Mutant WD-repeat protein in triple-A syndrome.

Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals. We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago. The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.

Glucose counterregulation in pre-school-age diabetic children with recurrent hypoglycemia during conventional treatment.

To determine whether immature or defective glucose counterregulation was responsible for the severe recurrent hypoglycemic episodes (3.6 per patient per year) observed during conventional therapy (CT) in six pre-school-age diabetic children, we investigated their metabolic and hormonal responses to insulin infusion (40 mU/kg i.v. for 60 min). Counterregulation was considered adequate because no patient experienced symptoms requiring discontinuation of the test, and blood glucose (BG) nadirs averaged 42 +/- 5 mg/dl. Glucose production rate decreased from 4.2 +/- 0.2 to 2.6 +/- 0.6 mg X kg-1 X min-1. Blood 3-hydroxybutyrate levels were elevated (approximately 3 mM) and did not change during insulin infusion. The responses of epinephrine (from 137 +/- 37 to 393 +/- 143 pg/ml), norepinephrine (from 145 +/- 33 to 347 +/- 152 pg/ml), and growth hormone (from 6.0 +/- 1.5 to 20.3 +/- 5.1 ng/ml) were normal for this age group. As previously observed in diabetic adults, glucagon response was deficient (from 117 +/- 30 to 114 +/- 18 pg/ml). The six children were subsequently treated with continuous subcutaneous insulin infusion (CSII), which resulted in a 20-fold decrease in the number of severe hypoglycemic reactions. Predisposition to severe hypoglycemia in this subset of diabetic children, which remains a refractory problem even after considerable efforts have been made to decrease them, may thus be sharply decreased with CSII therapy. During this therapy, a significant inverse correlation appeared between the individual frequency of BG values less than 40 mg/dl and BG nadir during the insulin infusion test (r = .94, P less than .001).

Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with low-dose cyclosporin.

Preliminary data from our group indicated that cyclosporin A induced frequent remissions of insulin dependency in a group of 40 insulin-dependent (type I) diabetic children if given at the onset of clinical manifestations of diabetes. We report a 2-yr analysis of the response to cyclosporin A in the group of 81 patients included in the initial study. As observed before, a remission could be obtained in most of the patients (65%) in association with a shorter duration of symptoms, less severe hyperglycemia, lower incidence of ketoacidosis, and higher plasma C-peptide concentrations. All remissions ended during the follow-up period after a mean +/- SE duration of 316 +/- 21 days (range 31-850 days). Two parameters were linked to the duration of remissions: the mean circulating level of cyclosporin during the first 3 mo and the duration of prediagnostic polyuria. We were unable to relate the end of a remission to variations in the cyclosporin regimen, titer of autoantibodies, or progression of beta-cell failure. The euglycemic clamp technique revealed that insulin sensitivity decreases with time in patients not taking insulin. At 24 mo, the patients who had a remission of insulin dependency had better glycemic control, lower insulin dosages, and C-peptide levels two- to threefold higher than the nonremission patients and four- to sixfold higher than the historical control subjects. The cyclosporin regimen was well tolerated over the observed period: more specifically, serum creatinine remained unchanged, and kidney biopsies performed at 18-24 mo of treatment were within normal limits.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenoleukodystrophy presenting as addison's disease in children and adults.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal genetic disorder that causes adrenal insufficiency, demyelination in the central nervous system, and increased levels of very long chain fatty acids in tissues and body fluids. Although most cases appear in childhood as a devastating degenerative disorder or in adulthood as a milder disorder affecting the spinal cord, many patients have adrenal insufficiency prior to the onset of their neurologic deterioration for many years. Addison's disease without neurologic involvement may also remain the only clinical manifestation of X-linked ALD. Because of the prognostic implications, the need for genetic counseling, and the potential benefit of therapeutic interventions, any boy or adult male with Addison's disease must be tested for X-linked ALD.

Risk of ketosis during intensive insulin therapy in pre-school-age diabetic children.

The risk of ketosis and its relationship to the mode of insulin therapy were studied in a subset of pre-school-age diabetic children. These five children, who initially responded poorly to standard in-hospital diabetes management, were selected for a program of intensified therapy directed at achieving more stable blood glucose control. Optimized conventional therapy was first employed for 16 +/- 5 mo and did not improve substantially blood glucose level or stability. During this period, there was an average of almost one episode of ketonuria per patient per month, and three diabetic ketoacidosis episodes were observed. Because of its limited efficacy, the treatment was then changed to continuous subcutaneous insulin infusion. This mode of therapy had a rapid favorable effect on blood glucose control, with no concomitant increase of the frequencies of ketonuria or diabetic ketoacidosis, most of which occurred during the first months of insulin pump therapy. Deliberate cessation of either conventional or subcutaneous insulin infusion therapy for 7 h under close in-hospital control resulted in similar metabolic changes: a slight nonconstant increase of blood glucose, and an abrupt rise of blood 3-hydroxybutyrate to 3 mM, with massive ketonuria. The management of these young diabetic children with insulin pump therapy was thus not associated with an increased frequency or an accelerated rate of development of ketosis. However, the possible failures originating from the infusing device and the rapid increase of ketosis in young ages require special vigilance from the parents, based on twice-daily urine testing for ketones and appropriate insulin supplementation.

Growth hormone treatment of children with short stature increases insulin secretion but does not impair glucose disposal.

Pediatricians willing to administer GH to non-GH-deficient children with short stature are concerned about the potential adverse effects of this hormone on glucose homeostasis and insulin action. This study was designed to determine the effects of GH therapy on carbohydrate metabolism in 10 prepubertal non-GH-deficient children with short stature. After 12 months of treatment with 0.3 U GH/kg BW.day, which resulted in an increase in height velocity from 4.0 +/- 0.3 (+/- SE) to 11.0 +/- 0.4 cm/yr, glucose tolerance was not impaired in these children. Not only were their fasting and postprandial plasma glucose concentrations unchanged from the pretreatment values, but basal glucose turnover did not vary; it was 0.53 +/- 0.04 before and 0.64 +/- 0.06 mmol/m2.min after GH treatment. Using the euglycemic clamp technique, the dose-response curves describing the effects of insulin on glucose disposal were comparable before and after GH treatment. There was a consistent 1.5- to 2-fold increase in plasma insulin and C-peptide concentrations during GH treatment, in both the basal and postprandial states, and after oral glucose or iv glucagon stimulation. We conclude that the GH regimen employed was remarkably effective in increasing growth velocity and devoid of detectable diabetogenic effects during a 1-yr treatment period in these non-GH-deficient children. (glucose, 1 mmol/L = 18 mg/dL; insulin, 1 pmol/L = 0.139 microU/mL; C-peptide, 1 pmol/L = 0.003 ng/ml).

Glucose metabolism in hyperinsulinemic infants: the effects of fasting and sodium DL-beta-hydroxybutyrate on glucose production and utilization rates.

Glucose metabolism was investigated in four infants aged 3-32 months with persistent hypoglycemia and hyperinsulinism of neonatal onset. Fasting hypoglycemia was found to be due both to an insulin-induced decrease in hepatic glucose output to 3.95 +/- 0.30 (SEM) mg/kg X min, a value about two thirds of normal, and to a glucose utilization rate of 4.25 +/- 0.32 mg/kg X min, which exceeded glucose production by about 8%. Simultaneously, and despite hypoglycemia, fasting plasma D-beta-hydroxybutyric acid concentrations were inappropriately low: 406 +/- 146 microM, presumably the result of elevated circulating insulin levels. The infusion of sodium DL-beta-hydroxybutyrate resulted in an increase of plasma glucose (48 +/- 7 vs. 32 +/- 7 mg/dl, P less than 0.01) and lactate (1704 +/- 217 vs. 964 +/- 149 microM, P less than 0.005), without detectable changes in insulin secretion estimated from circulating C-peptide values. Unexpectedly, the increase of plasma glucose was due to the restoration of glucose production up to 6.7 +/- 0.2 mg/kg X min. The individual increments of plasma lactate and glucose production rate were linearly correlated (P less than 0.01). These results together with the known inhibitory effect of ketone bodies on pyruvate dehydrogenation, suggest both increased production of lactate from peripheral recycling of glucose carbon and an increased conversion of this gluconeogenic precursor into glucose.

An enzyme linked immunoassay for anti-müllerian hormone: a new tool for the evaluation of testicular function in infants and children.

Anti-Müllerian hormone (AMH), also called Müllerian-inhibiting substance or factor was measured by an interspecific enzyme-linked immunoassay in the serum of 218 normal children and adults of both sexes and in 110 boys with various developmental disorders. AMH levels were high [81.67 ng/ml +/- 7.44(SEM)] in normal males under 2 yr of age, fell progressively in older boys and, decreased sharply at puberty. Serum AMH was not detectable in adults or in females at any age, with very rare exceptions. AMH serum concentrations were significantly decreased in infants with disorders of sex differentiation, particularly testicular dysgenesis, and increased in patients with delayed puberty. In contrast, levels were not significantly affected by either cryptorchidism or chorionic gonadotropin stimulation. AMH shows promise as a marker of testicular function in infancy.

Effects of hypopituitarism and growth hormone replacement therapy on the production and utilization of glucose in childhood.

Glucose metabolism during fasting was investigated in 10 children aged 1.5 month-11.5 yr with deficiency of GH with or without other pituitary hormone deficiencies. After 10-16 h of fasting, mean plasma glucose was 56 +/- 4 (SEM) mg/dl, the result of decreased hepatic production of glucose (3.3 +/- 0.3 mg kg-1 min-1) insufficient to match glucose utilization (3.6 +/- 0.4 mg kg-1 min-1). The diminution of plasma glucose and of glucose production was similar whether ACTH deficiency was present (3.2 +/- mg kg-1 min-1) or not (3.5 +/- 0.6 mg kg-1 min-1). These results indicate that the lack of GH was the primary cause of hypoglycemia. Fasting plasma alanine (212 +/- 41 mumol/liter) and lactate (1222 +/- 136 mumol/liter), the main gluconeogenic substrates, were normal and did not correlate with the decrease of hepatic glucose release. Both plasma FFA (552 +/- 35 microM) and beta-hydroxybutyrate (654 +/- 158 microM) were in the low normal range, and neither correlated with the rate of glucose utilization. hGH replacement therapy resulted in a normalization of fasting plasma glucose concentration (78.5 +/- 6 mg/dl, P less than 0.005) and hepatic glucose production (6.1 +/- 1.2 mg kg-1 min-1). No significant changes occurred in the plasma concentrations of gluconeogenic or lipid substrates. These results, together with the known stimulatory effects of GH on carbohydrate-induced insulin secretion and storage of hepatic glycogen, suggest that the changes in glucose production in untreated and GH treated patients reflect the degree of hepatic glycogen replenishment.

Longitudinal study of plasma testosterone in male pseudohermaphrodites during early infancy.

Plasma testosterone was longitudinally studied during the first months of life in 7 XY infants with male pseudohermaphroditism. In two, the physiological postnatal rise of plasma testosterone was absent or blunted. A combined adrenal and testicular enzymatic defect was demonstrated in these two boys. In 5, a normal postnatal testosterone rise demonstrated a normal Leydig cell function. The longitudinal study of the physiologic postnatal rise of testosterone may be useful to distinguish secretory defects from responsiveness abnormalities thus improving the choice of gender in male pseudohermaphrodites.

Short stature associated with intrauterine growth retardation: final height of untreated and growth hormone-treated children.

Short term studies have demonstrated the acceleration of growth velocity after the administration of GH in short children born with intrauterine growth retardation (IUGR). We report the final heights of 70 IUGR children whose short stature was attributed to idiopathic GH deficiency (peak plasma GH <10 ng/mL at 2 provocative tests) and treated with GH at a mean dosage of 0.4 +/- 0.1 U/kg x week during an average of 4.6 +/- 2.5 yr. They were compared to a control group of 40 untreated short children born with IUGR, without GH deficiency. At the time of evaluation, age, auxological data, and pubertal status were similar in the 2 groups (height, -2.9 +/- 0.8 and -2.8 +/- 0.7 SD score). Final heights were comparable in both groups of children (-2 +/- 0.7 and -2.2 +/- 1.1 SD score). A multivariate analysis identified 4 independent predictors of final height, namely target height, age and body mass index at evaluation, and GH treatment. Treatment was associated with a gain of 0.6 SD score, suggesting a final height gain of about 3.4 cm. Fifty-three of 70 treated children were reevaluated after completion of growth, and 43 of 53 had a peak plasma GH level of 10 ng/mL or more. Auxological characteristics of these 53 patients were not different from those of nonreevaluated patients. We believe that the transient character of the GH deficiency in most patients and the nonstringent initial criteria used for the diagnosis of GH deficiency render the spontaneous growth potentials identical in the 2 groups of patients. Our data, therefore, suggest that GH treatment at this dosage has a limited effect on the final height of short children born with IUGR.

Near normalization of final height with adapted doses of growth hormone in Turner's syndrome.

An adapted GH dose regimen was evaluated in 14 untreated patients with Turner's syndrome. The initial GH dose (0.7 U/kg.BW) was increased by 0.7 U/kg.BW, up to a maximum of 2.1 U/kg.BW, when growth velocity (GV) declined to less than 200% of the pretreatment level. These patients were compared to a group of 17 patients with similar initial characteristics, who received a fixed dose of 0.9 U/kg.BW GH. Tolerance to both GH regimens was excellent. The adapted GH doses only partially prevented the waning effect observed with conventional doses of GH, and the initial goal of doubling GV was only achieved in 42% of the 112 patient-semesters. Doubling the GH dose from 0.7 to 1.4 U/kg.BW increased the GV by 1.6 +/- 1.8 cm/yr (P < 0.006); increasing the GH dose from 1.4 to 2.1 U/kg.BW increased GV by 0.8 +/- 1.3 cm/yr (P = NS). The overall height gain during the 4-yr trial was 25.6 +/- 3.9 cm in the adapted dose group and 21.8 +/- 3.9 cm in the conventional group (P < 0.02). Final height (FH) results were obtained in 12 of 14 patients in the adapted dose group and all 17 patients in the conventional group and compared to the predicted FH using Lyon's method. The estimated height benefit was 10.6 +/- 3.8 cm in the adapted dose group compared to 5.2 +/- 3.7 cm in the conventional group (P < 0.01). Eighty-three percent of the patients in the adapted dose group had an FH superior or equal to -2 SD score for the general population compared to 29% in the conventional group. In conclusion, a marked increment in the GH dose in girls with Turner's syndrome associated with a relatively late age at introduction of estrogen therapy brought 83% of the patients into the lower range of the normal height distribution of the general population.

Different phenotypes in a family with androgen insensitivity caused by the same M780I point mutation in the androgen receptor gene.

Mutations in the coding sequence of the androgen receptor (AR) gene result in a wild range of androgen insensitivity (AI) syndromes. Differences in the clinical expression of the same mutation in unrelated patients have been reported. However, this study reports for the first time strikingly different phenotypes among three patients within the same kindred. Two of the patients had a feminine phenotype, suggesting complete AI, but for some pubic hair. The third subject was male with partial AI, perineoscrotal hypospadias, and cryptorchidism. 5 alpha-reductase activity measured in genital skin fibroblasts and binding capacity of the AR were higher in the male than in the two patients with female phenotype. Northern blot analysis of AR messenger RNA revealed a 10-kb band of normal intensity in the three subjects. Molecular analysis of the coding sequence of the AR revealed a unique M780I mutation in exon 6, changing a methionine 780 to isoleucine in the hormone-binding domain. In conclusion, the same mutation of the AR gene in the same family can result in clinical phenotypes characteristic of complete or partial AI. Therefore, the molecular defect of the AR gene may not alone predict the phenotype in families with AI.

Gonadotropin-releasing hormone agonist treatment of girls with constitutional short stature and normal pubertal development.

GnRH agonists have been proposed to improve final height in patients with constitutional short stature. We treated 31 girls, aged 11.9 +/- 1 yr (mean +/- SD), with short stature, recent pubertal onset and predicted final height of 155 cm or less with depot triptorelin. During the 23 +/- 4 months of treatment, bone age progression was 0.6 +/- 0.3 bone age yr/yr, and growth velocity declined from 7 +/- 2 to 4 +/- 0.8 cm/yr (P < 0.0001). Height prognosis, calculated by the Bayley-Pinneau method, progressed from 149.6 +/- 3.4 to 151.8 +/- 4 cm at the end of treatment (+2.2 +/- 2.6 cm; P < 0.0001). When treatment was interrupted, growth velocity slightly increased to 4.6 +/- 1.6 cm/yr, and bone age maturation was accelerated: 1.3 +/- 0.4 bone age yr/yr during the first posttreatment year. At the last visit, 26 +/- 9 months after interruption of treatment, bone age was 14.9 +/- 1.3 yr (> or = 13.5 yr in all patients), height was 149.1 +/- 4 cm, and final height prognosis was 150.6 +/- 3.6 cm. Final height prognosis was 1 +/- 2.3 cm greater than pretreatment height prognosis (P < 0.02) and 1.2 +/- 2.2 cm below the height predicted at the end of the treatment (P < 0.01). No major side-effect was observed. Height SD score decreased during treatment with GnRH agonist from -2.3 +/- 0.9 to -2.7 +/- 0.7 SD score (P < 0.0001). We conclude that 2 yr of depot triptorelin-induced pubertal delay has a limited effect on near-final height in girls with constitutional short stature and that the growth benefit observed does not currently justify the use of GnRH agonists, given their cost and potential side-effects.

Deletion hybrid genes, due to unequal crossing over between CYP11B1 (11beta-hydroxylase) and CYP11B2(aldosterone synthase) cause steroid 11beta-hydroxylase deficiency and congenital adrenal hyperplasia.

Chromosomal rearrangements are natural experiments that can provide unique insights into in vivo regulation of genes and physiological systems. We have studied a patient with congenital adrenal hyperplasia and steroid 11beta-hydroxylase deficiency who was homozygous for a deletion of the CYP11B1 and CYP11B2 genes normally required for cortisol and aldosterone synthesis, respectively. The genes were deleted by unequal recombination between the tandemly arranged CYP11B genes during a previous meiosis, leaving a single hybrid gene consisting of the promoter and exons 1-6 of CYP11B2 and exons 7-9 of CYP11B1. The hybrid gene also carried an I339T mutation formed by intracodon recombination at the chromosomal breakpoint. The mutant complementary DNA corresponding to this gene was expressed in COS-1 cells and was found to have relatively unimpaired 11beta-hydroxylase and aldosterone synthase activities. Apparently the 11beta-hydroxylase deficiency and the adrenal hyperplasia are due to the lack of expression of this gene in the adrenal zona fasciculata/reticularis resulting from replacement of the CYP11B1 promoter and regulatory sequences by those of CYP11B2.

Growth hormone response to thyrotropin-releasing hormone and oral glucose-loading tests in tall children and adolescents.

The effects of TRH and oral glucose loading on the release of GH were investigated in 10 children or adolescents with constitutional tall stature. Eight of these children had a family history of above average height. The mean (and SEM) baseline GH levels (3.12 +/- 2.0 ng/ml) were similar to those in control subjects. Somatomedin activity, measured by sulfate incorporation into chick embryo cartilage, was elevated. Oral glucose loading caused an early significant increase in plasma GH at 30 min in 2 of these subjects and a late rise at 180 min in 4 others. Intravenous injection of synthetic TRH (0.2 mg/m2) caused a marked increase in plasma GH (17 +/- 3.0 ng/ml) in 7 of the 10 patients; the peak of GH was observed within the first hour after the injection of TRH in 3 cases, while a later peak was observed in the second hour after injection in 4 others. Peak plasma PRL (47 +/- 3.8 ng/ml) and TSH (20 +/- 1.2 microU/ml) levels in response to TRH were normal. These results suggest a disorder of hypothalamo-pituitary regulation of GH secretion in certain children with apparently constitutional tall stature. Similar findings in a probably preacromegalic girl are reported.

Final height after long-term treatment with triptorelin slow release for central precocious puberty: importance of statural growth after interruption of treatment. French study group of Decapeptyl in Precocious Puberty.

The impact of treatment of central precocious puberty (CPP) with GnRH agonists on final statural height (FH) remains controversial, and guidelines on the optimal time point for interruption of these treatments have not been established. We analyzed the long term results of 58 girls and 8 boys uniformly treated with triptorelin slow release formulation (Decapeptyl, triptorelin-SR) for CPP and compared their FH with predicted height before treatment and with the FH of a historical group of patients not treated with GnRH agonist. The FH SD score was close to 0 and was not different from the genetic target height. In girls, FH was improved by 4.8 +/- 5.8 cm compared with predicted height before treatment and by 8.3 cm by comparison with a historical group. In boys, comparison with a historical group revealed a 13.7-cm improvement, whereas predicted height before treatment was similar to FH. Three variables were independently associated with FH in girls: the bone age/statural age ratio at the onset of treatment (negatively), the height SD score at the end of treatment, and the posttreatment growth spurt (delta FH - height at the end of treatment). The influence of the posttreatment growth spurt, itself dependent on age and bone age at the interruption of treatment, suggests that continuing treatment beyond the age of 11 yr in girls does not improve and could actually decrease FH. This point should be evaluated in a formal controlled trial.

Long term treatment of male and female precocious puberty by periodic administration of a long-acting preparation of D-Trp6-luteinizing hormone-releasing hormone microcapsules.

The efficacy and safety of a delayed release formulation of the LHRH agonist D-Trp6-LHRH (LHRH-A; im microcapsules) were tested in 16 girls, 0.9-8.8 yr old, and 10 boys, 2.0-10.5 yr old, with precocious puberty. All children had advanced bone age, breast or testis enlargement, and a pubertal LH response to LHRH. Precocious puberty was idiopathic in 19 subjects and secondary to a brain tumor or other central nervous system abnormality in 7. Nine girls and 6 boys had been previously treated unsuccessfully with medroxyprogesterone and/or cyproterone acetate. The microcapsules were made of 2% LHRH-A dispersed in a biocompatible biodegradable polymeric matrix of DL-lactide-coglycolide. Sixty micrograms of LHRH-A/kg BW were given im on days 1 and 21 and thereafter every 4 weeks for 10-27 months. Plasma LHRH-A levels were measured in 13 children by means of a specific RIA. On days 3, 7, 14, and 21, mean concentrations (+/- SEM) were 295 +/- 44, 218 +/- 31, 215 +/- 45, and 224 +/- 39 pg/ml, respectively. In girls, breast enlargement disappeared, and mean uterus size decreased from 44.4 +/- 2.5 to 38.1 +/- 3.1 mm (mean +/- SEM; P less than 0.02) within 6 months. Mean ovary length decreased from 23.0 +/- 1.5 to 16.2 +/- 1.5 mm (P less than 0.01). In boys, mean testis volume decreased from 8.1 +/- 1.2 to 6.7 +/- 1.2 ml (P less than 0.02) within 6 months. In both sexes, growth velocity decreased significantly, and bone maturation was generally reduced. Plasma levels of estradiol or testosterone and FSH levels decreased significantly within 3 weeks. The LH response to LHRH was reduced to normal prepubertal values after 7 weeks. No secondary clinical or biochemical escape occurred. In 1 boy, all biological features of puberty recurred within 1 month after omission of the fifth injection. No side-effects occurred, except for transient vaginal bleeding in girls after the first or second injection. No antibodies to LHRH-A were detected in the patients' sera. This study demonstrates the ability of a delayed release formulation of LHRH-A to achieve stable levels of the drug in plasma for at least 21 days after a single im injection and to suppress pituitary and gonadal secretion and pituitary response to LHRH for as long as 2 yr after therapy. This treatment appears to be more efficient in treating both clinical and biochemical abnormalities than does treatment with inhibitory steroids. Additionally, the method of administration is more practical and ensures better patient compliance.

Growth hormone testing for the diagnosis of growth hormone deficiency in childhood: a population register-based study.

Evaluation of GH secretion using pharmacological GH stimulation tests (GHST) remains a current practice, although the reliability of GHST has been questioned, and many pitfalls have been pointed out. We have analyzed all of the 6373 GH stimulation tests that led to the initiation of GH therapy in 3233 children treated in France from 1973-1989. Tests and GH measurements were performed by individual centers and collected by the Association France-Hypophyse. GH deficiency (GHD) was due to craniospinal irradiation (11%), was due to organic causes or associated with multiple deficiencies (22%), or was considered idiopathic (65%); 2% of the patients were considered non-GHD. Eleven different pharmacological tests were used, and 62 of the 66 theoretical pairs of tests were used at least once. The most frequent combination of tests (ornithine in one instance and insulin in another) was used in 12.7% of patients. The reliability of the GH peak measured by comparing the results of 2 tests in the same patient was poor, as measured by intraclass correlation coefficients below 0.8. Multivariate analysis identified several parameters positively or negatively associated with peak plasma GH: calendar year of initiation of treatment, etiology of GHD, height SD score, bone age SD score, puberty, weight SD score, genetic target height SD score, and the nature of the pharmacological agent used. We believe that several of these factors (weight SD score, genetic target height SD score, and nature of the agent) identify biases in the diagnosis of GHD. We conclude that GHST should be performed with a very limited number of agents, interpreted after the establishment of reference values in age-matched normal children, and associated with other clinical and biochemical parameters for establishing the diagnosis of GHD.

Anti-müllerian hormone in children with androgen insensitivity.

Anti-Müllerian hormone (AMH), also called Müllerian inhibiting substance or factor, is secreted in high amounts by the immature Sertoli cell; it is negatively regulated by testosterone at puberty. In the present study, we measured serum AMH in 20 patients with defects of androgen synthesis or action: 9 with complete androgen insensitivity syndrome, 9 with a partial form, 1 patient with 3 beta-hydroxysteroid dehydrogenase deficiency, and 1 with Leydig cell agenesis. AMH was also determined in 15 control patients with idiopathic male pseudohermaphroditism. The serum AMH concentration was elevated in all testosterone-insensitive or -deficient patients compared with control levels during the first year of life. From 1 yr of age to the onset of puberty, serum AMH levels in patients with androgen insensitivity returned to normal values, but after pubertal development began, AMH levels again rose to extremely high levels in the complete androgen insensitivity syndrome. These results suggest that AMH is negatively regulated by testosterone not only at puberty, but also during the postnatal period. An elevation of serum AMH appears to be an interesting marker of androgen resistance or defect of androgen production in sexually ambiguous male infants.