The GH dose-response effect of long-term continuous GH treatment on adult height (AH) was evaluated in 54 short children born small for gestational age (SGA) who were participating in a randomized, double-blind, dose-response trial. Patients were randomly and blindly assigned to treatment with either 3 IU (group A) or 6 IU (group B) GH/m(2).d ( approximately 0.033 or 0.067 mg/kg.d, respectively). The mean (+/-SD) birth length was -3.6 (1.4), the age at the start of the study was 8.1 (1.9) yr, and the height SD score (SDS) at the start of the study -3.0 (0.7). Seventeen of the 54 children were partially GH deficient (stimulated GH peak, 10-20 mU/liter). Fifteen non-GH-treated, non-GH-deficient, short children born SGA, with similar inclusion criteria, served as controls [mean (+/-SD) birth length, -3.3 (1.2); age at start, 7.8 (1.7) yr; height SDS at start, -2.6 (0.5)]. GH treatment resulted in an AH above -2 SDS in 85% of the children after a mean (+/-SD) GH treatment period of 7.8 (1.7) yr. The mean (SD) AH SDS was -1.1 (0.7) for group A and -0.9 (0.8) for group B, resulting from a mean (+/-SD) gain in height SDS of 1.8 (0.7) for group A and 2.1 (0.8) for group B. No significant differences between groups A and B were found for AH SDS (mean difference, 0.3 SDS; 95% confidence interval, -0.2, 0.6; P > 0.2) and gain in height SDS (mean difference, 0.3 SDS; 95% confidence interval, -0.1, 0.7; P > 0.1). When corrected for target height, the mean corrected AH SDS was -0.2 (0.8) for group A and -0.4 (0.9) for group B. The mean (+/-SD) AH SDS of the control group [-2.3 (0.7)] was significantly lower than that of the GH-treated group (P < 0.001). Multiple regression analysis indicated the following predictive variables for AH SDS: target height SDS, height SDS, and chronological age minus bone age (years) at the start of the study. GH dose had no significant effect. In conclusion, long-term continuous GH treatment in short children born SGA without signs of persistent catch-up growth leads to a normalization of AH, even with a GH dose of 3 IU/m(2).d ( approximately 0.033 mg/kg.d).

No abstract

To reduce the side effects of corticosteroid treatment, the administered dose of glucocorticoids (GCs) should be kept to a minimum while preserving therapeutically needed intracellular levels. Currently available assays to determine individual sensitivity to GCs are either imprecise or based on inhibition by GCs of lymphocyte proliferation following stimulation with phytohemagglutinin or other mitogens, which may influence the GC signal transduction pathway. Using the human lymphoblastoid cell line IM-9 as a model system, we studied whether the GC-induced increase of the mRNA encoding the 51-kDa FK506-binding protein (FKBP51) could be used for the development of a novel assay, ultimately to be used in native human peripheral blood mononuclear cells (PBMCs). GC addition to IM-9 cells resulted in a dose-dependent increase of FKBP51 mRNA levels within 2 h, followed by a further increase until 24 h. Northern blot analysis and real-time PCR yielded similar results. Coincubation of GCs with the GC receptor antagonist ORG 34116 or the protein synthesis inhibitor cycloheximide suggested a direct, GC receptor-mediated up-regulation of FKBP51 gene transcription. Expected differences in potency among different GCs could be readily demonstrated in this system. Extending our observations in IM-9 lymphoblasts to normal PBMCs, we found a dose-dependent increase of FKBP51 mRNA on ex vivo incubation of native human PBMCs with GCs, with a sensitivity of about 10(-9) M for dexamethasone. Moreover, dexamethasone ingestion increased FKBP51 mRNA in PBMCs in vivo, extending the use of this assay to the measurement of GC bioavailability. Finally, using this method we were able to demonstrate partial GC-insensitivity in a 6-month-old infant suffering from congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. We conclude that the induction of FKBP51 mRNA by GCs may be a suitable marker to assess individual GC sensitivity, the in vitro measurement of GC potency, and the in vivo determination of GC bioavailability.

Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries, which GH dosage to use and which age to start puberty induction are issues of debate. This study shows final height (FH) in 60 girls with Turner syndrome treated in a randomized dose-response trial, combining GH treatment with low dose estrogens at a relatively young age.Girls were randomly assigned to group A (4 IU/m 2 ⅐d; ϳ0.045 mg/kg/d), group B (first year, 4 IU/m 2 ⅐d; thereafter 6 IU/m 2 ⅐d), or group C (first year, 4 IU/m 2 ⅐d; second year, 6 IU/m 2 ⅐d; thereafter, 8 IU/m 2 ⅐d). After a minimum of 4 yr of GH treatment, at a mean age of 12.7 ؎ 0.7 yr, low dose micronized 17␤-estradiol was given orally. After a mean duration of GH treatment of 8.6 ؎ 1.9 yr, FH was reached at a mean age of 15.8 ؎ 0.9 yr. FH, expressed in centimeters or SD score, was 157.6 ؎ 6.5 or ؊1.6 ؎ 1.0 in group A, 162.9 ؎ 6.1 or ؊0.7 ؎ 1.0 in group B, and 163.6 ؎ 6.0 or -0.6 ؎ 1.0 in group C. The difference in FH in centimeters, corrected for height SD score and age at start of treatment, was significant between groups A and B [regression coefficient, 4.1; 95% confidence interval (CI), 1.4, 6.9; P < 0.01], and groups A and C (coefficient, 5.0; 95% CI, 2.3, 7.7; P < 0.001), but not between groups B and C (coefficient, 0.9; 95% CI, ؊1.8, 3.6). Fifty of the 60 girls (83%) had reached a normal FH (FH SD score, more than ؊2). After starting estrogen treatment, the decrease in height velocity (HV) changed significantly to a stable HV, without affecting bone maturation (change in bone age/change in chronological age). The following variables contributed significantly to predicting FH SD score: GH dose, height SD score (ref. normal girls), chronological age at start of treatment, and HV in the first year of GH treatment. GH treatment was well tolerated.In conclusion, GH treatment leads to a normalization of FH in most girls, even when puberty is induced at a normal pubertal age. The optimal GH dosage depends on height and age at the start of treatment and first year HV. (2), subnormal levels of GH and IGF-I have been reported (3, 4). It has been postulated that a diminished sensitivity for growth factors might explain their growth retardation (5, 6). Nevertheless, GH treatment in a supraphysiological dosage has been shown to accelerate growth (4, 7). Another clinical feature in most girls with TS is the absence of spontaneous pubertal development, for which estrogen substitution is necessary. Although GH treatment for short stature in TS is now an accepted treatment in many countries, reports on final height are inconsistent (8,9), and which dosage to use and which age to start puberty induction are issues of debate.Previously, we have demonstrated that long-term GH treatment in TS leads to normalization of height (4, 10). This study shows final height (FH) results in 60 girls with TS treated in a randomized dose-response trial comparing 3 dosage schedules. In addition, we show the effect of low dose estrogen treatment begun at a relatively ...