Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop.

OBJECTIVE: Our objective was to summarize important advances in the management of children with idiopathic short stature (ISS). PARTICIPANTS: Participants were 32 invited leaders in the field. EVIDENCE: Evidence was obtained by extensive literature review and from clinical experience. CONSENSUS: Participants reviewed discussion summaries, voted, and reached a majority decision on each document section. CONCLUSIONS: ISS is defined auxologically by a height below -2 sd score (SDS) without findings of disease as evident by a complete evaluation by a pediatric endocrinologist including stimulated GH levels. Magnetic resonance imaging is not necessary in patients with ISS. ISS may be a risk factor for psychosocial problems, but true psychopathology is rare. In the United States and seven other countries, the regulatory authorities approved GH treatment (at doses up to 53 microg/kg.d) for children shorter than -2.25 SDS, whereas in other countries, lower cutoffs are proposed. Aromatase inhibition increases predicted adult height in males with ISS, but adult-height data are not available. Psychological counseling is worthwhile to consider instead of or as an adjunct to hormone treatment. The predicted height may be inaccurate and is not an absolute criterion for GH treatment decisions. The shorter the child, the more consideration should be given to GH. Successful first-year response to GH treatment includes an increase in height SDS of more than 0.3-0.5. The mean increase in adult height in children with ISS attributable to GH therapy (average duration of 4-7 yr) is 3.5-7.5 cm. Responses are highly variable. IGF-I levels may be helpful in assessing compliance and GH sensitivity; levels that are consistently elevated (>2.5 SDS) should prompt consideration of GH dose reduction. GH therapy for children with ISS has a similar safety profile to other GH indications.

Idiopathic short stature: management and growth hormone treatment.

In the management of ISS auxological, biochemical, psychosocial and ethical elements have to be considered. In boys with constitutional delay of growth and puberty androgens are effective in increasing height and sexual characteristics, but adult height is unchanged. GH therapy is efficacious in increasing height velocity and adult height, but the inter-individual variation is considerable. The effect on psychosocial status is uncertain. Factors affecting final height gain include GH dose, height deficit in comparison to midparental height, age and first year height velocity. In case of a low predicted adult height at the onset of puberty, addition of a GnRH analogue can be considered. Although GH therapy appears safe, long-term monitoring is recommended.

Management of cryptorchidism.

The forces guiding testicular descent have not been completely elucidated. Both testosterone and anti-Müllerian hormone might play a role. Available evidence suggests that malfunction of the testes of some sort usually precedes maldescent. The proper management of cryptorchidism has long been a controversial issue. In unilateral cryptorchidism, hormonal function and fertility are generally normal. To maximize fertility in patients with bilateral cryptorchidism, surgical treatment should be completed ideally by the first birthday. GnRH is unlikely to be of much help in initiating testicular descent. Cryptorchidism is associated with a three- to tenfold increase in testicular cancer. Twenty percent of tumors in unilateral cryptorchidism are in the normally descended testes. The condition of all boys and men with a history of cryptorchidism should be followed by physicians their entire lives, and these boys and men must become proficient in self-examination.

Urinary excretion of IGF-I and growth hormone in children with IDDM.

OBJECTIVE: To compare the urinary output of insulinlike growth factor I (IGF-I) and growth hormone (GH) in prepubertal and pubertal children with insulin-dependent diabetes mellitus (IDDM) versus nondiabetic subjects and to analyze the relationship between the urinary excretion of these peptides and degree of metabolic control. RESEARCH DESIGN AND METHODS: Group 1 included 30 IDDM patients who had had diabetes for 4.9 +/- 0.7 yr and had normal renal function (mean age 11.6 +/- 0.9 yr); group 2 consisted of 31 control subjects (mean age 9.2 +/- 0.6 yr). Sensitive radioimmunoassays were used to measure IGF-I and GH in urine aliquots from 12-h timed overnight collections that had been dialyzed, concentrated 50-fold, and lyophilized. RESULTS: Significantly lower IGF-I and GH outputs per kilogram body weight per 12 h were observed in IDDM subjects compared with control subjects. When data were expressed per kilogram of body weight, no difference was observed between the urinary output of IGF-I and GH between prepubertal and pubertal subjects within group 1 or group 2. The prepubertal children had significantly lower HbA1 than the pubertal population; however, no correlation was found between urinary output of IGF-I or GH and HbA1. A positive correlation was observed between urinary IGF-I and GH (r = 0.85, P less than .001). CONCLUSIONS: Patients with long-standing IDDM excrete significantly lower urinary levels of IGF-I and GH compared with normal subjects. Serial measurements of these peptides from onset of IDDM are needed to define whether the changes observed are present at diagnosis or are secondary to duration of disease.

Diverse deletions in the growth hormone receptor gene cause growth hormone insensitivity syndrome.

Growth hormone insensitivity syndrome (GHIS; also known as Laron syndrome), is characterized by severe postnatal growth failure and normal growth hormone. The syndrome is frequently caused by point mutations in the growth hormone receptor gene (GHR). Here we report five families with GHIS and partial deletions of the GHR gene. The deletion breakpoints were sequenced and PCR-based diagnostic tests were developed. In a Cambodian family, a novel deletion removed part of exon 5 and 1.2 kb of the preceding intron. The deletion occurred by recombination within four identical nucleotides. In the mutant transcript, skipping of the truncated exon 5 leads to a frameshift and premature termination codon (PTC). A previously reported discontinuous deletion of GHR exons 3, 5, and 6 was identified in three Oriental Jewish families. An unaffected individual was heterozygous for the exon 5 and 6 deletion, but homozygously deleted for exon 3 suggesting that the exon 3 deletion is a polymorphism. The pathogenic deletion of exons 5 and 6 spans about 7.5 kb. Sequence analysis of the breakpoints revealed an imperfect junction between introns 4 and 6, with a four basepair insertion. A novel deletion of 13 nucleotides within exon 9 was identified in a Caucasian girl with GHIS who carries the I153T missense mutation on her other allele. The exon 9 deletion leads to a frameshift and PTC. The predicted protein retains the transmembrane domain and a short cytoplasmic tail. Four family members in three generations were carriers of this deletion, but only two of them were below normal for height, suggesting that this mutation by itself does not act as a dominant negative, as was reported for two other GHR mutations which lead to truncation of the intracellular domain.

Effect of pyridoxine on pituitary release of growth hormone and prolactin in childhood and adolescence.

The dopamine agonist, pyridoxine, was administered to 10 children being evaluated for short stature. Serum GH and PRL responses were contrasted to those after insulin-induced hypoglycemia (ITT) and L-dopa administration. Levels of GH did not change after pyridoxine, but PRL fell (P less than 0.05) to 42% of the zero time concentration. Significant increments of GH occurred during ITT and after L-dopa, while PRL was suppressed to a greater extent by L-dopa. We conclude that pyridoxine is not useful in assessment of hypothalamic-pituitary function.

Variable estimates of serum growth hormone concentrations by different radioassay systems.

Many different assays are being used to measure serum GH concentrations in children with disorders of growth. We assessed four readily available methods to determine the comparability of the immunopotency estimates: standard double antibody RIA with pituitary standards from the National Hormone and Pituitary Program (assay 1) and from a commercial source (assay 2), a double antibody RIA with serum standards (assay 4), and a commercial immunoradiometric assay (assay 3). There was a high degree of relative correlation between assays (r = 0.95-0.98), but absolute potency estimates differed. Assays 1 and 2 were almost identical. Assay 3 yielded serum GH levels about 65% those of assay 1 or 2 and 80% those of assay 4. Assay 4 gave intermediate values between the low readings in assay 3 and higher values in assay 1 and 2. We conclude that substantial variation occurs in potency estimates in different GH assays. Such differences can affect the interpretation of many GH provocative and sampling studies.

The response of pituitary gonadotropes to a constant infusion of luteinizing hormone-releasing hormone (LHRH) in normal prepubertal and pubertal children and in children with abnormalities of sexual development.

The pattern of LHRH-evoked release of LH and FSH by pituitary gonadotrophs and the concomitant gonadal steroid secretion were studied in 28 pubertal and 16 prepubertal children. LHRH was administered at doses of 100 mug and 10 mug by a constant-infusion pump over 3 hours following a 2-hour control period. Gonadotropin concentrations were measured at 15-minutes intervals. Mean LH concentrations rose from 2.0 +/- 0.4 (SE) mIU/ml (IRP-2-hMG) to 6.2 +/- 0.9 (P less than .001) in normal prepubertal and from 5.8 +/- 0.9 to 28.0 +/- 3.6 (P less than .001) in normal pubertal children. The peak rise of LH, the mean level attained during the LHRH infusion, and the area under the time-response curve were greater (P less than .001) in pubertal than prepubertal children. The serum LH rise had two components in pubertal children in contrast to a single-phased increase in prepubertal children. Pulsatile release of LH was demonstrated during the basal period in pubertal children and during the LHRH infusion in both groups. FSH release was greater in girls than boys at both stages of pubertal development. A 10 mug LHRH infusion released less LH than did 100 mug in the pubertal children, but more than in prepubertal children. In pubertal boys, plasma testosterone rose (P less than .001) from 222 +/- 45 ng/dl in the control period to 301 +/- 59 following 100 mug LHRH. There was no change in plasma testosterone in the prepubertal boys after 100 mug LHRH or in the pubertal boys following 10 mug LHRH. Plasma estradiol did not rise in girls of either maturity group. In children with hypogonadotropic hypogonadism and structural abnormalities of the hypothalamic-pituitary region, there was no LHRH-evoked gonadotropin release. In 2 agonadal girls, the secretion of LH and FSH was greatly exaggerated. The 3-hour LHRH infusion evoked a maturity-related pituitary LH release and a sex-specific FSH release; a 2-phased pattern of LH secretion was present in pubertal but not in prepubertal children; pulsatile LH release was evoked by the LHRH infusion in prepubertal children.

Early initiation of growth hormone treatment allows age-appropriate estrogen use in Turner's syndrome.

Because estrogen (E) accelerates skeletal maturation it can decrease final height attainable with GH therapy in girls with Turner's syndrome (TS). Nonetheless, as age-appropriate E administration does have psychobehavioral benefits for such patients, we asked whether E treatment in TS could occur without adverse impact on final adult height if GH therapy were started at an earlier age. Near adult height (NAH) was assessed in 344 girls with TS, who had received both GH and E and were followed in the National Cooperative Growth Study database. The groups were divided into quartiles based on age at initiation of GH (2-10, 10-12, 12-14, and 14-18 yr). The longest total and E-free period of GH treatment occurred in the girls who had started treatment in the youngest quartile (mean age, 8.2 +/- 1.5 (SD) yr); they were also exposed to E at the youngest age (12.7 +/- 1.6 yr). Although the girls in the youngest group received E at an earlier age, they had a significantly greater increase (1.8 +/- 0.8) in Lyon height SD score at NAH over Lyon predicted adult height than those in the oldest GH-treated group (0.8 +/- 0.6), which first received E at 15.9 +/- 1.3 yr. Multiple linear regression equations for gain in Lyon height SD score and in height (cm) showed greater increments with a longer period of E-free GH therapy. All four GH age groups had the same NAH, but the youngest quartile was youngest at NAH and likely still having more growth potential. Comparable data were found in 127 TS girls with spontaneous puberty. In conclusion, girls with TS starting GH at an early age have a greater gain in Lyon SD score at NAH compared with those starting later, even though they received E at a younger age. If GH therapy were started early, E treatment could be initiated at a younger, more age-appropriate time without compromising adult height.

Urinary excretion of immunoreactive gonadotropin-releasing hormone-like material in prepubertal and pubertal children.

A urinary product with immunological similarity to Gn-RH has been quantified by radioimmunoassay. The i-Gn-RH-like material apparently has a (partial) structure consistent with the 5 leads to 9 amino acid sequence of hypothalamic Gn-RH. It inhibits the binding of 125I-Gn-RH to anti Gn-RH serum in a manner parallel to synthetic standard, is absorbed by incubation with anti Gn-RH serum, and comigrates with synthetic Gn-RH on Sephadex column chromatography. The concentration of i-Gn-RH-like material is maximal in pubertal males. The total urinary excretion of this substance is two-fold greater in pubertal subjects of both sexes than in prepubertal children. There is no diurnal variation in the excretion of this material. There are significant positive correlations between the urinary content of iGN-RH-like material and LH and FSH. The site of origin, structure and physiological significance of this immunological product remain to be elucidated.

LH and FSH levels in urine and serum of prepubertal and pubertal children receiving a 3 hour infusion of LH-RH.

LH-RH was administered to 17 normal prepubertal and 14 pubertal children as well as to 6 GH deficient prepubertal patients. Urinary immunoreactive LH and FSH were measured in acetone extracts of 3 h collections prior to, during, and immediately after a 3 h infusion of 100 mug LH-RH. Peak LH excretion in response to LH-RH was higher in pubertal than prepubertal children. Girls excreted larger quantities of FSH after LH-RH than did boys. Serum LH and FSH increments evoked by LH-RH correlated significantly (P less than 0.01) with peak urinary gonadotropin excretion. These data suggest that measurement of urinary immunoreactive LH and FSH prior to and after LH-RH administration is clinically useful in evaluation of the reproductive endocrine system of young children and of individuals with low basal levels of gonadotropin.

Serum growth hormone (GH)-binding protein/receptor: an important determinant of GH responsiveness.

Individual growth rates (or responses to GH therapy) and adult heights vary over a wide range. The reasons for this variation are poorly understood. Based on the reciprocal relationship between GH production and serum GH-binding protein/receptor (GH-BP), we hypothesized that genetic growth potential was achieved by a specific combination of GH-BP/receptor and GH production in each individual. To address the question whether GH production regulates GH-BP, or vice versa, we studied GH-deficient children, where one of the parameters, GH exposure, could be controlled through exogenous administration. Forty-three untreated prepubertal GH-deficient children were studied before and after 6 and 12 months of GH replacement therapy (0.18 mg/kg.week). Growth velocity, height, bone age, weight and their respective Z scores, serum GH-BP, and serum insulin-like growth factor I (IGF-I) were measured at each time point. The patients responded with significant increases in serum IGF-I, age-adjusted growth velocity, and height (P < 10(-6) for all). Before therapy, GH-BP correlated directly with chronologic and bone age (P < 10(-4), but not with either growth velocity or IGF-I. In contrast, GH-BP correlated strongly with the response to therapy whether assessed as the incremental change in IGF-I (P < 10(-6)) or as the increase in growth velocity (P approximately 0.003). GH treatment had no consistent effect on GH-BP/receptor levels. These findings support the concept that the GH-BP/receptor endowment is characteristic for an individual and plays a pivotal role in somatic growth. The GH-BP/receptor system and its ontogeny appears relatively independent of regulation by GH. Differences in individual GH-BP/GH receptor complement account for some of the variability in the response to GH, and GH-BP levels may serve as a predictor for the degree of response. The reciprocal relationship between GH production and GH-BP in normal subjects probably results from adjustment of GH secretion to accommodate the prevailing GH-BP/receptor environment.

The role of body mass in the response to growth hormone therapy.

Obesity is associated with normal or increased growth despite diminished GH secretion compared to lean children. The mechanism by which adequate growth is maintained in the presence of low GH levels is unknown, but is possibly mediated at the GH receptor level. To probe this hypothesis, we examined the relationship between GH responsivity, body mass index (BMI) and plasma GH-binding protein (GH-BP)/receptor level in 43 GH-deficient children during treatment with a fixed dose of GH (0.18 mg/kg.week). Before treatment, BMI [expressed as standard deviation score (SDS) for age (BMI-SDS)] did not correlate with either growth velocity or serum insulin-like growth factor-I (IGF-I). In contrast, after 12 months of GH therapy BMI-SDS correlated directly with plasma IGF-I (P < 10(-5)) and growth velocity (P < 10(-3)). These findings parallel those obtained for GH-BP vs. the response to GH, suggesting that BMI and GH-BP are covariants. The interrelationships among BMI, GH-BP, and response to GH were further probed by multiple regression analysis. Partial correlation coefficients vs. response to GH were consistently stronger for GH-BP than for BMI-SDS, indicating that GH-BP is the dominant factor between these two covariants in determining responsiveness to GH. The data suggest a primary role for GH-BP/receptor levels in determining GH action, with secondary but significant effects of nutrition and degree of adiposity. The latter may be mediated through the impact of nutrition and body mass on GH-BP/receptor levels.

The response of pituitary gonadotropes to synthetic LRF in children with glucocorticoid-treated congenital adrenal hyperplasia: lack of effect of intrauterine and neonatal androgen excess.

Previous studies have demonstrated that the secretory reserve of the pituitary gland during childhood and adolescence is characterized by an age-related increase in LH secretion and a sex dichotomy of FSH secretion evoked by LRF. To determine if prenatal and neonatal androgen excess alters hypothalamic-pituitary-gonadal function, as in the neonatally androgenized rodent, we assessed pituitary sensitivity to 100 mug synthetic LRF in 9 girls and 2 boys with glucorticoid-treated congenital virilizing adrenal hyperplasia (CAH). In the 7 prepubertal girls with CAH, plasma LH following LRF rose to 2.0 plus or minus 0.4 (SE) ng/ml (LER 960) and did not differ from normal prepubertal children (1.7 plus or minus 0.1) and was lower (P less than 0.002) than in normal pubertal children (4.9 plus or minus 0.3). The 2 pubertal girls had LH rises in the pubertal range. In the 2 boys with CAH, the one with the more advanced bone age, 11-6/12 yr, developed true precocious puberty following initiation of cortisone treatment and had a pubertal LRF-evoked LH release on 3 occasions; the more immature boy, bone age 10, had a prepubertal LH rise. In the 7 prepubertal girls with CAH, plasma FSH rose to 8.1 plus or minus 1.6 (SE) ng/ml (LER 869), which did not differ from normal prepubertal girls (5.3 plus or minus 1.9), but was significantly (P less than 0.001) greater than in normal prepubertal boys (2.9 plus or minus 0.4). In these girls with CAH, basal plasma T (27.4 plus or minus 4.0 (SE) ng/dl) and 17-OHP (2703 plus or minus 1143 (SE) ng/dl) were greater than in prepubertal children, but plasma E1 and E2 were in the normal range. The pubertal boy had plasma T, E1, and E2 levels appropriate for his degree of sexual maturation. The results suggest: (1) age-related LH secretion evoked by LRF in glucocorticoid-treated CAH is appropriate for skeletal maturation; (2) the sex dichotomy of FSH secretion following LRF is preserved in CAH despite intrauterine and variable postnatal exposure to excess androgen and continuing slightly elevated plasma T during childhood; and (3) precocious puberty may follow initiation of cortisone treatment in a child with CAH whose bone age and secretory reserve of pituitary gonadotropins are in the pubertal range.

High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group.

GH production rates markedly increase during human puberty, mostly as an amplitude-modulated phenomenon. However, GH-deficient children have been dosed on a standard per kg BW basis similar to prepubertal children. This randomized study was designed to compare the efficacy and safety of standard recombinant human GH (rhGH) therapy (group I, 0.3 mg/kg x week) vs. high dose therapy (group II, 0.7 mg/kg x week) in GH-deficient adolescents previously treated with rhGH for at least 6 months. Ninety-seven children with documented evidence of GH deficiency (peak GH in response to stimuli, <10 ng/mL), with either organic or idiopathic pathology, were recruited. Both groups were matched for sex (group I, 42 males and 7 females; group II, 41 males and 7 females), age [group I, 14.0+/-1.6 (+/-SD) yr; group II, 13.7+/-1.6], standardized height (group I, -1.4+/-1.1; group II, -1.2+/-1.1), bone age (group I, 13.1+/-1.3 yr; group II, 13.1+/-1.3) etiology, maximum stimulated GH, previous growth rate, and midparental target height. All subjects were in puberty (Tanner stage 2-5) at study entry. Of the 97 subjects enrolled, 45 were treated for 3 yr or more; 48 completed the study. Of the subjects who discontinued the study, the most common reason was satisfaction with their height, although others discontinued for adverse events or personal reasons. The frequency of patients who discontinued was the same in both groups. The primary efficacy analysis was the difference between dose groups for near-adult height, defined as the height attained at a bone age of 16 yr or more in males and 14 yr or more in girls; all subjects who qualified were included in the analysis. This difference was statistically significant at 4.6 cm by analysis of covariance (ANCOVA; P < 0.001; n = 75). For subjects who received at least 4 yr of rhGH treatment, the difference between dose groups at that time point was 5.7 cm (by ANCOVA, P = 0.024; n = 20). The mean height SD score at near-adult height was -0.7+/-0.9 in the standard dose group and 0.0+/-1.2 in the high dose group. At 36 months the cumulative change in height (centimeters) was 21.5+/-5.3 cm (group I) vs. 25.1+/-4.9 (group II; P < 0.001, by ANCOVA); the change in Bayley-Pinneau predicted adult height was 4.8+/-4.2 cm (group I) vs. 8.4+/-5.7 (group II; P = 0.032). Median plasma IGF-I concentrations at baseline were 427 microg/L (range, 204-649) in group I and 435 microg/L (range, 104-837) in group II; at 36 months they were 651 microg/L (range, 139-1079) in group I vs. 910 microg/L (range, 251-1843) in group II (P = NS). No difference in change in bone age was detected between groups at any interval. High dose rhGH was well tolerated, with a similar safety profile as standard dose treatment and no difference in hemoglobin A1c or glucose concentrations between groups. In summary, compared to conventional treatment, high dose rhGH therapy in adolescents 1) increased near-adult height and height SD scores significantly, 2) did not increase the rate of skeletal maturation, and 3) appears to be well tolerated and safe. In conclusion, high dose rhGH therapy may have a beneficial effect in adolescent GH-deficient patients, particularly those who are most growth retarded at the start of puberty.

Urinary excretion of immunoreactive luteinizing hormone-releasing hormone-like material in children correlation with pubertal development.

Immunoreactive LRH (iLRH)-like material has been measured in extracts of urine from normal children and adolescents, adult men and women, and postmenopausal women. The urinary excretion of iLRH-like material was significantly greater in pubertal than in prepubertal subjects and in boys than girls at both stages of sexual maturation [prepubertal males, 3.26 +/- 0.49 ng/24 h (SE; n = 24); pubertal males, 5.94 +/- 1.36 (n = 12); prepubertal females, 1.14 +/- 0.21 (n = 19); pubertal females, 2.85 +/- 0.56 (n = 13)]. In adult males (n = 5) the urinary excretion of iLRH-like material was 7.8 +/- 1.3 ng/24 h, and in adult women in the follicular phase of the menstrual cycle (n = 8) it was 2.9 +/- 0.3. In five postmenopausal women the urinary iLRH-like content was 7.32 +/- 0.92 ng/24 h (P less than 0.01 relative to normal pubertal and adult women). In children the 24-h urinary excretion of iLRH-like material was positively correlated with chronological and bone ages, Tanner stage of genital (male) and breast (female) development, and the urinary excretion of LH and FSH in males. It did not correlate with the urinary excretion of either LH or FSH in females. Carboxymethylcellulose chromatography of extracts of urine from pubertal boys and girls, adult men and women, and postmenopausal women suggested that the iLRH-like material may be the 2-10 fragment of LRH rather than the intact decapeptide.

A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency.

Treatment of naive children with GH deficiency has relied upon long-term replacement therapy with daily injections of GH. The daily schedule may be inconvenient for patients and their caregivers, possibly promoting nonadherence with the treatment regimen or premature termination of treatment. We studied a new sustained release GH formulation, administered once or twice monthly, to determine its efficacy and safety in this population. Seventy-four prepubertal patients with documented GH deficiency were randomized to receive sustained release recombinant human GH at either 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by sc injection in a 6-month open-label study. Efficacy was determined by growth data from 69 patients completing 6 months and 56 patients completing 12 months in an extension study. Growth rates were significantly increased over baseline and were similar for the two dosage groups. The mean (+/-SD) annualized growth rate (pooled data) was 8.4 +/- 2.1 cm/yr at 6 months, and the growth rate was 7.8 +/- 1.8 at 12 months compared with 4.5 +/- 2.3 at baseline. Standardized height, bone age, and predicted adult height assessments demonstrated catch-up growth without excessive skeletal maturation. Injection site-related events (including pain, erythema, and nodules) were the most commonly reported adverse events; no serious adverse events related to treatment were reported. Laboratory studies documented no accumulation of trough GH or IGF-I levels during treatment, nor did glucose intolerance or persistent hyperinsulinism develop. Sustained release recombinant human GH is safe and effective for long-term GH replacement in children with GH deficiency. Patients achieved similar growth velocities when sustained release GH was given once or twice monthly. The enhanced convenience of this dosage form may result in greater long-term adherence to the treatment regimen.

Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor.

We have analyzed the GH receptor (GHR) gene in four individuals with Laron syndrome, and a missense mutation was identified for each patient in the extracellular domain of the GHR (D152H, I153T, Q154P, and V155G). The D152H mutation was previously reported. We have reproduced the three novel mutations in the GHR complementary DNA and analyzed their consequences in human 293 transfected cells. In cells expressing the I153T and V155G mutants, binding of [125I]human GH at the cell surface was very low, whereas binding to total membrane fractions was much less affected, suggesting impaired cell surface expression. Binding assays with cells expressing the Q154P mutant revealed severe defects both at the cell surface and in total particulate membrane fractions. Immunofluorescence experiments confirmed that cell surface expression of the three mutants was altered, and colocalization studies suggested that most of the mutant receptors are retained in the endoplasmic reticulum. Endoglycosidase H resistance tests also indicated that the majority of I153T and V155G GHRs are trapped in the endoplasmic reticulum. Thus, mutations on contiguous amino acids of the GHR result in various defects. The I153T, Q154P, and V155G mutations mainly affect intracellular trafficking and binding affinity of the receptor, whereas the D152H mutation affects receptor expression, dimerization, and signaling.

Absence of nonclassical congenital adrenal hyperplasia in patients with precocious adrenarche.

We studied 31 patients (28 girls and 3 boys), ranging in age from 3.2-7.9 yr, with precocious adrenarche defined by the presence of early sexual hair development, no signs of virilization, and bone age within +3 SD of the mean for chronological age. To determine if this symptom complex stemmed from any form of nonclassical (late-onset) congenital adrenal hyperplasia, an ACTH stimulation test was performed on each patient using a standard 0.25-mg dose of Cortrosyn, given as an iv bolus. Twelve pubertal children (7 girls and 5 boys) and 18 prepubertal children (11 girls and 7 boys) served as normal controls. Baseline and stimulated 17-hydroxypregnenolone (17-OHPreg), 17-hydroxyprogesterone, (17-OHP), 11-deoxycortisol, dehydroepiandrosterone, androstenedione, testosterone, and cortisol levels were measured. Using published nomogram standards for serum 17-OHP response to ACTH, no child with precocious adrenarche was diagnosed as having nonclassical 21-hydroxylase deficiency. Eight girls, however, had a stimulated 17-OHP value that exceeded the mean response for pubertal and prepubertal controls by more than +2 SD [range, 295-670 ng/dL (8.94-20.3 nmol/L)]. Stimulated 11-deoxycortisol values [less than 400 ng/dL (11.6 nmol/L)] ruled out any cases of nonclassical 11 beta-hydroxylase deficiency. No patient had nonclassical 3 beta-hydroxysteroid dehydrogenase deficiency, as defined by both the stimulated 17-OHPreg and the 17-OHPreg/17-OHP ratio to be more than +2 SD above the mean for pubertal children [1354 ng/dL (41.0 nmol/L) and 10.4, respectively]. In conclusion, we could not provide any biochemical evidence for nonclassical congenital adrenal hyperplasia in a large group of children with precocious adrenarche.

Serum bioactive gonadotropins during male puberty: a longitudinal study.

To evaluate the relative changes in serum bioactive (B) and immunoreactive (I) plasma gonadotropin concentrations during pubertal maturation, 28 healthy boys were enrolled at Tanner stage I and followed at 6-month intervals until achievement of Tanner stage V of pubertal maturation. At each visit, a careful interview, complete physical examination, sexual maturation staging, and bone age x-ray study were done, and a blood sample was obtained. Serum concentrations of PRL, dehydroepiandrosterone, and its sulfate, delta 4-androstenedione, estrone, estradiol, and testosterone (T) were determined by RIA. Samples from 20 boys were assayed for I-LH by RIA and for B-LH by the rat interstitial cell testosterone production assay, using 2 standards [Second International Reference Preparation-Human Menopausal Gonadotropin (2nd IRP-hMG) and LER 960]. Samples from 11 boys (3 from LH group and 8 others) were assayed for I-FSH by RIA and B-FSH by the rat Sertoli cell aromatase induction assay. The results were analyzed by regression analysis for B and I LH and FSH by Tanner stages of puberty, and by correlation of B to I LH and FSH as well as B and I LH and FSH to T. The results from both LH standards correlated well to each other (r = 0.967 and 0.882 for B- and I-LH, respectively), and the data are presented for 2nd IRP-hMG standard. In both groups of boys serum T concentrations increased progressively with pubertal development (P < 0.001). The boys bone age, testicular volume, serum T, dehydroepiandrosterone sulfate, dehydroepiandrosterone, delta 4-androstenedione, estrone concentrations correlated well with pubertal maturation, similar to previously published data and indicate that this group of boys had progressed through puberty in the expected normal manner. Mean serum I-LH concentrations increased progressively from Tanner stage I to V of puberty (P < 0.001), and serum B-LH exceeded the increase in serum I-LH levels. Mean serum I-LH concentrations were 2.0 +/- 0.1, 2.9 +/- 0.2, 4.7 +/- 0.4, 6.7 +/- 0.7, and 10.4 +/- 2.0 IU/L 2nd IRP-hMG whereas mean serum B-LH concentrations were 0.8 +/- 0.1, 2.2 +/- 0.2, 5.9 +/- 0.2, 10.3 +/- 1.2, and 22.3 +/- 3.8 IU/L 2nd IRP-hMG for Tanner stages I-V of puberty, respectively. This resulted in a progressive increase of LH B/I ratio with advancing pubertal maturation (P < 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)