Biomedical subjects
R Stanhope
Publications and source records attributed to R Stanhope.
Hazards of tests of growth hormone secretion.
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Hazards of pharmacological tests of growth hormone secretion in childhood.
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Is testosterone therapy for boys with constitutional delay of growth and puberty associated with impaired final height and suppression of the hypothalamo-pituitary-gonadal axis?
We report the treatment of 44 boys with constitutional delay of growth and puberty (CDGP) at a mean chronological age of 14.3 years (range, 12.4-17.1) and bone age of 12.1 years (range, 9.1-15.0). All were below the 3rd height percentile for chronological age. They received monthly intramuscular injections of depot testosterone esters (50 mg) for a mean period of 0.35 years (range, 0.25-0.5). Means (SD) height velocity was 4.5 (1.5) cm/year during a pretreatment period of 0.5 years. During a period of 0.9 years which included the period of treatment with depot testosterone, mean growth velocity increased to 8.8 (1.9) cm/year (P less than 0.001). In the initial 1.8 years following the cessation of treatment growth velocity was sustained at 7.0 (1.7) cm/year. Pretreatment height standard deviation score (SDS) for bone age was -0.89 and this gradually reduced over the next 1.5 years to a minimum of -1.48. Thereafter, height SDS for bone age gradually increased to attain a value of -1.2, 3 years after the commencement of therapy (P less than 0.02). The same pattern of an initial decrease, followed by an increase, in height prediction was also observed when TW2 height prediction was analysed. Sexual maturation progressed during treatment, with mean testicular volume increasing both during and after treatment, confirming the diagnosis of CDGP. The time interval for progress through puberty was shorter in boys with testosterone therapy than in the normal population. The mean duration of puberty was 2.2 years compared to 3.3 years in normal boys. We conclude that low-dose depot testosterone treatment is safe and effective for boys with CDGP.(ABSTRACT TRUNCATED AT 250 WORDS)
Growth hormone deficiency throughout puberty.
Growth during puberty does not appear to be the major determinate of final height in isolated GH deficient patients. Early diagnosis and commencement of therapy are probably the most important factors, as reflected by the correlation between final height and height at the onset of puberty. The cost effectiveness of increasing the dose of GH during puberty does not appear to represent any advantage from the data presently available. Indeed, such an approach may have a deleterious effect on final height by shortening the duration of pubertal maturation. Further prospective studies are required to demonstrate the effectiveness of manipulating the onset and duration of puberty using gonadotrophin releasing hormone analogues on final height in isolated GH deficiency.
Optimum method for administration of biosynthetic human growth hormone: a randomised crossover trial of an Auto Injector and a pen injection system.
The use of optimum conventional growth hormone administration, using a growth hormone vial combined with an Auto Injector, was compared with a pen injection system using a cartridge of growth hormone. In both methods of administration the concentration of growth hormone was 16 IU/ml. Thirty patients (22 boys, eight girls) who had all previously been treated with growth hormone (4 IU/ml) administered using needles and syringes (without an Auto Injector) were randomised into receiving one of either treatment for three months and then crossed over for a further three months. Fourteen patients (10 boys, four girls) initially received KabiVial 16 IU/ml combined with an Auto Injector while 16 patients (12 boys, four girls) were treated with KabiPen 16 IU/ml. Mean age in both groups was 9.6 years. The majority of patients in both groups were treated with a regimen of either 15 or 20 units/m2/week as a daily subcutaneous injection. Of the 30 patients who started in this trial, two who commenced using an Auto Injector refused to change to a pen system and were excluded from further analysis. When scored on a scale of -5 to +5 general convenience when changing from an Auto Injector to the KabiPen decreased from +4.7 to +1.0. When assessed for pain, the Auto Injector group scored +4.7, which decreased to -0.2 (more painful) for the pen. At the end of the trial 23 patients (82%) chose to continue with the KabiVial/Auto Injector combination as they found this less painful and the child did not see the needle or need to insert the needle manually. Five patients (18%) continued with the KabiPen as they considered the device smaller and easier to use. The accuracy of dosing using KabiVial was 100% compared with the range of 88% to 111% using KabiPen as the latter was available only in 0.5 unit increments. No growth hormone was wasted using KabiVial, although a mean of 0.6 units was wasted with every 16 IU cartridge in the KabiPen system. It is concluded that patients should be able to contribute to the choice of growth hormone delivery systems and that newer methods need careful assessment.
The effects of growth hormone therapy on spontaneous sexual development.
We have carried out a prospective randomised study in 52 (46 male, 6 female) children with isolated growth hormone (GH) deficiency treated with a GH regimen of 15 IU/m2/week administered as a daily subcutaneous injection. At the onset of the pubertal growth spurt, the patients were randomised to receive either an unaltered regimen (26 males, 1 female) or 30 IU/m2/week (20 males, 5 females). There was no change in the frequency of GH administration. The number of females in this study was too small to give a meaningful result. In contrast, the boys treated with either dose regimen showed no significant alteration in growth rate, but there was a faster than normal progression in pubertal maturation. It is concluded that the optimum final height of children with isolated GH deficiency may not be achieved in patients without the therapeutic manipulation of the onset and/or duration of puberty. 16 short normal children (9 males, 7 females) were treated with GH in a regimen of 25 IU/m2/week (range: 20-30) as a daily subcutaneous injection. The mean age for the onset of GH treatment was 11.5 and 11.0 years in the boys and girls, respectively. Our data suggest that both boys and girls had a more rapid rate of pubertal maturation than normal. It may be that in terms of final height prognosis, the events of puberty related to GH treatment counterbalance the improvement in growth prognosis during prepuberty.
"Catch-up" growth in steroid dependent dermatomyositis treated with cyclosporin-A.
OBJECTIVE: To improve the short-term growth, and hopefully final height attainment, of children with dermatomyositis treated with chronic daily corticosteroid regimens. METHODS: We have examined the growth of nine pre-pubertal children (7F, 2M), mean age 8.9 (range, 5.7-12.3) years, who had severe juvenile dermatomyositis and required persistent corticosteroid therapy. All were treated with cyclosporin-A. RESULTS: During a mean period of 1.3 years (range 1.0-1.7) cyclosporin-A treatment was associated with a marked decrease in the dosage of prednisolone, from a mean of 12.4 to 6.6 mg/day (p < 0.02), and an increase in height velocity standard deviation score from a mean of -1.37 to +1.39 at 6 months (p < 0.02) and -0.33 at one year. During the first year of treatment with cyclosporin-A, seven patients were able to either withdraw or reduce their prednisolone dose. No side effects of treatment were observed. CONCLUSIONS: Cyclosporin-A was a useful treatment modality in juvenile dermatomyositis and allowed a decreased dose of corticosteroids and associated "catch-up" growth.
Adjuvant whole abdominopelvic irradiation for high risk endometrial carcinoma.
Fifty-six patients with surgical Stage III or IV endometrial carcinoma, or earlier stage disease with two or more risk factors for peritoneal recurrence, were given postoperative whole abdomino-pelvic irradiation (WAPI) with nodal and vaginal boosts between November 1981 and May 1989. Mean age at diagnosis was 63 years. Twenty-seven patients were surgical Stage I-II, 17 Stage III, and 12 Stage IV. Thirty-seven (66%) had deep myometrial involvement, 34 (61%) had positive peritoneal cytology, 31 (55%) had high grade lesions, 20 (36%) had either serous-papillary or adenosquamous histologic variants, and 13 (23%) had up to 2 cm residual disease remaining after surgery. Mean overall follow-up was 45 months. The 7-year actuarial survival was 63.8% with a 7-year disease-free survival (DFS) of 60.9%. By surgical stage, the 7-year DSF was 77.1% for Stage I-II, 57.8% for Stage III, and 25.0% for Stage IV (p = 0.006). The 7-year DSF was 79.8% for those with lesions of Broder's grade 1 or 2, and 46.9% for grades 3 or 4 (p = 0.001). Multivariate analysis demonstrated that of all covariates considered, only surgical stage and histologic grade had prognostic significance for survival and disease-free survival. Acute toxicity has been common but mild; chronic toxicity has been almost entirely subclinical with the exception of three cases of moderate to severe bowel toxicity. These results suggest that post-operative WAPI is a safe and efficacious treatment alternative for patients with surgical Stage I through III high-risk endometrial carcinoma.
Pulsatile growth hormone secretion in peripubertal patients with chronic renal failure. Cooperative Study Group on Pubertal Development in Chronic Renal Failure.
The pubertal growth spurt has been associated with changes of physiologic pulsatile growth hormone (GH) secretion, and abnormalities of the central regulation of GH release have been found by pharmacologic testing in patients with chronic renal failure. To assess the characteristics of GH pulsatility in chronic renal failure and their relationship to pubertal growth, we studied spontaneous nighttime GH plasma profiles in 80 patients (61 boys) aged 10 to 20 years receiving conservative treatment (n = 29) or dialysis (n = 18) or after renal transplantation (n = 33). Tanner genital stages 1 to 4 in boys and breast stages 1 to 3 in girls were represented. Growth hormone pulse analysis was performed by the PULSAR algorithm. Growth hormone concentration profiles were pulsatile in each patient. Growth hormone mean and baseline levels and pulse amplitudes were higher in patients receiving conservative or dialysis treatment than in patients who had undergone renal transplantation. Peak frequency was similar in all treatment groups in boys but higher in girls who had undergone transplantation than in girls receiving conservative or dialysis treatment. Growth hormone peak amplitude and mean levels were lowest in patients in late puberty. The physiologic elevation of GH amplitudes around midpuberty was observed in boys receiving conservative and dialysis treatment but not after transplantation. Growth hormone mean and baseline levels were positively correlated with plasma androgen levels in boys. Growth hormone peak amplitude was correlated with 6-month height velocity after transplantation but not in patients receiving conservative treatment or dialysis. A strong inverse relationship was observed between GH peak amplitude and corticosteroid dosage in patients undergoing transplantation. The lack of relationship between circulating GH levels and growth in patients receiving conservative or dialysis treatment is compatible with end-organ hyporesponsiveness to GH. Pubertal growth failure despite successful transplantation appears to be related to steroid-induced GH hyposecretion.
Management of growth hormone deficiency through puberty.
As a model of the growth hormone (GH) dependence of growth in prepuberty and puberty, the growth of 182 children (93 boys, 89 girls) who survived in first remission for treatment of acute lymphoblastic leukaemia was examined. Chemotherapy regimens, including intrathecal methotrexate, were similar in all patients, but CNS treatment differed, in that one group received 2400 cGy cranial irradiation, while the other received 1800 cGy. There was a significant decrease in height SDS during prepuberty, which was equivalent in both sexes, whereas there was a much greater decrease in pubertal growth in girls than in boys. Girls treated with the lower dose regimen of cranial irradiation had their onset of pubertal maturation significantly advanced, to a mean of 9.9 years (p less than 0.001). Previous studies have indicated that the duration of puberty is shortened by GH treatment in patients with idiopathic multiple pituitary hormone deficiency or isolated GH deficiency (GHD). To determine whether an increase in the dose of GH administered during the adolescent growth spurt would improve final height, a prospective randomized trial was performed in 32 children (25 boys, 7 girls) with isolated GHD treated with a GH dose regimen of 15 IU/m2/week as daily s.c. injections. At the onset of the pubertal growth spurt, the patients were randomized either to an unchanged dose or to 30 IU/m2/week. There was no significant change in height velocity with the doubled dose of GH, but there was a trend in the advancement of pubertal maturation which was considered to be dose related. It is suggested that these findings are of relevance to the treatment of GHD in puberty, especially in girls with early or precocious puberty occurring as a consequence of low-dose cranial irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)
Does growth hormone treatment improve final height attainment of children with intrauterine growth retardation?
Twenty four children (five girls, 19 boys) who had intrauterine growth retardation were treated with daily subcutaneous biosynthetic human growth hormone, initially in a dose of either 15 or 30 U/m2/week for the first year and in the latter dose for the next two years. Six patients (one girl, five boys) had no dysmorphic signs and 18 (four girls, 14 boys) had signs of Russel-Silver syndrome. All had birth weights below the third centile when adjusted for gestation age and all the children were below the third height centile at the start of treatment. Mean age was 6.3 years (range 2.1-9.7) when growth hormone treatment was started. All had normal growth hormone secretion to either a pharmacological or physiological test. In the first year of treatment, height velocity SD score increased from -0.75 to +3.6 in the group treated with 30 U/m2/week, and from -0.77 to +1.4 in the lower dose group. After three years of treatment, mean height velocity SD score was +1.1, irrespective of which initial treatment dose had been administered during the first year. There was no difference in the growth response of children with or without dysmorphic features. However, despite the sustained increase in growth rate, there was no significant change in height for bone age SD score, pointing to an unaltered final height outcome.
Impaired pubertal growth in acute lymphoblastic leukaemia.
The growth of 182 patients who were long term survivors of childhood acute lymphoblastic leukaemia was retrospectively analysed. All remained in first remission and were treated with either 1800 or 2400 cGy of cranial irradiation. None had been treated with either testicular or spinal irradiation. Ninety three (51 boys, 42 girls) were treated with 2400 cGy and 89 (42 boys, 47 girls) were treated with 1800 cGy cranial irradiation. All patients were treated with standard chemotherapy including intrathecal methotrexate in similar dose regimens in either group. Mean age (SD) at diagnosis in the group treated with 2400 cGy was 4.8 (2.6) years and mean age in the group treated with 1800 cGy was 6.5 (3.3) years. Mean height SD score at diagnosis in the 2400 cGy group was +0.29 and final height achieved was -0.63. Mean height SD score at the start of treatment in the group treated with 1800 cGy was +0.40 and mean final height was -0.53. There was a similar reduction in height SD score in both groups during the pubertal growth spurt. The decrement in height SD score was greater when treatment was administered at less than 7 years of age in either dose regimen, both in prepubertal and pubertal growth. However, the decrease in height SD score was found to be greater in girls than boys. There was a trend in both sexes for the onset of puberty to be at a younger age with a lower treatment dose of radiotherapy. However, in girls treated with the lower dose regimen there was a significant reduction in the mean age of onset of puberty which was 9.9 years. Our data suggest that girls treated at less than 7 years of age have a severe impairment of pubertal growth, which is probably a combination of the dual endocrinopathy of premature puberty and growth hormone insufficiency.
Evaluation of a pen injector system for growth hormone treatment.
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Growth hormone treatment of growth failure secondary to total body irradiation and bone marrow transplantation.
Growth hormone was given to 13 children (nine boys, four girls) with acute leukaemia who had undergone treatment with cyclophosphamide and total body irradiation before bone marrow transplantation. Mean age at total body irradiation and bone marrow transplantation was 9.0 years (range 3.7-15.8). Endocrinological investigation was carried out at a mean of 2.0 years (range 0.4-4.0) after bone marrow transplantation. Peak serum growth hormone responses to hypoglycaemia were less than 10.0 micrograms/l (less than 20.0 mU/l) in 10, 10.5 micrograms/l (21.0 mU/l) in one, greater than 16.0 micrograms/l (greater than 32.0 mU/l) in two patients. Mean age of the patients at the start of growth hormone treatment was 12.2 years (range 5.8-18.2). The mean time between total body irradiation and bone marrow transplantation and the start of growth hormone treatment was 3.2 years (range, 1.1-5.0). Height velocity SD score (SD) increased from a mean pretreatment value of -1.27 (0.65) to + 0.22 (0.81) in the first year, +0.16 (1.11) in the second year, and +0.42 (0.71) in the third year of treatment. Height SD score (SD) changed only slightly from -1.52 (0.42) to -1.50 (0.47) in the first year, to -1.50 (0.46) in the second year, and -1.74 (0.92) in the third year. Measurement of segmental proportions showed no significant increase in subischial leg length from -0.87 (0.67) to -0.63 (0.65) in the first year, to -0.58 (0.70) in the second year, and -0.80 (1.14) in the third year of treatment. Our data indicate that children who have undergone total body irradiation and bone marrow transplantation respond to treatment with growth hormone in either of two dose regimens, with an increase in height velocity that is adequate to restore a normal growth rate but not to 'catch up', and that total body irradiation impairs not only spinal but also leg growth, possibly by a direct effect of irradiation on the epiphyses and soft tissues.
Growth prognosis and growth after menarche in primary hypothyroidism.
The long term growth of 20 girls and nine boys with juvenile primary hypothyroidism was studied until they reached final height. At diagnosis the girls had a mean age of 8.8 years (range 3.0-13.0); mean bone age was 5.4 years. The mean age of the boys at diagnosis was 9.5 years (range 3.7-14.2); mean bone age was 6.3 years. The patients were treated with thyroxine 100 micrograms/m2/day and serum thyroxine concentrations were maintained in the normal range. During treatment the rate of skeletal maturation exceeded the change in chronological age. Initial mean height SD score for bone age before treatment in the girls was +0.59 and after 11 years of treatment fell to -0.55 Mean height SD score for bone age in the boys decreased from +1.6 to -0.87 during treatment. In the girls the onset of puberty was 1.2 years later than the normal population but the duration of puberty was reduced. Mean age (SD) of menarche was 13.8 (1.7) years. The pattern of growth in girls with treated hypothyroidism was abnormal as growth continued after menarche, at a time when normal girls have almost stopped growing. During the second year after menarche our patients still had a mean growth velocity of 4.1 cm/year. Our data suggest that juvenile primary hypothyroidism results in a permanent height deficit. In addition, there is a loss of the normal harmony between growth and sexual maturation in girls, despite adequate treatment, in that growth continues for much longer after menarche than in normal girls.
Treatment of constitutional growth delay in prepubertal boys with a prolonged course of low dose oxandrolone.
Forty six prepubertal boys who had constitutional growth delay were treated with oxandrolone. Mean age at the onset of treatment was 11.9 years (range 9.0-14.0) and bone age delay was 1.9 'years'. The dose of oxandrolone used was a mean of 0.05 mg/kg (range 0.03-0.18) for a mean of 0.9 years (range 0.2-3.6). Height velocity increased from a mean (SD) before treatment of 4.0 (1.0) to 7.5 (1.2) cm/year with oxandrolone. Growth rate was sustained at 7.6 (2.2) cm/year in the period after treatment. Those boys who attained a testicular volume of 4 ml or greater at the end of the treatment period had the most pronounced sustained growth acceleration. Height for bone age SD score did not alter significantly from a mean of -1.0 before treatment to -1.2 after treatment. Oxandrolone is a safe and effective treatment for prepubertal boys with constitutional growth delay.
Long-term outcome of oxandrolone treatment in boys with constitutional delay of growth and puberty.
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