Maternal hypothyroidism causes oxidative stress and endoplasmic reticulum stress in the maternal-fetal interface of rats.

Maternal hypothyroidism is associated with pre-eclampsia and intrauterine growth restriction, gestational diseases involving oxidative stress (OS) and endoplasmic reticulum stress (ERS) in the placenta. However, it is not known whether hypothyroidism also causes OS and ERS at the maternal-fetal interface. The aim was to evaluate the fetal-placental development and the expression of mediators of OS and of the unfolded protein response (UPR) in the maternal-fetal interface of hypothyroid rats. Hypothyroidism was induced in Wistar rats with propylthiouracil and the fetal-placental development and placental and decidual expression of antioxidant, hypoxia, and UPR mediators were analyzed at 14 and 18 days of gestation (DG), as well the expression of 8-OHdG and MDA, and reactive oxygen species (ROS) and peroxynitrite levels. Hypothyroidism reduced fetal weight at 14 and 18 DG, in addition to increasing the percentage of fetal death and reducing the weight of the uteroplacental unit at 18 DG. At 14 DG, there was greater decidual and/or placental immunostaining of Hif1α, 8-OHdG, MDA, SOD1, GPx1/2, Grp78 and CHOP in hypothyroid rats, while there was a reduction in placental and/or decidual gene expression of Sod1, Gpx1, Atf6, Perk, Ho1, Xbp1, Grp78 and Chop in the same gestational period. At 18 DG, hypothyroidism increased the placental ROS levels and the decidual and/or placental immunostaining of HIF1α, 8-OHdG, MDA, ATF4, GRP78 and CHOP, while it reduced the immunostaining and enzymatic activity of SOD1, CAT, GST. Hypothyroidism increased the placental mRNA expression of Hifα, Nrf2, Sod2, Gpx1, Cat, Perk, Atf6 and Chop at 18 DG, while decreasing the decidual expression of Sod2, Cat and Atf6. These findings demonstrated that fetal-placental restriction in female rats with hypothyroidism is associated with hypoxia and dysregulation in placental and decidual expression of UPR mediators and antioxidant enzymes, and activation of oxidative stress and endoplasmic reticulum stress at the maternal-fetal interface.

Kisspeptin Treatment Restores Ovarian Function in Rats with Hypothyroidism.

Background: Hypothyroidism causes ovarian dysfunction and infertility in women, in addition to being associated with hyperprolactinemia and reduced hypothalamic expression of kisspeptin (Kp). However, it remains unknown whether and how Kp is able to reverse the ovarian dysfunction caused by hypothyroidism. Methods: Hypothyroidism was induced in adult female Wistar rats using 6-propyl-2-thiouracil for 3 months. In the last month, half of the animals received Kp10. Blood samples were collected for dosage of free thyroxine, thyrotropin (TSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2), and uteruses and ovaries were collected for histomorphometry. Body and ovarian weight and the number of corpora lutea were also evaluated. Half of the brains were evaluated by immunohistochemistry to Kp, and the other half had the arcuate nucleus of hypothalamus (ARC) and preoptic area microdissected for gene evaluation of Kiss1, Nkb, Pdyn, and Gnrh1. The pituitary gland and corpora lutea were also dissected for gene evaluation. Results: Hypothyroidism kept the animals predominantly acyclic and promoted a reduction in ovarian weight, number of corpora lutea, endometrial thickness, number of endometrial glands, and plasma LH, in addition to increasing the luteal messenger RNA (mRNA) expression of Star and Cyp11a1 and reducing 20αHsd. An increase in plasma PRL and P4 levels was also caused by hypothyroidism. Kp immunoreactivity and Kiss1 and Nkb mRNA levels in the ARC and Kiss1 in the anteroventral periventricular nucleus of hypothalamus were reduced in hypothyroid rats. Hypothyroid animals had lower pituitary gene expression of Gnrhr, Lhb, Prl, and Drd2, and an increase in Tshb. The treatment with Kp10 restored estrous cyclicality, plasma LH, ovarian and uterine morphology, and Cyp11a1, 3ßHsd, and 20αHsd mRNA levels in the corpora lutea. Kp10 treatment did not alter gene expression for Kiss1 or Nkb in the ARC of hypothyroid rats. Nevertheless, Kp10 increased Lhb mRNA levels and reduced Tshb in the pituitary compared with the hypothyroid group. Conclusions: The present findings characterize the inhibitory effects of hypothyroidism on the hypothalamic-pituitary-gonadal axis in female rats and demonstrate that Kp10 is able to reverse the ovarian dysfunction caused by hypothyroidism, regardless of hyperprolactinemia.

Maternal hypothyroidism reduces the expression of the kisspeptin/Kiss1r system in the maternal-fetal interface of rats.

Alterations of circulating and placental levels of kisspeptin have been associated with gestational diseases. However, there are still no studies on the placental and decidual expression of Kiss1 and its receptor Kiss1r in maternal hypothyroidism, which is the aim of this work. We demonstrate that the fetoplacental restriction caused by hypothyroidism in rats is associated with a reduction in the Kiss1r expression and reduced Kiss1 and Kiss1r mRNA levels in the decidua and/or placenta. This demonstrate that fetoplacental restriction in hypothyroid rats is linked with a suppression of the kisspeptin/Kiss1r system at the maternal-fetal interface.