Prenatal glucocorticoids: Short-term benefits and long-term risks

Abstract

Glucocorticoids are steroid hormones synthesized in the adrenal gland cortex, and most of their physiological effects are mediated by the glucocorticoid receptor (GR), that acts as a ligand-dependent transcription factor. Coordinate changes in metabolism under glucocorticoid influence provide energy that is instantly and selectively available to vital organs, an enables them to deal with immediate environmental demands, at the expense of anabolic pathways, such as bone formation, reproduction, immunological responses and other, that are being blunted or delayed, under glucocorticoid influence [1-3]. During fetal development the synthesis of adrenal glucocorticoids precedes the establishment of a definitive structure of the gland. In rats, secretion of the main glucocorticoid – corticosterone starts as early as on day 13 of development [4] (term=22 days, short gestation period), while in humans secretion of the main glucocorticoid – cortisol starts in the 8th week of pregnancy (term=40 weeks, long gestation period) [5]. Glucocorticoid receptor mRNA is present in the tissue derivatives of all three germ layers from fetal day 13 onwards, and increases gradually during rat fetal development [6]. Human fetal tissues express GR at the gestational age of 6 weeks, meaning that the machinery for hormone action is prepared at the early stages of development [5]. These facts suggest that endogenous glucocorticoids produced by the fetal adrenal glands have a crucial role in fetal growth and the development of individual fetal tissues [7]. In response to the prepartum rise in glucocorticoids a wide variety of changes known as “preparation for birth” occurs, meaning that the maturational changes in many fetal tissues, essential for neonatal survival, are intensified during the last third of gestation. Namely, circulating glucocorticoids induce fetal lung maturation and surfactant production, trigger a variety of physiological effects on brain cell differentiation and synaptogenesis, stimulate the production of hepatic gluconeogenic enzymes, affect pancreatic -cell development and insulin content, influence renal development and affect the maturation of the immune system [8-10]. Metabolic, cardiovascular and immune adaptations under glucocorticoid influence are fundamental to successfully overcoming birth-related stress and postnatal adaptation of the newborn to environmental challenges [11, 12]. Environmental conditions influence the prevailing nutritional and endocrine status in mothers and fetuses. Numerous animal and human studies have shown that adverse environmental conditions during pregnancy, such as maternal undernutrition [13, 14], stress [15, 16], illness, placental insufficiency [17, 18], as well as prenatal glucocorticoid exposure [19, 20] affect fetal development and postnatal outcome. Changes in the maternal hypothalamic-pituitary-adrenal (HPA) activity, transplacental diffusion of nutrients, hormones and growth factor supply, potently affect the fetal HPA axis influencing glucocorticoid output as well as other developing systems [21, 22]. Gestational age, at which an insult occurs, its nature and intensity, determines the specific tissue or organ which will be affected by the insult. Glucocorticoids are the key mediators between maternal environment and the fetus, and as such are involved in adaptations of the fetus to predicted postnatal environment. Even transient changes in glucocorticoid levels could have longlasting consequences. The outcome might be growth retardation and change in the developmental trajectory, in the direction that best suited to the expected environment [23, 24]. This phenomenon is known as programming. The adaptations caused by suboptimal intrauterine conditions are appropriate if the predicted and actual postnatal environments match, and lead to survival to reproduce in a deprived environment [25, 26]. If there is a mismatch between the environment predicted and the actual environment experienced postnatally, adaptations are inappropriate and result in the development of disease like hypertension, ischemic heart disease, glucose intolerance, insulin resistance and type 2 diabetes [27-29]. In this chapter the latest findings, with clear statements from the literature, as well as own results regarding the endocrine mechanisms of intrauterine programming mediated by glucocorticoids will be analyzed. The causal relationship between a prenatally programmed endocrine axes and their postnatal functioning that affect growth, stress response, metabolism and reproduction will be discussed. In order to better understand mechanisms of fetal glucocorticoid programming of endocrine axes, special attention will be paid to key points of their development.