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48: Obesity in pregnancy is associated with decreased placental estradiol biosynthesis

      Objective

      Estradiol is a critical modulator of insulin sensitivity and other key reproductive physiologic functions. Obese pregnant women (OP) have lower plasma estradiol levels compared to their normal weight counterparts (NWP). Since the placenta is the only source of estradiol (synthesized solely from cholesterol in the mitochondria), we hypothesized that maternal obesity alters placental cholesterol biosynthetic pathways (Figure 1), potentially affecting feto-placental function.

      Study Design

      Placenta and maternal blood were obtained at term elective C-section delivery in 24 women with a wide BMI range and insulin sensitivity (Table 1). Cholesterol was measured in placental mitochondria by ELISA. Gene expression of key enzymes in the estradiol biosynthetic pathways (Figure 1) was measured by real-time RT-PCR and placental cholesterol transport by western blot analysis of mithochondrial transporters.

      Results

      OP were hyperinsulinemic and insulin resistant compared to NWP. Mitochondrial cholesterol concentrations were lower in placenta of obese women (0.21 ± 0.06 vs. 0.37 ± 0.09 μg/mg protein, p<0.05). Several genes regulating cholesterol biosynthesis: ACAT1, ACAT2, LSS, SQLE, SC4MOL, NSDHL, CYP51A1 (Figure 1) were down-regulated (p<0.05) in placenta from OP compared to NWP. The expression of the primary placental cholesterol transporters, MLN64 and TSPO were both reduced by 30% (p<0.05). 17-beta-hydroxysteroid dehydrogenase (17βHSD), a key enzyme in estradiol production was down-regulated by 300% in placenta of OP (p<0.05).

      Conclusion

      Several key steps leading to cholesterol biosynthesis and estradiol production are altered in pregnancy associated with obesity and insulin resistance. These data highlight for the first time that obesity alters a major endocrine function of the feto-placental unit by decreasing its capacity to synthesize estradiol. We speculate that decreased placental estradiol function may relate to adverse pregnancy outcomes such as stillbirth, preterm delivery and glucose intolerance in OP compared with NW.
      Figure thumbnail fx1
      Schematic representation of placental steroid hormone biosynthetic pathways showing the down regulated genes in cholesterol biosynthesis, cholesterol transporters and genes involved in steroid hormone production.
      Tabled 1Characteristics of the study cohort (mean + SEM)
      Figure thumbnail fx2
      IR, insulin resistance; Mat, maternal; wt, weight.