Hipothyroidism produces change in the uterine vasculature during the implantation process

Abstract

Hypothyroidism is one of the most common endocrine abnormalities implicated in the recurrent loss of pregnancy. Our laboratory, have shown that hypothyroidism in the rat is associated with a lower number of pups per litter due to a lower number of implantation sites and a decrease in the proliferation of the endothelial and decidual cells during the process of implantation of the embryo. On the other hand, is known that angiogenesis is a critical process in the uterine endometrium for embryo implantation, maintenance of early pregnancy, and development of the placenta. During this period, steroid hormones (E2 and P4) stimulate the synthesis of vascular endothelial growth factor (VEGF-A), the main modulator of angiogenesis during peri-implantation period. Therefore we hypothesize that hypothyroidism affects the normal vascularization of endometrium during implantation. The aim of this work was to study the effect of hypothyroidism on the degree of vascularization of the uterine decidua during the implantation process. Hypothyroidism was induced in female Wistar rats by daily administration of 6-propyl-2-thiouracil (PTU) 0,1 g/L in drinking water. In addition, hormone replacement therapy with T3 was administered simultaneously to the treatment with PTU (PTU+T3), in daily physiological doses of 0.6ug/100g. Both groups were compared to rats that only drink tap water (Control),on day five (G5) and seven (G7) of gestation. Uterine vascularization was evaluated by immunofluorescence. Besides,mRNA expression of PECAM (Platelet endothelial cell adhesion molecule, an indicator of the presence of endothelial cells) and VEGF-A were evaluated during the same peri-implantation periods (G5 y G7)by RTqPCR. Our results demonstrate that hypothyroidism decreases vascularization density of the uterine tissue during the process of implantation of the embryo (p<0.05). On the other hand, our results demonstrated a significant increase of expression of VEGF mRNA when hypothyroid rats were treated with T3 before implantation, in comparison to the control group and hypothyroid group (p< 0.05). However, no changes were found in the levels of PECAM expression among the different groups. In conclusion, the failure of implantation due to hypothyroidism may be directly linked to expression of VEGF-A, and consequently to vascularization of the endometrium before implantation in early gestation. Although are necessary further studies that corroborate the exact mechanism, our results identify molecular targets regulated by thyroid hormones that may link hypothyroidism to implantation failure and recurrent miscarriage.