Cyclooxygenase and prostaglandins in testicular physiopathology

MATZKIN ME

Buenos Aires

Simposio; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Biología, Sociedad Argentina de Investigación Clínica, Sociedad Argentina de Andrología

Prostaglandins (PGs) are bioactive lipid substances derived from arachidonic acid. They are produced by almost all nucleated cells and can, therefore, be found in most tissues. PGs are generated in a complex biosynthetic pathway in which cyclo-oxygenase (COX) is the rate-limiting enzyme. Two isoforms of this enzyme have been described: COX-1 and COX-2. They are encoded by two separate genes and exhibit distinct cell-specific expression, subcellular localization and regulation. While COX-1, commonly known as the constitutive isoform, seems to mediate housekeeping functions, COX-2, the inducible isoform, seems to be expressed in response to varying stimuli such as growth factors and cytokines. Given their ubiquitous nature, PGs are involved in diverse physiological and pathological processes, including regulation of inflammatory and immune responses, cell growth, vascular tone, angiogenesis and tumorigenesis. Regarding reproductive function, interesting findings were described in the early 1990?fs using mouse models with targeted disruption of COX. While COX/PGs were found to be important regulators of female reproductive function (ovulation, uterine receptivity, implantation and parturition), fertility was not affected in male mice with COX deficiency, thus suggesting that PGs may not be critical for male reproductive function. However, this view has recently been challenged by novel observations stating essential roles for PGs in testicular physio-pathology.We have described a COX-2/PG system in the two key somatic cell types of the testis: Leydig and Sertoli cells. Our studies have provided insights into how several hormones and cytokines (i.e., follicle stimulating hormone, prolactin, testosterone and IL-1?À) modulate COX-2 expression and PG production in these somatic cells. Studies performed mainly in rodents indicate that some PGs (i.e., PGD2 and PGF2?¿) modulate androgen production in Leydig cells, while 15d-PGJ2 regulates glucose transport in Sertoli cells and, consequently, spermatogenic efficiency. Furthermore, using mouse models with delayed (Ames dwarf and growth hormone releasing hormone?]knockout mice) or accelerated (growth hormone?]transgenic mice) aging we have shown an inverse association between longevity and testicular COX2/PGD2 system. Relevant to male (in)fertility, we have reported that although COX-2 is not detected in human testes with no evident morphological changes or abnormalities, it is expressed in testicular biopsies of men with impaired spermatogenesis and infertility. In addition to its expression in Leydig and Sertoli cells, COX-2 has been detected in the seminiferous tubule wall, and in testicular macrophages and mast cells of infertile patients. These observations stress the possible relevance of PGs in testicular inflammation associated with idiopathic infertility.Collectively, these data indicate that the COX-2/PG system plays crucial roles not only in testicular physiology (i.e., steroidogenesis, spermatogenesis, reproductive aging), but also in the pathogenesis or maintenance of infertility status in the male gonad. Therefore, the study of COX and PG actions emerges as a promising field of research with potential impact on male fertility. Further advances in the knowledge of the role played by COX, PGs, and their receptors in the human testis, as well as future studies concerning the impact of drugs targeting COX/PGs at the testicular level, could lead to new therapeutic approaches in idiopathic male infertility.