Beta Estradiol Levels in Growth-Restricted Pregnancies

Introduction: Estrogen-Related Receptor gamma (ERRy) is an activator of mitochondrial (mt) biogenesis. Moreover, ERRy can affect the estrogen pathway by binding the Estrogen Receptor (ER) or modulating CYP19 expression, an aromatase involved in 17- 17Beta-Estradiol (E2) production. During pregnancy, the fetus-placenta unit is the primary source of estrogens. E2 is critical for placental function and fetal growth.Werecently observed reduced ERRy and mtDNA levels in trophoblast cells from growth-restricted (IUGR) placentas. To evaluate if these placental molecular alterations could affect 17-Beta Estradiol production, we measured E2 concentration in maternal plasma of the same IUGR pregnancies. Materials and Methods: Maternal venous blood collected before cesarean section (no labor) from 11 IUGR and 16 term normal pregnancies (Controls), centrifuged at 1500rpm x15 min. at R.T. and obtained plasma stored at -80 ◦C.IUGRclassified in2groups of increasing severity based on umbilical artery Pulsatility Index (PI) and Fetal Heart Rate (FHR). E2 levels measured with an electrochemiluminescence immunoassay (Elecsys Estradiol III- Cobas) and an automated Elecsys immunoanalyser. Clinical and molecular data analyzed with T-test and Pearson correlation (p < 0.05-SPSSv23.00). Results: Maternal age and BMI did not differ between IUGR and controls, while gestational age, placental and fetal weight, placental area and fetus/placenta ratio were significantly lower in IUGR (p≤0.001). 17-B Estradiol in maternal venous plasma resulted significantly lower in IUGR (14893.0±6746.6 pg/mL) versus controls (25351.2±10755.3 pg/mL)(p = 0.009)(Fig. 1). Analyzing IUGR cases depending on severity, E2 concentration was lower in both IUGR groups versus controls, reaching statistical significance in those with normal PI (15305.4±7211.1 pg/mL,n = 7-p = 0.036; abnormal PI:14171.2±6828,7 pg/mL, n = 4-p = 0.06). Maternal plasma E2 levels positively correlated with gestational age, fetal weight and placental area (p = 0.006,R = 0.516;p = 0.002,R = 0.570;p = 0.015,R = 0.489). A strong positive correlation linked plasma E2 with fetus-placenta ratio, an index of placental efficiency (p = 0.006,R = 0.512)(Fig. 2). Conclusions:in extra-placental tissues, 17-B Estradiol exerts a protective role against oxidative stress (OxS). This is mediated by ERalpha and its co-activator ERRy, possibly inducing a reduction of mt OxS. We recently showed that ERRy, which binds CYP19 promoter, was downregulated in IUGR trophoblast cells, where 17-B Estradiol is produced. The significant difference found in maternal plasma 17-B Estradiol may therefore confirm an altered status in IUGR placentas. These present reduced surface and efficiency and interestingly both parameters here correlate with E2 concentration. These data support the hypothesis that placental insufficiency may be characterized by an ERRy-mediated impairment in placental steroidogenesis that increases IUGR susceptibility to the oxidative intrauterine environment.Supported by FGP/MIUR.