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Short-term administration of human growth hormone to children with idiopathic short stature can improve mean growth rate and predicted adult height. It is yet unknown whether therapy would alter pubertal development or affect final height. Three-year treatment results in a group of children with idiopathic short stature are reported. For year 1 of the study, 121 prepubertal children were randomly selected to receive somatotropin, 0.3 mg/kg per week, administered subcutaneously three times weekly (n = 63), or to be nontreatment control subjects (n = 58). After 1 year, all subjects were again randomly selected to receive either three-times-weekly or daily dosing at the same total dose. For the 92 subjects who completed 36 months of treatment, mean growth rate increased from a mean of 4.6 cm/yr before treatment to a mean of 8.0 cm/yr in the first year of treatment. Daily dosing resulted in a significantly faster mean growth rate (9.0 cm/yr) than three-times-weekly dosing (7.8 cm/yr) (p = 0.0005). Mean growth rates were 7.6 and 7.2 cm/yr during years 2 and 3, respectively, and did not differ by dosing group. Mean standardized height for all subjects improved from -2.7 to -1.6 after 3 years. When the growth rate was standardized for bone age, however, subjects who remained prepubertal had a significantly greater gain in mean height SD score than subjects who became pubertal during that 3-year period (p < 0.02). Mean standardized Bayley-Pinneau predicted adult height SD score increased from -2.7 to -1.6 and was independent of the timing of pubertal onset, but for individuals this score was more variable. Year-1 growth response, expressed as growth rate or change in height SD score, was the best predictor of growth in subsequent years. Responses to therapy could not be reliably predicted from baseline anthropometric variables, plasma insulin-like growth factor I SD score, growth hormone levels. Final height assessment will be needed to determine the ultimate benefit of therapy.

We hypothesized that prepubertal girls with gonadotropin deficiency would produce less follicle-stimulating hormone (FSH) in response to synthetic gonadotropin-releasing hormone (GnRH) than would gonadotropin-sufficient children. To test this hypothesis, we performed 103 GnRH tests serially in 21 children who had idiopathic hypopituitarism with growth hormone deficiency. We tried to predict whether puberty would occur in the 17 girls with bone ages of 8 years or less. Of these 17 girls, 4 failed to have spontaneous secondary sexual characteristics by age 16 1/2 years, and 12 had spontaneous complete pubertal development. One girl had incomplete pubertal maturation with partial gonadotropin deficiency; her results were combined with those of the girls who had no spontaneous pubertal development. With increasing bone age, the girls with complete pubertal development had a decrease in the increment of FSH released in response to GnRH, although basal gonadotropin concentrations did not change. For GnRH tests performed at bone ages of 8 years or less, basal luteinizing hormone (LH) values did not differ between girls with complete puberty and those with absent or incomplete puberty. However, basal FSH and the incremental response of LH and FSH to GnRH were greater in those with complete puberty. Only two girls with prepubertal bone ages at the time of testing, who subsequently had complete puberty, had incremental FSH responses to GnRH that were less than 5 IU/L. Individual incremental LH responses to GnRH did not discriminate well between groups. None of the girls with adrenocorticotropic hormone deficiency, either originally or subsequently, had spontaneous puberty, but 4 of 12 girls with thyrotropin deficiency, either originally or subsequently, had complete puberty. We conclude that a significant increase in GnRH-stimulated FSH suggests that spontaneous pubertal development will occur in girls with idiopathic hypopituitarism. However, a low FSH response to GnRH may not be diagnostic of gonadotropin deficiency.

The pubertal maturation of five boys (Group A) who were initially thought to be gonadotropin deficient was studied over 10 to 58 months (mean 36 months) by serial physical examinatons and standard GnRH tests. Four were seen because of obesity, delayed sexual maturation, depression, and poor school performance. The other boy had acquired hypothalamic hypopituitarism at 13 years of age. Gonadotropin responses during the initial GnRH test were either absent or abnormally low as related to the degree of skeletal maturation. Subsequent responses showed progressive maturation into the normal range for adult males. These boys had normal olfaction and moderate-to-marked obesity, but initial assessment of testicular size, basal gonadotropins, and testosterone or gonadotropin responses to GnRH did not distinguish these boys from seven patients with isolated gonadotropin deficiency (Group B). Contrary to previous reports and expectations, these studies indicate that an absent or markedly blunted response to synthetic GnRH is not diagnostic of gonadotropin deficiency, even when skeletal age is 12 years or greater. Furthermore, unless a patient is hyposomic or anosmic, or has an associated anomaly such as cleft palate, isolated gonadotropin deficiency cannot be diagnosed reliably until late adolescence or early adulthood.

Eleven girls, ages 10/12 to 76/12 years, were evaluated because of early and rapid breast development. Initial clinical presentations and serum gonadotropin or estradiol determinations did not differentiate patient types. However, patients could be divided into two groups based on their responses to synthetic gonadotropin-releasing hormone: Group A consisted of seven girls with suppressed or prepubertail-type responses, and Group B consisted of four girls with pubertal or adult-type responses. Subsequent evaluation revealed that Group A patients had intermittent or unsustained isosexual precocity, whereas Group B patients had isiopathic prococious puberty. During initial evaluation, increased serum or urinary estrogen values were noted in ten of ten patients who were studied. The greatest serum E2 values (162 and 117 pg/ml) were noted in two Group A patients; three months and two years later, those patients had normal prepubertal responses to GnRH and serum E2 values of less than 4 and 14 pg/ml, respectively. Unsustained sexual precocoity in girls may be secondary to autonomous ovarian production of estrogens, and the GnRH test may be useful in evaluation of girls with isosexual precocity.

In the cord blood of seven infants with congenital hypothyroidism detected in our newborn screening programs, thyroxine values ranged from 2.5 to 6.7 mug/dl and thyrotropin, from 105 to 975 muU/ml; triiodothyronine values were normal. On follow-up, T3 levels increased to normal in five infants, there was a significant negative correlation between the T3 value and the severity of thyroprevia as reflected in the TSH levels and the number of clinical features present. This increase in T3 may explain in part why the diagnosis of this disease is difficult during the first few months of life and why early treatment is effective. This observation provides further rationale for the widespread institution of newborn screening programs for congenital hypothyroidism.

Thyroid antibodies were determined by three different techniques in the sera of 125 children and adolescents with thyroid disorders and in the sera of 53 short, normal children without thyroid dysfunction. The incidence of antithyroglobulin antibodies in patients with thyroiditis was highest when measured by radioimmunoassay (85%), less than when measured by hemagglutination (24%), and least by antimicrosomal antibodies (7%). No patient who had initially negative serum for RATA subsequently had positive tests during follow-up of five to 24 months, whereas eight of 31 patients with initially negative serum for ATA later developed positive tests. Treatment appeared to have a suppressive effect on RATA, but not on ATA titers, in hypothroid patients with clinical thyroiditis. The incidence of hypothyroidism in the patients with clinical thyroiditis on initial presentation was significant (37%) and suggests that identification of children and adolescents with thyroiditis is important to ensure adequate medical follow-up.

Sexual precocity in association with abnormalities of the central nervous system is well known, but its occurrence with hypothalamic hypopituitarism is most unusual. We report five females with septo-optic dysplasia, blindness, and multiple pituitary tropic hormone deficiencies: all were growth hormone and adrenocorticotropic hormone deficient; two had diabetes insipidus; one had sexual precocity, and one had early pubertal maturation, whereas three were prepubertal and responded to administration of synthetic gonadotropin-releasing hormone. These children retained ability to secrete gonadotropins despite the presence of anterior hypothalamic disease. Experimental data from primates plus our observations on these patients raise questions about the role of the anterior hypothalamus in gonadotropin secretion in man.

Serial concentrations of basal serum LH, FSH, testosterone, and LH and FSH responses to intravenous gonadotropin-releasing hormone were measured before and during six months of administration of fluoxymesterone or oxandrolone in 14 boys with constitutionally delayed growth and adolescence, in order to assess the effects of these androgens on maturation of the hypothalamic-pituitary-gonadal axis. Before therapy all boys had normal hormonal responses based on bone age. At the end of six months therapy 10 of the 14 boys had lower LH responses (34 to 89% reduction) to GnRH without consistent changes in FSH responses. With both androgens, there there was significant suppression of both basal serum FSH and testosterone. Eleven boys were restudied six months after completion of therapy; basal serum LH, FSH, and testosterone and responses to GnRH were equal to or greater than pretreatment levels, indicating recovery or progressive maturation of the HPGA. All boys had increased growth velocity and imporved weight gain without excessive bone age advancement; all had improved psychosocial adjustment.

Six girls, aged 5 to 15 years, presented with thyroid masses in otherwise nonpalpable thyroid glands and with normal serum thyroxine levels. Scintiscanning before and after TSH stimulation confirmed the presence of autonomous nodules in the four adolescents, of whom two had elevated T3 levels. Surgical exploration revealed adenomatous thyroid hyperplasia in three of the girls and papillary adenocarcinoma in the fourth. Scans in the other two girls revealed absence of the left lobe. One of them proved to have agenesis of the left lobe with enlargement of the right lobe because of lymphocytic thyroiditis. The other girl had an ectopic thyroid with chronic inflammation. A thorough diagnostic evaluation of single or multiple functioning thyroid masses in children and adolescents is essential in establishing the correct diagnosis. The possibility that carcinoma can occur in autonomous nodules as well as in hemiagenesis and ectopic thyroid tissue is discussed. An approach to the management of functioning thyroid masses in the pediatric age group is proposed.