Antioxidant defense system during endometrial receptivity in the guinea pig: effect of ormeloxifene, a selective estrogen receptor modulator

Abstract

The role of the antioxidant defense system during endometrial receptivity, a phenomenon crucial for implantation and decidualization, and the effect of ormeloxifene, a selective estrogen receptor modulator, were investigated in the guinea pig, a laboratory mammalian species with interstitial implantation and a long functional luteal phase during each estrous cycle. A sharp rise in the activity of superoxide dismutase (SOD) in both antimesometrial (AM) and mesometrial segments and peroxidase in the AM segment of the uterus was observed on the day of maximal endometrial receptivity. Pretreatment with ormeloxifene resulted in loss of endometrial responsiveness, as evidenced by inhibition of trauma-induced decidualization and the activity of ornithine decarboxylase, a marker of tissue growth and repair. This was associated with a decrease in SOD and estradiol dehydrogenase activities, with corresponding increases in estrone dehydrogenase activity and stimulation of uterine luminal epithelial cell height and a distension of the uterine and glandular lumen. A decrease in peroxidase activity was observed only in the AM segment of the uterus on the imminent day of maximal endometrial receptivity. No effect on peripheral plasma progesterone concentration or surface ultrastructure was evident. These findings demonstrate that SOD plays an important role, with peroxidase having a supplementary role, in the first line of defense against superoxide anion radicals during the period of maximal endometrial receptivity in the guinea pig. Inhibition of endometrial receptivity and decidualization by ormeloxifene administered during the pre-receptive phase appears to be due to a depressed antioxidant defense system via dysregulation of redox-sensitive signaling, resulting in altered cellular toxicity due to increased superoxide radicals, and might contribute to the contraceptive action of ormeloxifene. This might be related to its estrogen antagonistic activity and/or decreased bioavailability of estradiol at a cellular level due to its increased metabolism to biologically less-active estrone via activation of estradiol-17 beta-hydroxysteroid dehydrogenase and suppression of estrone-17 beta-hydroxysteroid dehydrogenase.

Proteome reprogramming of endometrial epithelial cells by human trophectodermal small extracellular vesicles reveals key insights into embryo implantation

“…A major class of proteins identified include antioxidant enzymes, for example glutathione peroxidases GPX1/3/4, and peroxiredoxins PRDX1/2/4/5/6, some of which (i.e., PRDX1/4) have previously iden-tified in trophoblast-derived sEVs [58]. It is now well-known that embryos release antioxidants (including SOD1) into spent culture medium [115], and that these play an important role in embryo development and implantation [156][157][158][159][160]. These EV antioxidants potentially scavenge or neutralise ROS in the immediate embryo vicinity and provide protection in an autocrine manner.…”

Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding

“…Like women, GPs exhibit spontaneous estrous cycling and hemochorial placentation [ 40 – 43 ] justifying previous use by our laboratory of GPs as a relevant animal model to study LAPC-mediated endometrial changes [ 44 , 45 ]. Our previous observations that LAPC administration reduced endometrial blood flow and induced local HX-mediated ROS generation in women [ 10 ], taken together with similar observations in the LAPC-treated GP endometrium [ 45 ], prompted evaluation of FKBP51 expression in the endometrium of GPs following administration of MPA.…”

Long-term progestin contraceptives (LTPOC) induce aberrant angiogenesis, oxidative stress and apoptosis in the guinea pig uterus: A model for abnormal uterine bleeding in humans

“…To further understand these mechanisms, we determined whether the guinea pig (GP) was a relevant model to study the uterine effects of LTPOC administration. The GP was chosen because its endometria display functional estrogen and progesterone receptors [15] as well as other properties closely related to the humans including spontaneous estrous cycling and hemochorial placentation [16-19]. In order to elucidate mechanisms underlying LTPOC-induced abnormal uterine bleeding, we evaluated the separate and interactive effects of estrogen and progestin on GP-endometrial weight, vascular morphology, oxidative stress and apoptosis.…”