Placental endocrine function shapes cerebellar development and social behavior

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO’s synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.

CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction

Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the 3H2O transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced (p ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced (p ≤ 0.01) umbilical IGF1 concentrations, as well as reduced umbilical nutrient uptakes (p ≤ 0.05) in CSH RNAi pregnancies. CSH RNAi also reduced (p ≤ 0.05) uterine nutrient uptakes as well as uteroplacental glucose utilization. These data suggest that CSH is necessary to facilitate adequate blood flow for the uptake of oxygen, oxidative substrates, and hormones essential to support fetal and uterine growth.

Placental Regulation of Energy Homeostasis During Human Pregnancy

Successful pregnancies rely on sufficient energy and nutrient supply, which require the mother to metabolically adapt to support fetal needs. The placenta has a critical role in this process, as this specialized organ produces hormones and peptides that regulate fetal and maternal metabolism. The ability for the mother to metabolically adapt to support the fetus depends on maternal prepregnancy health. Two-thirds of pregnancies in the United States involve obese or overweight women at the time of conception. This poses significant risks for the infant and mother by disrupting metabolic changes that would normally occur during pregnancy. Despite well characterized functions of placental hormones, there is scarce knowledge surrounding placental endocrine regulation of maternal metabolic trends in pathological pregnancies. In this review, we discuss current efforts to close this gap of knowledge and highlight areas where more research is needed. As the intrauterine environment predetermines the health and wellbeing of the offspring in later life, adequate metabolic control is essential for a successful pregnancy outcome. Understanding how placental hormones contribute to aberrant metabolic adaptations in pathological pregnancies may unveil disease mechanisms and provide methods for better identification and treatment. Studies discussed in this review were identified through PubMed searches between the years of 1966 to the present. We investigated studies of normal pregnancy and metabolic disorders in pregnancy that focused on energy requirements during pregnancy, endocrine regulation of glucose metabolism and insulin resistance, cholesterol and lipid metabolism, and placental hormone regulation.

Features of establishment of early lactation in women who gave birth after in vitro fertilization

Background Breastfeeding gives babies the best possible start in life and breastmilk works like a baby’s first vaccine. Pregnancy resulting from IVF is often associated with placental insufficiency in which the hormone-producing function of placenta can be compromised that may result in reduced lactogenesis. The aim was to study the emergence of early lactation after IVF in women with a history of infertility. Methods The study involved 34 women after IVF with a singleton full-term pregnancy with a history of tubal-peritoneal infertility. Control group comprised of 47 women with naturally occurred pregnancy. Delivery occurred naturally. All women were assessed for hormonal function of placenta for a period of 16-18, 28-32, and 37-38 weeks of pregnancy. The average daily amount of milk on a 5th day after delivery was measured. Results In the IVF group vs. control group there was a decrease in the production of hormones by the placenta (progesterone, estriol, placental lactogen) preparing the mammary glands for lactation (p < 0.05). At gestational age of 16-18 weeks progesterone level in IVF group was 172.2±10.72 nmol/l; 28-32: 274.2±8.45 nmol/l; 37-38 weeks: 343.2±9,1 nmol/l. The level of estriol at 16-18 weeks was 2.87±1.42 ng/ml; 28-32: 10.94±0.6 ng/ml; 37-38 weeks: 25.21±0.22 ng/ml. Placental lactogen at16-18 weeks: 1.15±0.2 nmol/l; 28-32: 6.39±0.69 nmol/l; 37-38 weeks: 7.23±0.59 nmol/l. On day 5 normal lactation was observed in 21(62%) and 43(91.5%) women in IVF and control group, respectively (p < 0.05). Conclusions Increased number of cases of hypolactation was observed in women after IVF, which was associated with decrease in the hormonal function of placenta. Women who have given birth to children after IVF require special attention from the side of medical personnel and from loved ones in the early stages of establishment of breastfeeding. Key messages IVF is a risk factor for hypolactation, which is associated with placental hormone-producing insufficiency. Women who have given birth after IVF require support aimed at promotion of early lactation and breastfeeding.

Dynamics of trophoblast differentiation in peri-implantation–stage human embryos

Single-cell RNA sequencing of cells from cultured human blastocysts has enabled us to define the transcriptomic landscape of placental trophoblast (TB) that surrounds the epiblast and associated embryonic tissues during the enigmatic day 8 (D8) to D12 peri-implantation period before the villous placenta forms. We analyzed the transcriptomes of 3 early placental cell types, cytoTB (CTB), syncytioTB (STB), and migratoryTB (MTB), picked manually from cultured embryos dissociated with trypsin and were able to follow sublineages that emerged from proliferating CTB at the periphery of the conceptus. A unique form of CTB with some features of STB was detectable at D8, while mature STB was at its zenith at D10. A form of MTB with a mixed MTB/CTB phenotype arose around D10. By D12, STB generation was in decline, CTB had entered a new phase of proliferation, and mature MTB cells had begun to move from the main body of the conceptus. Notably, the MTB transcriptome at D12 indicated enrichment of transcripts associated with IFN signaling, migration, and invasion and up-regulation of HLA-C, HLA-E, and HLA-G. The STB, which is distinct from the STB of later villous STB, had a phenotype consistent with intense protein export and placental hormone production, as well as migration and invasion. The studies show that TB associated with human embryos is in rapid developmental flux during peri-implantation period when it must invade, signal robustly to the mother to ensure that the pregnancy continues, and make first contact with the maternal immune system.