Adrenal function in thalassemia major following long-term treatment with multiple transfusions and chelation therapy. Evidence for dissociation of cortisol and adrenal androgen secretion

Eight patients with beta-thalassemia who were given long-term treatment with combined multiple transfusions and chelation therapy underwent adrenal testing. The six male and two female patients ranged in age from 7 to 19 years. Six of eight patients had delayed bone ages and height greater than 2.5 SDs below the mean. Of the six patients more than 13 years of age, two had clinical evidence of isolated adrenarche and only one had evidence of true puberty. Cortisol levels were similar in patients and controls at zero time (10.6 +/- 1.8 micrograms/dL [292 +/- 50 nmol/L] vs 10.8 +/- 1.4 micrograms/dL [298 +/- 39 nmol/L]) and at 60 minutes (26.6 +/- 2.5 micrograms/dL [734 +/- 69 nmol/L] vs 24.9 +/- 1.9 micrograms/dL [687 +/- 52 nmol/L]) after insulin hypoglycemia (all values are the mean +/- SE). During an eight-hour infusion of ACTH, cortisol responses in the patients with thalassemia were not significantly different from those of controls. Baseline levels of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were significantly lower in the subjects with thalassemia compared with controls of similar bone age and pubertal status. The prolonged ACTH infusion caused a significant increase in the DHEA level (79.2 +/- 14.7 ng/dL [2.74 +/- 0.51 nmol/L] vs 538.6 +/- 38.1 ng/dL [18.67 +/- 4.79 nmol/L]) and the DHEA-S level (37.5 +/- 10.8 micrograms/dL [1.02 +/- 0.29 mumol/L] vs 70.5 +/- 18.3 micrograms/dL [1.19 +/- 0.50 mumol/L]) in the patients. The patients' peak stimulated levels of DHEA-S were significantly lower than those of the controls, whereas peak levels of DHEA were similar in the patients and the controls. These results indicate that combined multiple transfusions and chelation therapy preserve the integrity of the ACTH-cortisol axis in patients with thalassemia. The reduced levels of adrenal androgens, short stature, and delayed puberty noted in our patients suggest, however, that alternative approaches to the therapy of thalassemia are needed.     

Insufficient adrenarche in patients with combined pituitary hormone deficiency caused by a PROP-1 gene defect

Adrenarche was evaluated in five patients, aged 17.4 +/- 3 years, with combined pituitary hormone deficiency (CPHD), caused by a PROP-1 gene defect. Adrenocorticotrophic hormone (ACTH), cortisol and dehydroepiandrosterone sulfate (DHEAS) were determined prior to and following the administration of corticotropin-releasing hormone (CRH) in four of the five patients, while only basal values of ACTH, cortisol and DHEAS were determined in the fifth. In the four patients in whom a CRH test was carried out, the mean basal values of cortisol, ACTH and DHEAS were 289 +/- 140 nmol/l, 4.5 +/- 1.7 pmol/l and 0.26 +/- 0.36 micromol/l, respectively. The corresponding post-CRH peak values were 584 +/- 204 nmol/l, 12.7 +/- 3.9 pmol/l and 0.43 +/- 0.41 micromol/l. In the fifth patient, basal ACTH, cortisol and DHEAS values were 4 pmol/l, 411 nmol/l, and 2.33 micromol/l, respectively. Thus the basal and post CRH values of DHEAS (a marker of adrenarche) were low for age, while basal and post-CRH cortisol and ACTH values were within normal limits. For the interpretation of these findings two hypotheses can be proposed: 1) The PROP-1 gene is only expressed in the pituitary, and the role of PROP-1 is related to the maturation of the cells which synthesize the presumed adrenal androgen stimulating hormone (AASH). 2) The PROP-1 gene is also expressed in the adrenal cortex and, when defective, the zona reticularis does not function appropriately. Regardless of the interpretation     

Atrial natriuretic peptide and other vasoactive hormones during treatment of severe diabetic ketoacidosis in children

Plasma concentrations of atrial natriuretic peptide (ANP), arginine vasopressin (AVP), renin activity (PRA), aldosterone, norepinephrine, and cortisol, and renal functions were investigated in nine children with diabetic ketoacidosis. Before therapy, blood glucose concentration was 608.4 +/- 142.2 mg/dL and base excess -21 +/- 1.9 mmol/L. The calculated volume depletion was 2505 +/- 1005 mL/1.73 m2. At the onset of the study, the plasma concentration of ANP (5.3 +/- 1.2 fmol/L) was low, and concentrations of AVP (159 +/- 44 pg/mL), PRA (59 +/- 19 ng angiotensin l/mL/hr), aldosterone (114 +/- 11 ng/dL), norepinephrine (430 +/- 67 pg/mL), and cortisol (33 +/- 2.1 micrograms/dL) were markedly elevated. Fluid replacement raised plasma ANP concentration, which reached physiologic levels on the first day of therapy. PRA, aldosterone, norepinephrine, and cortisol also normalized during the first 24 hours of therapy, whereas AVP remained above the physiologic range at 20.4 +/- 6.8 pg/mL on the third day. Our data indicate that in diabetic ketoacidosis, volume depletion, enhanced sodium excretion, and hyponatremia activated vasoconstrictor and sodium-retaining hormone systems and that secretion of the natriuretic and vasodilator hormone ANP is suppressed. All of these hormonal alterations seem directed at maintaining adequate fluid volume and sodium homeostasis.     

Hypothalamic-pituitary-adrenal axis function in very low birth weight infants treated with dexamethasone

The effect of dexamethasone therapy on hypothalamic-pituitary-adrenal axis function was prospectively investigated in very low birth weight infants with bronchopulmonary dysplasia. Ten infants (mean +/- SD birth weight 825 +/- 265 g, gestation 25.8 +/- 1.9 weeks, postnatal age 33.1 +/- 17.7 days) initially received intravenous dexamethasone, 0.5 mg/kg per day for 3 days, and then were weaned over a period of 45 +/- 19.0 days to a replacement dose, followed by a metyrapone test. Morning plasma cortisol and 11-deoxycortisol levels were measured before and after an oral metyrapone dose given at midnight. Five infants (group A: birth weight 876 +/- 313 g, gestation 26.2 +/- 1.3 weeks, age of entry 31.8 +/- 22.8 days) had normal metyrapone test results, and five infants (group B: 778 +/- 234 g, 25.4 +/- 2.5 weeks, 34.4 +/- 13.4 days) had suppressed test results. Group A infants, in comparison with group B infants, had higher basal cortisol plasma levels (14.52 +/- 12.53 and 3.00 +/- 1.38 micrograms/dL, P = .047), higher postmetyrapone 11-deoxycortisol plasma levels (3.11 +/- 3.93 and 0.55 +/- 0.51 micrograms/dL, P = .028), larger differences between basal and postmetyrapone cortisol levels (7.10 +/- 4.67 and 2.12 +/- 1.31 micrograms/dL, P = .047), and larger differences between basal and postmetyrapone 11-deoxycortisol levels (2.99 +/- 3.93 and 0.29 +/- 0.25 micrograms/dL, P = .009). The hypothalamic-pituitary-adrenal axis function in group B infants eventually returned to normal when they continued to receive low-dose dexamethasone therapy after a period of 36.8 +/- 16.6 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

A randomized, placebo-controlled trial of effects of dexamethasone on hypothalamic-pituitary-adrenal axis in preterm infants

As part of a blinded, randomized, placebo-controlled study of dexamethasone therapy in 27 preterm infants with bronchopulmonary dysplasia, we investigated the effect of 7 days of high-dose glucocorticoid therapy on the hypothalamic-pituitary-adrenal axis. Before therapy the median basal cortisol concentration in all infants was 8.2 micrograms/dl (226 nmol/L). After stimulation with 1-24 ACTH, the serum cortisol concentration rose in all infants to a median concentration of 23.5 micrograms/dl (649 nmol/L), resulting in a median rise of 13.4 micrograms/dl (37 nmol/L). Immediately after 7 days of glucocorticoid therapy basal and peak cortisol concentrations were significantly decreased in the dexamethasone group. The rise in serum cortisol following 1-24 ACTH, however, remained equivalent in both groups. Ten days after the end of therapy basal and peak cortisol concentrations in the dexamethasone group had returned to levels equivalent to those seen in the placebo group. Weight gain was markedly diminished while the infants were receiving dexamethasone. Weight gains were, however, equivalent 10 days after the end of treatment. These data indicate that 7 days of dexamethasone therapy has significant but short-term effects on cortisol secretion and possibly on weight gain.     

No evidence for a major beta-cell dysfunction in young adults born with intra-uterine growth retardation

The association between low birth weight and the later development of type 2 diabetes is well established. It has been hypothesized that in utero undernutrition may affect pancreatic beta-cell development, leading to an impaired beta-cell function in adulthood. We have previously demonstrated that intrauterine growth retardation (IUGR) is associated with insulin-resistance early in adulthood. The aim of this study was to test whether IUGR would affect beta-cell function in young adults. Twelve 25-yr-old insulin-resistant subjects with IUGR were matched for age gender and body mass index (BMI) to 13 controls. All of them had normal glucose tolerance. Mean fasting plasma glucose did not significantly differ between the group with IUGR and the control group (97 +/- 7 vs. 98 +/- 4 mg/dL; p = 0.83). Blood glucose was maintained at 124.8 +/- 6.5 vs. 126.2 +/- 7.5 mg/dL above the basal glycemia in the IUGR and control groups (p = 0.64) throughout the hyperglycemic clamp. Serum insulin concentrations did not significantly differ between the group with IUGR and the control group either during the first (0-10 min) phase (311 +/- 252 vs. 248 +/- 184 pmol/L, p = 0.85) or during the second (80-100 min) phase (575 +/- 284 vs. 559 +/- 413 pmol/L, p = 0.72). C-peptide concentrations were similar in both groups during the two phases (2.35 +/- 1.44 vs. 2.59 +/- 1.10 nmol/L, p = 0.39 and 4.86 +/- 1.36 vs. 4.96 +/- 1.41 nmol/L, p = 0.91). In conclusion, our data do not argue in favor of an impairment of beta-cell function at 25 yr of age as a consequence of in utero undernutrition, but rather suggest that insulin resistance might be the primary defect responsible for the development of metabolic disorders associated with IUGR in adulthood.     

Simultaneous stimulation of growth hormone, adrenocorticotropin and cortisol with L-dopa/L-carbidopa and propranolol in children of short stature

In 59 otherwise healthy children of short stature, the simultaneous response of growth hormone, cortisol and plasma adrenocorticotropin (ACTH) to L-dopa/L-carbidopa and propranolol at 45 and 90 min after administration were investigated. A growth hormone response of 10 microg/l or higher was considered positive. The definition of a positive cortisol response included either a hormone increase of at least 193 nmol/l or a peak hormone level of at least 497 nmol/l. The ACTH increase had to be fourfold above 11 pmol/l to be considered positive. In the 59 investigated children, the median basal growth hormone levels increased from 1.35 microg/l to 18.05 microg/l and 10.15 microg/l at 45 and 90 min after stimulation (p < 0.05). The median cortisol levels rose from 242 nmol/l to 439 nmol/l and 612 pmol/l, and the corresponding median ACTH levels from 2.94 pmol/l to 9.63 pmol/l and 11.13 pmol/l at 45 and 90 min after stimulation. Significant positive hormone response rates were 88.1% for growth hormone, 88.1% for cortisol and 69% for ACTH. These results could be attributed to the enhanced stimulating effect of the additional administration of L-carbidopa and propranolol. We conclude that the administration of L-dopa/L-carbidopa and propranolol is useful for the simultaneous evaluation of growth hormone, cortisol and ACTH secretion in children of short stature.     

Comparison of adrenal function tests in children--the glucagon stimulation test allows the simultaneous assessment of adrenal function and growth hormone response in children

The accurate assessment of adrenal function is necessary in many children with suspicion of pituitary insufficiency. The objective of this study was to evaluate the adrenal response during the glucagon stimulation test (GST) and its diagnostic utility in children. A total of 290 children, aged 10.1 +/- 5.0 years, were evaluated for adrenal function using the corticotrophin releasing hormone (CRH) test, the GST, and/or the insulin tolerance test (ITT). Glucagon stimulation provoked a substantial rise in cortisol and adrenocorticotropin (ACTH) that was independent of gender, age, or underlying growth hormone deficiency. There were no differences in peak cortisol levels in the GST compared to the CRH test in pair-wise intra-individual analyses in children with both tests performed within one year (615.4 +/- 30.5 vs 602.8 +/- 22.4 nmol/l, n=52). Similarly, there were no differences in the cortisol response between the ITT and CRH test. Peak cortisol levels in the CRH test correlated with the GST and the ITT. The magnitude of ACTH response, in contrast, was highest in the ITT with a 9.8-fold increase over baseline, while the increase in the GST (3.1-fold) and CRH test (1.6-fold) were more subtle. Since there is controversy concerning reliable cut-off values for adrenal function tests in children, we analyzed cut off levels in 186 children, including 26 children with adrenal insufficiency, using the CRH test. A peak cortisol level of 450 nmol/l provided the best balance of sensitivity (88.5%) and specificity (86.8%), while higher cut-off levels did not increase sensitivity but lost in specificity. In summary, the GST constitutes an1 equally sensitive test for the assessment of adrenal function in children that is not confounded by anthropometric parameters and is generally not accompanied by major side effects. It allows the simultaneous assessment of corticotroph and somatotroph function and may thus constitute a valuable alternative to the ITT.     

Efficacy and safety of high-dose inhaled steroids in children with asthma: a comparison of fluticasone propionate with budesonide

OBJECTIVE: To compare the efficacy and adverse effects of inhaled fluticasone propionate (FP), 400 microgram/d, with those of budesonide (BUD), 800 microgram/d, in children with moderate to severe asthma. METHODS: Three hundred thirty-three children, ages 4 to 12 years, receiving inhaled corticosteroids were enrolled in a double-blind, double-dummy, randomized, parallel-group study. After a 2-week run-in phase, 166 children received FP and 167 received BUD for 20 weeks. The primary outcome variable was mean morning peak expiratory flow; the 2 treatments were to be regarded as equivalent if the 90% CI for the treatment difference was within +/- 15 L/min. Pulmonary function, height, and diary cards were assessed at each visit; and morning serum cortisol levels were determined before and after treatment. RESULTS: Baseline peak expiratory flow was similar, FP 236 +/- 72 (SD) L/min and BUD 229 +/- 74, increasing after treatment to 277 +/- 41 and 257 +/- 28, a difference between treatments of 12 L/min (90% CI 6-19 L/min; P =.002). Symptom control and use of rescue medication were the same. Cortisol levels after treatment were 199 nmol/L (FP) and 183 nmol/L (BUD) (treatment ratio = 1.09; 90% CI 0.98-1.21; P =.172). Linear growth was less in those receiving BUD (mean difference, 6.2 mm; 95% CI 2.9-9.6; P =.0003). CONCLUSION: FP at half the dose was superior to BUD in improving peak expiratory flow and comparable in controlling symptoms. Growth was reduced with BUD compared with FP, but there was no difference in serum cortisol suppression or hepatic or renal function.     

Plasma thyroid hormones and prolactin in premature infants and their mothers after prenatal treatment with thyrotropin-releasing hormone.

We assayed TSH, triiodothyronine, free thyroxine, and prolactin (PRL) in plasma of women and infants participating in a trial of prenatal thyrotropin-releasing hormone (TRH) treatment for prevention of newborn lung disease. Women in labor at 26-34 wk of gestation received 400 micrograms of TRH i.v. every 8 h (one to four doses) plus 12 mg betamethasone (one or two doses); controls received saline plus betamethasone. Mean cord concentrations in control infants were TSH 9.7 mU/L, triiodothyronine 0.6 nmol/L (40.2 ng/dL), free thyroxine 14.4 pmol/L (1.13 ng/dL), and PRL 67.6 micrograms/L. TRH increased maternal plasma TSH by 100% at 2-4 h after treatment and decreased levels by 28-34% at 5-36 h. In cord blood of treated infants delivered at 2-6 h, TSH, triiodothyronine, and PRL were all increased about 2-fold versus control, and free thyroxine was increased 19%; the response was similar after one, two, three, or four doses of TRH. In treated infants delivered at 13-36 h, cord TSH and triiodothyronine levels were decreased 62 and 54%, respectively, and all thyroid hormones were lower after birth at 2 h of age versus control. We conclude that prenatal TRH administration increases thyroid hormones and PRL in preterm fetuses to levels similar to those normally occurring at term. Pituitary-thyroid function is transiently suppressed after treatment to a greater extent in fetus than mother, and infants born during the early phase of suppression do not have the normal postnatal surge in thyroid hormones.     

Serum beta-carotene, retinol, and alpha-tocopherol levels during mineral oil therapy for constipation

Twenty-five children with chronic constipation underwent serial monitoring of serum beta-carotene, retinol (vitamin A1), and alpha-tocopherol (vitamin E) levels during mineral oil therapy. Mineral oil was administered between meals. Patients were monitored for up to four months of therapy. Mean serum beta-carotene levels fell from 1.0 +/- 0.5 mumol/L (55.7 +/- 26.0 micrograms/dL) to 0.7 +/- 0.4 mumol/L (35.9 +/- 22.1 micrograms/dL) after the first month of mineral oil therapy and remained depressed throughout the remainder of the study. Serum alpha-tocopherol levels remained unchanged throughout the observation period. There was a modest increase in serum retinol levels during the study, especially after three months (from 1.48 +/- 0.84 mumol/L [42.3 +/- 24.1 micrograms/dL] to 2.22 +/- 0.77 mumol/L [63.5 +/- 22.1 micrograms/dL]). We conclude that while a short course of mineral oil can induce a reduction in the serum level of beta-carotene, the treatment has no adverse effect on serum levels of retinol and alpha-tocopherol.     

Effect of maternal administration of thyrotropin releasing hormone on the preterm fetal pituitary-thyroid axis

We evaluated the response of preterm fetuses to maternal intravenous injection of 400 micrograms of thyrotropin releasing hormone (TRH) between 30 minutes and 5 hours before delivery (n = 12). An additional seven mothers received saline solution and served as control subjects. There were no statistically significant differences in gestational age, birth weight, or Apgar scores between groups. At delivery, concentrations of maternal thyrotropin were elevated in the TRH group compared with the control group (12.0 +/- 1.6 vs 5.6 +/- 0.5 mU/L; p less than 0.005); however, maternal triiodothyronine (T3) values remained unchanged. Significant elevations of fetal thyrotropin and T3 were observed after maternal administration of TRH compared with control subjects (45.8 +/- 7.7 vs 8.4 +/- 0.9 mU/L (p less than 0.002) and 1.3 +/- 0.07 vs 0.7 +/- 0.04 nmol/L or 87 +/- 5 vs 49 +/- 3 ng/dl (p less than 0.001), respectively). Fetal thyroxine (T4) and prolactin values were also elevated after exposure to TRH (135 +/- 5 vs 86 +/- 10 nmol/L or 10.5 +/- 0.4 vs 6.7 +/- 0.8 micrograms/dl (p less than 0.001) and 212 +/- 31 vs 105 +/- 28 micrograms/L (p less than 0.05), respectively). Two hours after birth, a significant increase in T3 but not T4 levels was observed in both groups of infants. These data indicate that fetal exposure to a single dose of TRH via maternal administration of this hormone results in marked stimulation of the preterm fetal pituitary-thyroid axis, as in the fetus at term, and that this treatment does not inhibit the early postnatal surge of T3.     

Diagnostic significance of urinary growth hormone measurements in children with growth failure: correlation between serum and urine growth hormone

Twelve-h overnight urine and serum samples obtained simultaneously at 20-min intervals were assayed for growth hormone (GH). Ninety-one children, 5 to 16 y (Tanner stage 1 to 3) participated; group 1 were healthy children, group 2 were children with organic GH deficiency, and group 3 had idiopathic growth failure and normal GH stimulation tests. Serum pool GH concentrations in group 1 were similar to those in group 3 (3.3 +/- 0.3 versus 3.4 +/- 0.2 micrograms/L); group 2 had significantly lower GH concentrations (1.6 +/- 0.2 micrograms/L). Plasma IGF-I levels were significantly greater in groups 1 (14.2 +/- 2.6 nmol/L, p less than 0.001) than in groups 2 and 3 (2.6 +/- 0.5 and 5.5 +/- 0.7 nmol/L, respectively). Urinary GH (mean +/- SEM) standardized for body weight (micrograms/kg) in group 1 (0.31 +/- 0.02) was significantly greater than in group 2 (0.14 +/- 0.01) and group 3 (0.20 +/- 0.01). However, when expressed as microgram/mol creatinine, the output of GH was similar in group 1 (4.0 +/- 0.3) and group 3 (3.4 +/- 0.3); both groups had significantly greater output compared to group 2 (1.3 +/- 0.2). Urinary IGF-I (nmol/kg) in group 1 (0.22 +/- 0.02) was significantly greater than in group 2 (0.12 +/- 0.01) or group 3 (0.07 +/- 0.01). Urinary GH correlated with serum pool GH concentration (r = 0.64, p less than 0.001). Although urinary GH output reflects endogenous GH secretion, the overlap between groups 1 and 3 precludes using urinary GH measurements as a diagnostic test for GH deficiency in children with idiopathic growth failure.     

Residential deleading: effects on the blood lead levels of lead-poisoned children

Acute elevations of venous blood lead levels (PbB) are periodically reported in children with chronic lead poisoning, during deleading of their houses. To evaluate this phenomenon 114 preschool children who entered the Massachusetts Childhood Lead Poisoning Prevention Program case management system during 1984 and 1985 were retrospectively studied. PbB increased from a mean (+/- SE) of 1.76 +/- 0.03 mumol/L (36.4 +/- 0.6 micrograms/dL) prior to deleading to 2.03 +/- 0.07 mumol/L (42.1 +/- 1.5 micrograms/dL) during deleading (P less than .001). Among 41 subjects for whom deleading was done by dry scraping and sanding, the mean mid-deleading PbB was higher than the pre-deleading PbB by 0.44 +/- 0.12 mumol/L (9.1 +/- 2.4 micrograms/dL). However, when deleading was done by covering or replacement of painted surfaces in the residences of 12 subjects, mid-deleading PbB decreased 0.11 +/- 0.12 mumol/L (2.25 +/- 2.4 micrograms/dL) (P less than .005). In a subset of 59 subjects who had no chelation therapy and were available for follow-up 250 +/- 14 days after completion of deleading, PbB had decreased from 1.72 +/- 0.04 mumol/L (35.7 +/- 0.9 micrograms/dL) to 1.24 +/- 0.04 mumol/L (25.5 +/- 0.9 micrograms/dL) (P less than .001). The long-term effect of deleading is a significant reduction in PbB. However, deleading resulted in a significant, albeit transient, increase in PbB.     

Modulation of glucocorticoid secretion by growth hormone

We measured the cortisol and corticosterone responses to insulin-induced hypoglycemia in 13 growth hormone (GH)-deficient children and 30 short children without GH deficiency. Although there was no difference between the two groups in degree of hypoglycemia attained, baseline cortisol, baseline corticosterone, or cortisol 40 min after insulin injection, GH-deficient children had a significantly greater corticosterone response to this stress (3.6 +/- 0.4 versus 1.9 +/- 0.2 micrograms/dl). (All data are presented as mean +/- SEM.) In order to explore the effect of GH on corticosterone secretion, we measured cortisol and corticosterone responses to synthetic (1-24) ACTH before and after 3 days of exogenous GH (0.2 unit/kg/day). In 13 GH-deficient children, GH treatment caused a significant decrease in the corticosterone response to ACTH (2.2 +/- 0.2 micrograms/dl before GH to 1.6 +/- 0.2 micrograms/dl; t = 5.22, p less than 0.001; paired t test) despite the fact that there was no significant change in the cortisol response to ACTH (18 +/- 2 micrograms/dl before and 16 +/- 2 micrograms/dl after). When seven short children who were not GH deficient underwent a similar 3-day course of GH, the decrease in their corticosterone response was much less although still statistically significant (2.0 +/- 0.5 to 1.8 +/- 0.5 micrograms/dl; paired t test, p less than 0.05). Again, the stimulated levels of cortisol were not affected by GH treatment (19 +/- 4 versus 18 +/- 3 micrograms/dl) These results indicate that GH modulates the adrenal response to ACTH by suppressing corticosterone secretion without affecting cortisol secretion. In summary, this study presents two new findings.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of hypoxia on renal prostaglandin E2 production in human and rat neonates.

Effect of hypoxia on renal prostaglandin E2 (PGE2) production was shown in asphyxic newborn infants and experimental hypoxic rats. In asphyxic infants, at postnatal day 1, the urinary excretion of PGE2 in severe asphyxia (1.00 +/- 0.19 pg/kg/min, n = 10) was lower than that of the mild asphyxia (2.15 +/- 0.18 pg/kg/min, n = 10) or normal newborn infants (2.65 +/- 0.25 pg/kg/min, n = 8) (p less than 0.01). The urinary excretion of PGE2 was inversely correlated with the urinary N-acetyl-beta-D-glucosaminidase (r = -0.84, p less than 0.01). The urine volume in mild asphyxia (0.04 +/- 0.005 ml/kg/min) was higher in comparison to normal newborn infants (0.026 +/- 0.002 ml/kg/min) (p less than 0.01), but had no correlation with the urinary excretion of PGE2. In experimental hypoxic rats, the renal PGE2 concentration increased from 0.19 +/- 0.02 ng/mg protein to the maximum level of 0.59 +/- 0.03 ng/mg protein at 10 min of hypoxia. The renal PGE2 concentration then decreased to the minimum level (0.105 +/- 0.02 ng/mg protein) at 24 h after 20 min hypoxia. The renal ATP rapidly decreased during 20 min hypoxia, and gradually increased to 55.1 +/- 6.2 nmol/mg protein at 24 h after 20 min hypoxia, which recovered only about 60% of the control level. It seems likely that renal PGE2 does not play a major role in diuresis in mild birth asphyxia and that severe birth asphyxia suppresses the renal PGE2 production in early neonatal period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cortisol infusion decreases renin, but not PGHS-2, EP2, or EP4 mRNA expression in the kidney of the fetal sheep at days 109-116

Renal prostaglandins (PG), renin, and cortisol are necessary for normal kidney development and function during fetal life. We examined the effects of cortisol infusion before completion of nephrogenesis (d 109-116 gestation; 2.0-3.0 mg hydrocortisone succinate/24 h) on the renal mRNA expression of PGHS-2, the PGE(2) receptors, EP(2) and EP(4), and renin in fetal sheep. Cortisol infusion raised plasma cortisol levels to 42.8 +/- 6.0 nmol/L compared with saline infusion levels of 1.5 +/- 0.5 nmol/L (p < 0.001), but had no effect on fetal body weight, proportional kidney mass, or blood gases. Cortisol decreased significantly the relative expression of renin mRNA (saline: 0.93 +/- 0.06 units; cortisol: 0.32 +/- 0.03 units, p < 0.05), however it had no effect upon the expression of PGHS-2, EP(2), or EP(4) mRNA in fetal sheep kidney. Although there is substantial evidence that PGE(2) acting through either the EP(2) or EP(4) receptor stimulates renin synthesis in the adult kidney, our results have demonstrated that before the completion of nephrogenesis, cortisol down-regulation of renin mRNA expression is independent of any change in the expression of PGHS-2, EP(2), or EP(4) mRNA expression. During nephrogenesis, the insensitivity of PGHS-2, EP(2), and EP(4) expression to down-regulation by cortisol may permit continued PG regulation of renal development and urine formation.     

Serum leptin level in prepubertal children with simple obesity. Part II

The aim of the study was to determinate the serum leptin level, glucose concentration, lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride) and thyroid hormones level (triiodothyronine, thyroid stimulating hormone and free thyroxine) in a group of prepubertal children with simple obesity. Fourfold higher leptin concentration in obese (23.3 +/- 11.8 ng/mL) in comparison to a group of slim children (6.8 +/- 2.7 ng/mL), (p<0.0001) was shown. There was no significant difference in serum glucose level (87.3 +/- 9.7 mg/dL) between both studied groups. In obese subjects we showed higher triglyceride, insignificantly lower HDL-C concentrations and invariable other lipid fractions. Mean values of triiodothyronine (T3) were 3.0 +/- 0.7 nmol/L in obese children and 2.8 +/- 0.8 nmol/L in slim children. On the contrary, mean values of thyroid stimulating hormone (TSH) were 2.5 +/- 1.7 mIU/L and 2.8 +/- 0.7 mIU/L in the group of obese and normal children respectively. Free thyroxine (FT4) concentrations in our obese children were lower (11.5 +/- 2.9 pmol/L) than in slim subjects (14.6 +/- 3.1 pmol/L) but were within the reference range. The results obtained indicate that in children with simple obesity there was no dyslipidemia connected with leptin and thyroid hormones levels. However, higher triglyceride and lower HDL-C concentrations suggest a necessity of monitoring the body mass index and lipid profile in these patients.     

Normal values for free thyroxine, free triiodothyronine, reverse triiodothyronine, thyrotropin, thyroglobulin and thyroxine-binding globulin in umbilical cord blood of healthy mature newborn infants

The venous cord blood levels of free thyroxine (fT4), free triiodothyronine (fT3), reverse triiodothyronine (rT3), thyrotropin (TSH), thyroglobulin (TG) and thyroxine binding globulin (TBG) were studied in 56 mature and healthy newborns. Newborns with a gestational age less than 37 or more than 42 weeks, a delivery by forceps or cesarian section, a birth-weight less than 2500 g, a pH-value of the cord-artery blood less than 7.15, an Apgar-value after 1 minute less than 7 were excluded from the study. All mothers were non-smokers. The values of fT4 were 18.66 +/- 4.18 pmol/L, of fT3 were 1.59 +/- 0.75 pmol/L, of fT3 were 2152 +/- 666 pg/ml, of TSH were 7.83 +/- 4.49 mU/ml, of TG were 44.61 +/- 23.84 ng/ml, and of TBG were 25.61 +/- 5.42 micrograms/ml. A weak negative correlation was found between the TG-value and the pH-value of the cord-artery blood (r = -0.27, y = 191.55 - 22.82.x, p less than 0.05), and between the fT4 values and the gestational age (r = -0.34, y = 67.53-1.22.x, p = 0.01). The rT3-values were positively correlated to the gestational age (r = 0.29, y = -4571 + 167.x, p less than 0.03).     

Human fetal and maternal corticotrophin releasing hormone responses to acute stress

OBJECTIVES: To study the effect of acute stress, caused by intrauterine needling at the intrahepatic vein (IHV), on fetal plasma concentrations of corticotrophin releasing hormone (CRH), and to compare paired fetal and maternal samples for CRH concentration to determine the extent of their joint control. DESIGN: Venous blood samples were obtained from fetuses (gestational age 17-38 weeks) undergoing fetal blood sampling (n = 29) or intrauterine transfusion (n = 17) through either the IHV or the placental cord insertion (PCI). SETTING: The Centre for Fetal Care, Queen Charlotte's and Chelsea Hospital, London, UK. PATIENTS: Pregnant women undergoing clinically indicated fetal blood sampling or intrauterine blood/platelet transfusion. RESULTS: Fetal plasma cortisol increased with intrahepatic vein transfusion (mean (SD) cortisol response Delta64.7 (54.5) nmol/l; p < 0.0001, n = 11), and fetal corticotrophin concentrations were higher after IHV (n = 7) than PCI needling (n = 6). Neither fetal nor maternal plasma CRH increased after IHV transfusion. Fetal CRH levels did not rise with gestation, whereas maternal CRH levels did (r = 0.58; n = 36; p < 0.0001). There was a modest correlation between paired maternal and fetal values (r = 0.36; n = 36; p = 0.03). CONCLUSIONS: Acute fetal stress, caused by IHV needling of the fetal abdomen, resulted in hypothalamic-pituitary-adrenal axis activation, as shown by a rise in fetal cortisol and corticotrophin. However, it did not result in measurable CRH release into fetal plasma. This suggests that fetal plasma CRH is not derived from the hypophyseal-portal circulation, but from another source, presumably the placenta.