Elevation of serum creatine phosphokinase during growth hormone treatment in patients with multiple pituitary hormone deficiency

Serum creatine phosphokinase (s-CPK) increased to more than 500 U/l in 5 out of 21 patients with growth hormone (GH) deficiency during the 2 years of treatment with biosynthetic GH. In three of these five patients, s-CPK had elevated gradually after the start of GH treatment and remained high in one patient except in the period when GH injection was interrupted, and gradually decreased in the other two patients during treatment. These three patients had complete GH deficiency associated with multiple pituitary hormone deficiency due to pituitary stalk transection. One of the remaining two patients had Noonan syndrome and his s-CPK levels before therapy were relatively high. The fifth patient was a baseball athlete and the elevation of s-CPK seemed to be attributable to the strenous exercise.Conclusion s-CPK increases significantly in a certain group of patients with GH deficiency during GH replacement therapy. Measurement of s-CPK is to be included in the follow up laboratory tests at least in the 1st treatment year to evaluate the potential hazardous effects of GH on muscle.     

Malignant thymoma in a patient with growth hormone deficiency during growth hormone therapy

Malignant thymoma was found in an 8-year-old Japanese boy with growth hormone (GH) deficiency who had received GH therapy for 3 years and 5 months. There may be a possible relationship between the occurrence of malignant thymoma and GH therapy.     

Acute Lymphoblastic Leukemia in a Patient with Pituitary Dwarfism under Treatment with Growth Hormone

An 18-year-old male with pituitary dwarfism, who had been on replacement of growth hormone (GH) and thyroxine for 3.5 years, developed acute lymphoblastic leukemia (ALL). The GH replacement was discontinued, and he was treated with a conventional protocol for ALL. A complete remission was obtained after 10 weeks. Maintenance chemotherapy was given with reduced doses (1/4 to 1/2) of cytotoxic drugs. The platelet count soon reached 200,000/μL, but the hemoglobin level and white blood cell count improved only slowly, reaching 10.0 g/dL and 1,500/μL, respectively, after five months. He has been in complete remission with a hypocellular bone marrow for nearly 15 months. Since GH can stimulate the proliferation of some normal and leukemic hemato-lymphoid cells, the slow remission induction and the prolonged anemia and leukocytopenia after remission, may have been related to the absence of GH in this patient.     

Growth hormone therapy

Growth hormone (GH) therapy has revolutionized treatment of children with growth hormone deficiency (GHD). Improved height outcome with final height in the target height range has been achieved in these children. Identification of Creutzfeldt-Jakob disease, a deadly prion mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. Once daily subcutaneous administration of the freeze-dried preparation at evening is the recommended mode of GH therapy. Studies have led to use of higher dose of GH for improving height outcome (0.33 mg/kg/week or 0.14 IU/kg/day) albeit at a significantly high cost. Growth velocity increases from 3–4 cm/year before therapy to 10–12 cm/year during the first two years of therapy and is maintained at 7–8 cm/year after a period of two years. Close follow-up with regular clinical and laboratory monitoring is essential for achieving a desirable height outcome. A theoretical unlimited supply has led to wide spread use of GH in a variety of disorders other than GHD. Initially started in children with Turner syndrome, GH has now been used in chronic renal failure, idiopathic short stature and intrauterine growth restriction besides a wide array of newly emerging indications.     

Empty sella, growth hormone deficiency and pseudotumour cerebri: effect of initiation, withdrawal and resumption of growth hormone therapy

An 11- year-old boy with normal visus and eye fundus, but with empty sella, growth hormone (GH) deficiency and central diabetes insipidus was found to have intracranial hypertension with papilloedema after 6 months of catch-up growth under recombinant human GH (rhGH) replacement therapy. Withdrawal of rhGH therapy was associated with normalisation of intra‐cranial␣pressure within 1 week. Three months later, resumption of rhGH therapy at a lower dose was again followed by pronounced growth acceleration, but now without papilloedema. Conclusion Children with empty sella and GH deficiency may be prone to rhGH-induced pseudotumour cerebri which appears to be rapidly reversible and dose-dependent. Received: 4 August 1995 / 26 October 1995     

Growth hormone (GH) profiles in response to continuous subcutaneous infusion of GH-releasing hormone(1— 29)-NH2 in children with GH deficiency

Six children presenting with partial growth hormone (GH) deficiency (mean GH peak in two different tests, 8.0 k1.3 μ g/l ) aged 8–10.3 years (mean, 2.7 ± 0.9 years) were treated for 6 months by continuous subcutaneous infusion of GH-releasing hormone(1–29)-NH, (GHRH(1–29)-NH₂); 24-hour GH profiles and height velocity were measured. A biphasic effect of GHRH(1–29)-NH₂ infusion was observed. After an early substantial increase in the 24-hour integrated concentration of GH, from 1.6 ± 0.1 to 3.5 ± 0.7 μg/l/minute, a subsequent consistent decrease occurred by 3 months, which was more pronounced after 6 months (mean 24-hour integrated concentration of GH, 1.9± 0.9 μg/l/minute). This effect reflects modification of both pulse amplitude and frequency of GH secretion. At the end of the study, one child had complete suppression of GH secretion and two others showed only one peak above 5 μg/1 during a 24-hour period. No correlation was found between these changes and height velocity. Three children did not grow significantly; the other three children who had a growth response to GHRH(1–29)-NH₂ were those with the lowest 24-hour integrated GH concentration at the end of the study. The possible mechanisms involved in this biphasic effect, including GHRH antibodies, changes in somatostatin levels and/or desensitization of pituitary GHRH receptors, have been investigated.     

Increase of serum lipoprotein (a) levels during growth hormone therapy in normal short children

We studied the effect of growth hormone (GH) therapy on serum lipoprotein levels and the atherogenic index in short children without GH deficiency. Fasting blood samples were collected from ten (eight males) normal, short, prepubertal children, aged 6–12 years, before, during a 1-year course of GH therapy (0.1 IU/Kg/day), and 3 months after the cessation of GH administration. An increase in serum lipoprotein(a) [Lp(a)] levels of (mean% ± SEM) 43 ± 14, 58 ± 18, 61 ± 17 above the baseline levels was noted at 3 months (P<0.05), 6 months (P<0.01), and 1-year (P<0.01) respectively after the beginning of GH administration. (ANOVA, P<0.01). An inverse relationship between baseline serum Lp(a) concentrations and the percentage increment in Lp(a) after 9 months of GH therapy (r=−0.65,P<0.05) was observed. GH therapy over a period of 1 year had no effect on plasma cholesterol, triglycerides, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein cholesterol [HDL-C] concentrations and the atherogenic index. Three months after the cessation of GH therapy, serum Lp(a) levels were not significantly different from the pre-treatment values. Conclusions Serum Lp(a) concentrations remained above pretreatment values during a 1-year period of GH treatment in short children without GH deficiency and declined shortly after cessation of therapy. Since GH therapy for short children without GH deficiency usually continues for several years, we suggest that serum Lp(a) levels should be determined and followed regularly in such children under prolonged GH therapy. Received: 11 February 1997 and in revised form: 10 June 1997 / Accepted: 6 July 1997     

Growth hormone deficiency: a possible complication of glucose transporter 1 deficiency?

Glucose transporter 1 deficiency syndrome (GLUT1DS) is an autosomal dominant disorder of brain energy metabolism caused by impaired GLUT1-mediated glucose transport across the blood-brain barrier. Although the clinical spectrum of this disorder is expanding rapidly, the growth patterns and endocrine status of these patients are not well known. We report the case of a boy aged 12 years and 7 months who has GLUT1DS complicated by growth failure. His failure to grow had progressed since birth, and his body height was 125 cm (-3.6 SDS). Growth hormone stimulation tests showed severe growth hormone deficiency (GHD), and we initiated GH replacement therapy. After 2 years of treatment, the boy's growth rate recovered from 1.7 cm/year before treatment, to 7.5 cm/year and 4.3 cm/year after treatment with no adverse effects. We speculate that GHD is a possible complication of GLUT1DS and discuss the underlying causative mechanism. CONCLUSION: GHD may be a possible complication of GLUT1DS.     

Diagnostic value of growth hormone-releasing hormone test in children and adolescents with idiopathic growth hormone deficiency

Average growth hormone (GH) peaks following an i.v. growth hormone releasing hormone (GHRH) 1–29 stimulation test were significantly lower in 48 children and adolescents with GH deficiency (GHD) than in 20 age-matched controls (15.2+12.7 vs 37.5+28.1 ng/ml, 2P<0.001). Twelve patients exhibited a low GH peak (<5 ng/ml), 27 demonstrated a normal response (>10 ng/ml) and 9 showed an intermediate rise in plasma GH (5–10 ng/ml). Six of the 12 patients with low GH response to the first GHRH stimulation failed to respond to two other tests immediately before and after a 1 week priming with s.c. GHRH. These subjects with subnormal GH increase at repeat testing had total GHD (TGHD) and multiple pituitary hormone deficiency (MPHD) and had suffered from perinatal distress. On the contrary, 26 of 27 patients with normal GH response to the first test had isolated GHD and only a minority (8/27) had signs of perinatal distress. It is concluded that perinatal injuries primarily damage pituitary structures and that a pituitary defect more probably underlies more severe forms (TGHD and MPHD) of GHD.Presented in part at the 7th Meeting of the Italian Society for Paediatric Endocrinology (Milan, 20–21 October 1989)     

Adult height after cranial irradiation with 24 Gy: factors and markers of height loss

The decrease in adult height of children who have been given cranial irradiation (24 Gy) for acute lymphoblastic leukaemia is attributed to chemotherapy, growth hormone (GH) deficiency and early puberty. This study evaluates the factors involved in the height loss between irradiation and adult height and its markers in 43 patients irradiated at 5.8 ± 0.4 (SEM) years. The mean height loss was 0.9 ± 0.2 SD in the children with a normal GH peak ( n = 11), 1.7 ± 0.2 SD in those with a low GH peak and untreated ( n = 15) and 0.6 ± 0.2 SD in those treated with GH ( n = 17). The adult height was significantly lower than target height in all three groups. The height loss correlated negatively with the GH peak ( p < 0.02) and with the age at onset of puberty ( p < 0.05) in the first two groups with spontaneous growth, but not with the chemotherapy regimen or its duration, or the plasma insulin-like growth factor I (IGFI) and its GH-dependent binding protein (BP-3). Early puberty (onset at 8-10 years) occurred in 6 girls from the first two groups. At the first evaluation, 5.6 ± 0.4 years after irradiation, the GH peak values after arginine-insulin stimulation correlated with the age at irradiation ( p < 0.03), taking into account the time since irradiation. The plasma 1GF1 and BP-3 values were correlated with each other, but not with the GH peak. In conclusion, this study demonstrates the impact of GH deficiency and GH replacement therapy on adult height in children given cranial irradiation for leukaemia. They therefore should be evaluated for their GH secretion 1 2 years after the end of chemotherapy. GH therapy is indicated for those with low GH peak and decreased growth rate or no increase in growth rate despite puberty.     

Resolution of non‐alcoholic steatohepatitis after growth hormone replacement in a pediatric liver transplant patient with panhypopituitarism

NAFLD is a common condition linked to obesity, type 2 diabetes, and metabolic syndrome. Simple hepatic steatosis is a risk factor for inflammatory reactions in the liver (NASH), which may lead to cirrhosis. While the mechanism is unclear, NAFLD and NASH are associated with panhypopituitarism, which in the pediatric population often results from craniopharyngioma or pituitary adenoma and the sequelae of treatment, causing hypothyroidism, adrenal insufficiency, hypogonadotropic hypogonadism, and GH deficiency. Refractory NAFLD in panhypopituitarism may be amenable to GH replacement. Here, we report a pediatric case of NASH secondary to panhypopituitarism from craniopharyngioma, which recurred by 11 months after LDLT. Despite low‐dose GH replacement, the patient remained GH deficient. Pubertal dosed GH therapy led to rapid and complete resolution of hepatic steatosis, which we tracked using serial ¹H MRS. Pediatric patients with NASH cirrhosis secondary to panhypopituitarism can be good candidates for liver transplantation, but hormone deficiencies predispose to recurrence after transplant. High‐dose GH replacement should be considered in pediatric patients with GH deficiency and recurrent disease. A multidisciplinary team approach is essential for successful outcomes.     

重组人生长激素注射液治疗儿童生长激素缺乏症的临床评价

目的 生长激素缺乏症(GHD)有赖于生长激素替代治疗.生长激素注射液可简化注射过程,提高依从性.进一步评价中国重组人生长激素注射液治疗儿童GHD的疗效和安全性.方法 采用多中心、前瞻性、随机开放的研究方法 ,对31例[男20例,女11例,年龄(10.5±4.1)岁]确诊为完全件GHD的患儿,给予重组人生长激素注射液,0.25 mg/(kg·周)[0.107 U/(kg·d)],每晚睡前皮下注射1次,治疗3、6、9、12个月后进行随访,疗程12个月.比较治疗前后的身高增长量(△HT)、年生长速率(growth velocity,GV)、身高均值标准差积分(HT SDS)、血胰岛素样生长因子Ⅰ(IGF-1)、胰岛素样生长因子结合蛋白质3(IGFBP-3)、抗生长激素抗体和骨成熟情况的变化,并评估药物治疗的安全性.结果 (1)治疗3、6、9、12个月后△HT(cm)分别为4.0±1.3、7.0±2.0、10.3±2.6和12.9±3.3(P<0.01),显示治疗后呈良好线性生长;GV(cm/年)治疗前为2.7±0.9,治疗后分别升至16.0±5.1、14.1±4.0、13.7±3.5和12.9±3.3,显示治疗后追赶生长明显,治疗前后比较,差异有统计学意义(P<0.01);HT SDS治疗前为-4.62±1.46,治疗后分别为-3.80±1.53、-3.28±1.60、-2.86±1.75和-2.47±1.86,显示治疗后身高与同年龄同性别正常儿童差距逐步缩小,与治疗前相比差异有统计学意义(P<0.01);(2)血IGF-1(ug/L)治疗前为41±64,治疗后分别为179±155、202±141、156±155和159±167;IGFBP-3(mg/L)治疗前为1540±1325,治疗后分别为3891±1815、4051±1308、3408±1435和3533±1413,显示随着身高增长,IGF-1、IGFBP-3被药物激活到较高水平,治疗前后差异均有统计学意义(P<0.01);(3)在治疗6个月、12个月后进行骨龄评估,骨成熟程度(△BA/△CA)分别为1.01±0.57、1.07±0.75,显示骨龄无加速发展;(4)治疗期间未发生严重不良事件,与药物有关的伴随反应主要表现为甲状腺功能减低.结论重组人生长激素注射液足一种安全有效治疗儿童GHD的药物.     

GROWTH HORMONE DEFICIENCY FOLLOWING RADIOTHERAPY FOR ORBITAL AND PARAMENINGEAL SARCOMAS

Growth hormone deficiency (GHD) is a recognized late effect of successful treatment of tumors requiring cranial irradiation. Growth after treatment was assessed in 16 patients with sarcomas of the orbital and parameningeal regions. Median age at diagnosis was 6.35 years and median follow-up was 7.2 years. Treatment consisted of combination chemotherapy and radical radiotherapy, conventionally fractionated with a median dose 4500 cGy; the hypothalamic/pituitary region received a median dose of 4163 cGy. Height was measured every 6 months and 13/16 patients underwent tests of GH function. At GH testing median height standard deviation score (SDS) was 0.7, a median decrease of 0.55 since tumor diagnosis. Seven patients were treated with human GH (hGH) at a median of 3.7 years from tumor diagnosis and followed for a median of 2.7 years. Treatment with hGH resulted in a median increase in height SDS of 0.9. Careful surveillance with timely introduction of GH replacement is required for treatment of GHD following treatment of orbital and parameningeal sarcomas.     

Growth and endocrine disorders in optic glioma

Hypothalamo-pituitary function in children with optic glioma may be impaired by the tumour itself and by the high cranial radiation doses used in treatment. This study evaluates the effect of optic glioma and its treatment on patient growth and pubertal development. Twenty-one patients (13 boys, 8 girls), treated for optic glioma by cranial irradiation (45–55 Grays) at a mean age of 5.4 years, were evaluated before (n=10) and/or after (n=21) irradiation. Growth hormone (GH) deficiency was present in only 1 patient tested before irradiation and in all patients after irradiation. Precocious puberty occurred in 7/21 cases, before irradiation in 5 patients and after irradiation in 2 patients. The cumulative height loss during the 2 years after irradiation was 0.2±0.2 SD (m±SEM) in 7 patients with precocious puberty and 1.1±0.2 SD in 14 prepubertal patients (P<0.01). The corresponding bone age advance over chronological age, evaluated 1–3 years after irradiation, was 1.1±0.5 and –0.7±0.3 year in the two groups (P<0.01). The mean height loss between time of irradiation and the final height was 2.3±0.6 SD (n=6). Primary amenorrhoea, associated with low oestradiol levels, occurred in two of the three girls of pubertal age. These data indicate that the high dose of cranial radiation used to treat optic glioma invariably results in GH deficiency within 2 years and that hGH therapy is required when GH deficiency is documented. Precocious puberty, resulting in apparently normal growth velocity in spite of GH deficiency, should be treated with luteinizing hormone-releasing hormone analogues because of the risk of accelerated bone maturation and reduced final height.     

Growth impairment and growth hormone therapy in children treated for malignant brain tumours

Eighty-two children with malignant brain tumours were treated according to the “8 in 1” chemotherapy protocol in Finland during 1986 to 1993. Thirty-seven with brain tumours not involving the hypothalamic-pituitary region are still alive and tumour-free. The growth and response to growth hormone (GH) therapy in these children was analysed. Children who received craniospinal irradiation had the most severe loss of height SDS, being −1.07 within 3 years of the diagnosis. Even children with no irradiation to the hypothalamic-pituitary axis had a mean change in height SDS of −0.5 after 3 years. Fifteen of 23 children who received craniospinal irradiation and two out of eight children who received cranial irradiation have received GH therapy. A catch-up growth response to the daily GH therapy with the mean dose of 0.7 IU/kg per week was complete in 3 years (+1.87 SDS), irrespective of craniospinal irradiation, in children who were treated at prepubertal age but was seen in none of the children who had reached pubertal age. Conclusion Growth impairment and GH deficiency are common in children treated for malignant brain tumours. The response to GH therapy is good in prepubertal children in terms of increased growth velocity, although the final height is not yet known. Received: 10 September 1996 and in revised form: 28 January 1997 / Accepted: 11 February 1997     

Growth hormone treatment in a girl with Prader Willi syndrome

Prader Willi syndrome (PWS) is a rare endocrine-metabolic disorder that is characterised by neonatal hypotonia, hyperphagia, marked obesity, short stature, hypogonadism and behavioural problems. 7-20% percent of these children develop diabetes mellitus. A large number of individuals with PWS show growth hormone (GH) deficiency. Recent studies indicate beneficial effects of GH replacement therapy not only for their linear growth but also for correction of metabolic dysfunction. In the present communication this article details about the therapeutic outcome in a girl with PWS who received recombinant growth hormone (rGH), Genotropin. Some carry-over therapeutic benefits have been observed even after discontinuation of rGH.     

Relapse of intracranial germinoma 23 years postirradiation in a patient given growth hormone replacement

There is no clear evidence that growth hormone replacement therapy for treatment-related growth hormone deficiency in patients with childhood intracranial malignancies has a role in tumour relapse or second malignancy. A 16-year-old girl with an intracranial germinoma was treated with local radiotherapy, and subsequently received growth hormone replacement therapy as an adult. Three years after starting growth hormone therapy, 23 years after her radiotherapy treatment, the patient's tumour recurred. Surveillance requirements for patients receiving growth hormone in this setting are discussed. Med. Pediatr. Oncol. 29:41–44, 1997. © 1997 Wiley-Liss, Inc.     

Growth response to growth hormone therapy following craniospinal irradiation

Nineteen (12 male, 7 female) children, who have received craniospinal irradiation for the treatment of a brain tumour distant from the hypothalamic-pituitary axis, resulting in growth hormone (GH) deficiency (CS-PRGHD), have been treated with GH. Eight have completed growth. Comparison has been made with the growth of seven untreated children, whose heights and growth rates at presentation were normal despite GH deficiency secondary to irradiation. GH produced a significant increase in growth velocity over the first 3 years' treatment in CS-PRGHD patients with a mean first year increment of 3 cm/year. Patients, treated to completion of growth, showed a significant increase in leg length standard deviation (SD) score (SDS+0.2) compared to that of the untreated (SDS–0.9) (P<0.05). Stitting height SD scores decreased irrespective of GH therapy (by -1.7 for the treated and -2.2 for the untreated). The onset of puberty in the irradiated patients occurred at a mean bone age of 10.7 years in males and 9.9 years in females. This limited the time available for GH therapy. These factors resulted in a decrease in standing height SDS of 0.9 at completion of GH therapy in CS-PRGHD, but a decrease of 1.7 in those not treated with GH. Thus GH therapy failed to induce catch-up growth in irradiated patients, but it did prevent further loss of adult stature, with a mean final height SD score of -3.4 in CS-PRGHD patients.Abbreviations GH growth hormone - CS-PRGHD post craniospinal irradiation growth hormone deficiency - change in - SDS standard deviation score - ALL acute lymphatic leukaemia - IGHD isolated growth hormone deficiency - C-PRGHD post cranial irradiation growth hormone deficiency - FSH follicle stimulating hormone - LH luteinising hormone - BA bone age - TSH thyroid stimulating hormone - CA chronological age     

Bromocriptine treatment of prolactinoma restores growth hormone secretion and causes catch-up growth in a prepubertal child

A 13-year-old Japanese boy with pituitary prolactinoma whose growth had been retarded for more than 2 years was treated with bromocriptine alone for 140 weeks. After treatment, the serum level of prolactin, which was 1200 ng/ml before treatment, returned to normal and the pituitary tumour seen on the initial brain MRI had rapidly decreased in size after 16 weeks of treatment. Thereafter, his height improved (from -2.1 to -1.7 SDS). Conclusion:the favourable response obtained in this patient implies that bromocriptine monotherapy can be an effective first-line treatment for children with prolactinoma.Abbreviation GH growth hormone     

Growth and growth hormone in children during and after therapy for acute lymphoblastic leukaemia

Growth impairment and growth hormone (GH) deficiency have been reported in children treated for acute lymphoblastic leukaemia (ALL). We have studied growth and GH secretion in a group of 50 patients, affected by ALL, during a 2- to 5-year period after diagnosis, and in 12 long-term-survivors. We observed a significant decrease in growth velocity during the 1st year (in particular during the first 6 months) of therapy and a catch-up growth after the end of therapy. Longterm survivors did not exhibit a significant reduction of height standard deviation score (SDS), as compared to height SDS at diagnosis. None of the patients showed GH deficiency. Our data indicate that chemotherapy significantly affects growth of patients treated for ALL, whereas radiotherapy-at the doses used in this study-does not induce GH deficiency, at least not within 9 years after diagnosis.