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PubMed2002

The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function.

Prenatal exposure to glucocorticoids is associated with alterations in fetal growth and endocrine function. However, few studies have examined the effects of clinically relevant doses of glucocorticoids on postnatal hypothalamic-pituitary-adrenal (HPA) function. To determine the effects of maternal or fetal betamethasone administration (0.5 mg/kg maternal or estimated fetal weight) on postnatal HPA function at 6 months and 1 year postnatal age, pregnant ewes were randomized into the following treatment groups: no treatment (n=6); maternal saline (n=6); single maternal betamethasone (M1) (n=6); repeated maternal betamethasone (M4) (n=6); fetal saline (n=5); single fetal betamethasone (n=6) and repeated fetal betamethasone (F4) (n=6). Single injections were given at 104 days of gestation and repeated injections at 104, 111, 118 and 125 days. Lambs were born spontaneously and the ACTH and cortisol responses to i.v. corticotropin-releasing hormone (CRH) (0.5 microg/kg) plus arginine vasopressin (AVP) (0.1 microg/kg) were measured at 6 months and 1 year postnatally. At 6 months postnatal age, neither maternal nor fetal prenatal betamethasone administration altered significantly the ACTH and cortisol responses to CRH+AVP. However, in animals at 1 year postnatal age, a previous single injection of betamethasone to the mother (M1) resulted in significantly elevated basal and stimulated cortisol levels (P<0.05), without significant change in the ACTH response. In contrast, betamethasone administration to the fetus resulted in significantly attenuated ACTH responses to CRH+AVP at 1 year compared with control animals (P<0.05), but these were not associated with any significant changes in basal or stimulated cortisol levels. All control animals exhibited a significant increase in peak ACTH responses to CRH+AVP between 6 months and 1 year postnatal age (P<0.05). After prenatal betamethasone (F4, M4) the difference in peak ACTH response between animals at 6 months and 1 year postnatal age was abolished. We conclude that in sheep between 6 months and 1 year postnatal age, HPA function undergoes developmental changes that are influenced by prenatal glucocorticoid exposure. Furthermore, the effects of glucocorticoid on postnatal HPA responses may vary according to the time in gestation that the steroid was administered, and whether it was given directly into the fetal or maternal compartment.

Adrenocorticotropic Hormone↗
PubMed1977

Placental transfer and metabolism of betamethasone in human pregnancy.

The concentration of betamethasone has been measured in maternal peripheral plasma, umbilical cord artery and vein, and amniotic fluid following maternal administration of betamethasone phosphate and betamethasone acetate on 3 consecutive days. Betamethasone was measured by radioimmunoassay following column chromatography. The findings show that betamethasone is transferred across the human placenta, circulates in the fetus and appears in amniotic fluid. During the 3 days after the start of treatment, levels of the betamethasone were similar in maternal and umbilical cord blood and in amniotic fluid. Thereafter, although levels in the mother were measurable for up to 7 days after the initial injection, the drug was detected in the cord plasma of only one baby. In vitro incubation studies of human placental tissue with 3H betamethasone identified 11-keto betamethasone as the major metabolite of betamethasone.

Amniotic Fluid↗
PubMed1994

Metabolism and degradation of betamethasone 17-valerate in homogenized living skin equivalent.

The metabolism of betamethasone 17-valerate was estimated using an artificial living skin equivalent (LSE). Betamethasone 17-valerate, betamethasone 21-valerate and betamethasone were measured by a normal-phase high-performance liquid chromatographic (HPLC) method. Betamethasone 17-valerate was added to the culture medium with or without LSE homogenate. Degradation profiles (%) of betamethasone 17-valerate remaining in the culture medium with skin homogenate did not differ from those without homogenate. However, the conversion of betamethasone 21-valerate to betamethasone was accelerated by skin homogenate, indicating that LSE has a sufficient level of esterase.

Betamethasone↗
PubMed1988

Judgement of the hypothalamic-pituitary-adrenocortical function in psychiatric patients by betamethasone-induced cortisol suppressibility.

Betamethasone induced cortisol suppressibility was examined in 62 drug free consecutively admitted psychiatric inpatients. Betamethasone was choosen instead of the commonly used dexamethasone, because its double half-life compared to dexamethasone and its higher tissue availability. After a base-line evaluation with blood samples drawn at 8 a.m., 4 p.m., and 11 p.m., 0.5 mg or 1.0 mg betamethasone was given orally at 11 p.m. Postbetamethasone cortisol as well as betamethasone blood levels were then measured at the same time points as on the baseline day. In the groups receiving 1.0 mg betamethasone non-depressed patients had significantly (p less than 0.05) lower postbetamethasone cortisol levels than depressed patients for each time point measured whereas 0.5 mg betamethasone did not differentiate depressed from non-depressed patients. Patients with other depressions like schizoaffective psychosis-depressive subtype- or organic brain syndrome with depressive symptomatology demonstrated similar postbetamethasone cortisol profiles as the group of patients with major depression. Betamethasone plasma concentrations differed significantly (p less than 0.001) with respect to the oral dosage with higher values for the 1.0 mg betamethasone groups.

Adolescent↗
PubMed2004

The effects of antenatal betamethasone administration on fetal heart rate and behaviour depend on gestational age.

OBJECTIVE: We previously reported decreases in fetal heart rate (FHR) variability and body and breathing movements after maternal betamethasone administration. We now test the hypothesis that fetal responsiveness to betamethasone depends on the gestational age at which glucocorticoid therapy is started. DESIGN OF THE STUDY: 1-h recordings of FHR (n=350) and fetal movements (n=310) made during a 5-day period (days 0-4) were available for analysis. The recordings had been obtained from 63 pregnant women at high risk for preterm delivery who received betamethasone (two doses of 12 mg 24 h apart) between 26 and 34 weeks' gestational age (wGA). The response to betamethasone, i.e. the direction and magnitude of change in FHR and movement parameters compared with baseline (day 0), was studied in relation to gestational age at drug administration. RESULTS: Fetuses exposed to betamethasone at 29-34 wGA showed a decrease in FHR on day 1 (indicative of baroreceptor reflex), and reduced breathing activity and prolonged episodes of quiescence with a concomitant decrease in body movements on days 1 and 2. However, these changes were not observed if betamethasone administration occurred at 26-28 wGA. Betamethasone-induced reductions in FHR variability were similar in young and older fetuses. CONCLUSIONS: Age-related differential responsiveness to betamethasone was found for all studied fetal processes (body and breathing movements, FHR, and quiescence), except FHR variability. Our results suggest ontogenic changes in the mechanisms presumed to underlie these processes (glucocorticoid receptor (GR) maturation, cardiovascular and neuro-endocrine development).

Betamethasone↗
PubMed2005

Role of zinc in formulation of PLGA/PLA nanoparticles encapsulating betamethasone phosphate and its release profile.

The purpose of this study was to develop poly(D,L-lactic/glycolic acid) (PLGA) or poly(D,L-lactic acid) (PLA) nanoparticles of less than 200 nm in diameter that encapsulated water-soluble corticosteroid derivatives for sustained release and targeting to inflammatory sites. Nanoparticles were prepared with PLGA (or PLA), zinc, betamethasone phosphate and surfactant by an oil-in-water solvent diffusion method. With this method, the efficiency of encapsulating betamethasone phosphate in the nanoparticles and the particle size were significantly affected by various factors, such as the concentration of PLGA (or PLA) and the amount of zinc added. Nanoparticles ranging from 80 to 250 nm in diameter could be prepared, with a maximum betamethasone phosphate content of 8% (w/w). Betamethasone phosphate was gradually released from the nanoparticles in diluted serum, and the release rate depended on the glycolic/lactic acid ratio and on the molecular weight of PLGA or PLA. Betamethasone was gradually released over at least 8 days from murine macrophages that had internalized betamethasone phosphate-encapsulated nanoparticles in vitro, and the rate of release was slower than from nanoparticles prepared without zinc. These results suggest that zinc increases the efficiency of encapsulating betamethasone phosphate in nanoparticles and also promotes sustained release of betamethasone phosphate from the nanoparticles.

Animals↗
PubMed2006

Effect of betamethasone in vivo on placental adrenomedullin in human pregnancy.

OBJECTIVE: The aim of the current study was to determine the effects of in vivo administration of prenatal betamethasone in patients at risk for preterm delivery on adrenomedullin (AM) concentrations in maternal and fetal plasma and on AM localization in placenta and fetal membranes. METHODS: A total of 62 pregnant women between 25 and 35 weeks' gestation were studied. Forty-seven pregnant women received betamethasone (2 x 12 mg intramuscularly given 24 hours apart) for stimulation of fetal lung maturity. Blood samples were collected before betamethasone administration and at different time points after the first and the second dose. Further samples were collected at delivery and, in women who did not deliver, after 1 week and 30 days from betamethasone administration. At delivery, placenta and membranes were collected. Fifteen patients who delivered at the same gestational age not receiving betamethasone represented the control group. AM concentration was determined by radioimmunoassay. Localization of AM in placental tissues was assessed by immunohistochemistry. RESULTS: Betamethasone caused approximately 50% increase in maternal plasma AM at 1 week after administration, whereas in fetal plasma AM levels increased by about 90% at 48 hours after betamethasone administration. There was increased immunohistochemical staining for AM in fetoplacental tissues collected after betamethasone administration. CONCLUSION: These results provide the first evidence for in vivo stimulation of AM, likely of placental origin, by glucocorticoids in the third trimester human pregnancy.

Adrenomedullin↗
PubMed2003

Pharmacokinetics of betamethasone after maternal or fetal intramuscular administration.

OBJECTIVE: The purpose of this study was to determine the pharmacokinetics of betamethasone in maternal and fetal circulations after maternal or fetal intramuscular administration. STUDY DESIGN: Ewes that bore single fetuses underwent surgery at approximately 96 days of pregnancy for the implantation of fetal and maternal vascular catheters. At approximately 103 days, five ewes were injected intramuscularly with betamethasone (0.5 mg/kg body weight) or five fetuses received ultrasound-guided intramuscular injections of betamethasone (0.5 mg/kg estimated fetal weight). Maternal and fetal blood samples were collected serially for the measurement of plasma betamethasone concentrations. RESULTS: Fetal injection caused higher peak fetal betamethasone concentrations (341.2+/-23.7 nmol/L) than maternal injection (37.6+/-3.7 nmol/L; P<.001) and greater cumulative betamethasone exposure. The half-life of betamethasone in the fetal circulation was shorter after fetal injection (1.1+/-0.3 hours) than after maternal injection (8.5+/-2.0 hours; P=.006). CONCLUSION: The duration of fetal and maternal exposure to betamethasone can be minimized by direct fetal intramuscular administration that, in sheep, affords lung maturation without adverse effects on fetal growth.

Analysis of Variance↗
PubMed2001

Is betamethasone effective longer than 7 days after treatment?

OBJECTIVE: To determine whether perinatal outcomes are influenced by the interval between antenatal betamethasone administration and delivery. METHODS: We did a retrospective cohort analysis of live-born singleton neonates born between 28 and 34 weeks' gestation after a single course of betamethasone, defined as two 12-mg doses over 24 hours. Subjects were grouped according to length of interval between initial betamethasone dose and delivery (1-2 days, 3-7 days, and 8-14 days). We excluded women who had membranes ruptured for longer than 24 hours before delivery, delivery before the second dose of betamethasone, or more than two doses of betamethasone. Data were analyzed by Student t test, chi(2) test, or Fisher exact test. Multiple logistic regression analyses were done using suspected risk factors for respiratory distress syndrome (RDS) and intraventricular hemorrhage (IVH). We calculated that a sample of 200 women would provide more than 80% power to detect a 50% reduction in incidence of RDS for a two-sided test of significance at a critical level of.05. RESULTS: Among 216 women, 97 delivered in 1-2 days, 78 in 3-7 days, and 41 in 8-14 days after a single course of betamethasone. Groups were similar in selected demographics, tocolytic exposure, gestational age at delivery, modes of delivery, and mean birth weights. There were no significant differences in frequencies of RDS (39.2%, 41.1%, and 36.6%, respectively) or grades 3-4 IVH (1.1%, 1.3%, and 0%, respectively) between groups. Frequencies of selected perinatal infectious outcomes also were similar between groups. Multiple logistic regression analyses found no association between RDS or IVH and delivery more than 7 days from betamethasone therapy. CONCLUSION: There were no differences in perinatal outcomes in pregnancies delivered 8-14 days after antenatal exposure to betamethasone compared with those delivered within 7 days of exposure.

Adult↗
PubMedDate not supplied

Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial.

BACKGROUND: Antenatal betamethasone treatment is widely used for the prevention of neonatal respiratory distress syndrome in preterm infants and substantially reduces neonatal mortality and morbidity. Fetal exposure to excess glucocorticoids has been proposed as one of the core mechanisms of the fetal origins of adult disease hypothesis. We assessed whether antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome affects cardiovascular risk factors at 30 years of age. METHODS: We followed up at age 30 years 534 individuals whose mothers participated in a double-blind, placebo-controlled, randomised trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. Mothers received two doses of betamethasone or placebo given by intramuscular injection 24 h apart. Follow-up assessments included anthropometry; measurement of blood pressure, blood lipids (after overnight fasting), and early morning cortisol levels; and a 75 g oral glucose tolerance test. FINDINGS: There were no differences between those exposed to betamethasone and to placebo in body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, or history of cardiovascular disease. After a 75 g oral glucose tolerance test, participants exposed to betamethasone had higher plasma insulin concentrations at 30 min (60.5 vs 52.0 mIU/L; ratio of geometric means 1.16 [95% CI 1.03 to 1.31], p=0.02) and lower glucose concentrations at 120 min (4.8 vs 5.1 mmol/L; difference -0.26 mmol/L [-0.53 to 0.00], p=0.05) than did those exposed to placebo. INTERPRETATION: Antenatal exposure to betamethasone might result in insulin resistance in adult offspring, but has no clinical effect on cardiovascular risk factors at 30 years of age. Thus, obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.

Adult↗
PubMed2001

Effect of antenatal betamethasone therapy on maternal-fetal Doppler velocimetry.

BACKGROUND: The effect of antenatal betamethasone on fetal parameters includes a transient reduction of FHR variation and of fetal body movements. An effect on maternal-fetal blood flow has also been shown, with non-univocal results. AIMS: To evaluate the effect of antenatal betamethasone in third trimester singleton high-risk pregnancies by Doppler technology. SUBJECTS AND METHODS: Thirty-six pregnant women who received a full course of betamethasone (12 mg i.m. two times, 24 h apart) were studied. The Doppler examination included the assessment of the pulsatility index (PI) of the umbilical artery (UA PI), the middle cerebral artery (MCA PI) and of resistance index of uterine arteries (Ut RI) before treatment, and 48 and 96 h after second dose of betamethasone. RESULTS: No significant variation was noted in UA PI through betamethasone therapy. MCA PI decreased significantly 48 h from the last injection of betamethasone (P=0.002), and returned to basal values at 96 h. No difference was found for the other Doppler parameters examined. When serial Doppler studies were analyzed according to the gestational age, in the group <32 weeks' gestation, MCA PI decreased significantly after 48 h (P<0.006) and returned to pre-treatment values after 96 h from the last betamethasone dose. Conversely, no difference was found in Doppler serial measurements in any of the analyzed districts in the subgroup > or =32 weeks. CONCLUSION: Betamethasone treatment is associated with a significant, although transient, reduction of MCA PI, especially at gestational ages <32 weeks'.

Arteries↗
PubMed2002

Effect of betamethasone on maternal glucose.

OBJECTIVE: To determine the effect of single and multiple betamethasone courses on maternal fasting and postprandial glucose values. STUDY DESIGN: A prospective cohort study was performed in women receiving betamethasone at 24-34 weeks' gestation. Fasting and 1-h postprandial capillary glucose values were obtained daily following betamethasone therapy for hospitalized patients. A control group comprised outpatients who underwent weekly fasting and postprandial assessments for 3 weeks. Fasting and 1-h postprandial capillary glucose values were compared between control and betamethasone patients using an unpaired t test. RESULTS: Thirty-five women received a single course of therapy, 19 received multiple courses and 28 served as controls. Mean fasting glucose values for control patients fell within a narrow range of 81.6 +/- 10.3 to 82.2 +/- 6.4 mg/dl for weeks 1-3. Of women receiving betamethasone, 59% of fasting glucose values were greater than 90 mg/dl as compared to 16% of control fasting values (p < 0.00 1, chi2 test). Mean 1-h postprandial values for control women ranged from 107.7 +/- 15.1 to 112.3 +/- 20.0 mg/dl for weeks 1-3. Mean 1-h postprandial glucose values were < or = 140 mg/dl following one, two or three courses of betamethasone therapy. CONCLUSIONS: Betamethasone resulted in an acute increase in fasting glucose following a single course of betamethasone, whereas two or more courses of therapy resulted in a continuous elevation of fasting glucose values. One-hour postprandial values were not clinically abnormal.

Adult↗
PubMed2004

Betamethasone does not prevent nausea and vomiting induced by ipecacuanha.

BACKGROUND: Corticosteroids reduce the incidence of PONV but the mode of action is not known. The purpose of this study was to evaluate if betamethasone has serotonin (5-HT) antagonistic effects. Ipecacuanha is known to release serotonin and therefore it was used to induce nausea and vomiting. The 5-HT3 antagonist ondansetron was used as a control substance. METHODS: In a randomized, double-blind, cross-over, placebo-controlled study 10 healthy male and female volunteers (6 M/4F), mean age 19.5 (18-23) years, mean weight 69.7 (53-84) kg, were studied on three occasions separated by at least 1 week. They were randomly allocated to receive pretreatment with betamethasone 8 mg, ondansetron 8 mg, or normal saline 2 ml as placebo on each occasion, 15 min before oral ingestion of 30 ml of Ipecacuanha syrup. After ingestion of ipecacuanha, vomitings were recorded and the intensity of nausea was estimated with a visual analog scale during 2 h. RESULTS: During the first 2 h after ingestion of ipecacuanha nine of the 10 volunteers vomited both after betamethasone and placebo. No volunteer vomited after ondansetron (P < 0.01 vs. betamethasone and placebo). The max VAS for nausea was significantly higher after betamethasone and placebo compared to ondansetron (P < 0.01). There were no statistically significant differences of the max VAS for nausea between betamethasone and placebo. CONCLUSION: This study in volunteers has shown that betamethasone does not prevent nausea and vomiting induced by oral intake of ipecacuanha syrup. As ipecacuanha releases 5-hydroxytryptamin, it can be concluded that betamethasone does not have 5-HT3 antagonistic effects.

Adolescent↗
PubMed2000

Effects of betamethasone administration to the fetal sheep in late gestation on fetal cerebral blood flow.

Glucocorticoid administration to women at risk of preterm delivery to accelerate fetal lung maturation has become standard practice. Antenatal glucocorticoids decrease the incidence of intraventricular haemorrhage as well as accelerating fetal lung maturation. Little is known regarding side effects on fetal cerebral function. Cortisol and synthetic glucocorticoids such as betamethasone increase fetal blood pressure and femoral vascular resistance in sheep. We determined the effects of antenatal glucocorticoid administration on cerebral blood flow (CBF) in fetal sheep. Vehicle (n = 8) or betamethasone (n = 8) was infused over 48 h via the jugular vein of chronically instrumented fetal sheep at 128 days gestation (term 146 days). The betamethasone infusion rate was that previously shown to produce fetal plasma betamethasone concentrations similar to human umbilical vein concentrations during antenatal glucocorticoid therapy. Regional CBF was measured in 10 brain regions, using coloured microspheres, before and 24 and 48 h after onset of treatment, and during hypercapnic challenges performed before and 48 h after onset of betamethasone exposure. Betamethasone exposure decreased CBF in all brain regions measured except the hippocampus after 24 h of infusion (P < 0.05). The CBF decrease was most pronounced in the thalamus and hindbrain (45-50% decrease) and least pronounced in the cortical regions (35-40% decrease). It was mediated by an increase in cerebral vascular resistance (CVR, P < 0.05) and led to a decrease in oxygen delivery to subcortical and hindbrain structures of 30-40%, to 8.6 +/- 1.1 ml x (100 g)(-1) x min(-1), and 40-45 %, to 11.0 +/- 1.6 ml x 100 g(-1) x min(-1), respectively (P < 0.05). After 48 h of betamethasone treatment, the reduction in CBF was diminished to about 25-30 %, but was still significant in comparison to vehicle-treated fetuses in all brain regions except three of the five measured cortical regions (P < 0.05). CVR and oxygen delivery were unchanged in comparison to values at 24 h of treatment. The CBF increase in response to hypercapnia was diminished (P < 0.05). These observations demonstrate for the first time that glucocorticoids exert major vasoconstrictor effects on fetal CBF. This mechanism may protect the fetus against intraventricular haemorrhage both at rest and when the fetus is challenged. Betamethasone exposure decreased the hypercapnia-induced increase in CBF (P < 0.05) due to decreased cerebral vasodilatation (P < 0.05).

Animals↗
PubMed2005

Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomised controlled trial.

OBJECTIVES: To determine if antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome alters psychological functioning and health related quality of life in adulthood. DESIGN: Follow-up of the first and largest double blind, placebo controlled, randomised trial of a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. SETTING: Tertiary obstetric hospital in Auckland, New Zealand. PARTICIPANTS: 192 adult offspring, mean age 31 years, of mothers who took part in a randomised controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (87 exposed to betamethasone and 105 exposed to placebo). INTERVENTIONS: Mothers received two doses of betamethasone or placebo 24 hours apart. MAIN OUTCOME MEASURES: Cognitive functioning assessed with Wechsler abbreviated scale of intelligence; working memory and attention assessed with Benton visual retention test, paced auditory serial addition test, and Brown attention deficit disorder scale; psychiatric morbidity assessed with Beck depression inventory II, state-trait anxiety inventory, and schizotypy traits questionnaire; handedness assessed with Edinburgh handedness inventory; health related quality of life assessed with short form 36 health survey. RESULTS: No differences were found between groups exposed to betamethasone and placebo in cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life. CONCLUSIONS: Prenatal exposure to a single course of betamethasone does not alter cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life in adulthood. Obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.

Adult↗
PubMed1996

Antenatal betamethasone therapy potentiates nitric oxide-mediated relaxation of preterm ovine coronary arteries.

The present study was designed to test the hypothesis that betamethasone may potentiate nitric oxide-mediated relaxation of coronary arteries of preterm lambs. Isolated coronary arteries were obtained from lambs delivered at 128 days gestation. The lambs were treated intramuscularly with a single dose of betamethasone or saline 48 h before delivery and were killed after 3 h of ventilation after delivery. Vessel rings were suspended in organ chambers filled with modified Krebs-Ringer solution (95% O2-5% CO2, 37 degrees C), and their isometric tension was recorded. The endothelium-dependent relaxation induced by bradykinin and calcium ionophore A23187 was greater in arteries from antenatal betamethasone-treated lambs than in arteries from control lambs. The relaxation was abolished by N omega-nitro-L-arginine. Nitric oxide induced a greater relaxation in vessels from antenatal betamethasone-treated lambs and in vessels preincubated with betamethasone than in vessels from controls. Coronary arteries from control and antenatal betamethasone-treated lambs relaxed similarly to 8-bromoguanosine 3',5'-cyclic monophosphate. Nitric oxide induced a greater increase in guanosine 3',5'-cyclic monophosphate content in coronary arteries from antenatal betamethasone-treated lambs than in arteries from control lambs. Our data suggest that antenatal betamethasone therapy potentiates nitric oxide-mediated relaxation in coronary arteries from preterm lambs, probably by affecting the activity of soluble guanylate cyclase of vascular smooth muscle cells.

Animals↗
PubMed1997

Inhibition of fetal adrenal adrenocorticotropin receptor messenger ribonucleic acid expression by betamethasone administration to the baboon fetus in late gestation.

Throughout the majority of intrauterine development, the primate fetal adrenal gland is comprised primarily of fetal zone cells and only late in gestation do definitive zone cells, which express the enzyme delta5-3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) emerge to produce cortisol. The present study was designed to determine whether the induction of definitive zone ACTH receptor messenger RNA (mRNA) levels and components of the steroidogenic pathway known to be expressed specifically in the definitive zone, e.g. the 3beta-HSD enzyme, are dependent upon fetal pituitary ACTH. Fetal pituitaries and adrenal glands were obtained on day 165 (term = day 184) from untreated controls (n = 7) and from baboons in which betamethasone was administered im to the fetus (0.6 mg/100 microl; n = 4) or to the fetus (0.6 mg) and mother (6 mg/ml; n = 4) every other day between days 150 and 164 of gestation. Although fetal pituitary weight was not altered by betamethasone, POMC mRNA levels determined by in situ hybridization were lower (P < 0.05) in betamethasone-treated (0.34 +/- 0.07 arbitrary densitometric units) than in untreated controls (0.63 +/- 0.04). Associated with this decline in pituitary POMC, levels of the major 3.4-kb mRNA transcript for the ACTH receptor expressed as a ratio of beta-actin were approximately 80% lower (P < 0.05) in fetal adrenals of betamethasone-treated baboons (0.12 +/- 0.02) than in untreated controls (0.84 +/- 0.05). In situ hybridization indicated that ACTH receptor mRNA expression in the definitive zone exceeded that in the fetal zone and was reduced by betamethasone. Associated with the decrease in ACTH receptor expression, fetal adrenal weight was suppressed (P < 0.05) by 50% and reflected a marked reduction (P < 0.05) in the size of the cells of the definitive and fetal zones. Betamethasone treatment also induced a decrease (P < 0.05) in the width (microm) of the definitive zone (183 +/- 14 vs. 128 +/- 7; determined by immunohistochemical expression of 3beta-HSD), as well as the levels of the mRNA and protein for 3beta-HSD. Levels of the mRNA for the LDL-receptor and the enzymes 17alpha-hydroxylase-C(17,20) lyase and P450 cholesterol side chain cleavage were also suppressed in adrenals of betamethasone-treated baboons. These findings indicate that treatment of the baboon fetus with betamethasone in late gestation suppressed fetal pituitary POMC mRNA expression and ACTH receptor mRNA levels in the fetal adrenal gland, as well as the hypertrophy and ACTH receptor mRNA and 3beta-HSD mRNA/protein levels in the cells comprising the newly emerging definitive zone. We conclude that ACTH is necessary for the up-regulation of the mRNAs for the ACTH receptor and steroidogenic enzymes in the definitive zone of the primate fetal adrenal gland in late gestation.

Adrenal Glands↗
PubMed1992

Betamethasone-induced resistance to neuromuscular blockade: a comparison of atracurium and vecuronium in vitro.

Steroids induce resistance to neuromuscular blocking drugs. Betamethasone-induced resistance to vecuronium has been demonstrated in vitro, and a presynaptic site of interaction has been suggested. This study investigated whether atracurium is similarly affected. Rat phrenic nerve-hemidiaphragm preparations were bathed in a physiologic solution, and one-half were exposed to betamethasone (1 mumol/L). Dose responses were recorded for atracurium (8-13 mumol/L) and vecuronium (2-12 mumol/L) for control and betamethasone-treated preparations. In comparison to control, the betamethasone groups had significantly less depression of muscle contraction force at all concentrations of atracurium (P = 0.0004) and vecuronium (P = 0.002). The calculated ED50 (50% depression of muscle contraction force, expressed as mean +/- SEM) for atracurium was 8.83 +/- 0.62 mumol/L for controls and 11.19 +/- 0.54 mumol/L for betamethasone-treated preparations. The calculated ED50 for vecuronium was 4.72 +/- 0.41 mumol/L for controls and 6.84 +/- 0.66 mumol/L for betamethasone-treated preparations. Betamethasone therefore increased the ED50 for atracurium by 27% and vecuronium by 45%; however, the magnitudes of these differences were not significant (P = 0.74) between the neuromuscular blocking agents. These results indicate that betamethasone-induced resistance to nondepolarizing neuromuscular blockade affects both atracurium and vecuronium to similar degrees in vitro.

Animals↗