Glucosamine Inhibits Decidualization of Human Endometrial Stromal Cells and Decreases Litter Sizes in Mice1

Abstract

Embryo implantation in the uterus depends on decidualization of the endometrial stromal cells (ESCs), and glucose utilization via the pentose phosphate pathway is critical in this process. We hypothesized that the amino sugar glucosamine may block the pentose phosphate pathway via inhibition of the rate-limiting enzyme glucose-6-phosphate dehydrogenase in ESCs and therefore impair decidualization and embryo implantation, thus preventing pregnancy. Both human primary and immortalized ESCs were decidualized in vitro in the presence of 0, 2.5, or 5 mM glucosamine for 9 days. Viability assays demonstrated that glucosamine was well tolerated by human ESCs. Exposure of human ESCs to glucosamine resulted in significant decreases in the activity and expression of glucose-6-phosphate dehydrogenase and in the mRNA expression of the decidual markers prolactin, somatostatin, interleukin-15, and left-right determination factor 2. In mouse ESCs, expression of the decidual marker Prp decreased upon addition of glucosamine. In comparison with control mice, glucosamine-treated mice showed weak artificial deciduoma formation along the stimulated uterine horn. In a complementary in vivo experiment, a 60-day-release glucosamine (15, 150, or 1500 lg) or placebo pellet was implanted in a single uterine horn of mice. Mice with a glucosamine pellet delivered fewer live pups per litter than those with a control pellet, and pup number returned to normal after the end of the pellet-active period. In conclusion, glucosamine is a nonhormonal inhibitor of decidualization of both human and mouse ESCs and of pregnancy in mice. Our data indicate the potential for development of glucosamine as a novel, reversible, nonhormonal contraceptive. decidualization, glucosamine, human endometrial stromal cells, pentose phosphate pathway

[Retracted] Glucosamine Supplementation in Premating Drinking Water Improves Within‐Litter Birth Weight Uniformity of Rats Partly through Modulating Hormone Metabolism and Genes Involved in Implantation

“…In contrast, several studies demonstrated an inhibitory effect of GlcN on litter size and embryo development. Tsai et al [25] reported that litter size decreased when a sustained-release GlcN (15, 150 or 1500 μg) was implanted into uterine horn ten days before coitus and during pregnancy compared with that in the placebo-implanted control group. Further, deteriorated implantation and reduced litter size on day 18 of gestation have been reported when 8-weekold mice were injected intraperitoneally with 20 or 400 mg/ kg GlcN during periconception [26].…”

Anandamide restricts uterine stromal differentiation and is critical for complete decidualization

“…Additionally, decidualization is required for successful embryo implantation and establishment of pregnancy in human (Tsai et al, 2013). Thus, inappropriate differentiation or a decreased number of stromal cells undergoing decidualization may lead to implantation failure.…”

The Role of Hexosamine Biosynthesis and Signaling in Early Development

“…Intriguingly there appeared to be an age dependency to different outcomes with reduced litter size independent of dose in younger mothers compared with a significantly higher incidence of fetal congenital abnormalities in older mothers, similar to and consistent with pathologies associated with hyperglycemic or diabetic mice (Schelbach et al 2013). It is difficult to know the relevant contribution of effects on embryonic development versus maternal perturbations, given that maternal systemic glucosamine supplementation may also impact on decidualisation (Tsai et al 2013) and by implication subsequent placentation to contribute to altered fetal growth in response to an adverse environment.…”