Prenatal Glucocorticoids: Short-Term Benefits and Long-Term Risks

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

Development and differentiation of Nucleus paraventricularis and nucleus supraopticus of the hypothalamus during the perinatal period in rats

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The effects of dexamethasone treatment of pregnant rats on maternal, fetal and neonatal ACTH-cells

Adrenocorticotropic hormone (ACTH) is secreted in response to a number of stimuli and it influences growth, differentiation and adrenal steroidogenesis. Rat pituitary ACTH-cells are differentiated at 14-16 days of fetal life, while synthesis of adrenal glucocorticoids starts from the 17th day of gestation as a result of increased synthesis and release of ACTH. The aim of this work was to examine the effect of dexamethasone (Dx), administered to gravid females, on the synthetic ability of their pituitary ACTH-cells as well as those of their fetal and neonatal offspring. The experimental group of pregnant females received Dx (1.5 mg/kg bw) on day 16 of gestation, while the control group received an equal volume of diluent at the same time. Plasma ACTH and cortisol concentrations were determined by RIA. The ACTH-cells were examined under light and electron microscopes. The results obtained indicate that single Dx-treatment of pregnant rats suppresses differentiation of fetal adrenocortical cells and the release of ACTH. However, in neonatal rats the number of ACTH- and precursor cells and their proliferation increased, as well as ACTH and cortisol synthesis and release, i. e. stimulation of synthesis and secretion of ACTH was noticed after suppression in the fetal period. The numerous changes observed in the fetuses and early neonates of dams treated with a single dose of Dx during pregnancy had disappeared in 30-day-old offspring.Adrenokortikotropni hormon (ACTH) se oslobađa kao odgovor na brojne stimuluse i utiče na rast, diferencijaciju i sintezu steroidnih hormona adrenalne žlezde. ACTH ćelije u hipofizi pacova diferenciraju se između 14. i 16. dana fetalnog života, dok sinteza glukokortikoidnih hormona nadbubrežne žlezde počinje 17. fetalnog dana kao rezultat povećane sinteze i oslobadanja ACTH. Cilj ovoga rada je bio da se ispita efekat deksametazonskog (Dx) tretmana gravidnih ženki na ACTH ćelije fetusa i potomaka tokom neonatalnog perioda. Paralelno je ispitivana i sintetska aktivnost ACTH ćelija majki. Eksperimentalna grupa gravidnih ženki tretirana je Dx (1.5 mg/kg/tt) 16. dana gestacije, dok je kontrolna grupa u istom periodu primila odgovarajuću količinu fizioloskog rastvora. Koncentracija ACTH u plazmi određena je RIA metodom. ACTH ćelije fetusa, neonatalnih pacova i gravidnih ženki ispitivane su svetlosnom i elektronskom mikroskopijom. Rezultati ovog istraživanja ukazuju da jednokratni Dx tretman gravidnih ženki inhibitorno utiče na diferencijaciju ACTH ćelija hipofize fetusa i oslobađanje ACTH. Međutim, u neonatalnom periodu broj prekursorskih ACTH ćelija i njihova proliferacija su povećani, kao i sinteza i oslobađanje ACTH i kortizola, tj nakon perioda inhibicije u fetalnom dobu dolazi do stimulacije u pogledu sinteze i sekrecija ACTH ćelija tokom neonatalnog perioda. Brojne promene opisane tokom fetalnog i neonatalnog perioda kod potomaka majki jednokratno tretiranih Dx 16. dana gestacije iščezavaju kod potomaka starih mesec dana.nul

Inhibitory effect of SRIH-14 on ACHT cells in neonatal female rats

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Development and differentiation of Nucleus paraventricularis and nucleus supraopticus of the hypothalamus during the perinatal period in rats

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The effects of dexamethasone treatment of pregnant rats on maternal, fetal and neonatal ACTH-cells

Adrenocorticotropic hormone (ACTH) is secreted in response to a number of stimuli and it influences growth, differentiation and adrenal steroidogenesis. Rat pituitary ACTH-cells are differentiated at 14-16 days of fetal life, while synthesis of adrenal glucocorticoids starts from the 17th day of gestation as a result of increased synthesis and release of ACTH. The aim of this work was to examine the effect of dexamethasone (Dx), administered to gravid females, on the synthetic ability of their pituitary ACTH-cells as well as those of their fetal and neonatal offspring. The experimental group of pregnant females received Dx (1.5 mg/kg bw) on day 16 of gestation, while the control group received an equal volume of diluent at the same time. Plasma ACTH and cortisol concentrations were determined by RIA. The ACTH-cells were examined under light and electron microscopes. The results obtained indicate that single Dx-treatment of pregnant rats suppresses differentiation of fetal adrenocortical cells and the release of ACTH. However, in neonatal rats the number of ACTH- and precursor cells and their proliferation increased, as well as ACTH and cortisol synthesis and release, i. e. stimulation of synthesis and secretion of ACTH was noticed after suppression in the fetal period. The numerous changes observed in the fetuses and early neonates of dams treated with a single dose of Dx during pregnancy had disappeared in 30-day-old offspring.Adrenokortikotropni hormon (ACTH) se oslobađa kao odgovor na brojne stimuluse i utiče na rast, diferencijaciju i sintezu steroidnih hormona adrenalne žlezde. ACTH ćelije u hipofizi pacova diferenciraju se između 14. i 16. dana fetalnog života, dok sinteza glukokortikoidnih hormona nadbubrežne žlezde počinje 17. fetalnog dana kao rezultat povećane sinteze i oslobadanja ACTH. Cilj ovoga rada je bio da se ispita efekat deksametazonskog (Dx) tretmana gravidnih ženki na ACTH ćelije fetusa i potomaka tokom neonatalnog perioda. Paralelno je ispitivana i sintetska aktivnost ACTH ćelija majki. Eksperimentalna grupa gravidnih ženki tretirana je Dx (1.5 mg/kg/tt) 16. dana gestacije, dok je kontrolna grupa u istom periodu primila odgovarajuću količinu fizioloskog rastvora. Koncentracija ACTH u plazmi određena je RIA metodom. ACTH ćelije fetusa, neonatalnih pacova i gravidnih ženki ispitivane su svetlosnom i elektronskom mikroskopijom. Rezultati ovog istraživanja ukazuju da jednokratni Dx tretman gravidnih ženki inhibitorno utiče na diferencijaciju ACTH ćelija hipofize fetusa i oslobađanje ACTH. Međutim, u neonatalnom periodu broj prekursorskih ACTH ćelija i njihova proliferacija su povećani, kao i sinteza i oslobađanje ACTH i kortizola, tj nakon perioda inhibicije u fetalnom dobu dolazi do stimulacije u pogledu sinteze i sekrecija ACTH ćelija tokom neonatalnog perioda. Brojne promene opisane tokom fetalnog i neonatalnog perioda kod potomaka majki jednokratno tretiranih Dx 16. dana gestacije iščezavaju kod potomaka starih mesec dana.nul

Development of pituitary ACTH and GH cells in near term rat fetuses

This study describes the development of ACTH and GH cells in 19- and 21-day-old rat fetuses using immunohistochemistry and morphometric measurements. Between days 19 and 21 of pregnancy, the total volume of fetal ACTH cells was unchanged, while their volume density and number per unit of area decreased significantly. ACTH-like immunopositivity in the pars intermedia increased during the examined period. The cell volume, volume density and number of GH cells per unit of area all markedly increased in parallel with fetal development, i.e., from gestational days 19 to 21. GH-like immunopositivity is demonstrated in the pars intermedia of 21-day-old fetuses for the first time.Prezentovano istraživanje opisuje razvoj ACTH i GH ćelija hipofize fetusa pacova, neposredno pred rođenje korišćenjem imunohistohemije i morfometrijskih merenja. Od 19. do 21. dana gestacije volumen ACTH ćelija fetusa bio je nepromenjen, dok su volumenska gustina i broj ćelija po jedinici površine značajno smanjeni. Intenzitet ACTH imunopozitivnosti u pars intermedia povećavn je tokom ispitivanog perioda. Volumen GH ćelija, volumenska gustina i brojnost po jedinici površine značajno su povećani tokom završnog perioda fetalnog razvoja, tj. od 19. do 21. dana gestacije. GH imunopozitivnost prvi put je demonstrirana u ćelijama pars intermedia kod fetusa starih 21 dan.nul

Calcium administration decreases thyroid functioning in middle-aged female rats

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Inhibitory effect of SRIH-14 on ACHT cells in neonatal female rats

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Histological and morphometric aspects of ridge preservation with a moldable, in situ hardening bone graft substitute

Biphasic calcium phosphates (BCP) are widely used in alveolar ridge regeneration as a porous scaffold for new bone formation. The aim of this case series was to evaluate the regenerative effect of the combination of BCP and polylactide-co-glycolide (PLGA) which can serve as a barrier membrane during bone regeneration. The study included five patients. Four months into the healing period, bone samples were collected for histological and morphometric analyses. The results of morphometric analysis showed that newly formed bone represented 32.2 ± 6.8% of the tissue, 31.9 ± 8.9% was occupied by residual graft and 35.9 ± 13.5% by soft tissue. Active osteogenesis was seen around the particles of the graft. The particles were occupied mostly by immature woven bone and connective tissue. The quality and quantity of newly formed bone, after the use of BCP/PLGA for ridge preservation, can be adequate for successful implant therapy after tooth extraction