididymal anomalies and UDT (Husmann & Levy, 1995;Shenker et al, 2006) There are animals in which the epididymis descends and the testis remains intra abdominal, but there are no animals in which the testis descends and epididymis remaines intraabdominal a crucial information in understating laparoscopic finding of impalpable testes (Hadziselimovic &Adham, 2007) If the testis is agenetic, one would expect that the ipsilateral mullerian structure not be suppressed. The absence of Mullerian remnants means that the there has been a testis at one stage of development that survived well above the 9 th week of gestation.…”

“…The explanation to these phenomena is related to the embryological development of the wolfian system separately from the testis with the gubernacular attachment to the epididymis rather than the testis. (Hadziselimovic, 2007) Fig. 5.…”