Adult height after cranial irradiation for optic pathway tumors: relationship with neurofibromatosis

OBJECTIVE: Optic pathway tumors decrease adult height by central precocious puberty (PP) or hypothalamic-pituitary disorders, particularly growth hormone (GH) deficiency caused by the tumor, management of the tumor, or associated neurofibromatosis 1. The objective of this study was to evaluate the respective roles of these factors on disorders and adult height. STUDY DESIGN: Thirty-five patients with optic pathway tumors diagnosed at 6.4 +/- 0.6 years treated by cranial irradiation (30-56 Gy) reached adult height after treatment with GH alone (n = 16), gonadotropin hormone-releasing hormone analogue alone (n = 2), or both (n = 16). RESULTS: Central precocious puberty occurred before irradiation in four cases and after irradiation in 18. Eleven of the 17 patients with neurofibromatosis 1 had PP. Before irradiation, five of 21 patients lacked GH, zero of 21 lacked thyroid-stimulating hormone, and zero of 13 lacked adrenocorticotropin. After irradiation, 35 of 35 lacked GH, 28 of 35 lacked thyroid-stimulating hormone, and six of 35 lacked adrenocorticotropin; puberty was delayed in 15 patients.Adult height was -0.8 +/- 0.2 SD, below target height (0.2 +/- 0.2 SD, P <.0001), similar in patients with and without PP, but lower in those with neurofibromatosis 1 (-1.4 +/- 0.4 SD) than in those without (-0.3 +/- 0.3 SD, P =.04). CONCLUSIONS: Optic pathway tumors cause PP, but cranial irradiation causes most of the other hypothalamic-pituitary disorders. Adult height of patients given GH or gonadotropin hormone-releasing hormone analogue seems to depend on neurofibromatosis 1.     

Combined therapy with GnRH analog plus growth hormone in central precocious puberty

GnRH analogues (GnRHa) arrest pubertal development, and slow growth velocity (GV) and bone maturation, thus improving adult height in central precocious puberty (CPP). In some patients, however, GV decreases to such an extent that it compromises the improvement in predicted adult height (PAH) and therefore the addition of GH is suggested. Of 20 patients with idiopathic CPP (treated with GnRHa [depot-triptorelin] at a dose of 100 microg/kg every 21 days i.m. for at least 2-3 yr) whose GV fell below the 25th percentile for chronological age (CA), ten received, in addition to the GnRHa, GH at a dose of 0.3 mg/kg/wk, s.c. 6 days weekly, for 2-4 yr. Ten patients matched for BA, CA, and duration of GnRHa treatment who showed the same growth pattern but refused GH treatment, served to evaluate the efficacy of the addition of GH. No patient showed classical GH deficiency. Both groups discontinued treatment at a comparable BA (mean +/- SEM): 13.2 +/- 0.2 yr in GnRHa + GH vs 13.0 +/- 0.1 yr in the control group. At the conclusion of the study all the patients had achieved adult height. Adult height was considered to be attained when the growth during the preceding year was less than 1 cm, with a BA of over 15 yr. Patients of the group treated with GH + GnRHa showed an adult height significantly higher (p<0.001) than pretreatment PAH (160.6 +/- 1.3 vs 152.7 +/- 1.7 cm). Height SDS for BA significantly increased from -1.5 +/- 0.2 at start of GnRHa to -0.21 +/- 0.2 at adult height (p<0.001). Target height was significantly exceeded. The GnRH alone treated group reached an adult height not significantly higher than pretreatment PAH (157.1 +/- 2.5 vs 155.5 +/- 1.9 cm). Height SDS for BA did not change (from -1.0 +/- 0.3 at start of GnRHa to -0.7 +/- 0.4 at adult height). Target height was just reached but not significantly exceeded. The gain in centimeters obtained calculated between pretreatment PAH and final height was 7.9 +/- 1.1 cm in patients treated with GH combined with GnRH analogue while in patients treated with GnRH analogue alone the gain was just 1.6 cm +/- 1.2 (p=0.001). Furthermore, no side effects, bone age progression, or ovarian cysts, were observed in GnRHa + GH treated patients. In conclusion, a gain of 7.9 cm in adult height represents a significant improvement which justifies the addition of GH for 2-3 yr to conventional treatment with GnRH analogues in patients with central precocious puberty, and with a decrease in growth velocity so marked as to impair predicted adult height to below the third percentile.     

Response to growth hormone treatment and final height after cranial or craniospinal irradiation

Growth hormone (GH) deficiency (GHD) induced by cranial irradiation has become a frequent indication of hGH substitutive therapy. This study analyses the growth response to hGH therapy and the factors involved in the decrease in growth velocity observed after cranial irradiation. One hundred children (61 boys and 39 girls) given cranial radiation for pathology distant from the hypothalamo-pituitary area were studied. Fifty-six of them received hGH therapy for GHD resulting in decreased growth velocity. The initial annual height gain in the cranial-irradiated group was comparable to that of patients treated for idiopathic GHD; additional spinal irradiation significantly reduced the growth response. Twenty-eight hGH-treated patients reached final heights which were compared to those of 2 untreated irradiated groups, one with GHD (n = 27) and the other with normal GH secretion (n = 17). The height SD score changes observed in hGH therapy were +0.3 in the cranial (n = 10) and -1.2 SD in the craniospinal (n = 18) groups. GH deficiency had contributed to a mean height loss of 1 SD and spinal irradiation to a loss of 1.4 SD. The small effect of hGH therapy on final height is probably linked to the small bone age retardation at onset of hGH therapy and to the fact that irradiated children entered puberty at a younger age in terms of chronological age (10.6 +/- 0.3 yr in girls and 11.0 +/- 0.3 yr in boys) and bone age (9.6 +/- 0.4 yr in girls and 12.6 +/- 0.3 in boys) than the idiopathic GHD patients. These data suggest that the results of hGH therapy in irradiated children might be improved with higher and more fractionated hGH doses and, in some patients, by delaying puberty using luteinizing hormone releasing hormone analogs.     

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.     

Cranial irradiation induces premature activation of the gonadotropin-releasing-hormone

BACKGROUND: CNS-irradiation in prepubertal children with leukemia or brain tumors can lead to precocious or in high doses to delayed puberty. The underlying mechanisms of these disorders are unknown. METHODS: A new animal model of experimentally induced pubertal disorders by cranial irradiation has been developed. In infantile or juvenile (12 - 23 days old) female rats precocious or delayed puberty have been induced by selective cranial Co60-irradiation (4 - 18 Gy). At age of 32 - 38 days or 3 months relevant hormone parameters have been studied basal and after stimulated conditions. RESULTS: Low radiation doses (5 or 6 Gy) led to accelerated onset of puberty as well as elevated LH- and estradiol levels. High radiation doses (9 - 18 Gy) caused retardation of sexual development, lower gonadotropin levels and growth retardation associated with growth hormone deficiency. After cranial irradiation with 5 Gy the release rates of the inhibitory neurotransmitter gamma-aminobutyric-acid (GABA) from hypothalamic explants were significantly lower (p < 0,05). The gonadotropin-releasing-hormone (GnRH) expression in the hypothalamic preoptic area of irradiated animals (5 Gy) was significantly higher than in controls (p < 0,05). CONCLUSION: The GnRH-pulse generator is very radiosensitive as low dose irradiation causes precocious puberty, whereas high dose irradiation is associated with delayed sexual maturation. Radiation induced precocious puberty might be caused by damage to inhibitory GABAergic neurons leading to desinhibition and premature activation of GnRH neurons. Our animal model of cranial irradiation seems to be suitable to study neurotransmitter disorders, molecular mechanisms and potential preventive intervention of radiation induced pubertal changes.     

Cranial irradiation of female rats causes dose-dependent and age-dependent activation or inhibition of pubertal development

Cranial irradiation in prepubertal children with leukemia or brain tumors can lead to precocious or in high doses to late puberty. To unravel the underlying mechanisms, we developed a rat model with selective cranial Co60-irradiation technique. Infantile (12-16 d old) or juvenile (21-23 d old) female Sprague-Dawley rats received a single dose of 4, 5, 6, 9 or 2 x 9 Gy (at days 21 and 23). Each group consisted of 7-20 animals. High radiation doses (9 Gy and more) caused retardation of sexual development, whereas low radiation doses (5 or 6 Gy) led to accelerated onset of puberty in 20% of infantile irradiated rats animals as determined by vaginal opening. Interestingly, at peripubertal age (postnatal day 32-34), 5 or 6 Gy infantile irradiated rats had significantly higher serum LH levels stimulated by GnRH and estradiol levels (p < 0.05). 2 x 9 Gy irradiated rats had at the age of 3 mo a marked growth retardation and significantly lower GH levels than the controls (p < 0.05) whereas prolactin, FSH, TSH, T4, and corticosterone levels were comparable with controls. These studies demonstrate that the GnRH-pulse generator is very radiosensitive as precocious activation occurred after low dose irradiation (5 or 6 Gy) of infantile rats without any other endocrine disorder. High radiation doses (9 or 2 x 9 Gy) induced retardation of sexual maturation and later on growth hormone deficiency. Moreover this model of cranial irradiation seems to be suitable to study the molecular mechanisms of radiation induced pubertal changes.     

Adult height in advanced puberty with or without gonadotropin hormone releasing hormone analog treatment

Advanced puberty is defined as the onset of puberty in girls at 8-10 years of age and in boys at 9-11 years. This study analyzes adult height in 57 children with advanced puberty to evaluate the results of treating children (9 girls and 8 boys) with gonadotropin hormone releasing hormone (GnRH) analog and the impact of advanced puberty on adult height in untreated children (31 girls and 9 boys). For treated girls, adult height predicted at the onset of treatment (151.9+/-1.7 cm) was similar to the final adult height (155.3+/-1.4 cm), but lower than target height (157.2+/-1.6 cm, p = 0.04). For untreated girls, adult height predicted at the initial evaluation (156.7+/-1 cm) was also similar to adult height (157+/-1 cm), but lower than the target height (157.6+/-1 cm, p = 0.03). The adult heights of both treated and untreated girls were similar to their target heights. For treated boys, adult height predicted at the onset of treatment (173.2+/-3.1 cm) was greater than the final adult height (164.1+/-2.1 cm, p = 0.01), which was lower than target height (170.4+/-1.2 cm, p = 0.01). For untreated boys, adult height predicted at the initial evaluation (170.8+/-2.7 cm) was similar to both the adult height (169.1+/-1.9 cm) and target height (170.2+/-1.2 cm). Height gains between the onset of puberty and adult height were similar in treated (29.9+/-2.3 cm in girls and 29.8+/-1.7 cm in boys) and untreated (28.6+/-1 and 33.1+/-2 cm) children. When expressed as SD, the adult height was significantly shorter than that at 4 years in treated girls (difference 1 SD, p = 0.03), in untreated girls (difference 0.9 SD, p = 0.0002) and in treated boys (difference 0.9 SD, p = 0.02), but it was similar to that in untreated boys. Adult height was below target height by >5 cm in seven girls (two of them treated) and five boys (four of them treated). In conclusion, treating advanced puberty did not change the adult height reached by girls, and was associated with reduced growth potential in boys. The adult heights of untreated children were similar to those predicted at the initial evaluation and to target heights, but in girls they were 1 SD lower than the height at 4 years. These data suggest that advanced puberty decreases the growth potential by about 5 cm, and that GnRH analog treatment does not prevent this.     

Disproportionate short stature after cranial irradiation and combination chemotherapy for leukaemia

The effect of combination chemotherapy and cranial irradiation on final height and body proportions was retrospectively examined in a cohort of 142 children treated for acute lymphoblastic leukaemia (ALL). Eighty four children (48 girls, 36 boys) received 24 Gy cranial irradiation and 58 (35 girls, 23 boys) 18 Gy. None had received testicular or spinal irradiation. A significant reduction in standing height SD score from diagnosis to final height was seen in all groups. Of the 109 children in whom sitting height measurements were available, 88 (81%) had relatively shorter backs than legs and in 25 (23%) this disproportion was of a marked degree. After mathematical correction for sitting height loss there was no longer a significant reduction in standing height SD score at final height in all except the 24 Gy group of girls. These data suggest that disproportion is a common finding after treatment for ALL and that, at least in some children, much if not all of the height loss seen is due to a reduction in sitting height. Possible explanations for this disproportion include a disturbance of puberty or an effect of chemotherapy on spinal growth, or both.     

Disproportionate short stature after cranial irradiation and combination chemotherapy for leukaemia.

The effect of combination chemotherapy and cranial irradiation on final height and body proportions was retrospectively examined in a cohort of 142 children treated for acute lymphoblastic leukaemia (ALL). Eighty four children (48 girls, 36 boys) received 24 Gy cranial irradiation and 58 (35 girls, 23 boys) 18 Gy. None had received testicular or spinal irradiation. A significant reduction in standing height SD score from diagnosis to final height was seen in all groups. Of the 109 children in whom sitting height measurements were available, 88 (81%) had relatively shorter backs than legs and in 25 (23%) this disproportion was of a marked degree. After mathematical correction for sitting height loss there was no longer a significant reduction in standing height SD score at final height in all except the 24 Gy group of girls. These data suggest that disproportion is a common finding after treatment for ALL and that, at least in some children, much if not all of the height loss seen is due to a reduction in sitting height. Possible explanations for this disproportion include a disturbance of puberty or an effect of chemotherapy on spinal growth, or both.     

Response to Growth Hormone Treatment and Final Height after Cranial or Craniospinal Irradiation

ABSTRACT. Growth hormone (GH) deficiency (GHD) induced by cranial irradiation has become a frequent indication of hGH substitutive therapy. This study analyses the growth response to hGH therapy and the factors involved in the decrease in growth velocity observed after cranial irradiation. One hundred children (61 boys and 39 girls) given cranial radiation for pathology distant from the hypothalamo-pituitary area were studied. Fifty-six of them received hGH therapy for GHD resulting in decreased growth velocity. The initial annual height gain in the cranial-irradiated group was comparable to that of patients treated for idiopathic GHD; additional spinal irradiation significantly reduced the growth response. Twenty-eight hGH-treated patients reached final heights which were compared to those of 2 untreated irradiated groups, one with GHD (n=27) and the other with normal GH secretion (n= 17). The height SD score changes observed in hGH therapy were +0.3 in the cranial (n=10) and - 1.2 SD in the craniospinal (n = 18) groups. GH deficiency had contributed to a mean height loss of 1 SD and spinal irradiation to a loss of 1.4 SD. The small effect of hGH therapy on final height is probably linked to the small bone age retardation at onset of hGH therapy and to the fact that irradiated children entered puberty at a younger age in terms of chronological age (10.6±0.3 yr in girls and 11.0± 0.3 yr in boys) and bone age (9.6 ± 0.4 yr in girls and 12.6 ± 0.3 in boys) than the idiopathic GHD patients. These data suggest that the results of hGH therapy in irradiated children might be improved with higher and more fractionated hGH doses and, in some patients, by delaying puberty using luteinizing hormone releasing hormone analogs.     

Growth hormone secretion, puberty and adult height after cranial irradiation with 18 Gy for leukaemia

The dose of prophylactic cranial irradiation given to patients for acute lymphoblastic leukaemia has been decreased from 24 to 18 Gy, but the beneficial effect of this decrease on growth is controversial. This study compares the growth hormone (GH) secretion and growth of 35 patients (20 boys) given 18 Gy at 3.7 ± 0.3 (SE) years, and routinely evaluated 5.4 ± 0.4 years after irradiation to define the indications for GH treatment in these patients. Of these, 63% had a low GH peak (<10 μg/l) after one (22 cases) or two (17 cases) stimulation tests. The plasma concentrations of insulin-like growth factor I and its GH-dependent binding protein were normal for age in all but two cases. The height changes between irradiation and evaluation were correlated with the GH peaks (P < 0.03) and were concordant, except in patients with early puberty. This occurred in 16 patients including all 12 girls irradiated before 4 years of age. A significant (P < 0.03) reduction in height (SD) between irradiation and adult height occurred in untreated GH-deficient patients (−1 ± 0.3, n = 6), but not in GH-deficient patients given GH (−0.6 ± 0.3, n = 8) or in those with normal GH peak (−0.4 ± 0.3, n = 7). Conclusion In children irradiated for acute lymphoblastic leukaemia, GH deficiency is frequent after 18 Gy but its impact on adult height is smaller than after higher doses. We suggest that the indications for gonadotropin releasing hormone analogue therapy should be broad in patients with early or rapidly progressing puberty and those for GH therapy in those patients with a below average constitutional height before irradiation. Received: 17 November 1997 / Accepted: 9 February 1998     

Effect of growth hormone-releasing factor on growth hormone release in children with radiation-induced growth hormone deficiency

Five male children who received cranial irradiation for extrahypothalamic intracranial neoplasms or leukemia and subsequently developed severe growth hormone (GH) deficiency were challenged with synthetic growth hormone-releasing factor (GRF-44), in an attempt to distinguish hypothalamic from pituitary dysfunction as a cause of their GH deficiency, and to assess the readily releasable GH reserve in the pituitary. In response to a pulse of GRF-44 (5 micrograms/kg intravenously), mean peak GH levels rose to values higher than those evoked by the pharmacologic agents L-dopa or arginine (6.4 +/- 1.3 ng/mL v 1.5 +/- 0.4 ng/mL, P less than .05). The peak GH value occurred at a mean of 26.0 minutes after administration of GRF-44. These responses were similar to those obtained in children with severe GH deficiency due to other etiologies (peak GH 6.3 +/- 1.7 ng/mL, mean 28.0 minutes). In addition, there was a trend toward an inverse relationship between peak GH response to GRF-44 and the postirradiation interval. Prolactin and somatomedin-C levels did not change significantly after the administration of a single dose of GRF-44. The results of this study support the hypothesis that cranial irradiation in children can lead to hypothalamic GRF deficiency secondary to radiation injury of hypothalamic GRF-secreting neurons. This study also lends support to the potential therapeutic usefulness of GRF-44 or an analog for GH deficiency secondary to cranial irradiation.     

Management of Growth Hormone Deficiency Through Puberty

ABSTRACT. 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 < 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. It is concluded that optimum final heights may not be achieved in these patients without the therapeutic manipulation of the onset and/or duration of puberty.     

Reduction of adult height in childhood acute lymphoblastic leukemia survivors after prophylactic cranial irradiation

BACKGROUND: Impaired linear growth is a well-recognized complication in long-term childhood ALL survivors who received cranial irradiation. However, as many patients achieve a final height between the 5th and the 95th centile, the true incidence of linear growth impairment might be underestimated. METHODS: Reduction of adult height (RAH) was estimated in adult childhood ALL survivors with and without cranial irradiation. RAH was calculated as the difference between target height (TH) and final height (FH). TH was calculated according to the formula TH = {[(height father + height mother +/- 12)/2] + 3}. RAH was assessed in 79 adult childhood ALL survivors in first complete remission who had received cranial irradiation 25 Gy (Group I, n = 53), 18 Gy (Group II, n = 10) or chemotherapy alone (controls, n = 16). RESULTS: RAH was 8.6 +/- 8.2 cm in Group I (P = 0.001 vs. controls), 6.2 +/- 3.2 cm in Group II (P = 0.01 vs. controls), and 1.7 +/- 4.6 in controls (chemotherapy only). There was no significant difference between Group I and Group II. In Group I females had more RAH than males (P = 0.02). RAH was related to younger age at diagnosis (P = 0.001). CONCLUSIONS: The deficit between target height and final height highlights the reduction of adult height in the majority of male and female childhood ALL survivors who had received prophylactic cranial irradiation, in particular in those who were diagnosed at a younger age. This reduction would have been masked if patients FH was only compared with standard methods. RAH might be a sensitive predictor for growth hormone deficiency as these results suggest that radiation-induced growth hormone deficiency in these patients is the rule rather than the exception.     

Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution

Out of 35 girls with idiopathic central precocious puberty (CPP) treated with gonadotropin-releasing hormone agonist (GnRHa) (depot-triptorelin) at a dose of 100 microg/kg every 21 days i.m. for at least 2-3 years whose growth velocity fell below the 25th percentile for chronological age (CA), 17 received growth hormone (GH) in addition at a dose of 0.3 mg/kg/week, s.c., 6 days per week, for 2-4 years. The other 18, matched for bone age (BA), CA and duration of GnRHa treatment, who showed the same growth pattern but refused GH treatment, remained on GnRHa alone, and were used as a control group to evaluate GH efficacy. No patient was GH deficient. Both groups discontinued treatment at a comparable BA (mean +/- SD): BA 13.4 +/- 0.6 in GnRHa plus GH group vs 13.0 +/- 0.5 years in the GnRHa alone group. The 35 patients have reached adult height (i.e. growth during the preceding year was less than 1 cm, with a BA of over 15 years). Patients of the group treated with GH plus GnRHa showed an adult height (161.2 +/- 4.8 cm) significantly higher (p < 0.001) than pre-treatment predicted adult height (PAH) calculated according to tables either for accelerated girls (153.2 +/- 5.0 cm) or for average girls (148.6 +/- 4.3 cm). The adult height of the GnRH alone treated group (156.6 +/- 5.7) was not significantly higher than pre-treatment PAH if calculated on Bayley and Pinneau tables for accelerated girls (153.9 +/- 3.8 cm), whilst it remained significantly higher if calculated on tables for average girls (149.6 +/- 4.0 cm) (p < 0.001). The gain between pre-treatment PAH and final height was 8.2 +/- 4.8 cm according to tables for accelerated girls and 12.7 +/- 4.8 cm according to tables for average girls in patients treated with GH plus GnRHa; while in patients treated with GnRH alone the gain calculated between pre-treatment PAH for accelerated girls was just 2.3 +/- 2.9 cm and 7.1 +/- 2.7 cm greater than pre-treatment PAH for average girls. The difference between the gain obtained in the two groups (about 6 cm) remained the same, however PAH was calculated. The addition of GH to GnRHa in a larger cohort of patients with CPP with a longer follow-up confirms the safety of the combined treatment and the still significant but more variable gain in the group with the combined treatment, probably due to the larger number of patients analyzed. Caution is advised in using such an invasive and expensive treatment, and there is need for further studies before widespread clinical use outside a research setting.     

Young adult survivors of childhood acute lymphoblastic leukemia: spontaneous GH secretion in relation to CNS radiation

BACKGROUND: Young adults who are long-term survivors of acute lymphoblastic leukaemia (ALL) in early childhood usually do well and do not have to go to regular medical checkups. Many of these survivors did receive prophylactic cranial radiotherapy during their oncological treatment. The effect of cranial irradiation on the hypothalamus is considered to be progressive. Therefore, late effects, such as reduced growth hormone (GH) secretion, may remain undetected until adulthood. PROCEDURE: Records from all patients treated for ALL before the onset of puberty in the region of West Sweden, between 1 January 1973 and 31 December 1985 were included, provided they were in first remission with a minimum follow-up time of 15 years, and a minimum age of 20. These criteria were met by 47 young adults aged 20-32 years, of whom 35 agreed to participate. We studied spontaneous GH secretion over 24 hr, IGF-I and IGFBP-3, final height and BMI. The patients had been treated according to three consecutive Swedish childhood leukaemia group protocols. The median follow-up time was 20 years, and 19 of the patients had been treated with cranial irradiation (CRT+), 16 had not (CRT-). RESULTS: CRT+ patients had significantly lower maximal peaks of GH than CRT- patients. Fifty percent of the CRT+ patients had a GH(max) below the cut-off level (3.3 microg/l), for GH treatment. CRT- patients all had GH(max) levels considered within the normal range. Final height of all the patients, except one CRT+ women, was in the range of expected midparental height, the median loss in final height in the CRT+ patients was 0.8 standard deviation (SD). No patient in this study was obese by definition (BMI <30 kg/m(2)). IGF-I and IGFBP-3 concentrations did not correlate to variations in spontaneous GH secretion in these patients. CONCLUSIONS: In spite of the little effect on final height, we found impaired spontaneous GH secretion in 79% of young adults 20-32 years of age, and GH deficiency (GHD) in 47% after low-dose cranial irradiation in early childhood. The consequences of this low-GH secretion need to be investigated.     

Phenotypic analysis and growth response to different growth hormone treatment schedules in two siblings with an inactivating mutation in the growth hormone-releasing hormone receptor gene

Mutations in the GHRH receptor (GHRHR) gene (GHRHR) are emerging as a common cause of familial isolated growth hormone deficiency (IGHD) type IB. The use of gonadotropin-releasing hormone (GnRH) analogues has been advocated as a tool to delay puberty in patients with isolated GH deficiency (IGHD), allowing longer time for the beneficial effect of exogenous human GH (hGH) treatment on growth. We describe two male siblings with IGHD due to a homozygous missense GHRHR mutation who, because they were started on hGH therapy at different ages, presented with different height SDS at the onset of puberty and therefore had different predicted target heights. The shorter brother was treated with GnRH analogue plus hGH for 3 years, whereas the other brother received only hGH. Despite different predicted heights at the onset of puberty, they attained similar final heights. We conclude that in patients with IGHD, GnRH analogue treatment should be considered to delay puberty and obtain a maximal growth response if hGH treatment is started in late childhood and the predicted height at puberty onset is below the genetic target.     

Combined Treatment with Gonadotropin-releasing Hormone Analog and Anabolic Steroid Hormone Increased Pubertal Height Gain and Adult Height in Boys with Early Puberty for Height

Twenty-one boys with a height of 135 cm or less at onset of puberty were treated with a combination of GnRH analog and anabolic steroid hormone, and their pubertal height gain and adult height were compared with those of untreated 29 boys who enter puberty below 135 cm. The mean age at the start of treatment with a GnRH analog, leuprorelin acetate depot (Leuplin^®) was 12.3 yr, a mean of 1.3 yr after the onset of puberty, and GnRH analog was administered every 3 to 5 wk thereafter for a mean duration of 4.1 yr. The anabolic steroid hormone was started approximately 1 yr after initiation of treatment with the GnRH analog. The mean pubertal height gain from onset of puberty till adult height was significantly greater in the combination treatment group (33.9 cm) than in the untreated group (26.4 cm) (p<0.0001). The mean adult height was significantly greater in the combination treatment group (164.3 cm) than in the untreated group (156.9 cm) (p<0.0001). The percentage of subjects with an adult height of 160 cm or taller was 90.5% (19/21) in the combination treatment group, and it was 13.8% (4/29) in the untreated group (p<0.0001). Since growth of the penis and pubic hair is promoted by the anabolic steroid hormone, no psychosocial problems arose because of delayed puberty. No clinically significant adverse events appeared. Combined treatment with GnRH analog and anabolic steroid hormone significantly increased height gain during puberty and adult height in boys who entered puberty with a short stature, since the period until epiphyseal closure was extended due to deceleration of the bone age maturation by administration of the GnRH analog and the growth rate at this time was maintained by the anabolic steroid hormone.     

Long-term complications following bone marrow transplantation in children

Abstract Seventeen children who underwent bone marrow transplantation (BMT) between 1975 and 1985 and survived for more than 2 years were evaluated for growth and development. The patients had a follow up of 2.1-13.1 years. Prior to transplant, children with malignancy had received multi-agent chemotherapy and nine had also received central nervous system irradiation. Transplant preparation for malignancy (group 1; n = 13) included high-dose cyclophosphamide (CPA) 120–200 mg/kg and total body irradiation (TBI) 10–13.2 Gy, whereas conditioning for non-malignant disorders (group 2; n = 4) included high-dose CPA 200 mg/kg with or without busulphan. Patients in group 1 showed a steady decline in height velocity following initial chemotherapy and cranial irradiation and the decline was even greater following BMT. Growth hormone (GH) deficiency developed in eight of nine children tested, hypergonadotrophic hypogonadism developed in 11 who reached puberty, thyroid hormone abnormalities were encountered in four out of 10 tested and 11 of 13 developed cataracts. Patients in group 2 did not show decline in linear growth rate, thyroid hormone abnormalities or cataracts after BMT. The only child tested had normal GH levels and the two patients who reached puberty showed delayed but complete gonadal recovery. Our data demonstrate that TBI leads to significant late effects on growth and gonadal function. Contrary to previous reports, a high incidence of cataract formation is observed after fractionated TBI. Conditioning regimens without TBI should be considered in children undergoing BMT.     

Accelerated versus slowly progressive forms of puberty in girls with precocious and early puberty. Gonadotropin suppressive effect and final height obtained with two different analogs

OBJECTIVES: To distinguish which children with precocious puberty (PP) and early puberty (EP) should be treated and which followed without therapy. To determine the effect of GnRH analog treatment on the final height of treated patients and compare the effect of two different analogs on gonadotropin suppression and final height. STUDY DESIGN: Sixteen females with PP or EP with a mean chronological age (CA) of 8.8 +/- 1.4 years and a mean bone age (BA) of 10.8 +/- 1.3 years were treated for a mean of 2.7 +/- 1.0 years with a GnRH analog (triptorelin or leuprolide acetate; group A), while 21 girls with a mean CA of 8.5 +/- 1.0 years, a mean BA of 9.7 +/- 1.4 years and a predicted adult height of >155 cm were followed without therapy (group B). Criteria for treatment were one of: a. predicted adult height (PAH) of <155 cm initially or at any time during follow up; b. PAH over 155 cm with a dramatic decrease in PAH over a 6-month follow-up period; c. advanced and rapidly progressing breast development for age (Tanner 3 before the age of 9 years). RESULTS: GnRHa therapy suppressed gonadotropins in group A, while gonadotropins increased gradually in group B. Height velocity (HV) decreased in group A, while it remained accelerated in group B; BA increased a mean of 1.7 +/- 0.5 years in group A and 3.2 +/- 0.3 years in group B. This resulted in a height increase in group A from a baseline PAH of 153.7 +/- 1.2 cm to a final height (FH) of 160.9 +/- 4.0 cm (p <0.001), clearly above their target height (TH) of 157.7 +/- 4.2 cm. The height of group B children did not change over time (164.1 +/- 4.1 cm before therapy and 166.0 +/- 6.0 cm at FH), both above their TH. The mean leuprolide acetate dose utilized in this study decreased during treatment, while both the initial and final triptorelin dose remained unchanged. Adequate gonadotropin suppression (peak level of LH and FSH of <2 IU/l after i.v. GnRH stimulation) was noted with both leuprolide acetate and triptorelin, although LH suppression was slightly more pronounced with triptorelin. BA advanced 1.8 +/- 0.4 years during leuprolide acetate treatment and 1.5 +/- 0.3 years with triptorelin, so that FH increased a mean of 5.5 +/- 1.3 cm with leuprolide acetate and 8.7 +/- 2.2 cm with triptorelin. CONCLUSIONS: PAH of <155 cm before or during therapy, PAH of >155 cm with a dramatic decrease in predicted height over a 6-month follow-up period and/or advanced and rapidly progressing breast development in girls with PP or EP were useful parameters in deciding which patients to treat. GnRHa therapy suppressed gonadotropins, HV and bone maturation in children with an accelerated form of PP or EP, resulting in a significant height increase. Final height remained stable over time in untreated patients. Adequate gonadotropin suppression was noted with both analogs, although with the doses of analog used in our study, LH and BA suppression were more pronounced with triptorelin, resulting in a larger height gain.