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Intrauterine growth restriction (IUGR) is associated with an increased risk for short stature and diseases in adulthood thought to be inflicted by fetal programming. We hypothesized that placental endocrine systems involved in perinatal growth might also play a role in postnatal growth after IUGR. In a prospective controlled multicenter study, placental gene expression of IGF-binding protein-1 (IGFBP-1), leptin and 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) were measured in 14 IUGR infants and 15 children born appropriate for gestational age (AGA) proven by serial ultrasound examinations. Postnatally, IUGR infants experienced a significantly higher growth velocity than AGA neonates (at 1 y: p = 0.001). Gene expression of 11beta-HSD2 at birth correlated positively with birth length (r = 0.55, p = 0.04) and inversely with growth velocity in the first year of life (r = -0.69, p = 0.01) in the IUGR, but not in the AGA group. There was no correlation between gene expression of placental IGFBP-1, leptin and birth weight, length and growth velocity during the first year of life. AGA infants showed significantly higher concentrations of cortisone in venous cord blood after birth (p = 0.02) as a surrogate of a higher 11beta-HSD2 activity in the fetoplacental unit. In conclusion, placental 11beta-HSD2 gene expression might predict postnatal growth in IUGR.

The conversion of cortisol (F) to cortisone (E) is catalyzed by 11beta-hydroxysteroid dehydrogenase type 2. The present study was designed to investigate the changes of F and E plasma concentration as an indirect measurement of 11beta-hydroxysteroid dehydrogenase activity in infancy and childhood. Plasma samples were obtained from 262 healthy children and adolescents aged 1 d to 18 y. Plasma F and E were measured, using specific radioimmunoassays after extraction and automated Sephadex LH 20 chromatography. The F/E ratio was calculated to assess 11beta-hydroxysteroid dehydrogenase activity. During the first year of life, plasma F levels rose significantly (r(2) = 0,24; p = 0.01), and thereafter no further increase was seen until adulthood (r(2) = 0.01; p = 0.86). In contrast, plasma E significantly decreased during the first year of life (r(2) = -0.35; p

Plasma aldosterone (A), corticosterone (B), deoxycorticosterone (DOC), progesterone (P), 17-hydroxyprogesterone (17-OHP), cortisol (F), and cortisone (E) were measured simultaneously by specific radioimmunoassays in small plasma samples obtained from 174 normal infants and children between 2 hr and 15 yr of age. The significantly elevated neonatal mean levels (ng/ml) of 2.5 (A), 4.1 (DOC), 53.0 (P), and 6.6 (17-OHP) dropped significantly during infancy reaching prepubertal levels between 3 months and 3 yr of age, with a transient, significant DOC increase between 1--7 yr. The glucocorticoids F andB declined significantly from means of 68 and 4.4 to 11.4 and 0.28 ng/ml, respectively, during the first weeks of life, then increased significantly reaching adult levels between 1--3 yr of age. Mean E fell progressively from 74 ng/ml after birth to 10 ng/ml during 1--5 yr (P less than 0.0001), then slightly increased to adult levels. After age 7 yr, P and 17-OHP, in contrast to the other steroids, rose significantly in both boys and girls relative to pubertal development. The observed changes are thought to be due to (1) adaptation of the adrenal neocortex to extrauterine life after disruption of the fetoplacental unit, (2) a physiologic lack of corticosteroid binding globulin (CBG) during infancy due to maturation of hepatic CBG biosynthesis, (3) the functional immaturity of the infant kidney compensated by an increased activity of the renin-angiotensin-aldosterone system, and (4) gradually increasing gonadal secretion of progestins during puberty.

The small adrenal cortex of SGA infants may play a role in the pathogenesis of their frequent postnatal problems. We therefore evaluated adrenocortical function of SGA infants at birth and during postnatal adaptation. In 22 vaginally delivered term infants (SGA

Influence of the Mode of Delivery on Umbilical and Postnatal Plasma Levels of 7 Corticosteroids in the Newborn

85 SIGNIFICANCE OF THE ADRENALS AND THE TESTES FOR THE PRODUCTION OF TESTOSTERONE (T) AND ANDROSTENEDIONE (A) DURING MALE INFANCY

Increased mortality with long-term E infusions in intensive care patients has been reported and evidence is accumulating that E causes reversible adrenocortical suppression with decreased serum cortisol levels. A direct inhibition of adrenal steroidogenesis has been suggested, but so far data on the mechanism of this action are lacking. A 6 1/2 year old boy with convulsions due to encephalitis was treated with constant E infusions (1 - 2 mg/kg/h). Prior to E administration, adrenocortical function was normal as tested by an ACTH-test. 5 days after institution of therapy and 14 days after discontinuation, plasma levels of 11-deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S) and cortisol (F) were measured by RIAs after Sephadex LH-20 chromatography. During E therapy DOC and S levels were highly elevated, while B was in the lower normal range and F was markedly decreased. Likewise the ratios of B/DOC and F/S, which reflect adrenocortical 11 β-hydroxylase activity, were extremely decreased (B/DOC:0.06 vs 27 in controls; F/S:0.009 vs 230 in controls). After discontinuation of therapy, the absolute values as well as the ratios returned to normal. These results show, that E is a potent inhibitor of adrenal 11 β-hydroxylation.Increased precaution seems to be necessary when this drug is used in patients who are under considerable amount of stress.

To clarify the origin of estrogens in infant blood, we measured E1 and E2 in the gonads of 50 girls and 64 boys deceased by sudden death between birth and 2 years of age. In both sexes, E2 was the major gonadal estrogen which exceeded E1 almost tenfold in the ovaries and twice in the testes. Thus, there was a clear sex difference in gonadal estrogen concentrations. On an average, girls had 8 times higher E2 and twice as high E1 concentrations in their gonads than boys. As in plasma, E2 concentrations were highest in ovaries of 2 to 4 months old girls (2 - 55 ng/g) and in testes of 1 to 3 months old boys (0.6 - 6.4 ng/g). Ovarian E2 concentrations decreased to values below 3 ng/g until the end of the 1st year of life, testicular E2 reached values below I ng/g already by 6 months of age. The gonadal steroidogenic activity paralleled changes in gonadal morphology. Ovarian weights showed a similar pattern of rise and fall as the E2 concentrations, the biggest ovaries consisting of multiple macroscopic cysts. In boys, testicular E2 closely correlated with Leydig cell development and testicular testosterone concentrations. We conclude that the surge of E2 in the blood of infant girls and boys originates from ovarian follicles and testicular Leydig cells, respectively, which develop under the influence of the characteristic post-natal gonadotropin surge.

81 DEMONSTRATION OF MINERALOCORTICOID RECEPTOR DEEICIENCY IN TWO SIBLINGS WITH PSEUDOHYPOALDOSTERONISM(PH)

We are reporting the first case of combined ectopic ACTH syndrome and “humoral hypercalcemia of malignancy” in a child with a liver tumor: A 6 9/12 y o girl presented with Cushing's syndrome, hypercalcemia and a large liver tumor. Serum CRF was undetectable. ACTH ranged from 184 to 819 pg/ml and was unresponsive to CRF and dexamethasone (2 and 8 mg). All urinary steroids, except for THAldo, were greatly elevated. By contrast, serum multisteroid analysis revealed high levels of only Cortisol, corticosterone and DHAS, whereas progestins (Prog, 17-OHProg) and mineralocorticoids (DOC, Aldo) were normal. Serum Ca was 14.2 ng/dl, P 2.2 mg/dl, 1,25-(OH)2D 61 pg/ml (normal: 20-40), urinary cAMP 6.7 nmol/dl GF (normal: T.6-4.9) and P reabsorption 1.6 mg/dl (normal: 4.5-6.8). Serum PTH(44-68), 25-(OH)D, AP, osteocalcin and urinary Pro-OH were normal, and PTH(intact) was suppressed, suggesting the presence of a PTH-like factor distinct from PTH. The tumor was surgically removed and proved to be a hepatoblastoma. Extraction yielded 8.3 ng/gm of ACTH and 0.04 ng/gm of CRF. Histochemical staining was positive for ACTH and CRF. By electron microscopy, multiple hormone granules were demonstrated in individual tumor cells. Postoperatively, ACTH and Ca levels rapidly reverted to normal. 4 m later, basal and CRF-and ITT-stimulated ACTH and Cortisol results were normal, and the girl was clinically doing well.

The apparent inability of elevated atrial-natriuretic peptide (ANP) levels to cause natriuresis and diuresis in children with heart failure may be related to a reduced response of target organs to ANP. The cellular effects of ANP seem to be mediated by cGMP as the second messenger of ANP. Simultaneous measurement of ANP and cGMP has been shown to be a useful tool to study the cellular response to ANP. Therefore, plasma ANP and cGMP levels were measured by radioimmonoassay in 168 healthy children and in 47 children with congenital cardiac diseases. In healthy children ANP and cGMP plasma levels were measured in the range of 5-109 pg/ml (mean 45.5) and 0.2-2.8 pmol/ml (mean 1.3) respectively. In children with cardiac diseases significantly higher ANP (range 30-980, mean 280 pg/ml) and cGMP levels (range 0.2-6.0, mean 2.8 pmol/ml) were determined. There was a highly significant correlation between the two in children with cardiac diseases (p

The adrenal cortex seems to play an important role in the newborn's adaptation to extrauterine life. Since systematic studies on multiple CS in the same human newborn have not yet been reported, progesterone (P), deoxycorticosterone (DOC), 17α-hydroxyprogesterone (17α), corticosterone (B), aldosterone (A), cortisone (E) and cortisol (F) were followed in a single 250 μl peripheral plasma sample in 12 vaginally delivered full-term infants of either sex. Mean concentrations (after automated LH-20 multi-column chromatography and specific radioimmunoassays) were in ng/ml: Besides marked materno-fetal CS differences, P, 17α and DOC (predominantly of placental origin) disappear rapidly with varying half lives. A, B, E and F, however, remain elevated in comparison with later infancy, reflecting high adrenal biosynthetic activity. *(Approved by parents and Hospital's Ethical Committee)