G Cesaretti

Combination treatment with growth-hormone and gonadotropin-releasing-hormone analogs in short normal girls

To improve final adult height, we treated with growth hormone (0.65 +/- 0.07 (mean +/- SD) IU.kg-1.wk-1) and gonadotropin-releasing hormone analogs (66 +/- 9 micrograms.kg-1 every 28 days) a group of seven short normal girls in early puberty with a chronologic age (CA) of 11.50 +/- 0.95 years, predicted adult height (PAH) lower (0.003 < p < 0.001) than mean target height, and without any endocrine abnormalities. The results were compared with those obtained in a similar group of seven untreated girls considered as control subjects. The mean period of combined therapy was 2.01 +/- 0.52 years; in two subjects treatment is still in progress. The value of height standard deviation score for bone age (BA) improved from -1.69 +/- 0.47 to -1.04 +/- 0.56 (p = 0.001); height age (HA)/BA ratio also increased from 0.83 +/- 0.05 to 0.90 +/- 0.04 (p < 0.01), as did PAH (from 146.8 +/- 4.4 to 152.9 +/- 3.6 cm; p < 0.002). The ratio of gain in HA to gain in BA was 2.08 +/- 0.78. Pubertal stages showed an arrest in five cases and a regression in the other two girls. After administration of gonadotropin-releasing hormone analogs was interrupted, in four of five girls growth hormone was administered alone for a further period of 6 to 18 months to improve their physiologic growth spurt. The present height in five girls is higher than PAH before therapy. In the treated girls the height values for BA, for BA/CA and HA/BA ratios, and for PAH were higher (0.002 < p < 0.04) than those in control subjects. This preliminary study demonstrates that combination therapy with growth hormone and gonadotropin-releasing hormone analogs in short, endocrinologically normal girls may be useful in improving both height prognosis and predicted adult height. Further studies are necessary to reach definitive conclusions regarding the efficacy of this kind of therapy.

Evaluation of L-thyroxine replacement therapy in children with congenital hypothyroidism

The outcome of L-thyroxine (L-T4) replacement therapy in children with congenital hypothyroidism (CH) remains to be completely evaluated. In this paper the overall pattern of response to L-T4 replacement therapy was studied in a group of 19 children with CH diagnosed by neonatal screening (10 with hypoplastic/aplastic thyroid disease, group H/A; 9 with gland ectopy, group E) who were followed-up for 60 ± 27 months (mean ± SD). With 1 exception serum T4 at diagnosis was > 2 µg/dl in children of group E and < 2 µg/dl in those of group H/A. The initial dose of L-T4 (8–10 µg/kg BW/day) was modified in relation to age and weight in order to maintain serum TSH ≼ 5 µU/ml and FT3 in the normal range. A general inverse correlation between serum TSH and FT4 or FT3 concentrations was found, and the mean levels of serum FT4 and FT3 were significantly higher according to the following order of TSH results: low TSH (0–0.5 µU/ml) > normal (>0.5–5 µU/ml) > elevated TSH (>5 µU/ml). TSH levels < 5 µU/ml were associated with FT4 values in the upper half of the normal range (54% of observations) or even higher (46%). Elevation of serum FT4 alone with FT3 values in the normal range did not result in clinical thyrotoxicosis, alteration of growth or premature craniosynostosis. Mean L-T4 doses (µg/kg BW/day) administered to CH children were: 7.0 ± 1.6 between 1 and 6 months; 5.2 ± 0.9 between 6 and 12 months; 4.0 ± 0.6 between 1 e 5 yr; 3.4 ± 0.6 over 6 yr. In general, the mean L-T4 closes given to children showing low, normal or elevated TSH were widely overlaped. Growth in weight and height was normal, no significant difference being observed in children of group H/A vs. those of group E. Mental development was within the normal range, but at age 12 months children in group H/A had significantly lower DQ scores than those in group E, and at age 3 yr both groups of CH children had significantly lower IQ scores than unaffected controls. In conclusion: i) in children with CH serum TSH can be suppressed to normal or even subnormal concentrations provided that enough L-T4 is given to maintain FT4 in the upper half of the normal range or slightly higher; ii) sporadic elevations of TSH during treatment could be attributed to: failure to reassess the dose of L-T4 following the infant’s rapid gain in weight, lack of compliance, malabsorption of the drug, misunderstanding of prescription; iii) neuropsychological development was within the normal range of tests; however, the absence of functioning thyroid tissue, as shown by low T4 at diagnosis and by negative radioisotope imaging, was a risk factor for lower mental scores.

The Italian screening program for primary congenital hypothyroidism: Actions to improve screening, diagnosis, follow-up, and surveillance

The Italian screening program for primary congenital hypothyroidism (CH) is an integrated system including neonatal screening, diagnosis, treatment, follow-up, and nationwide surveillance of the disease. The aim of the Italian screening program for CH is to identify not only babies with severe permanent CH (core target), but also babies with mild persistent and transient forms of CH who could have a benefit from an early replacement therapy (secondary target). In the last years, despite the important results obtained in terms of standardization of screening and follow-up procedures, it has become clear the need of optimizing the program in order to harmonize the screening strategy and the screening procedures among Regions, and to improve the diagnostic and therapeutic approach in all affected infants. On the basis of available guidelines, the experience of the Italian screening and clinical reference centers, and the knowledge derived from the nation-wide surveillance activity performed by the Italian National Registry of Infants with CH, the Italian Society for Pediatric Endocrinology and Diabetology together with the Italian Society for the Study of Metabolic Diseases and Neonatal Screening and the Italian National Institute of Health promoted actions aimed at improving diagnosis, treatment, follow-up and surveillance of CH in our country. In this paper the most important actions to improve the Italian screening program for CH are described.

GHRH-test in short children with "non classic" GH deficiency. A comparison with "classic" GH deficiency and short normal stature.

In this study GHRH-test has been performed (2 μg/Kg of an iv bolus of GHRH 1–44) sampling for GH measurement every 15 min over 2 hours in three groups of short children. Group 1 consisted of 10 subjects with classic GH deficiency (CGHD): GH response < 10 ng/ml to two conventional tests and 24-h mean GH concentration (MGHC) < 3 ng/ml; group 2 consisted of 16 subjects with non-classic GH deficiency (NCGHD): response > 10 ng/ml to at least one conventional test and MGHC < 3 ng/ml; group 3 consisted of 18 subjects with short normal stature: GH response > 10 ng/ml to at least one conventional test and MGHC >3 ng/ml. GH peak and area under the curve (AUC) values were significantly lower in group 1 than groups 2 and 3 and in group 2 than group 3. GH peak and AUC values statistically correlated with height, height velocity, bone age/chronological age ratio and MGHC. Six children in group 1,14 children in group 2 and all 18 children in group 3 showed after GHRH a GH peak > 10 ng/ml and were considered as ‘responders’. Considering only the responders, GH peak and AUC values were significantly lower in group 1 than groups 2 and 3 and in group 2 than group 3. In conclusion, our data have shown that 87% of children with NCGHD responded to a single bolus of GHRH with an increase in GH levels > 10 ng/ml and that their responses were intermediate compared to those of CGHD and short normal subjects.