Urinary Growth Hormone and Insulin-like Growth Factor I Effects of Growth-Hormone

Injection Schedule

Christine H. Albini, M.D., Ph.D.* Teresa Quattrin, M.D.* Barbara Mills, B.A., R.N.*

Barry Sherman, M.D.** Ann Johanson, M.D.** *

Margaret H. MacGillivray, M.D.

Summary: Urinary growth hormone (GH) and insulin-like growth factor I (IGF-1) excretion profiles were compared in children receiving biosynthetic GH. Group 1 included 18 healthy controls. Group 2 included nine children given biosynthetic GH three times a week. Group 3 included 14 children given daily GH injections. Overnight urine samples were collected for three consecutive nights in all groups. No significant day-to-day variation in urinary GH output was observed in group 1. In group 2, urinary GH output was significantly higher on day one following injection than on days two and three. Urine GH outputs in group 2 were significantly lower on days two and three than the values observed on all days in group 3. Throughout the three-day study, subjects in group 3 excreted similar amounts of GH significantly higher than those of controls. Urinary IGF-I output (nmol/kg) was similar on all three study days in groups 1 and 3. Group 2 had significantly lower urinary IGF-I output on day three compared with day one. Urinary IGF-I output on day three was also significantly lower in group 2 than in group 3. We conclude that urinary GH and IGF-I outputs are influenced by the frequency of GH administration. Introduction or



human GH administered three times weekly. A regimen based on

decades, the

growth-hormone conventional

ciency *


of defi(GH) consisted of injections of treatment

daily subcutaneous injections equaling the same weekly dose has been recently shown to yield growth rates which are significantly greater than

Department of Pediatrics, Children’s Hospital of Buffalo, and School of Medicine, State University of New York at Buffalo Genentech Inc., South San Francisco, California Address correspondence to: Christine H. Albini, M.D., Ph.D., Children’s 219 Bryant Street, Buffalo, NY 14222


Hospital of Buffalo,

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those observed with


therapy.’-4 However, the plasma concentrations of insulin-like growth facter I (IGF-I) in the children rehave not ceiving daily GH injections differed significantly5 We previously reported that measurements of urinary GH and IGF-I provide quantitative information about the excretion of these hormones in infants and children with normal and abnormal

Table I

3 included 14 subjects with GH deficiency and two


~il rp-,- ~i ~1 1 - ~ -

(12 with

idiopathic growth failure) already being treated with daily subcutaneous injections of biosynthetic GH (0.3 mg/kg/week) . In our trial, the injections were given at 8 p.m. on three consecutive nights, which cowho


We also have shown that urinary GH and IGF-I levels correlate positively; that urinary IGF-I is GH-dependent; that both measured peptides are authentic, based on high-performance liquid chromatography characterization ; and that urinary GH reflects endogenous GH secretion.9 The purpose of this study was to determine whether two different GH treatment regimens gave differing outputs of urinary GH and IGF-I output in a population of children with severe growth failure. To accomplish this goal, we quantitated the urinary excretion of GH and IGF-I in one group of children receiving biosynthetic GH administered daily and in another group receiving the same total amount of GH but three times weekly and then compared the data to the output of these peptides in healthy children.

growth. 6-8

teered to collect 12-hour


night urines on three consecutive nights (8 p.m. to 8 a.m.). All were growing between the fifth to 95th percentile for height, and none had constitutional growth delay. Subjects in groups 2 and 3 included 23 children who at the onset of GH treatment were > -2 SD below the mean for height and whose growth rates were < 5 cm/year. Seventeen were GH-deficient, based on a peak GH response of < 10 ng/mL measured on polyclonal antibody radioimmunoassay after two or more stimulation tests (insulin-induced

hypoglycemia, L-arginine infusion,


L-dopa). Six had idiopathic growth failure, based on pretreatment GH responses > 10 ng/mL to provocative stimuli. Group 2 comprised nine children (five with GH deficiency and four with idiopathic growth failure) who were already receiving biosynthetic GH by subcutaneous injection three times daily. In our

Forty-one children who were known to be responsible and consistently compliant were recruited to participate in this study after their parents gave written informed consent. Age, sex, and pubertal status of the study participants are shown in Table 1. The subjects were divided into the following three groups: Group 1 included 18 healthy children who volun-

trial, four children were treated with 0.15 mg/kg/week, and five were treated with 0.3 mg/kg/week, all divided t.i. w Because urinary GH and IGF-I levels were similar in both dosage regimens, the data were combined. The injections were given at 8 p.m. on day one and 12hour overnight urines were collected, starting at 8 p.m., for three consecutive nights. No GH injections were given on day two or day three.



incided with the start of the overnight 12-hour urine collections. There was no significant difference in the mean duration of treatment among children in group 2 vs group 3 (1.5 vs 1.9 years).

Methods Twelve-hour

urine 8 a.m.) were specimens (8 p.m. collected in a plastic container and kept at 4°C throughout the collection period. A 50-cc aliquot of urine was cen-

overnight to

trifuged to remove particulate matand subsequently dialyzed, lyophilized, and reconstituted in 1 mL 0.04 M phosphate buffer containing ter

0.5% serum albumin (Albuminar~5, Pharmaceuticals Co., Kankakee, IL) and 0.9% sodium


chloride (as previously described) .6-9 Urine GH was measured in duplicate by a standard double-antibody radioimmunoassay method using a polyclonal GH antibody and GH standards obtained from the National Hormone and Pituitary Program. 10,1 The intra-assay and interassay coefficients of variation for GH were 2.1 % and 4.0%, respectively. The IGF-I in urine concentrates was quantitated in duplicate by radioimmunoassay (Nichols Institute Diagnostics, San Juan Capistrano, California). The intra- and interassay coefficients of variation were 5.7% and 8.6%, respectively. Previous studies have shown that serial dilutions of urine concentrates demonstrate direct proportionality between concentration and dilu-

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tion for both GH and IGF-L~’ Urinary GH and IGF-I outputs were standardized by body weight and per gram of creatinine. Since the sample size was small and a normal distribution of data was not expected, the nonparametric Mann-Whitney test was used to analyze the data.

GH based on body weight did not vary significantly during the three days (0.27 ± 0.03, 0.27 ± 0.03, and 0.26 ± 0.03 pg/kg) . Prior to starting GH treatment, children in groups 2 and 3 had low outputs of urinary GH (0.13 ± 0.03 and 0.14 ± 0.01 mg/kg, respectively) as well as low excretion of urinary IGF (0.06 ± 0.01 and 0.07 ± 0.01 nmol/kg, respectively. In contrast, the mean outputs of GH and IGF-I in the healthy subjects were 0.27 ± 0.03


Results GH output (mean ± for the three study groups, SEM) standardized for body weight ( pg /kg) and urine creatinine (~Lg/mol creatinine), for the three consecutive nights is shown in Table 2. In group 1 (healthy children) the output of


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pg/kgand 0.16 nmol/kg, respectively. Children receiving GH injections t.i.w. (group 2) had significantly higher urinary GH values per kg body weight (pg/kg) on day one postinjection (0.78 ± 0.11 ) compared with days

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Urinary growth hormone and insulin-like growth factor I. Effects of growth-hormone injection schedule.

Urinary growth hormone (GH) and insulin-like growth factor I (IGF-I) excretion profiles were compared in children receiving biosynthetic GH. Group 1 i...
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