Ronald W. Gotlin

Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome

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.

Three-year results of a randomized prospective trial of methionyl human growth hormone and oxandrolone in Turner syndrome

Seventy girls with Turner syndrome, 4 to 12 years of age, participated in a prospective, randomized study to determine the effects on growth of methionyl human growth hormone (met-hGH) or oxandrolone. Subjects were randomly assigned to receive either no treatment (control) or met-hGH (0.125 mg/kg three times per week), oxandrolone (0.125 mg/kg/day), or combination met-hGH plus oxandrolone. At the end of an initial period of 12 to 20 months, patients in the original control and oxandrolone groups were given combination met-hGH plus oxandrolone. At that time the dosage of oxandrolone was lowered to 0.0625 mg/kg/day. Sixty-five subjects have now completed the first 3 years of the study. Compared with the control growth rate for year 1 (3.8 cm/yr), significant increases in growth rate were seen in all 3 years of combination therapy (9.8, 7.4, and 6.1 cm/yr, respectively) and in the first 2 years of treatment with met-hGH alone (6.6, 5.4, and 4.6 cm/yr). When growth velocity was expressed as standard deviation for age in girls with Turner syndrome, significant increases relative to the control group for year 1 (-0.1 SD) were seen in all three years of both combination therapy and met-hGH alone (combination, +6.6, +4.3, +3.0 SD; met-hGH, +3.1, +2.0, +1.4 SD). After 3 years of treatment, predicted adult height by the method of Bayley-Pinneau increased 4.5 cm in the met-hGH group and 8.2 cm in the combination group.

Methionyl human growth hormone and oxandrolone in Turner syndrome: Preliminary results of a prospective randomized trial

Seventy girls with Turner syndrome, 4 to 12 years of age, were randomly assigned to receive either no treatment (control) or methionyl human growth hormone (0.125 mg/kg three times per week), oxandrolone (0.125 mg/kg/day), or combination hGH plus oxandrolone therapy. Baseline growth rates averaged 4.3 cm/yr, and all were within 2 SD of mean growth velocity for age in girls with Turner syndrome. Sixty-seven girls remained in the study for a minimum of 1 year. Growth rates and growth velocity (in standard deviations for age in girls with Turner syndrome) were control 3.8 cm/yr (-0.1 SD), hGH 6.6 cm/yr (+2.3 SD), oxandrolone 7.9 cm/yr (+3.7 SD), and combination therapy 9.8 cm/yr (+5.4 SD). Mean bone ages advanced 1.0 years (hGH), 1.3 years (oxandrolone), and 1.6 years (combination). However, median increments in height age/bone age (delta HA/delta BA) ratios ranged from 1.0 to 1.1 for treatment groups, compared with 0.8 for the controls. Predicted adult height by the method of Bayley-Pinneau increased 2.5 cm for hGH or oxandrolone alone, and 3.2 cm for combination treatment. These data indicate that both hGH and oxandrolone can significantly stimulate short-term skeletal growth in patients with Turner syndrome, and potentially increase final adult height.

Cerebral Gigantism Triad of Findings Helpful in Diagnosis

Four cases of cerebral gigantism are reported, and their historical, phys ical and investigative findings are compared with those of other re ported cases. The triad of a period of rapid growth, advanced bone age and absence of precocious sexual development is characteristic of this syndrome and is seen rarely in other conditions. Extensive growth hormone and other pertinent assays, including circadian studies, failed to demonstrate any excess of endocrine secretions.

LACK OF DIETARY REGULATION OF JEJUNAL GLYCOLYTIC ENZYMES AND DISACCHARIDASES IN OBESITY: THE ROLE OF INSULIN

Dietary regulation of jejunal glycolytic regulatory enzymes and disaccharidases were studied in 9 obese subjects, aged 9 to 18 years. These subjects were divided into two groups on the basis of altered carbohydrate metabolism as measured by circadian insulin levels and flux of glucose, inorganic phosphorus, and insulin measured during a 5-hr oral glucose tolerance test. Those patients with nocturnal hyperinsulinemia and abnormal carbohydrate flux showed no adaptation of jejunal enzymes. These data suggest that both glycolytic regulatory enzymes and disaccharidases are susceptible to insulin regulation.

COMPARISON OF HYPOTHALAMUS PITUITARY ADRENAL AXIS SUPPRESSION (HPAS) FROM TOPICAL STEROIDS BY STANDARD ENDOCRINE FUNCTION TESTING AND GAS CHROMATOGRAPHY MASS SPECTFOMETRY(GCMS)

We compared GCMS with plasma and urinary free cortisol concentrations to determine indices of HPAS in urine samples obtained from subjects treated with topical steroids. The subjects were 37 males requiring treatment for severe psoriasis valgaris. Two topical ointments betamethasone diproprionate (A) and Clobetasol 17-proprionate (B) were studied employing a double blind, randomized, parallel matrix. Over a 12 weeks we compared standard endocrine function tests (plasma and urinary free oortisol) with GCMS. Twenty-four hour urines and a.m. plasma were obtained prior to, during and after the treatment; treatment efficacy was evaluated by one of the investigators in each phase.A dramatic and similar treatment response was observed with both agents and laboratory indices of HPAS were correlated with clinical response. While no difference in treatment response between the ointments was seen, HPAS was more marked with agent B (84%) than A (22%) and persisted longer.GCMS provided a sensitive index of HPAS and revealed evidence of adrenal adrogen as well as glucocorticoid suppression. We found that plasma cortisol though less sensitive than GOB does provide a rapid and practical estimate of cotaneous absorption of topical steroids and HPAS.

SALT LOSS AND MINERALOODRTICOID RESISTANCE IN AN INFANT: A VARIANT OF PSUEDOHYPOALDOSTERONISM

Gas Chromatography/Mass Spectrometry (GC/MS) analysis of urinary steroid derivatives has extended our understanding of a variety of metabolic disease states. GC/MS was used to evaluate a suspected case of adrenal hyperplasia. A 4 week-old male presented with failure to thrive, absence of excessive virilization, hyponatremia (Na 120 mmol/L) and hyperkalanic metabolic acidosis. Serum 17-OHP and urinary 17-ketosteroids and pregnanetriol were normal. Treatment with IV saline and IM DOCA resulted in improvement, but α-fluorocortisone alone was ineffective and NaCl supplements at doses of 8mmol/kg/day were needed. Plasma aldosterone was 840 pmol/L (27 ng/dL); PRA was 125ng/ml/hr after 5 months of treatment. An older brother with salt losing in infancy had responded to sodium and α-fluorocortisone and was considered to be an 18 hydroxylase complex deficiency. GC analysis confirmed the normalcy of glucocorticoid and androgen pathways as well as an abnormal elevation of THB. In addition, there was a marked elevation of THA (TH corticosterol), confirmed by MS, which has not been previously reported. In contrast with other cases of pseudohypoaldosteronism and abnormalities in aldosterone biosynthesis, the present combination of features suggests problems in both aldosterone synthesis and tubular insensitivity to mineralocorticoids. The latter may possibly result from competitive inhibition by THA.

454 EXTRAUTERINE ONTOGENETIC DEVELOPMENT OF ADRENOCORTICAL FUNCTION IN THE HUMAN PREMATURE

While clinical signs suggestive of adrenal glucocorticoid and mineralocorticoid insufficiency are common in the human premature, previous biochemical estimations of newborn adrenal function employing a variety of biochemical methods have reported normal to high blood and urine concentrations of adrenal corticosteroids. Our studies were designed to examine longitudinally biochemical indices of adrenal function in premature and term infants between 30 and 42 weeks of gestational age. Urinary profiles from twenty-four hour urine samples collected in 4 hour aliquotes at weekly intervals were enzymatically hydrolyzed, derivatized to form methyloxime-trimethylsilyl ethers and analyzed by gas chromotography and mass spectrometry-selected ion capture. Severely ill infants were not studied but subjects were not otherwise excluded on the basis of clinical presentation or course. Clinical course including light-darkness (eye patching) and treatment were monitored.The urinary steroid profiles from premature infants of 30–37 weeks gestational age do not reflect a continuous transition from the fetal 16 hydroxy 5-ene pattern to the 17 hydroxy-4-ene pattern of the mature adrenal. The results indicate that adrenal glucocorticoid and mineralocorticoid insufficiency may be a common finding in premature infants and may result in characteristic clinical features requiring replacement therapy. (Supported in part by NIH Grants RR01152 and RR69).