Preeclampsia (PE) is a pregnancy‑specific hypertensive syndrome that results in substantial maternal and fetal morbidity and mortality. The exact cause of PE has not been completely elucidate, although abnormal formation of the placenta has been considered. The placenta connects the developing fetus to the uterine wall, producing a large quantity of steroid hormones to maintain pregnancy. Although steroid hormones, particularly progesterone (P4) and estrogen (E2), in the serum of women with PE have been studied, steroidogenesis in the placenta has not well been established. The present study compared the concentrations of steroid hormones, including pregnenolone (PG), P4, dehydroepiandrosterone (DHEA), testosterone (T) and E2, in the serum and placenta of women with PE. PG, P4, DHEA and E2 concentrations tended to be decreased in PE serum and placentas, and the results were statistically significant for P4 and E2 in the serum. Quantification of genes associated with steroidogenesis in the placenta was performed, and the expression of the P4‑ and E2‑synthesizing enzymes testosterone 17‑β‑dehydrogenase 3 and 3 β‑hydroxysteroid dehydrogenase/δ5 4‑isomerase type 1 was reduced. Notably, aromatase, an enzyme required for the production of E2, was upregulated in the PE placenta, suggesting that steroidogenic enzymes may be dynamically regulated and may affect the symptoms of PE. In conclusion, the results of the present study suggested that the levels of steroid hormones, including P4 and E2, in the serum and placenta of women with PE are downregulated, which may be mediated by the regulation of steroidogenic enzyme expression in the PE placenta.

Female sex steroid hormones such as estrogen and progesterone have a pivotal role in maintaining pregnancy in human and animals. Especially, estrogen exerts specific effects on the cardiovascular system and angiogenesis, and thus affects significantly on placentation. Although the functions of estrogen have been emphasized during pregnancy, their signaling pathways in the placenta have not been fully understood. In this study, estrogen signaling was evaluated according to gestational age. Human placenta samples were collected and divided into early preterm (n = 10), late preterm (n = 18), and term (n = 20) groups. First, serum estrogen concentration and corticotropinreleasing hormone (CRH) mRNA expression, which is known as gestation clock gene, were increased following gestation age in our experimental condition, as we expected. Next, the expression of estrogen receptors (ERs) and steroid receptor coactivators (SRCs) in the placenta was evaluated. ERα (ESR1) and ERβ (ESR2) were expressed highly at term period compared with early preterm. In addition, SRC family including SRC1, SRC2, and SRC3 was expressed in the human placenta, and the levels of SRC1, SRC2, and SRC3 were increased in the placenta at the late stage of gestation. The interaction of ERs with SRCs was also examined, which was significantly enhanced at term period. In the immunostaining results, it was indicated that ERs and SRCs were all dominantly expressed in syncytiotrophoblast cells. These results suggested that SRC1, SRC2, and SRC3 were expressed and interact with ERs highly at the late stage of gestation, and may amplify the signaling of estrogen in the placenta to maintain pregnancy.

Estrogen and progesterone are the main pregnancy hormones produced by the placenta. It is well understood that estrogen stimulates angiogenesis in the uterus during the reproductive cycle. Although the estrogen and progesterone signaling pathways are assumed to be associated with placental vascularization and preeclampsia, expression of estrogen receptors (ESRs) and progesterone receptor (PGR) in the placenta have not been well studied. The present study examined the expression patterns of steroid hormone receptors in placentas. Human placenta samples were collected and divided into normal and preeclampsia groups. Results revealed that expression levels of ESR1 were reduced, whereas ESR2 and PGR were elevated in preeclamptic placentas. To generate an in vitro preeclampsia environment, human placenta‑derived BeWo cells were incubated under hypoxic conditions, or treated with catechol‑O‑methyl transferase inhibitor (COMT‑in) or L‑NG‑nitroarginine methyl ester (L‑NAME). Expression levels of ESR1, ESR2 and PGR in hypoxic cells demonstrated similar regulation as those in placentas from women with preeclampsia. Although COMT‑in and L‑NAME did not significantly regulate the expression levels of the receptors, COMT‑in translocated ESR2 and PGR from the nucleus to the cytoplasm, indicating that these receptors were inactivated. These results suggested that ESRs and PGR are associated with symptoms of preeclampsia in the placenta. The expression of ESR1 was reduced in preeclamptic placenta and hypoxic BeWo cells. In addition, the activation of ESR2 and PGR was blocked in placenta cells subjected to COMT‑in treatment. The reduced ESR1 expression and inactivation of ESR2 and PGR proteins may affect the physiological complications of preeclampsia in the placenta.

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Female sex steroid hormones, including estradiol (E2) and progesterone (P4), serve significant physiological roles in pregnancy. In particular, E2 and P4 influence placenta formation, maintain pregnancy and stimulate milk production. These hormones are produced by ovaries, adrenal glands and the placenta, of which the latter is a major endocrine organ during pregnancy. However, the mechanism of hormone production during pregnancy remains unclear. In the present study, the regulation of steroid hormones and steroidogenic enzymes was examined in human placenta according to gestational age. In human placental tissues, expression levels of steroidogenic enzymes were determined with reverse transcription-quantitative polymerase chain reaction and western blotting. The mRNA and protein expression of CYP17A1, HSD17B3 and CYP19A1, which are associated with the synthesis of dehydroepiandrosterone (DHEA) and E2, was elevated at different gestational ages in human placenta. In addition, to evaluate the correlation between serum and placental-produced hormones, steroid hormone levels, including pregnenolone (PG), DHEA, P4, testosterone (T) and E2, were examined in serum and placenta. Serum and placenta expression of DHEA and E2 increased with gestational age, whereas T and P4 were differently regulated in placenta and serum. To confirm the mechanism of steroidogenesis in vitro, placental BeWo cells were treated with E2 and P4, which are the most important hormones during pregnancy. The mRNA and protein expression of steroidogenic enzymes was significantly altered by E2 in vitro. These results demonstrated that concentration of steroid hormones was differently regulated by steroidogenic enzymes in the placenta depending on the type of the hormones, which may be critical to maintain pregnancy.