Evidence for partial growth hormone insensitivity among patients with idiopathic short stature. The National Cooperative Growth Study.

OBJECTIVE: To determine whether some patients with idiopathic short stature have partial resistance to growth hormone (GH). Patients with idiopathic short stature have decreased serum levels of the GH receptor-related GH-binding protein (GHBP), and low GHBP levels are associated with complete GH insensitivity (Laron) syndrome. We hypothesized that patients with idiopathic short stature and low GHBP levels may also have a degree of GH insensitivity. DESIGN: Retrospective analysis of patients in a multicenter study. SETTING: Ninety-six National Cooperative Growth Study centers in the United States and Canada. SUBJECTS: Five hundred eleven patients with idiopathic short stature who were treated with GH. All patients had a baseline height standard deviation score of less than -2 and a maximum stimulated GH level greater than 10 micrograms/L. Of these, 101 (20%) had a baseline GHBP standard deviation score of -2 or less. RESULTS: The patients with low GHBP levels, in comparison with those with normal GHBP levels, had a lower mean extracted standard deviation score for insulin-like growth factor I (-3.3 +/- 1.1 vs -2.5 +/- 1.4; p < 0.0001) but mean 12-hour GH values (2.8 +/- 1.1 vs 2.3 +/- 1.1 micrograms/L; p <0.0001). The differences between groups were statistically significant after control for age and weight-for-height standard deviation score. Among prepubertal patients, there was no significant difference between the low and normal GHBP groups in mean pretreatment or first-year growth rate (p = 0.74, 0.61 respectively) with comparable doses of GH. CONCLUSIONS: Patients with idiopathic short stature and low GHBP levels, compared with those with normal GHBP levels, had significantly lower standardized levels of insulin-like growth factor I, and higher mean 12-hour GH levels, which suggest partial GH insensitivity. There was no significant correlation of GHBP levels with the growth response to exogenous GH.

Properties of spontaneous growth hormone secretory bursts and half-life of endogenous growth hormone in boys with idiopathic short stature. Genentech Collaborative Group.

We analyzed endogenous GH secretory dynamics and MCRs by a novel quantitative deconvolution technique in 20 boys with idiopathic short stature (ISS) and 35 boys of normal stature in Tanner stage I of puberty. We tested the null hypotheses that 1) ISS is not associated with any alterations in the frequency, mass, amplitude, or duration of spontaneous GH secretory bursts and/or the 24-h GH production rate; and 2) the half-life of endogenous GH is not altered in ISS. The boys with ISS had a mean (+/- SEM) bone age of 8.0 +/- 0.42 yr and a chronological age of 10 +/- 0.50 yr. The latter was similar to the chronological (and bone) age of the normal boys of 9.8 +/- 0.23 (and 9.3 +/- 0.34) yr. Mean height SD scores were significantly lower in ISS boys, viz. -2.7 +/- 0.15 in ISS vs. +0.34 +/- 0.13 in normal boys (P less than 0.001). Plasma insulin-like growth factor-I concentrations were similar in the two groups, as were (24-h) mean serum GH concentrations, viz. 3.5 +/- 0.29 micrograms/L in ISS and 4.1 +/- 0.49 micrograms/L in normal boys (P = NS). Deconvolution analysis revealed that the mean number of GH secretory events per 24 h was similar in normal and ISS boys, viz. 9.6 +/- 0.76 (normal) vs. 8.4 +/- 0.55 (ISS), and that there was no significant difference in mean GH interburst intervals. The amplitude, mass, and duration of computer-resolved GH secretory bursts also did not differ in normal and ISS boys. The half-lives of endogenous GH were estimated to be 16 +/- 0.77 min in the ISS and 18 +/- 0.93 min in the control boys (P = NS). The calculated daily GH secretion rate per unit distribution volume was not significantly reduced in ISS, i.e. 194 +/- 19 micrograms/L.day in ISS vs. 177 +/- 19 micrograms/L.day in control boys. Moreover, daily GH secretion rates corrected for body mass index (weight/height2) in the twp groups were not significantly different. In summary, the present cohort of boys with ISS manifested no significant alterations in GH secretory burst frequency, duration, mass, or amplitude or in the half-life of endogenous GH compared to normal boys in Tanner stage I of pubertal development. Indeed, whether daily GH secretion rates are expressed per unit distribution volume or per unit body mass index, groups of boys with ISS and normal height controls secrete similar total amounts of GH. We conclude that the overall dynamics of GH secretion and clearance in boys with ISS considered as a whole cannot be distinguished readily from physiological patterns observed in prepubertal boys of normal height.

Imipramine effect on hypothalamic-pituitary-adrenal axis response to hypoglycemia.

Six control subjects underwent an insulin tolerance test before and after the administration of therapeutic doses of imipramine hydrochloride for 10 days to investigate effects of tricyclic antidepressants on hypothalamic-pituitary-adrenal axis response to hypoglycemia. The mean steady-state tricyclic blood level was 141 (SD = 66) ng/ml. Baseline levels of glucose, cortisol, and adrenocorticotropic hormone (ACTH) were not affected by the administration of imipramine. After administration of imipramine for 10 days, subjects uniformly had a significantly lower glucose nadir than before its administration (before imipramine: mean = 32 mg/dl; SD = 5; after imipramine: mean = 24 mg/dl; SD = 6). There was no difference in ACTH or cortisol response before and after the administration of imipramine. These findings suggest that imipramine hydrochloride increases sensitivity to the hypoglycemic effects of insulin, but does not alter the counterregulatory response of ACTH and cortisol.

Decreased metabolic clearance of endogenous growth hormone and specific alterations in the pulsatile mode of growth hormone secretion occur in prepubertal girls with Turner's syndrome. Genentech Collaborative Group.

We have used deconvolution analysis to test the hypothesis that specific facets of GH secretion and clearance differ in young patients with Turner's syndrome and normal prepubertal girls. To this end, we sampled blood at 20-min intervals for 12 h overnight in 50 girls, 37 of whom had Turner's syndrome and 13 of whom were healthy Tanner stage I controls. Deconvolution analysis revealed that the half-life of endogenous GH in Turner's syndrome was significantly prolonged at 14 +/- 0.93 vs. 11 +/- 0.44 min in normal girls (P = 0.029). The number of significant GH secretory bursts was reduced in Turner's patients to 4.7 +/- 0.27 vs. 6.8 +/- 0.60 events/12 h in healthy girls (P less than 0.01). GH secretory burst half-duration was significantly prolonged in Turner's syndrome, viz. 23 +/- 1.3 vs. 15 +/- 0.87 min (controls; P less than 0.001). The changes in GH secretory burst frequency, duration, and half-life were specific, since neither the mass of GH secreted per burst nor the maximal rate of GH secretion attained per burst (amplitude of the secretion pulse) was significantly different in the 2 study groups. Thus, although 12-h GH secretion rates corrected for body weight were similar (3.9 +/- 0.76 in Turner's patients and 3.3 +/- 0.76 micrograms/L.kg/12 h in the control girls), equivalent GH production rates were achieved by different mechanisms in the 2 groups. We conclude that specific alterations in GH secretory burst frequency and duration and endogenous GH half-life can be documented in young girls with Turner's syndrome.

Recombinant human growth hormone treatment of children following renal transplantation.

Nine growth-retarded renal allograft recipients received either thrice weekly or daily subcutaneous recombinant human growth hormone (rhGH) for 6-30 months. The annualized growth velocity for the initial year of rhGH treatment was significantly greater than that of the preceding year (2.5 +/- 2.1 vs 5.7 +/- 2.7; P less than 0.0001). There was no advancement in bone age greater than the increase in chronological age, no significant increase in the mean fasting serum glucose or insulin levels, nor significant decrease in the calculated creatinine clearance following rhGH treatment. However, two patients experienced rejection episodes following rhGH treatment indicating the potential adverse consequences of the treatment on allograft function. This will require further delineation in prospective controlled studies. The serum insulin-like growth factor-1 levels significantly increased at 6 months (P less than 0.009) and 12 months (P less than 0.002) following rhGH treatment compared with baseline values. These preliminary data indicate that rhGH treatment may be effective in improving the growth velocity of growth-retarded renal allograft recipients.

Growth hormone treatment in the United States: demographic and diagnostic features of 2331 children.

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.

Effects of short term administration of recombinant human growth hormone to elderly people.

We evaluated the effects of recombinant human GH (rhGH) in 16 men and women more than 60 yr of age. After 10 days of dietary equilibration and control collections, subjects were randomly assigned to receive 0.03, 0.06, or 0.12 mg/kg rhGH by daily injection for 7 days. A brisk rise in circulating somatomedin-C (insulin-like growth factor-I) occurred in all subjects, and this rise was dose dependent. rhGH produced striking changes in nitrogen retention, sodium excretion, and the parathyroid-vitamin D axis. Twenty-four-hour urinary nitrogen excretion decreased from 8.00 +/- 0.33 to 5.01 +/- 0.33 g (P less than 0.001), and sodium excretion decreased from 45.9 +/- 2.96 to 21.2 +/- 3.48 mmol/day (P less than 0.001). Serum calcium concentrations did not change, but serum inorganic phosphorus levels of 1.08 +/- 0.04 mmol/L at baseline increased significantly after rhGH treatment to 1.33 +/- 0.04 mmol/L (P less than 0.001). Increases were also observed in circulating PTH (53.2 +/- 6 vs. 39.5 +/- 4.2 ng/L; P less than 0.01) and calcitriol (82.8 vs. 65.8 pmol/L; P less than 0.05). A rise in serum osteocalcin (10.3 +/- .86 vs. 8.0 +/- 0.5 micrograms/L; P less than 0.05) was accompanied by increased urinary excretion of hydroxyproline (628 +/- 63 vs. 406 +/- 44 mumol/day; P less than 0.01). Despite the reduction in sodium excretion, marked increases were observed in urinary calcium (6.04 +/- 0.97 vs. 3.27 +/- 0.40 mmol/day; P less than 0.01). rhGH significantly impaired oral glucose tolerance and reduced insulin sensitivity, but was otherwise well tolerated and produced no systematic changes in weight or blood pressure. The results of this study indicate that rhGH requires further study as a potential agent for attenuating or reversing the loss of muscle and bone in elderly people.

Recombinant human growth hormone (rhGH) treatment of children undergoing peritoneal dialysis.

The authors studied the effect of recombinant growth hormone (rhGH) treatment on 5 growth retarded children, age 2 2/12 to 17 8/12 years, who had end-stage renal disease (ESRD) and were undergoing continuous cycling peritoneal dialysis (CCPD). Patients received 0.125 mg/kg of subcutaneous rhGH 3 times weekly. Accelerated height velocity compared to the previous year of CCPD was noted in 2 patients and improvement in the standard deviation score (SDS) as a parameter of improved growth velocity was noted in a third patient. This was associated with an increase in weight and improvement in the midarm muscle circumference (MAMC) suggesting an anabolic effect of rhGH treatment. Bone age advancement was consistent with the period of observation; no advancement greater than that expected for the increase in chronological age was observed. No significant side effects were attributable to rhGH therapy. These preliminary results indicate some growth retarded children without growth hormone deficiency with ESRD undergoing CCPD may respond to exogenous rhGH therapy with an acceleration in growth velocity: However, the failure to achieve uniform acceleration of height velocity indicates the need for controlled studies before rhGH can be recommended for all growth retarded children with ESRD undergoing peritoneal dialysis.

Accelerated growth after recombinant human growth hormone treatment of children with chronic renal failure.

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.

Growth hormone testing in short children and their response to growth hormone therapy.

Because current concepts of growth hormone (GH) testing and GH treatment have become controversial, we investigated the GH secretory patterns in children with normal and short stature. Twenty-four-hour serum GH levels were evaluated in three groups of children. Group 1 was composed of children with normal height (mean height = 0.02 SD, n = 33); group 2 was composed of short children (less than 5th percentile, n = 63) with normal results on provocative GH testing; and group 3 was composed of short children (less than 5th percentile, n = 7) with subnormal results on provocative GH testing. Mean +/- SD (range) GH levels during 24-hour studies of GH secretion were 1.6 +/- 1.1 (0.5 to 5.6), 1.8 +/- 1.2 (0.6 to 6.3), and 0.9 +/- 0.4 (0.5 to 1.7) ng/ml in groups 1, 2, and 3, respectively. No statistical difference existed in mean GH levels between groups 1 and 2 or between groups 1 and 3. The mean GH concentration from 24-hour studies in group 2 children did not correlate with chronologic age, height standard deviation, growth rates, or insulin-like growth factor 1 levels. The linear growth rate of 26 of 28 children in group 2 who received GH therapy for 6 months improved by 2 cm/yr or more; the mean +/- SD growth rate was 4.0 +/- 1.3 and 8.8 +/- 2.0 cm/yr during control and treatment periods, respectively, for these 28 children. Mean GH levels from testing did not predict response to GH during 6 months of therapy. Children with slower growth rates responded better to GH therapy (p less than 0.05). We conclude that (1) in 24-hour studies, GH levels in normal children overlapped with those of short children, including those with classic GH deficiency, (2) in 24-hour studies, GH levels did not predict responses of linear growth to short-term GH treatment, nor did they correlate with children's heights or growth velocities, and (3) the majority of short children in group 2 treated with GH for 6 months had an increase in linear growth velocity, the mean +/- SD change being 4.8 +/- 2.0 cm/yr.

Variability in the quantitation of circulating growth hormone using commercial immunoassays.

The quantitation of human GH in a serum sample is not consistent among various commercially available immunoassays. We measured serum GH concentrations with four RIAs [Cambridge, Kallestad, National Hormone and Pituitary Program, and Radioassay Systems Laboratories (RSL)] and two immunoradiometric assays (IRMAs; Hybritech and Nichols). Serum GH concentrations measured by the RIAs were between 1.9 and 2.8 times higher than those determined by the Hybritech IRMA, whereas the concentrations measured by the Nichols IRMA were approximately 3.0 times higher than the Hybritech values. We evaluated the effects of differences in standards, assay diluents, and antibody specificity on GH measurement in the various assays. When GH standards from each of the assays were measured in the Hybritech IRMA, only the RSL standard was less immunoreactive than the other assay standards. Different assay diluents also resulted in varying GH values. In the RIAs, GH diluted in serum was more immunoreactive than GH diluted in phosphate-buffered saline-0.5% BSA. This enhanced immunoreactivity appeared to be due to a nonspecific effect generated by serum. The Nichols and Hybritech IRMAs provide standards diluted in horse serum. In the Nichols assay, GH diluted in human serum was more immunoreactive than GH diluted in horse serum, whereas the immunoreactivity of GH diluted in either serum was equal in the Hybritech IRMA. These IRMAs also differ in that the Nichols assay detected the 20K variant of GH, whereas the Hybritech assay did not. Considering these discrepancies, comparison of data obtained using different assays should be made carefully.

Absorption of recombinant human growth hormone (rhGH) following intraperitoneal instillation.

Recombinant human growth hormone (rhGH) was instilled intraperitoneally (i.p.) in six children undergoing continuous cycling peritoneal dialysis (CCPD). Immediate absorption was noted with either 0.250 mg/kg, 0.125 mg/kg, or 0.050 mg/kg of rhGH. Peak serum growth hormone (GH) levels occurred 4 and 8 h following i.p. administration, and the serum GH levels had returned to baseline values at 24 h. In one patient, a higher dosage demonstrated adequate absorption, whereas the lower dosage produced a flat absorption curve. These data indicate that daily i.p. administration of rhGH could be utilized in clinical trials directed toward improving the growth velocity of children undergoing CCPD.

The acute effects of human growth hormone administration on thyroid function in normal men.

GH replacement therapy may lead to alterations in serum TSH and/or thyroid hormone values in GH-deficient patients, but there is no consensus on the explanation for these changes. We examined the effect of GH administration (0.125 mg, sc, daily for 4 days) on thyroid function in 20 normal men. Serum T4 levels decreased by 8%, and serum free T4 index values decreased by 5%. In contrast, serum T3 levels increased by 21%; serum rT3 did not change. These changes were accompanied by a 54% decrease in the mean serum TSH level. While it is not possible to draw conclusions about hormone production and disposal rates from changes in serum levels, these data are most consistent with enhanced extrathyroidal (including intrapituitary) conversion of T4 to T3 and a compensatory decrease in TSH secretion.

Accelerated growth following treatment of children with chronic renal failure with recombinant human growth hormone (somatrem): a preliminary report.

Five male children with chronic renal failure (CRF) and growth retardation were treated with recombinant human GH (somatrem) three times weekly for 6 months. The patients ranged in age from 35 to 91 months and had a mean SD score for height of -3.03 +/- 1.0 at initiation of therapy. Their mean pretreatment height velocity was 4.94 +/- 1.40 cm/year for the year prior to somatrem treatment. Following 6 months of treatment all children had a significant increase in annual height velocity, with the mean annual value for the group being 10.08 +/- 1.97 cm/year (p less than 0.01). Glucose tolerance was monitored and was not significantly affected nor were there any other complications of note. These data indicate that somatrem can produce short-term accelerated height velocity in the child with growth retardation associated with CRF. The long-term benefits of therapy in this group of children is under investigation.

A National Cooperative Growth Study of Protropin.

Nearly 2000 hGH deficient patients have been enrolled in a study of Protropin and followed up for up to 1 year. This has provided valuable information on the character of this population and its response to therapy. Overall there was a predominance of males, with a disproportionate number of short mothers. The mean Protropin dose was 0.07 mg/kg, given three times/week. There was a significant dose-response relationship up to 0.125 mg/kg three times/week.

Prolactinoma and adrenal androgens.

Theories about the relationship between hyperprolactinemia and hyperandrogenism are conflicting. Several reports assert that prolactin affects the delta 5 and delta 4 pathways through its effect on the activity of 3beta-hydroxysteroid dehydrogenase (3beta-OHSD). We measured delta 5 and delta 4 steroids, prolactin and cortisol in 18 amenorrheic, hyperprolactinemic women before and after resection of prolactinomas. Similar determinations of delta 5: delta 4 steroids were made in a control group of five women. The ratios of individual delta 5: delta 4 steroids were also analyzed. Our results support a modification of delta 5, delta 4 pathways through an effect on the rate-limiting enzyme 3 beta-OHSD. In hyperprolactinemic women the differences between the preoperative and postoperative steroid levels were significant. Further, since the androgens decreased irrespective of the prolactin following surgery, there probably is a factor other than ACTH and prolactin modulating the adrenal androgens.

Long term follow-up of women with surgically treated prolactin-secreting pituitary tumors.

To examine the long term effectiveness of transsphenoidal microsurgery for patients with PRL-secreting pituitary tumors, we studied 54 women at yearly intervals after transsphenoidal surgery. Five years after surgery, 19 women (35%) had normal serum PRL concentrations, and 23 (43%) had persistent hyperprolactinemia. Hyperprolactinemia recurred in 12 of 31 patients (39%) who had normal PRL concentration 6 weeks after surgery. None of the patients with recurrent hyperprolactinemia had radiographic evidence of tumor regrowth, and only 3 of 12 had amenorrhea. A serum PRL level below 6 ng/ml 6 weeks after surgery occurred more frequently in cured patients than in those who had a recurrence. PRL responses to TRH were normal in cured patients 1 and 5 yr after surgery and abnormal in those who had recurrent hyperprolactinemia. The PRL responses to chlorpromazine- and insulin-induced hypoglycemia were blunted in patients with normal as well as elevated PRL levels. Patients with recurrent, as well as those with persistent, hyperprolactinemia had no nocturnal rise in serum PRL 5 yr after surgery. The 39% recurrence rate of hyperprolactinemia and persistent abnormalities in pituitary-hypothalamic regulation of PRL secretion after transsphenoidal surgery raise important questions about the choice of primary therapy for patients with PRL-secreting tumors.