Sources and functions of prostaglandins in the testis: evidences for their relevance in male (in)fertility

FRUNGIERI MB

Campinas

Workshop; III Workshop on Male Reproductive Biology; 2011

Prostaglandins (PGs) are derived from arachidonic acid by the action of the constitutively expressed cyclooxygenase isoenzyme type 1 (COX1) and the inducible isoenzyme type 2 (COX2). Initial knockout studies in mice have described that female COX2 deficient mice are infertile. In contrast, male fertility is not affected in COX2 mutant mice suggesting that PGs may not be important for the functioning of the testis. This early general view is being challenged by recent observations in other species, including our studies in human and hamster. COX2 is not detected in human testes with normal spermatogenesis, but it is expressed in the interstitial compartment, presumably in Leydig cells and macrophages (MAC), of patients with impaired spermatogenesis and male infertility. Reasons for testicular expression of COX2 and consequences of its actions are not fully known, but cellular and ex -vivo studies provided insights. Mast cells and MAC appear to be involved. Both are significantly increased in the testis of infertile men and correlate with the degree of fibrosis of the tubular wall, a change typically associated with impaired spermatogenesis. The major mast cell product, tryptase, through protease-activated receptors (PAR2) increased the expression of COX2. Subsequently, one of the PGs produced, 15d-PGJ2, acting via the nuclear peroxisome proliferator-activated receptor g (PPARg) was found to induce human fibroblast proliferation. Our studies have also shown that all components of the signalling pathway (tryptase-positive mast cells, COX2 and PPARg) are present in testes of infertile men and could be responsible for human testicular fibrosis. Although we have not yet tested the role of MAC products, IL1ß expression correlates with COX2 in the human testis. In order to overcome limitations associated with the investigation of human testes, we explored whether animal models may exist.  After screening species ranging from mice to monkeys, we identified a reproductively active seasonal breeder, the Syrian hamster as a readily available model. In hamsters, Leydig cells express COX2 and produce PGD2 and PGF2a. Moreover, they express DP and FP receptors. Whereas PGD2 has a stimulatory effect on basal testosterone production, PGF2a exerts an inhibitory role in the expression of StAR and 17b-hydroxysteroid dehydrogenase, as well as in the synthesis of testosterone induced by hCG/LH. How COX2 is regulated in hamsters is not fully known, but we found that testosterone significantly induces COX2 expression and PGF2a production in hamster Leydig cells. Thus, we assume the existence of a regulatory loop. Testosterone induces COX2 expression and PGF2a production, but COX2/PGF2a inhibits StAR and 17b-HSD expression and consequently, testosterone production thereby setting a brake on testicular steroidogenesis. This regulatory loop might be of relevance in physiological conditions and/or pathological states. In conclusion, investigations carried out during the last years indicate that COX2 and PGs may play key roles in testicular patho-physiology. The study of these actions appears as a promising field of research with special relevance to male fertility. Further advances in the knowledge of the actions of COX/PGs in the human testis could lead to new therapeutical approaches in idiopathic male infertility. (Grants from CONICET, UBA and Fundación Roemmers).