Placental Endocrine Activity: Adaptation and Disruption of Maternal Glucose Metabolism in Pregnancy and the Influence of Fetal Sex

Abstract

The placenta is an endocrine fetal organ, which secretes a plethora of steroid- and proteo-hormones, metabolic proteins, growth factors, and cytokines in order to adapt maternal physiology to pregnancy. Central to the growth of the fetus is the supply with nutrients, foremost with glucose. Therefore, during pregnancy, maternal insulin resistance arises, which elevates maternal blood glucose levels, and consequently ensures an adequate glucose supply for the developing fetus. At the same time, maternal β-cell mass and function increase to compensate for the higher insulin demand. These adaptations are also regulated by the endocrine function of the placenta. Excessive insulin resistance or the inability to increase insulin production accordingly disrupts physiological modulation of pregnancy mediated glucose metabolism and may cause maternal gestational diabetes (GDM). A growing body of evidence suggests that this adaptation of maternal glucose metabolism differs between pregnancies carrying a girl vs. pregnancies carrying a boy. Moreover, the risk of developing GDM differs depending on the sex of the fetus. Sex differences in placenta derived hormones and bioactive proteins, which adapt and modulate maternal glucose metabolism, are likely to contribute to this sexual dimorphism. This review provides an overview on the adaptation and maladaptation of maternal glucose metabolism by placenta-derived factors, and highlights sex differences in this regulatory network.

Increased basal insulin sensitivity in late pregnancy in women carrying a male fetus: a cohort study

“…One plausible mechanism of this involves differences in placental structure or function, most of the placenta being fetal in origin [ 10 , 18 ], leading to differential secretion of placental hormones and/or other biologically active molecules into the maternal circulation. Of the various placental hormones whose maternal circulating concentrations differ according to fetal sex [ 18 ], one candidate which has been shown to be secreted in decreased amounts into the circulation with male fetuses [ 11 ] is human placental lactogen (hPL). hPL stimulates increased circulating non-esterified fatty acid levels [ 29 ], which in turn can increase hepatic glucose output [ 30 ] and glucose-stimulated insulin secretion [ 31 ].…”

“…Another potential candidate hormone is oestradiol, whose circulating concentrations are lower in women carrying males, at least in early pregnancy [ 37 ]. These reduced oestradiol concentrations are associated with increased insulin sensitivity [ 18 ]. Like the role of hPL, therefore, the role of oestradiol in affecting insulin sensitivity and secretion in pregnancy is only partially consistent with what was observed in the present analysis.…”

“…Results from the present analysis add to those in the literature suggesting that in pregnancy the maternal glucose-insulin axis can be influenced by the fetal sex, albeit our associations had modest effect sizes. Unfortunately, these actual potential effects of fetal sex appear to vary according to the makeup of the populations tested [ 12 – 18 ]. Our results come from a relatively homogeneous cohort living in a comparatively affluent area of England [ 19 ], potentially limiting confounding.…”

“…Another study found that mothers carrying male fetuses were actually more insulin resistant than those carrying females, when tested early in pregnancy [ 17 ]. A recent review of how placental endocrine function varies according to fetal sex called for more studies of fetal sex-mediated differences in the regulation of glucose metabolism in pregnancy in relatively homogeneous populations to try and clarify discrepancies in the literature in this area [ 18 ]. We therefore sought clarification of this matter using a largely ethnically homogeneous contemporary birth cohort, the Cambridge Baby Growth Study (CBGS).…”

Early Human Trophoblast Development: From Morphology To Function

“…Moreover, the placenta acts as an endocrine organ, secreting a plethora of steroid and protein hormones, metabolic proteins, growth factors, and cytokines to adapt maternal physiology to pregnancy [138]. The key placental cell type involved in all these processes is the trophoblast, a term derived from the two ancient greek words trephein and blastos, which mean 'to feed' and 'germinator'.…”