Acute symptomatic hyponatremia and cerebral salt wasting after head injury: an important clinical entity.

Hyponatremia is a well known complication of traumatic and nontraumatic cerebral injury, often related to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Nonetheless, it also can be associated with a different entity, the syndrome of cerebral salt wasting (CSW). The authors report the case of a 4.5-year-old boy presenting with major head injury who at day 6 after admission had generalized tonic-clonic seizures caused by severe acute hyponatremia (serum sodium level, 119 mmol/L) and signs of dehydration. Despite initial isotonic rehydration, hyponatremia persisted because of excessive renal salt losses and concomitant enormous water losses, necessitating increasing amounts of sodium, up to 160 mmol/kg/d, and large amounts of intravenous fluids, up to 27 L/d. Highly increased levels of atrial natriuretic peptide (ANP) confirmed the diagnosis of CSW. The occurrence of a CSW has to be recognized early in the clinical course for adequate treatment and remains one of the important differential diagnosis of SIADH in hyponatremic states in patients with cerebral disorders, especially after head injury.

Psychological evaluation of young women after medical treatment for central precocious puberty.

OBJECTIVE: This study aimed at the evaluation of the subjective experience and long-term behavioral and psychological effects of precocious puberty (PP). METHODS: 19 female patients who had been treated with GnRH agonists participated in a semistructured interview and completed two standardized checklists. Their parents completed the Child Behavior Checklist (CBCL). RESULTS: The CBCL yielded significantly elevated Internalizing and Total Behavior Problem scores. An elevated risk was found for patients with short adult stature and a relatively late onset of PP. The latter tended to neuroticism, to accentuation of their physical appearance, and felt significantly more insecure than age-related non-PP girls. CONCLUSION: Our findings suggest that PP can lead to specific behavioral problems, and that patients with a risk factor may need psychosocial support.

Transcription factors as regulators of steroidogenic P-450 enzymes.

Steroid hormones are essential for normal sexual development, accommodation to stress, and regulation of fluid and electrolyte balance. Biosynthesis of these different classes of steroids and its appropriate regulation requires the precisely controlled expression of six different cytochrome P-450 enzymes and two hydroxysteroid dehydrogenases in different tissues. The molecular mechanism of the tissue-specific and pituitary hormone-regulated expression of the genes encoding P-450 enzymes in the steroidogenic tissues is the central problem of long-term regulation of steroidogenesis. Orphan members of the nuclear receptor superfamily play an important role in mediating transcriptional regulation of several steroid hydroxylase genes. Two of these transcription factors, steroidogenic factor-1 (SF-1) and DAX-1, will be reviewed here in detail.

Disorders of the aldosterone synthase and steroid 11beta-hydroxylase deficiencies.

The most potent corticosteroids are 11beta-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 11beta-hydroxylase activity, catalysing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11beta-hydroxylase (P450c11), is expressed on high levels in the zona fasciculata and is regulated by ACTH. CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. Aldosterone synthase has 11beta-hydroxylase activity as well as 18-hydroxylase activity and 18-oxidase activity. The substrate for CYP11B2 is 11-deoxycorticosterone, that of CYP11B1 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency. This disorder is characterized by androgen excess and hypertension. Mutations in CYP11B2 cause congenital hypoaldosteronism (aldosterone synthase deficiency) which is characterized by life-threatening salt loss, failure to thrive, hyponatraemia and hyperkalaemia in early infancy. Both disorders have an autosomal recessive inheritance. Classical and nonclassical forms of 11beta-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11beta-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). In infants with congenital hypoaldosteronism, a comparable frequency of 18-hydroxylase deficiency (aldosterone synthase deficiency type I) and of 18-oxidase deficiency (aldosterone synthase deficiency type II) can be found. Molecular genetic studies of the CYP11B1 and CYP11B2 genes in 11beta-hydroxylase deficiency or aldosterone synthase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. In some of the patients with 18-oxidase deficiency (aldosterone synthase deficiency type II) no mutations in the CYP11B2 gene were identified. Refined methods for steroid determination are the basis for the diagnosis of inborn errors of steroidogenesis. Molecular genetic studies are complementary; on the one hand, they have practical importance for the prenatal diagnosis of virilizing CAH forms and on the other hand, they are of theoretical importance in terms of our understanding of the functioning of cytochrome P450 enzymes. Copyrightz1999S.KargerAG, Basel

[Growth and collagen synthesis disorders in asthmatic children treated with inhaled steroids]. / Troubles de la croissance et de la synthèse du collagène chez des enfants asthmatiques traités par des stéroïdes en inhalation.

We report the case of an atopic patient aged 16 with a perannual asthma. He has been treated since the age of 4 with inhaled corticosteroïds. His growth was regular until he was 14 when beclomethasone was replaced by fluticasone (both administered by pressurized inhaler) due to adrenal suppression. Growth inhibiting effects of different inhaled corticosteroids are discussed focusing mainly on their effect on collagen synthesis.

Should we monitor more closely the dosage of 9 alpha-fluorohydrocortisone in salt-losing congenital adrenal hyperplasia?

In salt-losing congenital adrenal hyperplasia (CAH), continuous therapy with glucocorticoids and 9 alpha-fluorohydrocortisone (9 alpha-F) remains the golden rule. Previous reports showed a growth promoting effect of 9 alpha-F therapy. In addition, 9 alpha-F seemed to have a negligible glucocorticoid action. To confirm these facts, we analyzed the clinical data and the biological markers of control of therapy in two groups of patients with salt-losing CAH aged from 2 to 12 years: group I: before (time 0) and 6 months after the increase in 9 alpha-F dosage (time +6); group II: at time 0 and time +6 but without change in 9 alpha-F dosage. Groups were similar in terms of mean age, bone age and hydrocortisone dose. The mean dose of 9 alpha-F was 68.2 +/- 5.0 micrograms/m2/d at time 0 and was increased to 98.6 +/- 7.7 micrograms/m2/d at time +6 in group I; it remained similar in group II. In group I, height velocity decreased significantly from 8.1 +/- 0.6 at time 0 to 6.3 +/- 0.3 cm/yr at time +6 (p < 0.01) while in group II there was no significant change. In group I, plasma renin activity decreased from 10.4 +/- 1.6 at time 0 to 3.9 +/- 1.1 ng/ml/h at time +6 (p < 0.005) and showed no change in group II. These preliminary results suggest that careful monitoring of 9 alpha-F is essential to control a proper growth rate.

Sex-related alterations in hypothalamic growth hormone-releasing hormone mRNA-but not somatostatin mRNA-expressing cells in genetically obese Zucker rats.

The possibility that the growth hormone (GH) suppression associated with obesity is due to alterations in hypothalamic GH-releasing hormone (GHRH) and/or somatostatin (SRIH) has been considered, but the data are not consistent. In the present study, we sought to clarify the roles of GHRH and SRIH in obesity by using in situ hybridization to localize and quantify the level of expression of GHRH mRNA- and SRIH mRNA-containing neurons in the hypothalamus of male and female lean and obese Zucker rats (12 weeks of age; n = 6 per group). In lean animals, the number of GHRH mRNA-expressing cells in the arcuate nucleus and SRIH mRNA-containing neurons in the periventricular nucleus was 2- to 3-fold higher in males compared to females. The obese phenotype in the male was associated with a striking reduction in arcuate GHRH mRNA expression, both in terms of number of cells (-71%; p < 0.01) and grains/cell (-44%; p < 0.05). In contrast, in obese females, there was a marked augmentation (+ 175%; p < 0.05) in the number of GHRH mRNA-containing cells in the arcuate nucleus compared to their lean littermates. The small population of GHRH mRNA-containing neurons of the ventromedial nucleus was not modified in male obese rats, while it was considerably increased (p < 0.05) in obese females. Neither the number of labeling density of SRIH mRNA-containing neurons in the periventricular and arcuate nuclei of obese rats of either sex was changed when compared to their sex-matched lean counterparts. These results demonstrate that: (1) the obese male Zucker rat exhibits a marked diminution in hypothalamic GHRH mRNA expression, while a reverse pattern is evident in the obese female; (2) hypothalamic SRIH mRNA-containing neurons are not significantly altered in obese rats of both sexes. Our findings suggest that the impaired GH secretion of the obese Zucker rat is due, at least in part, to alterations in hypothalamic GHRH gene expression and that SRIH does not play a major role.

Effects of 14-day infusions of growth hormone and/or insulin-like growth factor I on the obesity of growing Zucker rats.

The response of fat tissue to GH or insulin-like growth factor I (IGF-I) differs between humans with hypopituitarism and those with exogenous obesity; the effects of combined GH and IGF-I administration have not been compared in these two situations. In GH-deficient dwarf rats (who have a primary GH deficiency), the excessive fat deposition induced by a high fat diet is completely reversed by combined infusion of GH and IGF-I. Whether the same phenomenon would be observed in genetically obese Zucker rats (in whom, as in obese humans, the decrease in GH secretion is secondary to the obese state) remained to be determined. Growing (6-week-old) female obese Zucker rats received a continuous sc infusion of vehicle, recombinant human GH, recombinant human IGF-I, or GH plus IGF-I for 14 days (3 mg/kg x day for both GH and IGF-I). Combined GH and IGF-I stimulated body weight gain and in naso-anal length to the same extent as IGF-I alone, whereas GH alone was less potent. Because all treatments stimulated weight linear growth proportionately, the progression of obesity was similar in treated and control animals. However, GH plus IGF-I (but not either agent alone) induced a 25% decrease in the relative weight of inguinal fat. GH and IGF-I exerted distinct effects on the relative weights of liver, kidney, and spleen and on the circulating levels of IGF-I and IGF-binding protein-3. Circulating glucose and insulin levels did not change in any group. In summary, GH plus IGF-I infusions decrease the relative weight of inguinal fat in Zucker rats as in obese GH-deficient dwarf rats; however, this effect is of more modest magnitude despite the use of a 2- to 3-fold higher dose and is limited to the inguinal site. Thus, GH plus IGF-I infusions did not influence the obesity index in Zucker rats. Inasmuch as Zucker rats are a better model of childhood-onset obesity than dwarf rats fed a high fat diet, the present results do not appear promising for extrapolation to clinical studies in children. The mechanisms by which the primary vs. secondary nature of the decreased GH secretion influences the effect of GH plus IGF-I on obesity remain to be determined.

Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment.

We have previously reported that despite neonatal screening, children with severe congenital hypothyroidism treated at 5 weeks of age with 6 micrograms/kg.day levothyroxine have clinically significant intellectual impairment, whereas those with the moderate form of the disease are indistinguishable from controls. The developmental outcome of children with severe congenital hypothyroidism treated earlier with higher initial doses of levothyroxine remained to be determined. In the present study, 45 infants with permanent congenital hypothyroidism detected by neonatal screening are described. For the group, the median age at starting treatment was 14 days, and the median initial dose of levothyroxine was 11.6 micrograms/kg.day. Based on the area of their knee epiphyses at diagnosis, the patients were divided into 2 subgroups: severe (< 0.05 cm2; n = 10) and moderate (> or = 0.05 cm2; n = 35). The psychomotor development of 8 patients in each subgroup, matched for the socioeducational level of their families, was assessed at 18 months. Mean plasma free T4 levels were supraphysiological during the first few months of life, but mean plasma T3 levels remained within the normal range, and there were no signs or symptoms of hyperthyroidism. The mean plasma TSH concentration was less than 4.5 mIU/L 4 weeks after starting treatment. Bone maturation remained delayed at 12 months in the severe cases and was not unduly advanced in the moderate cases. The mean (+/- SD) developmental quotients at 18 months were similar in severe and moderate cases (107 +/- 10 and 110 +/- 5, respectively). We conclude that with earlier treatment and a higher initial dose of levothyroxine, the early developmental outcome of infants with severe congenital hypothyroidism is now indistinguishable from that of infants with the moderate form of the disease who were used as controls.

The growth hormone (GH)-independent growth of the obese Zucker rat is not due to increased levels of GH receptor messenger RNA in the liver.

Obese Zucker rats maintain normal rates of linear growth and circulating concentrations of insulin-like growth factor-I (IGF-I) and of IGF-binding protein-3 (IGFBP-3) in spite of low GH secretion. The mechanisms underlying this GH-independent growth in obesity are unknown. To assess whether the liver expression of the GH receptor (GHR) messenger RNA (mRNA) is increased and/or if the liver expression of IGFBP-3 mRNA is maintained in the obese, Zucker rats of both genders and phenotypes (four groups, n = 6/group) were studied at 12 weeks of age. By Northern analysis, mRNA levels for GHR and GHBP were not increased in obese rats compared to their sex-matched lean littermates; the expression of these two transcripts was sexually dimorphic and the changes in GHBP mRNA/GHR mRNA ratios associated with obesity were sex-specific. In both genders, IGFBP-1 and IGFBP-3 mRNAs were decreased in the obese. We concluded that the GH-independent growth of obese Zucker rats is not due to increased GHR mRNA or to maintained IGFBP-3 mRNA levels in the liver.

Mammosomatotroph adenoma causing gigantism in an 8-year old boy: a possible pathogenetic mechanism.

The pathophysiology of mammosomatotroph adenomas remains unclear. We studied a mammosomatotroph adenoma removed from an 8-year old boy with a 5-year history of growth acceleration and acromegalic gigantism at presentation. Elevated basal GH (mean 28 micrograms/l) and PRL (mean 120 micrograms/l) plasma levels were observed, as well as paradoxical responses of GH to L-dopa, TRH and oral glucose administration; PRL was reduced by L-dopa and slightly increased by TRH; GHRH stimulated release of both GH and PRL. Two operations were required to remove the very large tumour and the patient was treated with bromocriptine before the second. Hormonal secretion by tumour explants in culture was evaluated under basal conditions and after stimulation or inhibition. High levels of GH and PRL were secreted for up to 24 days. Furthermore, GHRH and TRH caused a dose-related stimulation of both hormones, while somatostatin and dopamine were effective in suppressing either basal or stimulated hormone release only at very high (microM) concentrations. Intracellular events were studied by determination of the guanosine triphosphate binding (G) protein levels and adenylate cyclase (AC) activity in the tumour tissue. Before bromocriptine treatment, AC activity was very high in the tumour and could be further stimulated by various agents; very high levels of the AC-stimulatory G protein alpha subunit Gs alpha and very low amounts of the AC-inhibiting G protein alpha subunit Gi3 alpha and of the phospholipase C-stimulating G protein alpha subunit Gq alpha were found in the tumour. After bromocriptine, baseline AC activity was normalized and could no longer be stimulated; Gs alpha and Gi3 alpha levels were unchanged while those of Gq alpha were normalized. Screening of tumour DNA after amplification by polymerase chain reaction followed by single-strand conformational polymorphism analysis did not reveal any mutations in the hot spots of G protein alpha subunits (alpha s, alpha i2, alpha o2 and alpha 11) genes or in the H-ras and p53 genes. Gs alpha and GH transcription factor-1 (pit-1) expression were evaluated by amplification of cDNA. While the mRNA expression of pit-1 decreased after bromocriptine treatment, that of Gs alpha increased. These data suggest the possibility of an oncogenic process involving overexpression of Gs alpha, resulting in chronic activation of adenylate cyclase. Furthermore, our results suggest that the anti-secretory and anti-proliferative effects of bromocriptine may be mediated through a decrease in Pit-1 secondary to the inhibition of adenylate cyclase activity.

Effects of thyroxine, triiodothyronine and reverse triiodothyronine on the neonatal hypothyroid rat cerebellum.

In order to develop a model of thyroid hormone action, we studied the effect of small doses of T3 and T4 on the development of the hypothyroid neonatal cerebellum of rat pubs. Using granulosa cell death at postnatal d15 (picnotic index) as a criterion of hypothyroidism, it was found that a single injection of 50 ng T3/10g bw or 180 ng T4/10 g bw would reduce the picnotic index to levels found in euthyroid rat cerebelli. We further tested if rT3, known to be an excellent blocker of deiodinase type 2 activity, would be able to block the effects of T4. 20 micrograms rT3/10g bw had to be given to be an effective inhibitor in vivo. This dose did not affect the potency of T4 and control experiments with rT3 alone indicated that rT3 was capable of reducing the picnotic index to euthyroid levels. It is speculated that rT3 might act at the nuclear receptor but also at the cell membrane.

Human recombinant interleukin-1 beta decreases plasma thyroid hormone and thyroid stimulating hormone levels in rats.

Thyroid function was investigated in rats treated sc with a single injection of human recombinant interleukin-1 beta (hrIL-1). In 5 h 12.5 micrograms hrIL-1 decreased total serum T4 levels by 30 +/- 2% (P less than 0.01) and serum T3 levels by 35 +/- 4% (P less than 0.001). However free T4 and T3 fractions increased markedly within the first 140 min by 162 +/- 20% (P less than 0.001) and by 55 +/- 4% (P less than 0.001) resulting in a 88 +/- 20% increase in the free T4 concentration (P less than 0.001) but no increase in the free T3 concentration. Serum TSH concentration fell in the 5 h after the hrIL-1 injection by 77 +/- 3% (P less than 0.001). A similar decrease was observed with 0.125 micrograms hrIL-1. Five hours of starvation did not change serum TSH levels, suggesting that the effect of hrIL-1 on TSH was not due to decreased food intake. In order to test whether the decrease in serum TSH was due to an intrapituitary increase in T3, hrIL-1 was injected in hypothyroid rats: the fall of serum TSH was not prevented and it fell in 5 h from 14.05 +/- 0.56 to 9.66 +/- 0.98 ng/ml (31%, P less than 0.01, n = 14). These results suggest that hrIL-1 acts independently of thyroid hormones. Peripheral metabolism of T4 was studied by implanting [125I]T4 secreting minipumps during 14 days. There was no difference in T4 plasma clearance rate between control and treated animals. The fall of serum T4 was therefore explained by decreased secretion and not by increased catabolism since ether link cleavage of T4 and changes in hepatic deiodinase could not be detected. We therefore suggest that hrIL-1 inhibits thyroid function mainly at the hypothalamic-hypophyseal level.

[Diagnostic value of blood TSH levels in seriously ill patients]. / Valeur diagnostique du dosage de la TSH sérique chez les grands malades.

Undetectable serum TSH values measured by immunoradiometric methods are highly suggestive of hyperthyroidism. However, serum TSH levels can also be very low in severely ill patients and in this case thyroid disease can be ruled out by thyroid hormone measurements. The authors have determined the frequency of low thyroid hormone values and of low serum TSH measurements in hospitalized patients. They investigated 276 euthyroid patients, 21 of whom were found to have decreased values for serum total T4 and free T4 index (FTI). Serum TSH was below the lower limit of detection (less than 0.2 mU/l) in 4 of these 21 patients (19%) and normal in 17 others. Serum TSH measurements are therefore considered more reliable than thyroid hormone measurements in ruling out primary hypothyroidism. Interestingly, serum TSH was also found to be unmeasurable in 7 of 248 patients with normal total serum T4 and FTI (3%). An unmeasurable TSH value is therefore not synonymous with low T4 in sick patients, which indicates that both measurements are needed in this category of patients. Data are also included on 7 patients with high serum total T4 and FTI but still normal serum T3, in whom as measurable serum TSH concentration rules out hyperthyroidism.