Placental Hormones and the Control of Fetal Growth

Abstract

The weight of a child at birth is a critical determinant of neonatal morbidity and mortality and the risk of metabolic disease throughout the life span: growth retarded [intrauterine growth retardation/small for gestational age (SGA)] infants are predisposed to hypoglycemia, hypocalcemia, hypothermia, asphyxia, and cognitive dysfunction; those who have rapid catch-up weight gain in early childhood are at increased risk for adult-onset type 2 diabetes, hypertension, preeclampsia, dyslipidemia, and ischemic heart disease (1). Likewise, large for gestational age (LGA) infants are predisposed to childhood weight gain, type 2 diabetes, and the metabolic syndrome (2). Despite a wealth of investigation, the molecular mechanisms controlling fetal weight gain and growth remain poorly understood. The paper by Mannick et al. (3) in this month’s Journal provides new insight into the roles of placental hormones in the regulation of fetal growth in normal and pathological pregnancies. The placenta controls fetal growth through delivery of blood, oxygen, and nutrients to the fetus and clearance of fetal waste products including carbon dioxide and urea. The substrates for uteroplacental transport are derived from maternal nutrient stores (4). In early and mid-gestation, maternal food intake increases 10–15%, intestinal calcium absorption doubles, and there is a 60% rise in first-phase insulin secretion. Because insulin sensitivity is preserved during the first half of pregnancy, the increase in insulin secretion promotes lipogenesis and limits fatty acid oxidation, facilitating maternal fat storage. In mid- and late gestation, maternal food intake and fat mass escalate, but maternal metabolism is transformed by the emergence of insulin resistance. This facilitates maternal utilization of free fatty acids as an energy source, sparing glucose, amino acids, essential fatty acids, and ketones for placental-fetal transport and fetal growth. The metabolic adaptations of pregnancy are orchestrated by hormones produced by the placenta and maternal pituitary gland, which undergo dramatic changes during gestation (4). After involution of ovarian sex steroid production by wk 6, placental estrogen and progesterone production increases exponentially to term. Concurrently, there are progressive increases in prolactin (PRL), produced by the maternal pituitary gland and decidua, and human chorionic somatomammotropin (CSH, also called human placental lactogen), which has structural similarities to GH and PRL. CSH binds with high affinity to PRL receptors (Kd 0.1 nm) but with low affinity to human GH receptors (Kd 770 nm), suggesting that it functions as a lactogen rather than as a somatogen during pregnancy. Interestingly, levels of pituitary GH (GH1) decline sharply during early and mid-pregnancy and are no longer detected in maternal serum after 24 wk gestation. GH1 is replaced by a variant GH [GH2 or placental GH (PGH)] produced by the syncytiotrophoblast. In contrast to pituitary GH, the variant GH is secreted tonically and in increasing amounts throughout the second half of gestation, reaching levels (20–40 ng/ml) comparable to those in acromegaly. PGH binds with high affinity to GH receptors but with low affinity to PRL receptors. Thus, the mother in mid- and late gestation is bathed in high levels of two lactogenic hormones (PRL, peak 150–180 ng/ml; and CSH, peak 5000–7000 ng/ml) and a nearly pure somatogen (PGH). CSH is also secreted directly into the fetal circulation, reaching levels approximating 20–30 ng/ml, whereas fetal pituitary PRL levels can climb as high as 200–300 ng/ml; in contrast, PGH is detected only in maternal blood. Previous studies had found low maternal levels of PGH and CSH in pregnancies complicated by hypertension, preeclampsia, and intrauterine growth retardation (5, 6). Mannick et al. (3) extend this work by exploring the relation between PGH and CSH expression and birth weight in normal term pregnancies. The expression of PGH and CSH transcripts was assessed by a sophisticated fluorescent RT-PCR assay coupled with gene-specific restriction analysis. Their study has a number of strengths. Most important, the cohort was a homogeneous population of healthy Caucasian women without known underlying metabolic or pregnancy-related diseases. Mothers with diabetes or toxemia and infants with fetal anomalies or genetic or infectious diseases were excluded. This design eliminates a number of major complicating factors and may provide a window into the physiological, rather than strictly pathological, role of PGH and CSH in fetal growth regulation. Five of the 15 women in the SGA group were smokers, but the authors have controlled for this confounder in their multiple regression analysis. Their findings are novel. First, they show that half of the PGH transcripts detected in term placenta encode proteins with C termini distinct from the major GH2 product (GH2-1); the functions of these alternative proteins are unknown