Role of sex steroids and their receptors in human preterm infants: Impacts on future treatment strategies for cerebral development.

Preterm birth is a major risk factor for cerebral complications, such as hemorrhage or periventricular leukomalacia, which lead to lifelong neurodevelopmental deficits. Hypoxia/ischemia, inflammation, hyperoxia, and prematurity itself contribute to the extent of impaired neurodevelopment. Preterm birth leads to disruption of the placental supply of estrogens and progesterone. Postnatally, the plasma levels of estrogens and progesterone drop 100-fold. Preterm infants are deprived of the placental supply of these hormones for up to sixteen weeks. Thus, supplementation of estradiol and progesterone to mimic intrauterine conditions may potentially improve a premature infant́s extrauterine development and help protect the brain against neurological complications. However, preliminary clinical studies did not find improved outcomes except for a trend towards less cerebral palsy. The decrease in estrogen and progesterone concentrations is accompanied by persistent, high postnatal production of fetal zone steroids, mainly dehydroepiandrosterone, which serve as precursors for maternal estrogen synthesis during pregnancy. This commentary will combine knowledge from endocrinology, pharmacology, and neonatology to explain the discrepancies between promising animal models and clinical findings. Most important targets will be classical and non-classical estrogen receptors, which interact differently-not only with estrogens but also with fetal zone steroids. The fetal zone is unique among humans and higher primates. Therefore, a clearly defined model is required to study the role of sex steroids and their receptors before further clinical studies begin.