me%2e2015-1042

Minireview: The Impact of Antenatal TherapeuticSynthetic Glucocorticoids on the DevelopingFetal Brain

Melanie E. Peffer,* Janie Y. Zhang,* Leah Umfrey, Anthony C. Rudine,A. Paula Monaghan, and Donald B. DeFranco

Program in Integrative Molecular Biology (M.E.P., D.B.D.), Department of Pharmacology and ChemicalBiology (M.E.P., J.Y.Z., L.U., D.B.D.), and Newborn Medicine Program (A.C.R.), Children’s Hospital ofPittsburgh, and Department of Neurobiology (A.P.M.), University of Pittsburgh School of Medicine,Pittsburgh, Pennsylvania 15260

The life-threatening, emotional, and economic burdens of premature birth have been greatlyalleviated by antenatal glucocorticoid (GC) treatment. Antenatal GCs accelerate tissue develop-ment reducing respiratory distress syndrome and intraventricular hemorrhage in premature in-fants. However, they can also alter developmental processes in the brain and trigger adversebehavioral and metabolic outcomes later in life. This review summarizes animal model and clinicalstudies that examined the impact of antenatal GCs on the developing brain. In addition, wedescribe studies that assess glucocorticoid receptor (GR) action in neural stem/progenitor cells(NSPCs) in vivo and in vitro. We highlight recent work from our group on two GR pathways thatimpact NSPC proliferation, ie, a nongenomic GR pathway that regulates gap junction intercellularcommunication between coupled NSPCs through site-specific phosphorylation of connexin 43 anda genomic pathway driven by differential promoter recruitment of a specific GR phosphoisoform.(Molecular Endocrinology 29: 658–666, 2015)

Glucocorticoids (GCs) are essential for mobilizing bi-ological processes not required for fetal viability dur-

ing the transition of the mammalian fetus from intrauter-ine to extrauterine life. The overall action of endogenousfetal GCs is to trigger organ maturation, enabling thelungs, liver, gastrointestinal tract, thyroid gland, adre-nals, and kidneys to function and sustain life outside theuterine environment (1). Various tissues in the developingfetus express the glucocorticoid receptor (GR), and it isthese primary organs that undergo a maturational shift toprepare the infant for parturition and ex utero survival.For example, in the lungs GCs trigger thinning of thealveolar septae and rapid maturation of alveoli, produc-tion of collagen and elastin, and production and release ofsurfactant proteins and phospholipids (2–5). GCs also

improve the ability of the lungs to resorb fluids by increas-ing ion channels in the pulmonary epithelium and up-regulating �-adrenergic receptors (4, 6, 7). In the liver,GCs increase protein and glycogen synthesis as well asalter the expression of gluconeogenic enzymes, fatty acidsynthase, aminotransferases, and thyroid hormone me-tabolism (1, 8–12). GC responses in the gut lead to in-creases in the number and height of villi and migration ofenterocytes. As a result, digestive activity and hormonerelease are augmented (1, 13–18). The increase in the fetalkidney’s resorptive ability and decrease in the fraction ofexcreted sodium are due in part to GC up-regulation ofthe Na�/H� exchanger and Na�/K� ATPase (19–23).Erythropoietin production decreases as do renin levelsand angiotensin II receptor expression, but the renin-an-

ISSN Print 0888-8809 ISSN Online 1944-9917Printed in U.S.A.Copyright © 2015 by the Endocrine SocietyReceived February 6, 2015. Accepted March 4, 2015.First Published Online March 12, 2015

* M.E.P. and J.Y.Z. contributed equally to this work.Abbreviations: Beta, betamethasone; CAH, congenital adrenal hyperplasia; Cav-1, caveo-lin-1; Cx43, connexin 43; Dex, dexamethasone; E, embryonic day; EGF, epidermal growthfactor; FGF-1, fibroblast growth factor-1; GC, glucocorticoid; GR, glucocorticoid receptor;HPA, hypothalamus-pituitary-adrenal; HSD, hydroxysteroid dehydrogenase; IVH, intra-ventricular hemorrhage; LBW, low birth weight; NSPC, neural stem/progenitor cell; RDS,respiratory distress syndrome.

M I N I R E V I E W

658 mend.endojournals.org Mol Endocrinol, May 2015, 29(5):658–666 doi: 10.1210/me.2015-1042

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giotensin system becomes more responsive to hypovole-mia (24–28). GCs also hasten thyroid maturation,increasing thyroid hormones that are critical to neurode-velopment (1). Finally, in the fetal adrenals GCs impactcytoarchitecture of the zona fasciculata and inducecytochrome P450s, phenylethanolamine N-methyltrans-ferases, and ACTH receptors (1). These specific develop-mental requirements for GCs are reflected in the ontogenyof circulating GC levels in the fetus. Specifically, humanfetal serum cortisol levels as measured in the umbilicalcord demonstrate a fall in midgestation and a rapid rise inlate gestation (Table 1) (29).

Therapeutic use of synthetic GCs in pregnantwomen to reduce complications ofpremature birth

Synthetic GCs are prescribed to women at risk for pre-term labor to decrease the morbidity and mortality asso-ciated with prematurity. This therapeutic modality wasoriginally tested in fetal sheep in the late 1960s (30) andbecame a part of clinical practice after a 1972 landmarkstudy. In that report, Liggins and Howie (30, 31) foundthat a 2-day course of synthetic antenatal GCs decreasedrespiratory distress syndrome (RDS) and intraventricularhemorrhage (IVH), specifically in infants under 32 weeks’gestation whose mother had at least 24 hours betweensteroid administration and delivery. Subsequent large co-hort studies determined that antenatal GC therapy alsoreduced necrotizing enterocolitis and infant mortality(32, 33). Two types of synthetic GCs have historicallybeen used for antenatal administration, dexamethasone(Dex) and betamethasone (Beta). Although Dex and Betaare very similar structurally, varying only in the positionof one methyl group, they differ in their recommendeddosing schedules, placental metabolism, affinity for GR insome fetal tissue, and potency of nongenomic effects (34–36). Recent studies suggest that the preparation of Dex orBeta may also contribute to their differing clinical effectsas well (37, 38).

Currently used regimens for antenatal GCs were deter-mined empirically and later established by a 1994 Na-tional Institutes of Health Consensus Conference and ameta-analysis of 18 trials by Crowley (32) and have re-

mained unchanged since the study by Liggins and Howiein 1972 (31). The plasma unbound GC level achieved bythis regimen is physiological; Ballard et al (39) found thatit is comparable with stress-level plasma GCs as a result ofendogenous cortisol production in premature infantswith RDS. However, decreasing GCs to one single dose ofBeta has long been considered, and a study using sheephas found that this permits lung maturation and im-proved cardiac and renal function (40, 41). Historically,multiple courses of GCs have been administered if thedelivery does not occur within 7 days, although the re-cently published Multiple Courses of Antenatal Cortico-steroids for Preterm Birth study suggests that multiplecourses of antenatal GCs lead to a decreased length,weight, and head circumference at birth, compared with asingle course (42). However, in multiple placebo con-trolled trials using weekly administration of GCs, the in-cidence of RDS and mortality was similar to one singlecourse (43).

Complicating the issue is a recent Cochrane reviewsuggesting there is benefit with regard to RDS in multiplecourses of antenatal GCs when given to women who re-main at risk of preterm delivery after 7 days since theinitial course (44). Currently the same dosing regimen isused for singletons and multiple gestations (45), includingwhether multiple gestations are composed of one or moreplacentas. A recent study suggests that, at least for Beta,umbilical cord concentrations of Beta are similar for sin-gleton or multigestational pregnancies and also suggeststhat there is no significant difference in cord concentra-tions if the mother is obese or of optimal habitus (46). Theroute of administration has traditionally been intramus-cular because oral antenatal GCs have been linked to anincreased risk of early-onset neonatal sepsis and IVH(47). Finally, neither gender nor race is taken into accountin dosing regimens, despite a clear difference in some out-comes of Caucasian males and females compared withthose of African descent (48, 49).

Recent studies have examined whether one particularsynthetic GC preparation is substantially more beneficialthan another. Although Dex may generate a more pro-nounced decrease in IVH and possibly time under neona-tal intensive care (50), Beta may be more effective at pre-venting respiratory complications in very low-birthweight infants (51) and in mice (37) and may decreaseincidence of periventricular leukomalacia in human stud-ies (52). However, conflicting results have precluded thedesignation of an optimal GC dosing regimen (50, 51). Inthe United States, Beta is preferred over Dex for antenataluse in women at risk for preterm delivery.

A more controversial historical use of antenatal GCs isfor the treatment of congenital adrenal hyperplasia

Table 1. Serum Cortisol Levels in the HumanFetus (29)

Weeks of GestationAverage Fetal SerumCortisol, ng/mL

15–17 8.417.5–20 435–36 2037.5–40 45.1

doi: 10.1210/me.2015-1042 mend.endojournals.org 659


(CAH). CAH is an autosomal recessive disorder primarilyaffecting the adrenal cortex. Ninety-five percent of CAHcases are caused by deficiency of 21-hydroxylase, the en-zyme that converts 17-hydroxyprogesterone to 11-de-oxycortisol. This results in deficiencies of cortisol andaldosterone and excess of androgens (53). Although clas-sical CAH may result in childhood virilization in males, inutero virilization and the development of ambiguous gen-italia uniquely affect females, and for this indication, GCshave been given early in gestation and continued through-out pregnancy for any fetus at risk for CAH based onparental genetics (53, 54). However, seven eighths of in-fants treated, all males and unaffected females, receive nobenefit due to the need to treat before the earliest possibletime for prenatal genetic testing (54). Additionally, inboth rodent and primate models, GC treatment for CAHhas been associated with hypertension, hyperinsulinemia,hyperglycemia, fatty liver on a high-fat diet, hypothala-mus-pituitary-adrenal (HPA) hyperreactivity, and poorerlearning and memory (55–57). Children who receivedtreatment have experienced low birth weight (LBW),failure to thrive, developmental delay, mood distur-bance, poor school performance, and social anxiety(58 – 61). Given this, antenatal GCs for prevention offemale virilization in CAH are currently reserved forclinical trials (62).

Unlike endogenous GCs, Dex and Beta are not inacti-vated by enzymes found in the placenta (63). Further-more, GCs easily cross the blood-brain barrier via simplediffusion (64) and therefore have access in the fetal brainto GR. In contrast to their beneficial effects on variousfetal organ systems, synthetic GCs may negatively impactdevelopment of the fetal brain. In nonhuman primatestreated with antenatal GCs and either delivered prema-turely or at term, treatment was associated with lowerbrain and cerebellum weight and reductions in the dentategyrus and cornu Ammon (CA) region of the hippocam-pus. These cellular abnormalities are associated withlower levels of the presynaptic protein synaptophysin andmicrotubule associated proteins in the frontal region (65).At 20 months of age, young monkeys who received ante-natal GCs still had a reduction in hippocampal volume,which may be due to a chronically elevated cortisol levelcausing neurotoxicity (66). In nonhuman primates, ante-natal GCs were associated with poorer concentration,learning and memory, and hyperactivity (67, 68). Simi-larly in rats and mice, antenatal GCs were associated withdecreased learning and memory along with increasedanxiety (69, 70). Antenatal GC administration was asso-ciated with changes in basal and stress-induced HPA axisfunction in a variety of mammals, but these effects are notgeneralizable across age and species. In species with

young born at an advanced stage of development, ante-natal synthetic GCs suppress HPA axis function early inlife and in adulthood and briefly increase it in the juvenileperiod. In species with young born in an underdevelopedstate, the HPA axis function is generally elevated by an-tenatal GCs throughout the life span (71).

In humans, antenatal GCs have been associated withstructural changes in the brain. For example, antenatalGCs trigger cortical thinning specifically in the rostralanterior cingulate cortex in children 6–10 years of agewho were born at term (63) as well as decreased corticalsurface area and complexity of cortical folding in infantsborn at term (72) and periventricular leukomalacia inpremature infants assessed at 2 years adjusted age (73). Inclinical studies, antenatal GCs have been linked to neu-ropsychiatric changes in children, including attention def-icits (74), decreased scores in cognitive tests (75), distract-ibility, and aggressive behavior (76). Thinning of the leftrostral anterior cingulate cortex, as reported above, isassociated with increased incidence of affective disorders(63). Although the mechanism(s) responsible for thesealterations are not fully established, they may involvechanges in neural stem cell proliferation and/or differen-tiation, thereby disrupting the development of neuronalcircuits essential for higher order cognitive or behavioralfunction. GC effects in isolated neurons and glia are wide-spread, triggering a decrease in glucose uptake, inhibitionof proliferation, decreased neuronal excitability, and in-creased dendritic atrophy (64). In a rodent model of an-tenatal GC administration, a single course of Beta pro-duced significant anatomical differences in interneuronsof the hippocampus (77). Antenatal GCs leads to poten-tially long-lasting alterations of the HPA axis in humansas well (78). For example, antenatal GCs are associatedwith increased stress reactivity (greater elevation in cor-tisol level when faced with stress) in female children, evenwhen these children were born at term and maternal stressduring pregnancy was controlled for (79).

Maternal stress and programming of thefetal brain

In addition to synthetic GCs, maternal stress has beenshown to detrimentally affect fetal programming andbrain development through elevated levels of endogenousGCs. In several animal studies, prenatal stress has beenassociated with reduced volume in several brain regions,including the amygdala, cerebral cortex, hippocampus,and the corpus callosum (80). Human studies have alsoshown that the timing of maternal stress has differentialeffects on fetal development. Maternal stress during lategestation leads to a decreased stress response in childhoodand adolescence as measured by cortisol levels. By con-

660 Peffer et al Antenatal Glucocorticoids and Neurodevelopment Mol Endocrinol, May 2015, 29(5):658–666


trast, maternal stress throughout the second half of ges-tation increased stress responses. Girls born to motherswho experienced anxiety during the first trimester werefound to have an increased susceptibility to affective dis-orders, whereas children whose mothers experiencedstress during late gestation were more prone to develop-ing attention deficit hyperactivity disorder (71).

A possible mechanism by which maternal stress altersfetal development is by changing gene expression patternsin the placenta. Male placentas of mice exposed to pre-natal stress early in gestation (early prenatal stress) werefound to have significantly increased expression of genesregulating growth and development. These changes wereassociated with maladaptive stress behaviors in adultearly prenatal stress male mice (81). In humans, endoge-nous GCs have also been found to affect placental func-tion by stimulating the placenta to synthesize and releaseCRH, which could subsequently stimulate the fetal HPAaxis (82). Importantly, maternal stress affects pathwaysdistinct from synthetic GCs. For instance, endogenousGCs bind to both GR and mineralocorticoid receptorwith equal affinity, whereas synthetic GCs bind only toGR. Synthetic GCs can also bind other orphan nuclearreceptors in the brain. Furthermore, placental 11�-hy-droxysteroid dehydrogenase (HSD) preferentially inacti-vates endogenous GCs to cortisone during early gesta-tion; however, levels of 11�-HSD decrease during lategestation, a period in which maternal stress may potenti-ate the actions of synthetic GCs (82). Finally, endogenousGCs are secreted in a pulse-like fashion, resulting in tran-sient, acute changes in transcription unlike synthetic GCs,which continue to affect transcription after they havebeen withdrawn. This biological rhythmic secretion ofGCs may serve a physiological role by programming cellsto respond rapidly to stress, a response that may be im-paired due to prolonged exposure to synthetic GCs (83).

Studying the impact of GCs on neuraldevelopment using primary stem cell cultures

To provide mechanistic details of the neurodevelop-mental consequences of antenatal GC exposure, ourgroup (84, 85) and others have studied the effects of GCson primary murine fetal neural stem/progenitor cell(NSPC) cultures. GCs exert an antiproliferative effect onNSPCs via multiple mechanisms. In rat NSPCs cultured asneurospheres, Dex treatment triggers cyclin D1 degrada-tion via the ubiquitin-proteasome system, thereby inhib-iting cell-cycle progression and proliferation (86). In afollow-up study, Dex mediated a decrease in NSPC pro-liferation through an independent mechanism, the down-regulation of BRUCE/Apollon, a member of the inhibi-tors of apoptosis protein family found in neuroblasts (87).

Dex regulates BIR repeat-containing ubiquitin-conjugat-ing enzyme (BRUCE) at the mRNA and protein level,partially by up-regulating the deubiquitinating enzymeUsp8/Ubpy, which then stabilizes the ubiquitin ligaseNrdp1 and enables it to target BRUCE for degradation(87). Similar studies using gene expression profiling inNSPCs derived from whole brains, found that Dex up-regulated ferritin heavy chain 1 and IGF binding protein3, which exerted inhibitory effects on cyclin D1 and nes-tin, a marker of NSPCs (88). These studies also demon-strated that Dex down-regulated the endothelin receptortype B, a change that has been associated with apoptosisin the dentate gyrus and cerebellum and decreased prolif-eration in the cerebellum (88).

The antiproliferative effects of GCs on NSPCs havealso been demonstrated in vivo. Embryonic rats treatedwith Dex at embryonic day (E) 14 or E15.5 for 3 daysexhibited decreased levels of proliferating NSPCs in thestriatum and hippocampus (86) as well as dentate gyrus(70). Administering Dex to neonatal rats from postnataldays 1–7 led to apoptosis and depletion of the NSPC poolin the subgranular zone of the dentate gyrus (89, 90).Endogenous GCs may in fact underlie the reduction in theNSPC pool with increasing age (89). Although not withinthe scope of this review, GCs have also been found to havesimilar antiproliferative effect on adult NSPCs in vitroand in vivo (91–93).

Early prenatal exposure to GCs is associated with be-havioral changes later in life. Evidence that early exposureto GCs leads to long-lasting changes in the molecularprofile of NSPCs comes from several sources. In NSPCsisolated from E15 rat cerebral cortices, the antiprolifera-tive effects of Dex are associated with acute and chronicup-regulation of the cell cycle inhibitors p16 and p21.These alterations are accompanied by changes in targetgenes involved in senescence, such as Bmi1 and Hmga1(94). Because senescence is related to mitochondrial dys-function and susceptibility to oxidative stress, Dex down-regulated the mitochondrial proteins nicotinamide ad-enine dinucleotide hydroxide dehydrogenase 3 andcytochrome b and increased the production of reactiveoxygen species and apoptosis when challenged with anoxidative stress inducer (94). The Dex-induced changesin mitochondrial and senescence genes and Dex-in-duced changes in DNA methylation after several pas-sages suggest an epigenetic reprogramming of NSPCs(94).

Evidence for cell type-specific effects of Dex has comefrom several studies. Whereas prior studies used 10�6 MDex in neural stem cells (94), Yu et al (89) found that10�5 M Dex induced apoptosis in a rat hippocampal cul-ture affecting mitotic and resting cell populations and



both neurons and NSPCs but not astrocytes. In humanNSPC cultures derived from gestation weeks 16–19, Dexsimilarly decreased proliferation but also decreased thepercentage of neurons in differentiating cultures whileincreasing the proportion of glia (95). These Dex effectswere mediated by GR binding to the promoter of Dick-kopf1, leading to up-regulation of its expression and sub-sequent repression of canonical Wnt signaling (95). Sev-eral lines of evidence also support a role for GC-inducedchanges in oligodendrocytes (96, 97). In utero exposureto GC is associated with hypomyelination, although theseeffects are not due to direct changes in oligodendrocyteprogenitor cell proliferation, maturation, or survival andare thought to be secondary to deficits in the primarycellular targets, microglia, and astrocytes (98). Dose- anddrug-specific responses determine cellular outcome withhigh doses of Dex, reducing myelination by alteringgenomic responses (such as Olig 1 in microglia), whereasastrocyte production relies on the GR nongenomic orrapid pathway (99).

Although many studies demonstrate antiproliferativeand proapoptotic effects of GCs, one study reported adose-dependent proproliferative effect of GCs, includingDex, Beta, and hydrocortisone, on human induced pluri-potent stem cell-derived NSPCs, leading to an increase inthe number of microtubule-associated protein 2-positiveneurons (100). In particular, hydrocortisone stimulatedNSPC and neuronal proliferation, even under conditionsof oxidative stress, which was hypothesized to be due tothe effects of mineralocorticoid receptor activation by hy-drocortisone or selective 11�-HSD2 inactivation of hy-drocortisone (100).

Similar to Li et al, our studies use primary NSPCs iso-lated from E14.5 mouse cerebral cortex and cultured asthree-dimensional neurospheres (84). To maintain theirundifferentiated state, neurospheres are cultured on ul-tralow adherence plates in the presence of epidermalgrowth factor (EGF) and/or fibroblast growth factor-1(FGF-1) (Figure 1). EGF and FGF are crucial for promot-ing renewal and expansion of the NSPCs. NSPCs derivedfrom E14.5 brain are advantageous for analysis of ante-natal GC effects because GR is expressed in NSPC do-mains in the developing cerebral cortex in vivo at this age(101). Notably, this is a time when embryonic exposure toendogenous GCs is minimal. The major advantage of thismodel lies in the ability of neurospheres to properly reca-pitulate the in vivo differentiation order of neurons andglia under in vitro conditions (102, 103) as well as in themaintenance of cell-cell coupling even in the in vitro set-ting (85), allowing the study of gap junction intracellularcommunication. Finally, alterations in the developmentof the cerebral cortex, such as those caused by a fetal

exposure to GCs can contribute to neurodevelopmentaldiseases such as schizophrenia, anxiety, depression, au-tism spectrum disorders, and attention deficit hyperactiv-ity disorder (104).

Using NSPCs isolated from the cerebral cortex, recentwork from our laboratory has identified a novel rapidsignaling pathway that impacts synchronized calciumwaves in coupled cells and proliferation (85). Specifically,plasma membrane-associated GR regulates gap junctionintercellular communication in coupled NSPCs through arapid c-Src- and MAPK-dependent phosphorylation ofthe gap junction protein connexin 43 (Cx43) (85). Fur-thermore, the mobilization of this rapid GR signalingpathway occurs in lipid rafts and requires caveolin-1(Cav-1) (85). The impact of Cx43-dependent propaga-tion of synchronized calcium waves on NSPC prolifera-tion observed in our primary cultures (85) has also beenobserved in the developing cerebral cortex in vivo andmay therefore be a general feature of coordinated NSPCproliferation responsible for the generation of appropri-ately connected neural circuits (105).

Figure 1. Outline of NSPC culture system. Cerebral cortices fromE14.5 mice are dissociated into single cells and cultured in thepresence of EGF and FGF-1 to form neurospheres (85). After thedissociation of neurospheres, continued growth in EGF and FGF-1 willproduce secondary neurospheres, whereas plating in the absence ofEGF and FGF-1 can lead to differentiation.



As observed with other steroid receptors (106), therapid signaling pathway we identified in NPSCs is linkedto classical genomic GR signaling leading to gene-specificeffects on GR targets (84). Specifically, analysis of Dextreated (ie, 4 h) NSPCs derived from mice null for Cav-1by microarray revealed approximately 100 genes withaltered GR transcriptional regulation (84). The mechanis-tic basis for Cav-1 effects on GR transcription targets isdue in part to its impact on site-specific GR phosphory-lation. For example, in the absence of Cav-1, GC-inducedGR phosphorylation at serine 224 (mouse equivalent ofhuman GR serine 211) is dramatically reduced, whereasphosphorylation at serine 234 (mouse equivalent of hu-man GR serine 226) is unaffected (84). Furthermore,some GR target genes with reduced transcriptional re-sponses to GC in Cav-1 null NSPCs (ie, Fkbp-5 andSgk-1) exhibit diminished promoter recruitment of GRphosphorylated at serine 224 as revealed by chromatinimmunoprecipitation assays (84). Analogous to theunique cistromes of individual GR phosphoisoforms(107), selective effects of the Cav-1 on GR phosphoryla-tion could impact GR target gene selection in NSPCs andthereby influence various responses of these cells to GCs(Figure 2). For example, the lack of an antiproliferativeresponse to GCs in Cav-1 null NSPCs could be due to theloss of hormone induction of Sgk-1, a gene previouslyestablished to mediate antiproliferative responses of GCsin cultured human hippocampal progenitor cells (108).

Future perspectives: reaching an improvedtherapy: how can the study of NSPCs informantenatal synthetic GC treatment?

As stated above, both Dex and Beta are administeredantenatally to reduce the complications of prematurity.

Although upon initial glance the two GCs appear func-tionally equivalent, the action of these two hormones var-ies significantly and current studies reveal no consistentlybetter GC for antenatal use (37). Strikingly, although Betaand Dex have similar affinities for the GR and similargenomic potencies, Dex has a 5-fold greater potency forthe rapid action of GR than Beta in rat thymocytes (36).Different GR signaling modalities (ie, genomic vs rapid)may exert discrete influences on the developing brain andperipheral organ systems. Thus, the analysis of GR sig-naling pathways and functional responses of NSPC tonovel therapeutic alternatives to synthetic GC adminis-tration could provide insights into treatment modalitiesthat maintain beneficial effects in vulnerable organ sys-tems in the premature infant (eg, lung) but limit theiradverse neurodevelopmental effects. In addition, to im-prove antenatal GC therapies, we need a better under-standing of the genetic or uterine environmental factorsthat could modulate GC responses. In term-born childrentreated during the fetal period with GCs, there is no dif-ference in cortisol reactivity if the child was treated withDex or Beta (79). However, despite reporting sexuallydimorphic changes in cortisol secretion, this study did notseparate the Dex/Beta-treated groups by sex prior to anal-ysis. Gender-specific responses of NSPCs to GCs mayexist because there are significant gender differences inoutcome and infant mortality in response to antenatalGCs in both humans and animal models (79, 109, 110)(reviewed in reference 111). For example, LBW maleshave a higher risk of IVH and greater mortality than LBWgirls (109). Fetal gender is not taken into account in cur-rent treatment guidelines, so there is a clear need to de-velop antenatal GC regimens that would be selectivelyrobust in preterm male vs preterm female infants.

In summary, as additional molecular details of GRaction in NSPCs are uncovered, antenatal synthetic GCregimens established more than 40 years ago may be up-dated to continue to provide life-saving benefits of GCs topremature infants while limiting adverse neurologicaloutcomes that may take many years to be revealed.

Acknowledgments

Address all correspondence and requests for reprints to: DonaldB. DeFranco, PhD, Department of Pharmacology and ChemicalBiology, University of Pittsburgh School of Medicine, 7041 Bio-medical Sciences Tower 3, 3501 Fifth Avenue, Pittsburgh, PA15620. E-mail: [email protected].

This work was supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Dis-eases Grant U24 DK097746.

Figure 2. Model of integration of genomic and nongenomic GRsignaling in NSPCs. Ligand binding (Dex shown in figure) to plasmamembrane-associated GR can trigger nongenomic activation of specificprotein kinases that can either directly regulate gap junctionintercellular communication (GJIC) through phosphorylation of Cx43 orgenomic actions through direct phosphorylation of GR or othertranscription factors.



mailto:[email protected]

Disclosure Summary: The authors have nothing to disclose.

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