Aberrant Synthesis, Metabolism, and Plasma Accumulation of Circulating Estrogens and Estrogen Metabolites in Preeclampsia Implications for Vascular Dysfunction

Abstract

Estrogens and estrogen metabolites have important functions in cardiovascular and other physiology, yet the patterns of estrogen synthesis, metabolism and the individual plasma profile of estrogens and estrogen metabolites during human pregnancy as well as in preeclampsia remain undetermined. We performed liquid chromatography mass spectrometry on plasma samples from normotensive pregnant women (normP; n = 8), women with mild (mPE; n = 8) and severe (sPE; n = 8) preeclampsia at labor. Compared to normP, estrone was lower in sPE, whereas plasma level of estradiol-17β was significantly lower in women with mPE and sPE. Estriol was lower in sPE but not in mPE. Although, 2-hydroxyestrone was lower in mPE and sPE, 4-hydroxyestrone was high in sPE. 16-α-hydroxyestrone was higher in mPE but not in sPE. 2-hydroxyestradiol in women with mPE and sPE were lower compared to normP. Compared to 2-methoxyestrone in normP, levels were lower in sPE. 3-methoxyestrone and 4-methoxyestrone were unchanged. 2-methoxyestradiol was lower in mPE and sPE; however, 4-methoxyestradiol was low only in sPE. Compared to normP, 16-keto-estradiol levels were significantly higher in sPE whereas 16-epi-estriol and 17-epi-estriol were lower in women with sPE. Our findings show that preeclampsia is characterized by aberrant synthesis, metabolism and accumulation of estrogens and estrogen metabolites that are likely to be associated with alterations in vascular function. These results underscore the need to investigate the functional vascular and other physiology of estrogens and estrogen metabolites in the pathophysiology of preeclampsia.

Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

“…Preeclampsia is a multiorgan syndrome of pregnancy that most commonly affects first-time pregnancies in the second trimester of pregnancy (2-7%) and it is a leading cause of maternal and fetal morbidity and mortality (41). Lower levels of estriol have been associated with this pathology (42).…”

Imbalance between proliferation and apoptosis−related impaired GPR30 expression is involved in preeclampsia

“…Previous studies have suggested that oestrogens and oestrogen metabolites are associated with alterations in vascular function in PE [4,5]. As a novel oestrogen receptor, GPR30 has been shown to regulate many of the rapid vascular effects attributable to oestrogens [16], moreover, multiple studies have demonstrated that GPR30 is associated with the pathogenesis of hypertension [9,[11][12][13][14][15].…”

“…The inner chambers were coated with 70 ml of 10 μg/ml Matrigel (BD Biosciences) for 2 hrs in 37°. 1.0×10 5 HUVECs were inoculated into each of the inner chambers and 650 μl medium supplemented with 10% FBS was added to the outer chambers of each well. The cells were then exposed to H/R (4 hrs of hypoxia followed by 2hrs of reoxygenation) or normoxia at 37° for 6hrs.…”

“…Previous studies have reported significantly reduced plasma levels of oestrogens and oestrogen metabolites in patients with PE compared with normotensive pregnant women [4,5]. The effects of oestrogen in PE have been attributed to the classical oestrogen receptors (ERs), namely, ERα and ERβ [6,7].…”

Decreased Maternal Serum 2-Methoxyestradiol Levels are Associated with the Development of Preeclampsia

“…Meanwhile, Jobe et al (2013) recently reported mean maternal plasma 2-ME levels (2186 pg/ml, ∼ 7 nM) in normotensive full term pregnant women was significantly higher than those in mild PE (mPE, 1813 pg/ml, 6 nM) and severe PE (sPE, 982 pg/ml, 3nM) as 2-ME was measured using liquid chromatography mass spectrometry [16]. In addition, another study showed that 2-ME levels in plasma at the first trimester (11-14th weeks) from women who developed PE later in pregnancy were significantly lower (1.9±2.0 vs. 61.7±27 pg/ml, ∼0.006 nM vs. 0.204 nM) than those in normal controls [8].…”