The effects of the aromatase inhibitor fadrozole hydrochloride on fetuses and uteri in late pregnant rats

Abstract

It is well known that progesterone and estrogen are essential hormones for maintaining pregnancy in most mammals. Some specific roles of progesterone for the maintenance of pregnancy have been clarified, but the role of estrogen is not well known. This study examines the effects of the aromatase inhibitor, fadrozole hydrochloride (Fad), on fetuses, uterine physical properties and the mRNA expression of the uterine enzymes that are related to collagen metabolism during late pregnancy in rats. Continuous s.c. infusion with 300 µg/day Fad from day 14 of pregnancy (day 1=the day of sperm detection) reduced the concentration of plasma estradiol-17 (E 2 ), and did not change that of plasma progesterone, compared with controls. The treatment increased the intrauterine pressure and reduced the size and compliance of the uterine tissue framework. It also caused injuries (hematomata on the extremities) in about one-quarter of fetuses by day 20. The collagen content of the uterine ampullae was not changed by the treatment. Uterine mRNA expressions of matrix metalloproteinase-1 (MMP-1), which degrades collagens, and of lysyl oxidase (LO), which is necessary for the formation of intra-and inter-molecular cross-links of collagen, were examined by quantitative RT-PCR. The treatment with Fad had no effect on the expression of MMP-1 mRNA and increased that of LO mRNA. Daily s.c. injection with 0·2 µg E 2 restored the changes in uterine physical properties and the mRNA expression of LO caused by the Fad treatment, and prevented fetal injury, indicating that the influences of Fad treatment are due to estrogen deficiency but not to toxicological effects of Fad. These results imply that estrogen deficiency during late pregnancy in rats obstructs development of the uterine tissue framework so as to cause fetal injury. It is possible that an increase in the uterine expression of LO gene may be involved in this obstruction.

Impact of Aldosterone Synthase Inhibitor FAD286 on Steroid Hormone Profile in Human Adrenocortical Cells

“…FAD286 did not affect pregnenolone, progesterone, and 17-OH-progesterone concentrations. Similar results were shown in previous studies using NCI-H295R cells [34] and pregnant rats [35]. Interestingly, Ang II treatment lowered progesterone and 17-OH-progesterone concentrations.…”

A predictive data-driven framework for endocrine prioritization: a triazole fungicide case study

“…Further, aromatase inhibitors have been associated with multiple developmental effects in rats, including decreased survival, fetal hematomata, and skeletal anomalies (Tamada et al. 2004 ; Tiboni et al. 2008 , 2009 ), but these effects were not observed in the rat (or rabbit) developmental studies.…”

PATHFAST, a novel chemiluminescent enzyme immunoassay for measuring estradiol in equine whole blood and serum

“…It induces estrus and prepares the uterus for fertilization and implantation by promoting endometrial growth, development of the uterine gland, and secretion of uterine and vaginal mucus [6]. The physiological function of estradiol is to induce embryo implantation in the uterus and maintain uterine conditions for the growing fetus during pregnancy [7,8,9,10,11,12]. Therefore, measurement of estradiol is useful for detecting follicular and placental function in cyclic and pregnant mares.…”

“…Remarkable fetal growth occurs in the uterus during the late stages of pregnancy in all mammals. The most important factor involved includes the rapid elongation and cylindrical changes in the uterus to maintain fetal survival at the stage of rapid fetal growth during the late stages of pregnancy [9,10,11,12]. Progesterone, estrogen, prolactin and relaxin play key roles in the implantation of embryos, maintenance of pregnancy, and induction of parturition.…”

“…Progesterone, estrogen, prolactin and relaxin play key roles in the implantation of embryos, maintenance of pregnancy, and induction of parturition. Although the synergistic action of progesterone and estrogen is generally essential for mares, as in most mammals, for maintaining successful pregnancy, estrogen plays a dominant role in the maintenance of uterine elongation when the fetus grows rapidly in late pregnancy [9,10,11,12]. Therefore, monitoring circulating estradiol and progesterone is useful for detecting clinical signs of abortion, stillbirth, and perinatal fetal death during late pregnancy in mares [19,20,21,22].…”