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OBJECTIVE: To carry out a multicenter, prospective, randomized trial of human growth hormone (GH), alone or in combination with oxandrolone (OX), in patients with Turner's syndrome (TS). METHODS: In an initial phase lasting 12 to 24 months, 70 girls with TS, verified by karyotype, were randomly assigned to one of four groups: (1) observation, (2) OX, (3) GH, or (4) GH plus OX. After completion of the first phase, group 3 subjects continued to receive GH only. All other subjects were treated with GH plus OX. Subjects were followed up until attainment of adult height and/or cessation of treatment. Data from this trial were compared with growth characteristics of 25 American historical subjects with TS (matched for age, height, parental target height, and karyotype) who never received either GH or androgens. RESULTS: Of the 70 subjects enrolled, 60 completed the clinical trial. The 17 subjects receiving GH alone all completed the trial and reached a height of 150.4+/-5.5 cm (mean +/- SD), 8.4+/-4.5 cm taller than their mean projected adult height at enrollment (95% confidence interval [CI]: 6.3 to 10.6 cm). The 43 subjects receiving GH plus OX attained a mean height of 152.1+/-5.9 cm, 10.3+/-4.7 cm taller than their mean projected adult height (95% CI: 8.9 to 11.7 cm). The historical control subjects had a mean adult height of 144.2+/-6.0 cm, precisely matching their original projected adult height of 144.2+/-6.1 cm. CONCLUSIONS: GH, either alone or in combination with OX, is capable of stimulating short-term growth and augmenting adult height in girls with TS. With early diagnosis and initiation of treatment, an adult height of more than 150 cm is a reasonable goal for most girls with TS.

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11 males, aged 2.5-16.3 years (6.8 +/- 4.1) with growth retardation (Standard Deviation Score--SDS > -2.00) consequent to chronic renal failure (CRF) received recombinant human growth hormone (rhGH) for 18 to 60 mo (40.9 +/- 15.4). Growth velocity (GV) increased from 5.4 +/- 2.2 for the year prior to rhGH to 8.9 +/- 1.6 (p = 0.00001), 7.4 +/- 1.7 (p < 0.03), 7.6 +/- 1.6 (p < 0.006), 6.5 +/- 1.0 (p < 0.05) and 7.5 +/- 1.3 (p = NS) cm/yr following 12, 24, 36, 48 and 60 mo respectively of treatment. The mean SDS for height decreased from -3.21 at baseline to -0.85 at 60 mo (p = 0.0004); 7 of 8 pts treated for > 36 mo had a SDS more positive than -2.00; 3 reached the 50th percentile on the growth curve. In 2 patients the dosage was doubled to achieve the increase in GV; in one patient it took 5 yrs to reach a SDS more positive than -2.00. A significant increase in weight gain and mid-arm muscle circumference over baseline values were indicative of the anabolic effect of rhGH. The mean increase in bone age was similar to the increase in chronologic age; the delta bone age-delta height age was not significant indicating no loss of growth potential following rhGH. Although 3 patients required the initiation of dialysis following rhGH treatment, the mean calculated creatinine clearance did not decrease significantly. No significant adverse effects were noted. These data indicate that long-term rhGH treatment is effective in improving the GV of children with CRF and facilitating catch-up growth without loss of growth potential.

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To identify factors influencing the response to GH therapy, we used a multiple regression model to analyze data from 632 naive prepubertal children with GH deficiency (GHD). There were 523 children with idiopathic and 109 children with organic GHD. They were treated with the same preparation of biosynthetic methionyl GH (somatrem, Protropin) for at least 1 yr. In children with idiopathic GHD, six variables predicted 40% of the response to treatment. They were (listed in relative importance, all P < 0.0001): age, log maximum GH, weight adjusted for height, dosing schedule, dose, and midparental height. Three variables, pretreatment growth rate, log maximum GH, and age, predicted 20% of the GH response in children with organic GHD. When data for all children were analyzed using analysis of covariance, children with idiopathic GHD grew better than those with organic GHD (mean +/- SD, 9.2 +/- 2.4 vs. 8.8 +/- 2.6 cm/yr; P < 0.0001). The children (both organic and idiopathic GHD) who did not respond well to treatment were younger and thinner than those who did. Early diagnosis and initiation of therapy should be beneficial to ultimate height attainment. The best response to GH therapy should be in young children with severe idiopathic GHD who receive daily weight-adjusted doses. The use of GH daily in higher doses would be expected to be most beneficial in older children with acquired and/or less severe GHD or in children who are underweight for height.

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Although GH has been available as a therapeutic agent for the GH-deficient child for more than 30 years, the conditions of its use have yet to be optimized. The availability of biosynthetic material has provided researchers with the opportunity to develop the protocols necessary to begin to finally answer the most fundamental questions pertaining to dose, frequency, and duration of treatment. It has also permitted the initiation of prospective trials in a large number of conditions that result in childhood short stature, with the expectation that some or many of them will be treated effectively and safely. Finally, it has opened the door to an entire spectrum of potentially new uses of GH and other growth factors for so-called nonconventional indications. That these have implications that range from the short-term rapid healing of a burn graft site, to the more efficient induction of ovulation, to the long-term preservation of lean body mass has excited the interest of investigators in many fields of medicine and physiology. Thus, the recent progress reported in this paper is really the beginning of the new research that will take place with GH and growth factors.

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Seventy girls with Turner syndrome, verified by karyotype, were randomly assigned to observation or treatment with human growth hormone (hGH), oxandrolone, or a combination of hGH plus oxandrolone for a period of 12 to 24 months, to assess the effect of treatment on growth velocity and adult height. Subsequently, all subjects received either hGH alone or hGH plus oxandrolone. Data are presented for 62 subjects treated for a period of 3 to 6 years. When compared with the anticipated growth rate in untreated patients, the growth rate after treatment with hGH, both alone and in combination with oxandrolone, showed a sustained increase for at least 6 years. Treatment is continuing in over half of the subjects; at present, 14 (82%) of 17 girls receiving hGH alone and 41 (91%) of 45 girls receiving combination therapy exceeded their expected adult heights. Thirty girls have completed treatment; mean height for these 30 patients is 151.9 cm, compared with their mean original projected adult height of 143.8 cm. We conclude that therapy with hGH, alone and in combination with oxandrolone, can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome.

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Germ cell tumors may cause various aberrations in pubertal development. In prepubertal boys, these tumors may secrete human chorionic gonadotropin, resulting in precocious puberty. Human chorionic gonadotropin and alpha-fetoprotein are both useful as germ cell tumor markers in the diagnosis and detection of recurrence. Pregnancy-specific beta 1-glycoprotein, another oncoplacental antigen, has been used as a tumor marker for trophoblastic neoplasms, but not previously for human chorionic gonadotropin-producing tumors associated with precocious puberty. Patients with germ cell tumors may also have abnormal karyotypes. Herein, we describe six male pediatric patients with germ cell tumors and pubertal derangements seen during an 8-year period. We confirm the high incidence of associated sexual precocity, the usefulness of alpha-fetoprotein, human chorionic gonadotropin, and pregnancy-specific beta 1-glycoprotein as tumor markers in the diagnosis and follow-up of these patients, and the occurrence of sex chromosomal abnormalities.

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Treatment of nine boys, aged 2.8-16.3 years, with growth retardation consequent to chronic renal failure (CRF), with recombinant human growth hormone (rhGH) for 12-36 months demonstrated a significant improvement in growth velocity at each 12-month interval compared with that achieved the year prior to treatment. Despite the acceleration in growth velocity the bone age did not increase more than the increase in chronological age during the period of treatment. The mean calculated creatinine clearance did not decrease significantly during the 36 months of treatment; however, two patients required institution of dialysis at 18 and 30 months following the initiation of rhGH treatment. There was no exacerbation of the glucose intolerance of uremia following rhGH treatment. Currently, six of seven patients who have been treated for more than 24 months have achieved sufficient acceleration of growth velocity to attain a standard deviation score that was more positive than -2.00, and are above the 5th per centile for chronological age on the growth curve. These data indicate that rhGH treatment of growth-retarded children with CRF results in accelerated growth velocity during the 2nd and 3rd years of treatment, and demonstrate the potential for such children to achieve normal stature for chronological age despite the continued presence of renal failure.

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It has become evident that locally produced insulin-like growth factors-I and -II (IGF-I and IGF-II) play an important role in the medication of GH action upon tissues. To explore this concept with respect to immunocompetent cells, we analyzed IGF production and clonogenic responsiveness of immortalized human T-cell lines established from seven normal controls and four Laron dwarfs. While the normal T-cell lines showed significant augmentation of basal colony formation in response to both IGF-I and GH, little increase in clonogenesis in response to GH was seen with the Laron T-cell lines. Assay of basal and GH-stimulated conditioned media demonstrated low, but measurable, levels of IGF-I and IGF-II from both normal and Laron T-cells. Under serum-free incubation conditions, GH stimulation of normal T-cell lines failed to generate significant increases in mean IGF-I or IGF-II concentration and no increase in the mean IGF-II concentration in conditioned medium were observed after GH stimulation of Laron T-cell lines. Nevertheless, the increased cloning efficiency of the normal T-cell lines in response to either GH or IGF-I was nearly completely abrogated by preincubation of cells with antibodies to either IGF-I or the type I IGF receptor. These studies, thus, support a role for locally generated IGF-I in the mediation of GH action on T-lymphocytes and indicate that this effect is mediated via the type I IGF receptor.

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Demographic, diagnostic, and baseline clinical data were collected for a large cohort (N = 2331) of children who started treatment with biosynthetic human growth hormone (GH) between October 1985 and October 1987. Eighty-one percent met classic criteria for GH deficiency and were classified as having idiopathic GH deficiency (59%), organic GH deficiency (18%), or septo-optic dysplasia (4%). The remaining 19.8% had short stature of varied causes. Height standard deviation score at diagnosis, maximum GH response to stimulation, and heights of parents were examined according to gender, race, age at diagnosis, and previous treatment history. The predominance of boys in all subgroups except septooptic dysplasia, and the observation that girls with idiopathic GH deficiency were comparatively shorter than boys at diagnosis, suggest ascertainment bias. Black children with idiopathic GH deficiency were shorter than white children at diagnosis, and their low overall representation (6.0%) compared with their percentage in the at-risk population (12.9%) also suggest ascertainment bias among races. These data provide a profile of GH deficiency as it is currently defined and expose possible inherent biases in the diagnostic process. Now that GH supply is no longer limited, criteria for its use should be formulated to avoid apparent underascertainment or late diagnosis of GH deficiency in girls and black children.

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The clinical entity of Laron dwarfism is characterized by resistance to both endogenous and exogenous GH and may be due to a deficiency or absence of functional GH receptors. We previously showed that two types of hematopoietic cells derived from these patients are resistant to the in vitro growth-promoting action of GH at concentrations below 500 micrograms/L. In the current study we found that Laron T-cell lines had a mean peak augmentation of basal colony formation of 22 +/- 3.4% above baseline in response to a GH concentration of 10,000 micrograms/L. Since cloned cDNAs for human and rabbit GH receptors and rat PRL receptors show a high degree of sequence homology, we undertook studies of PRL action in cells from patients with Laron dwarfism to determine if the Laron defect was also associated with PRL unresponsiveness. Quantitating the augmentation of colony formation by T-lymphoblast cell lines established from three Laron dwarfs, we found normal responsiveness to PRL at concentrations of 25-10,000 micrograms/L. It is, thus, possible that the responsiveness of Laron T-cell lines to very high concentrations of GH could be mediated through an intact PRL (or other lactogenic) receptor based on the known affinity of GH for these receptors in other systems. These data suggest that cells from patients with Laron dwarfism have normal in vitro responsiveness to PRL and that the defect in Laron dwarfism appears to be specific to the GH receptor-effector pathway. It remains to be determined whether intact alternative lactogenic receptor mechanisms subserve any clinical effects of GH in patients with Laron dwarfism.

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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.

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We studied the effect of recombinant human growth hormone treatment on five boys, aged 4.6 +/- 1.8 years, who had chronic renal failure secondary to congenital renal diseases (mean creatinine clearance (+/- SD): 18.3 +/- 6.3 ml/min/1.73 m2 (0.32 +/- 0.11 ml/sec/1.73 m2]. Patients received 0.125 mg/kg of growth hormone three times per week for 1 year. Before beginning treatment, the children had a mean annual growth velocity of 4.9 +/- 1.4 cm/yr (range 3.0 to 6.3 cm/yr), with a mean standard deviation score for a height of -2.98 +/- 0.73 (range -2.16 to -3.59). At the end of therapy, the mean growth velocity had increased to 8.9 +/- 1.2 cm/yr (range 7.5 to 10.7 cm/yr), and the mean height standard deviation score improved to -2.36 +/- 0.83 (range -1.15 to -3.18). Bone age advancement was consistent with the period of growth. Routine laboratory determinations, including results of glucose tolerance testing, did not vary significantly from pretreatment levels. These preliminary data indicate that growth-retarded children with chronic renal failure can respond to exogenous growth hormone therapy with a marked acceleration in growth velocity.

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We recently identified a female leprechaun infant with marked hyperinsulinemia [as high as 10,975 microU/ml (78,746 pmol/liter)], presumably secondary to insulin resistance. She had two physical findings suggestive of possible insulin action: cystic ovarian enlargement with gonadotropin-independent steroid secretion and persistent, severe myocardial hypertrophy. To examine the pathophysiology of this disorder we measured the in vitro sensitivity to insulin and other growth factors of erythroid progenitors and a T-lymphoblast cell line derived from her peripheral blood. Resistance to insulin was demonstrated by failure of her circulating erythroid progenitor cells to augment proliferation in response to physiologic concentrations of insulin (1-10 ng/ml). An immortalized T lymphoblast cell line was established by transforming the cells with the human retrovirus human T cell leukemia virus II. This cell line showed little or no response to physiologic concentrations of insulin contrary to consistently observed stimulation of colony formation by cell lines similarly derived from normals. The patient's T lymphoblasts, however, showed normal sensitivity to insulin-like growth factor I. In response to supraphysiologic insulin concentrations (25-1000 ng/ml), leprechaun T lymphoblasts showed significant augmentation of colony formation (peak 189% above baseline at 50 ng/ml); normal T lymphoblasts also showed responsiveness at these high insulin concentrations. Preincubation with a monoclonal antibody against the insulin-like growth factor I receptor (alpha IR-3 at 5000 ng/ml) blocked the in vitro effect of physiologic concentrations of insulin-like growth factor and supraphysiologic concentrations of insulin on leprechaun and control T lymphoblast colony formation, but had no clear effect upon the response to physiologic insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

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We use an antithyroid drug for the treatment of hyperthyroidism due to Graves' disease in children and adolescents for as long as the patients are willing to comply and/or tolerate the drug. In more than 60 patients treated since 1961, the remission rate was 25% in the first 2 yr. This report looks at these same patients again, followed for an additional 5 yr. Survival analysis methods applied to the follow-up data on 63 children confirm our original statistical findings and suggest a continuing remission rate of 25% every 2.1 +/- 0.4 (+/- SE) yr regardless of the duration of previous therapy. The median time to remission was 4.3 +/- 1.5 yr, and 75% of patients are predicted to be in remission in 10.9 +/- 2.3 yr. Of 36 patients who went into remission, defined by their being euthyroid for 1 yr after cessation of therapy, 1 relapsed, and 2 developed spontaneous hypothyroidism; the remainder are euthyroid 1-11.7 yr after therapy was discontinued. Of 14 who switched from medical therapy, 2 of 7 treated surgically and 4 of 7 treated with 131I are hypothyroid. Only 1 patient had a significant adverse reaction to both methimazole and propylthiouracil. While medical therapy may have some direct effect on the autoimmune response in hyperthyroidism, its role in affecting the time to ultimate remission is unknown. These data, however, describe the course of children so treated and allow us to present therapeutic options initially or during treatment based on statistically derived probabilities of outcome.

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