Significance of glutathione peroxidases in endometrium function: facts, hypotheses, and research perspectives

Abstract

Enzymes of glutathione peroxidase (GPX) family, together with peroxiredoxins, form thiol peroxidase superfamily, the property of which is the thiol-dependent catalysis of the hydroperoxide reduction. This property determines them as antioxidant protectors. Among human GPXs the eight forms are known, five of which are selenium-dependent (GPX1,2,3,4, and 6). The most number of facts supporting the substantial role of GPX in functioning of endometrium are linked with the GPX3, which is the secretory GPX. The number of candidate progesterone response elements in the promoter of GPX3 gene prevails over the number of candidate estrogen response elements; GPX3 is upregulated gene during postovulatory phase of reproductive cycle and during pregnancy; in the endometrial stroma, the transcription of Gpx3 is stimulated through the transcription factor HIF1α. Using laboratory animals, the spatial and temporal coincidence of Gpx3 activation and blastocyst implantation was observed. It was confirmed that GPX3 decreases hydrogen peroxide concentration in endometrium in pregnant animals and during in vitro decidualization. The vulnerability of reproductive function to physiological stress at the insufficient expression of GPX3 is hypothesized. The GPX3 enzymatic activity in endometrium is poorly investigated. The has been hypothesized that selenium-containing medications are effective in the endometrium receptivity improvement and in the supporting the normal embryo development (especially during the influence of physiological stressors) by the maintenance of the posttranscriptional, selenium-dependent stage of GPX3 biosynthesis in endometrium. Probably, the GPX3 expression can be increased by the steriods with gestagenic activity (through the increase of Gpx3 transcription, analogously to effect of progesterone). In contrast with the «classic» GPX (GPX1) and probably with most of other members of GPX family, GPX3 has a wide thiol specificity. It is proposed to assess the activity of GPX3 using the reduced homocysteine and cysteine as thiol substrates instead of the reduced glutathione.