No abstract

This study was designed to determine the benefit of therapy on final height (FHt) in girls with central precocious puberty (CPP). A total of 102 patients were evaluated – 28 untreated, 26 treated with cyproterone acetate (CyA), and 48 treated with GnRH analogue (GnRHA) – and their achieved FHt was compared to the respective target height (THt). Of the untreated girls, half (14/28) had a slow course of puberty and reached THt ± 0.5 SD (FHt 160.2 ± 7.1, THt 159.5 ± 6.6 cm); the other half (14/28) had an accelerated course of puberty with a FHt well below THt (FHt 150.8 ± 4.3, THt 159.2 ± 5.9 cm) and in most cases (10/14) below the height-SDS of both parents. The treated girls (both regimens) reached THt or above (CyA group: FHt 157.8 ± 5.1, THt 156.8 ± 5. 1 cm; GnRHA group: 159.6 ± 6.3, THt 157.7 ± 5.7 cm). We conclude that without treatment the FHt of girls with CPP may be significantly compromised and that therapy is more beneficial if started before bone age exceeds 12 years. Our data also showed that for final height predictions in CPP the Bayley and Pinneau tables for average children should be used, regardless of the advanced bone age of the patients.

Objective: Few data are available on the pubertal development of children born small for gestational age (SGA) who fail to show catch-up growth. Design: A longitudinal analysis compared the pubertal course of persistently short children born SGA compared to children with idiopathic short stature who were appropriate for gestational age (AGA). One hundred and twenty-eight short children (height SDS , 21.7), including 76 (31 boys) born SGA and 52 (22 boys) born AGA, were regularly followed from early childhood to completion of puberty. Results: Puberty was attained at normal age (10.5 -14 years in boys, 9.5-13 years in girls) for most children in both the SGA and AGA groups (boys, 80% and 77%; girls, 76% and 78% respectively). The duration of puberty was similar in the SGA and AGA groups. Menarche occurred at normal age range but was significantly earlier in the SGA girls (P , 0.01 by ANOVA). Despite the similar total pubertal growth, the patterns of growth differed significantly: SGA group -accelerated growth and bone maturation rates from onset of puberty with peak height velocity at Tanner stages 2-3, followed by a decelerated growth rate and earlier fusion of the epiphyses; AGA group -steady progression of bone elongation and maturation throughout puberty (pubertal growth, P , 0.05 in both sexes; bone maturation, P , 0.001 in both sexes). Final height in the SGA group was compromised compared with their target height (P , 0.001). Conclusion: Children born SGA have a normal pubertal course with a distinct pubertal growth pattern. This pattern may represent an altered regulation of their growth modalities.

No abstract

Insulin-induced hypoglycemia (IIH) is the gold standard test for assessment of the integrity of the hypothalamic-pituitary-adrenal (HPA) axis, but it may be hazardous. We sought to determine whether the standard (250 micrograms) or low-dose (1 microgram/1.73 m2) short ACTH test can replace IIH in patients with idiopathic multiple pituitary hormone deficiencies (MPHD). Three groups of subjects were studied: 1) control group, children with early or accelerated puberty and no other evidence of adrenal or pituitary pathology (n = 13, age 10.1 +/- 2.2 yr, 3 males); 2) patients with idiopathic hypothalamic pituitary insufficiency and either isolated GH deficiency or MPHD and preserved HPA function (n = 20, age 13.7 +/- 4.4 yr, 13 males); and 3) MPHD patients with impaired HPA axis function (n = 10, age 16.8 +/- 4.8 yr, 9 males). IIH and the 250 micrograms and 1 microgram/1.73 m2 ACTH tests were performed in groups 2 and 3; group 1 underwent only the ACTH tests. Pass peak cortisol level was defined as 520 nmol/L. No significant difference was noted between the standard and low-dose tests in the 30-min cortisol response to ACTH. Basal and peak cortisol levels attained on both ACTH tests were similar in groups 1 and 2 and significantly lower in group 3 (P < 0.0001). Both the 250 and 1 microgram ACTH tests were highly correlated with IIH (r = 0.71, P < 0.0001 for the 250 micrograms, r = 0.7, P < 0.0001 for the 1 microgram, n = 30), and both demonstrated high sensitivity (90% each) and specificity (100% and 90%, respectively) compared with IIH. We conclude that in idiopathic MPHD patients, both the standard and low-dose ACTH tests are equivalent to IIH in detecting HPA insufficiency. We suggest that they can replace IIH as a screening test for the integrity of the HPA axis in children with suspected MPHD.

The course of Graves' thyrotoxicosis in 7 prepubertal children (6.4 Ϯ 2.4 yr) was compared with that in 21 pubertal (12.5 Ϯ 1.1 yr) and 12 postpubertal (16.2 Ϯ 0.84 yr) patients. In the prepubertal group the main complaints were weight loss and frequent bowel movements (86%), whereas typical symptoms (irritability, palpitations, heat intolerance, and neck lump) occurred significantly less often (P Ͻ 0.01). The most prominent manifestation at diagnosis was accelerated growth and bone maturation: their height SD score was significantly greater than that of the pubertal and postpubertal patients (2.6 Ϯ 0.7 vs. 0.15 Ϯ 0.65 and 0.15 Ϯ 0.9, respectively, P Ͻ 0.001), and their bone age to chronological age ratio was 1.39 Ϯ 0.35 compared with 0.98 Ϯ 0.06 in the pubertal children (P ϭ 0.02). T 3 levels were also significantly higher than in the other two groups (9.9 Ϯ 2.9 nmol/L vs. 6.32 Ϯ 1.9 nmol/L and 6.02 Ϯ 2.0 nmol/L, P ϭ 0.01).All patients were initially prescribed antithyroid drugs (ATDs). Overall, adverse reactions to ATDs occurred in 35%, with a higher rate among the prepubertal children (71%) than the pubertal (28%) and postpubertal (25%) patients (P ϭ 0.08). Major adverse reactions were noted in two children, both prepubertal. Remission was achieved in 10 patients (28%). Although the rate of remission did not differ among the three groups, time to remission tended to be longer in the prepubertal children (P ϭ 0.09).In conclusion, thyrotoxicosis has an atypical presentation and more severe course in prepubertal children. Considering their adverse reactions to ATD, overall low remission rate, and long period to remission, definitive treatment should be considered earlier in this age group. (J Clin Endocrinol Metab 85: 3678 -3682, 2000)

Objective: To evaluate whether genotype differences can explain the clinical variability of non-classical steroid 21-hydroxylase de®ciency (NC21-OHD) and to determine if genotype is related to ethnic origin. Design: Genotyping for mutations in the steroid 21-hydroxylase (CYP21) gene was performed in 45 unrelated Israeli Jewish patients (nine males) with NC21-OHD (60 min 17-hydroxyprogesterone (17-OHP), 45±386 nmol/l) who were referred for evaluation of postnatal virilization or true precocious/ early puberty. Eleven siblings diagnosed through family screening were genotyped as well. Methods: Patients were divided by genotype into three groups: (A) homozygous or compound heterozygous for the mild mutations (V281L or P30L) (n=29; eight males); (B) compound heterozygous for one mild and one severe mutation (Q318X, I2 splice, I172N) (n=12; no males); (C) mild mutation detected on one allele only (n=4; one male; peak 17-OHP 58±151 nmol/l). We then related the genotype to the ethnic origin, clinical phenotype and hormone level. Since group C was very small, comparisons were made between groups A and B only. Results: At diagnosis, group B tended to be younger (5.863.0 vs 8.164.3 years, P 0.09), had greater height SDS adjusted for mid-parental height SDS (1.661.1 vs 0.761.4, P 0.034), tended to have more advanced bone age SDS (2.961.5 vs 1.762.1, P 0.10) and had a higher peak 17-OHP level in response to ACTH stimulation (226692 vs 126662 nmol/l, P < 0.01). Group B also had pubarche and gonadarche at an earlier age (5.162.4 vs 7.462.2 years, P < 0.01 and 7.461.8 vs 9.961.4 years, P < 0.001, respectively) and a higher rate of precocious puberty (50 vs 17%, P 0.04). Stepwise logistic regression analysis (excluding males) yielded age at gonadarche as the most signi®cant variable differentiating the two groups, with a positive predictive value of 86% for a cut-off of 7.5 years. Conclusions: The ®ndings suggest that genotype might explain some of the variability in the phenotypic expression of NC21-OHD. Compound heterozygotes for one mild and one severe mutation have a higher peak 17-OHP associated with pubarche and gonadarche at an earlier age and more frequent precocious puberty. Hence, the severity of the enzymatic defect might determine the timing and pattern of puberty.

Early and fast puberty (EFP) in girls, defined as pubertal onset at age 8-9 yr, with an accelerated course, may cause compromised final height (FHt) and psychosocial distress. Treatment with a gonadotropin-suppressive agent is controversial, because the improvement in FHt is equivocal and there may be risk of obesity. We analyzed the data of 126 girls with EFP: 63 treated with GnRH analog (GnRHA) since Tanner stage 3, for 2-4 yr; and 63 untreated. Age at onset of puberty; accelerated time of transition from Tanner stage 2 to 3 (<1.3 yr); and clinical, hormonal and sonographic findings were similar in the 2 groups. The girls given GnRHA treatment had a significantly prolonged pubertal course, compared with the accelerated course in the untreated girls (4.7 +/- 0.4 vs. 2.45 +/- 0.4 yr, P < 0.001). After therapy, they reached Tanner stages 4 and 5 and FHt at a significantly older age than the untreated group (P < 0.001), and their menarche was delayed (12.8 +/- 0.6 vs. 10.8 +/- 0.5 yr, P < 0.001). However, the different pace of puberty in the 2 groups did not change the total pubertal growth and the bone maturation rate. The Ht gain from Tanner stage 3 to 4 (10.4 +/- 2.7 vs. 11.2 +/- 3.1 cm) and from Tanner stage 4 to FHt (8.2 +/- 2.7 vs. 8.8 +/- 3.6 cm) was similar in the treated and untreated girls, as were absolute Ht and bone age at each pubertal stage. The weight gain of the treated girls was more pronounced during treatment (P = 0.0016), but it was arrested after discontinuation of therapy; and by the time FHt was reached, the body mass index was similar in the 2 groups. The treated and untreated girls achieved a similar mean FHt, which was not significantly different from their respective mean target Ht (THt). Individual analysis revealed that 70% of the treated girls and 67% of the untreated girls attained their THt range (THt +/- 0.5 SD) or surpassed it. In conclusion, treatment with GnRHA affected only the pace of EFP. The similar Ht gain and bone maturation rate at each pubertal stage in the treated and untreated girls may suggest that the total pubertal growth is not dependent on pubertal duration and pace and is probably determined already at the onset of the normal pubertal development. The treatment did not compromise the FHt and did not cause long-lasting obesity. Therefore, GnRHA therapy may be suggested for use in girls who have psychosocial difficulties in coping with EFP.