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Growth Hormone Releasing Hormone Or Growth Hormone Treatment in Growth Hormone Insufficiency?

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Growth Hormone Releasing Hormone Or Growth Hormone Treatment in Growth Hormone Insufficiency? Arch Dis Child: first published as 10.1136/adc.63.6.629 on 1 June 1988. Downloaded from Archives of Disease in Childhood, 1988, 63, 629-634 Growth hormone releasing hormone or growth hormone treatment in growth hormone insufficiency? P J SMITH AND C G D BROOK Endocrine Unit, Middlesex Hospital, London SUMMARY Sixteen prepubertal children who were insufficient for growth hormone were treated with growth hormone releasing hormone (GHRH) 1-40 and GHRH 1-29 for a mean time of nine months (range 6-12 months) with each peptide. Eleven children received GHRH 1-40 in four subcutaneous nocturnal pulses (dose 4-8 [sg/kg/day) and eight (three of whom were also treated with GHRH 1-40) received GHRH 1-29 twice daily (dose 8-16 [ig/kg/day). Altogether 73% of the children receiving GHRH 1-40 and 63% receiving GHRH 1-29 showed a growth response. Double the daily dose of GHRH 1-29 was required to obtain equivalent growth response to pulsatile GHRH 1-40. A significant linear correlation was shown between growth hormone secretion and height velocity on GHRH 1-40 but not on GHRH 1-29 and there was a significant correlation between plasma GHRH and serum growth hormone concentrations during GHRH 1-40 administration. copyright. Response to conventional growth hormone treatment in a matched group of children was significantly better than the response after GHRH. A significant improvement in height velocity was observed in the children transferred to growth hormone replacement. Growth hormone remains the treatment of choice in growth hormone insufficiency. GHRH treatment may be of benefit in children with less severe growth hormone insufficiency in the presence of pulsatile endogenous growth hormone secretion. http://adc.bmj.com/ Growth hormone secretion is controlled by inhibi- with bone ages of less than 10 years were recruited tory somatostatin and stimulatory growth hormone to the study between January 1985 and July 1986. releasing hormone (GHRH). 1-3 In subjects with The pretreatment clinical details are summarised in growth hormone sufficiency or insufficiency in- table 1. Auxological observation over a period of travenous GHRH results in growth hormone release one year had shown a low growth velocity, and from the pituitary.6 Preliminary reports indicate on September 26, 2021 by guest. Protected that GHRH may have a therapeutic role in the Table 1 Pretreatment clinical data treatment of children who are growth hormone (n=16) insufficient.7-9 Evaluation of different treatment Mean (SD) Range regimens, however, has been limited. The aims of this study were to investigate the relation between Age (years) 8-5 (2-2) 4-9 to 11-9 GHRH Bone age (TW2) 5-9 (2-1) 2-5 to 8-8 administration and growth hormone secre- Height SDS -2-4 (1-0) -4-8 to -06 tion and the therapeutic effects of alternative modes Height velocity (cm/year) 3-8 (0-9) 1-7 to 5-7 of administration and dose regimens of GHRH in Height velocity SDS -2-2 (0-8) -4-1 to -0-9 children with growth hormone insufficiency and to Maximum growth hormone concentration (on insulin compare the linear growth response with conven- tolerance test) (mU/i) 6-5 (5-3) 1-9 to 17-0 tional growth hormone replacement. Maximum growth hormone concentration (during Patients and methods sleep) (mU/l) 9 3 (5.7) 4-0 to 26-0 Sum % of 24 hour growth hormone Sixteen prepubertal children (11 boys, five girls) pulse amplitude (mU/1) 27-0 (24-0) 4-0 to 93-0 629 Arch Dis Child: first published as 10.1136/adc.63.6.629 on 1 June 1988. Downloaded from 630 Smith and Brook hypothalamo pituitary assessment, using insulin of the study period. The remaining five children induced hypoglycaemia with thyrotrophin releasing received the higher dose regimen throughout the hormone and luteinising hormone releasing hor- GHRH 1-40 study period. mone stimulation, confirmed isolated growth hor- Eight children received GHRH 1-29 (KabiVit- mone insufficiency in 10 children and multiple rum) subcutaneously into anterior abdominal wall in pituitary hormone deficiencies in six children. The an initial dose of 4 ig/kg/dose (8 rig/kg/day) twice children with multiple pituitary hormone deficien- daily for three months followed by a dose of 8 cies received appropriate hormonal replacement Rg/kg/dose (16 [igIkg/day) for the remaining treat- before GHRH, and pituitary hypoplasia was shown ment period. Three GHRH 1-40 'responders' were in all cases by high resolution computed tomography transferred directly to GHRH 1-29. The mean (GE 8800). One child had been treated with human treatment duration on both GHRH peptides was growth hormone for four years but stopped treat- nine months (range 6-12 months). ment three months before starting GHRH. The On completion of the GHRH study each child was remaining children had received no treatment for transferred to somatrem (Somatonorm, KabiVit- growth hormone insufficiency. rum) in a dose of 2 IU growth hormone sub- The studies were approved by the Middlesex cutaneously six times a week. The growth results Hospital Clinical Investigation Committee, the De- (age, bone age, height SDS, height bone age SDS, partment of Health and Social Security, and USA and height velocity SDS) on GHRH were compared Food and Drugs Administration. Written parental with a matched group of naive idiopathic insufficient consent was obtained. children who received somatrem from January 1986 Before starting GHRH a 24 hour endogenous in an identical regimen. growth hormone profile was obtained from each child by withdrawing blood samples (1 ml) every 20 GROWTH HORMONE ASSAY minutes. Serum growth hormone profiles were also Serum growth hormone concentration was assayed obtained throughout the study during each treat- using a Tandem R human growth hormone im- ment regimen. An intravenous GHRH study (1 munoradiometric assay kit (Hybritech) with the copyright. [tg/kg) was performed before GHRH treatment and standards calibrated against the National Institute of in 11 children at intervals of three months through- Health human growth hormone reference prepara- out the study (blood samples taken at -20, -10, tin HS 2243E. The mean intra-assay coefficient of 0, 2, 5, 10, 20, 30, and at 15 minute intervals up to variation was 6-3% at 4-9 mU/l with an interassay 120 minutes). coefficient of variation of 9-6%. All samples from During the GHRH 1-40 regimen profiles for the same sampling period were stored at -20C and plasma immunoreactive GHRH concentrations assayed together. http://adc.bmj.com/ were obtained on each dose schedule in six children in conjunction with serum growth hormone estima- GHRH 1-40 ASSAY tions. Plasma immunoreactive GHRH was assayed by Anthropometric measurements were made every radioimmunoassay using a specific rabbit GHRH three months by the same observer using standard 1-40 antiserum (NIBSC code No 84/591) as pre- techniques, and bone age assessment was performed viously described.'3 Sensitivity of the assay was at the beginning of the study and after any change in 10-20 pg/ml and at a dilution of 1 in 300 000 the on September 26, 2021 by guest. Protected treatment."' 1 The measurements obtained were antiserum bound 30-40% of freshly labelled described as raw height velocity (cm/year) when GHRH. Intra-assay and interassay coefficients of assessing the short term (three month) results or as variation were 6-5% and 9% respectively at a the standard deviation score (SDS) when assessing concentration of 400 pg/ml. the overall results. 12 STATISTICS GHRH TREATMENT Analysis of variance was used to compare the The first 11 children received GHRH 1-40 (supplied pretreatment characteristics of children receiving by Professor MO Thorner) by nocturnal pulsatile GHRH and growth hormone. Analysis of variance, infusion every three hours for four pulses per night. multiple regression analysis, and Mann-Whitney U A minipump (Zyklomat, Ferring) delivered each test were used to analyse the response to treatment. pulse over one minute via a 27 gauge infusion needle inserted subcutaneously into the anterior abdominal Results wall. A dose of 1 [tg/kg/pulse (4 rig/kg/day) was given for the first three months in six children Both regimens were well tolerated with only one followed by 2 ktg/kg/pulse (8 rig/kg/day) for the rest child experiencing slight stinging at the injection site Arch Dis Child: first published as 10.1136/adc.63.6.629 on 1 June 1988. Downloaded from Treatment of growth hormone insufficiency 631 X,\ _ vwmnl response to GHRH 1-40. In one child a diminishing growth hormone response with time was observed in association with a falling growth rate. In another child GHRH administration resulted in a high 4,R 60 frequency growth hormone response which was a 0 Ec 20 0 IZ 169 Pretreatment 40 5'L 0~ oL E 20 2 2 2 2 (I) 50 i i u --A 40 Time (minutes) onths Fig 1 95% Confidence limits after I pglkg GHRH 1-40 30 given intravenously in growth hormone insufficient children M and normal (adult) subjects { :D 20 E (GHRH 1-29). Most of the children in each group -. undertook their own injections under parental 0 10 supervision (GHRH 1-40, nine children; GHRH E F copyright. 1-29, six children). 0 All children responded to intravenous GHRH _c -C 0 (mean 31 mU/l; range 5.7-107) (fig 1). The response 2 2 2 2 0 30 i + + i to intravenous GHRH was highly variable both to between and within subjects throughout the study :3 6 months and there was no correlation with the growth CJ) 20 response observed.6 The 95% confidence limits of the growth hormone response to GHRH in normal http://adc.bmj.com/ adults and the study children is shown in fig 1.
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