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.     

Adult height after growth hormone (GH) treatment for GH deficiency due to cranial irradiation

BACKGROUND: The indications and factors affecting the growth in response to treatment with growth hormone (GH) of patients with cranial irradiation-induced GH deficiency remain unclear. PROCEDURE: The adult heights of 56 patients treated with GH (0.4-0.6 U/kg/week) as daily sc injections were analysed. They had been given 18 or 24 Grays (Gy) cranial irradiation for leukemia (group 1, 26 cases), 50 +/- 1 Gy for various tumors (group 2, 13 cases), 46 +/- 1 Gy for retinoblastoma (group 3, 8 cases), or 34 +/- 2 Gy with spinal irradiation for medulloblastoma (group 4, 9 cases). Twenty- five of these 56 patients had early puberty and were also treated with gonadotropin-releasing hormone (GnRH) analog. RESULTS: The standing (-1.0 +/- 0.2 in group 1, -0.7 +/- 0.3 in group 2, -1.1 +/- 0.3 in group 3, and -2.0 +/- 0.4 SD in group 4) and sitting (-1.8 +/- 0.2 in group 1, -0.4 +/- 0.4 in group 2, -1.2 +/- 0.4 in group 3, and -3. 4 +/-0.4 SD in group 4) adult heights were shor ter (P < 0.05 for standing and P < 0.001 for sitting heights) for group 4 than for each of the other groups. Of the 47 patients given cranial (and not craniospinal) irradiation, sitting adult height was shorter (P = 0. 02) and the difference between standing adult and target heights greater (P = 0.03) in those patients in whom puberty occurred at a normal age than in those treated with GnRH analog. Conclusion. The incomplete catch-up of growth seems to be mainly due to the reduction in sitting height of patients given spinal irradiation and in whom puberty occurred at a normal age. This suggests that GnRH analog treatment should be more widely used to treat children with early and/or rapidly progressing puberty after cranial irradiation.     

Magnetic resonance imaging in the diagnosis of growth hormone deficiency.

Forty-six patients with idiopathic growth hormone deficiency were examined by magnetic resonance imaging at a mean (+/- SEM) age of 9 +/- 1 years (range 15 days to 20 years). They were classified into two groups according to MRI images: group 1 (n = 29) had pituitary stalk interruption syndrome and group 2 (n = 17) had normal pituitary anatomy. All patients with pituitary stalk interruption had a pituitary height at less than -2 SD for age; three had no visible anterior pituitary lobe. By contrast, the pituitary height was less than normal in only 10 patients (60%) with normal pituitary anatomy. Growth hormone deficiency was transient in one of the seven patients with normal pituitary anatomy and height. The group with pituitary stalk interruption had the first symptom of growth hormone deficiency at an earlier age (2.8 +/- 0.6 vs 5.5 +/- 1.2 years; p less than 0.001), were of smaller stature (-4 +/- 0.2 vs -3 +/- 0.2 SD; p less than 0.01) and had lower GH peak response to provocative testing (3 +/- 0.4 vs 5 +/- 0.5 ng/ml; p less than 0.001) than did the group with normal pituitary anatomy. Their pituitary gland was also shorter (2.5 +/- 0.2 vs 3.5 +/- 0.2 mm; p less than 0.01). All the patients with multiple pituitary deficiencies except one (n = 19) belonged to this group. One girl with pituitary stalk interruption and deficiencies in growth hormone and thyroid-stimulating hormone had advanced central precocious puberty. We conclude that the evaluation of the shape and height of the pituitary gland by MRI is an additional tool for the diagnosis of growth hormone deficiency. The presence of pituitary stalk interruption confirms this diagnosis and is predictive of multiple anterior pituitary deficiencies. The lack of a significant increase in perinatal abnormalities in this group and the association of pituitary stalk interruption with microphallus and with facial or sella abnormalities suggest that this appearance may have an early antenatal origin. The finding of a familial case of pituitary stalk interruption suggests a genetic origin.     

Height prognosis of children with true precocious puberty and growth hormone deficiency: effect of combination therapy with gonadotropin releasing hormone agonist and growth hormone.

We evaluated height prognosis and therapeutic efficacy of long-term, combination therapy with gonadotropin releasing-hormone agonist and growth hormone (GH) in five children (three girls) with coexistent precocious puberty and GH deficiency. Their clinical characteristics and growth response were compared with those of 12 girls with idiopathic true precocious puberty and eight prepubertal GH-deficient children (one girl). Precocious GH-deficient subjects were older than the precocious GH-sufficient children (9.5 +/- 1.8 years vs 6.5 +/- 1.3 years; mean +/- SD), but bone ages were comparable (12 +/- 3.7 years vs 10 +/- 0.9 years); their chronologic age was similar to that of the prepubertal GH-deficient children (9.6 +/- 2.1 years), but bone age was significantly more advanced (6.9 +/- 2.3 years). The mean height velocity of the prepubertal GH-deficient children (3.8 +/- 1.5 cm/yr) was lower than that of the precocious GH-deficient subjects (6.7 +/- 1.6 cm/yr) and the precocious GH-sufficient children (9.5 +/- 2.9 cm/yr). Baseline adult height prediction z scores were significantly lower in the precocious GH-deficient children (-3.7 +/- 1.0) than in either the precocious GH-sufficient children (-2.2 +/- 1.0) or the prepubertal GH-deficient subjects (-1.5 +/- 0.8). During therapy with gonadotropin releasing-hormone agonist, growth rates slowed to an average of 3.7 cm/yr in the precocious GH-deficient children but increased after the addition of GH to 7.4 cm during the first year of combination therapy. After 2 to 3 years of combination therapy, height predictions increased an average of 10 cm, compared with an increase of 2.8 cm in the precocious GH-sufficient group treated with gonadotropin releasing-hormone agonist alone. We conclude that combination treatment with gonadotropin releasing-hormone agonist and GH improves the height prognosis of children with coexistent true precocious puberty and GH deficiency, but falls short of achieving normal adult height potential.     

Growth hormone deficiency impedes the rise in plasma insulin-like growth factor I levels associated with precocious puberty

We tested the hypothesis that growth hormone (GH) mediates the rise in insulin-like growth factor I (IGF-I) concentrations in children with precocious puberty. We studied three groups of patients. Group 1 included six children with GH deficiency and precocious puberty (precocious GH-deficient); group 2 included 10 GH-sufficient patients with idiopathic true precocious puberty (precocious GH-sufficient); and group 3 included 9 prepubertal children with GH deficiency (prepubertal GH-deficient). Growth rates, pubertal status, and plasma IGF-I concentrations were determined at regular intervals. The precocious children with GH deficiency had a mean (+/- SD) growth rate of 7.2 +/- 2.1 significantly below that of the precocious GH-sufficient patients (10.5 +/- 2.5 cm/yr, p less than 0.05) but above that of the prepubertal GH-deficient children (3.9 +/- 1.4 cm/yr, p less than 0.05). The mean IGF-I concentration in the precocious GH-deficient children was 0.77 +/- 0.39 U/ml, significantly lower than the mean level of 2.2 +/- 0.67 U/ml in the precocious GH-sufficient patients (p less than 0.01). However, precocious GH-deficient patients had significantly higher IGF-I values than the prepubertal GH-deficient children (0.24 +/- 0.10 U/ml, p less than 0.05). IGF-I values did not rise with the onset of precocious puberty in four of the precocious GH-deficient children evaluated before and after the development of precocious puberty. However, three patients who began GH treatment did have a rise in plasma IGF-I concentrations to levels of 1.2, 3.4, and 3.7 U/ml, respectively. These findings are compatible with the concept that sex steroids increase IGF-I levels in precocious puberty primarily by increasing GH production. A small but direct effect of sex steroids on IGF-I production may also exist. The onset of precocious puberty in children with organic GH deficiency may mask the abnormal growth pattern of these children and delay diagnosis; determinations of plasma IGF-I concentrations may be helpful in assessing the GH status of these patients.     

Hypothalamic dysfunction after chemotherapy

Cranial irradiation with or without chemotherapy can cause hypothalamic-pituitary dysfunction. Chemotherapy without cranial irradiation has not been thought to cause such deficiency. In order to determine whether chemotherapy without cranial irradiation can lead to hormonal deficiency, we reviewed the medical records of 362 childhood cancer patients who underwent full hypothalamic-pituitary evaluation because of altered growth and development after oncological therapy (1987-2002). Of these, 31 received chemotherapy but no cranial or total body irradiation and had no CNS tumor: 18 had hematological malignancy and 13 had a solid tumor of the torso or extremity. Duration of follow-up was 13.0 +/- 4.1 years (mean +/- SD). Growth hormone deficiency (GHD) was identified in 15 (48%), central hypothyroidism (TSH-D) in 16 (52%), and pubertal abnormalities in 10 (32%). Pubertal abnormalities included precocious puberty in two (6%), gonadal failure in five of 27 who were old enough to assess puberty (19%), and gonadotropin deficiency in three of 27 (11%). GHD and TSH-D were co-existent in eight patients (26%). Overall, 81% (n = 25) had GHD, TSH-D, precocious puberty, and/or gonadotropin deficiency. None had ACTH or ADH deficiency or primary hypothyroidism. Of note, this was not a study of prevalence, but rather an evaluation of clinically referred patients. In conclusion, hypothalamic dysfunction may occur in survivors of non-CNS tumors who receive chemotherapy but do not receive cranial irradiation. We recommend at least annual observation of growth rate and pubertal development of all children treated for pediatric malignancies, with evaluation for GHD, TSH-D, pubertal abnormalities, and other hypothalamic dysfunction in all poorly-growing cancer survivors, even those not treated with cranial irradiation.     

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.     

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.     

Growth, puberty and hypothalamic-pituitary function in children with suprasellar arachnoid cyst

A suprasellar arachnoid cyst may cause disorders of growth, puberty and hypothalamic-pituitary function, due to the proximity of the cyst to the hypothalamic-pituitary area. A total of 30 patients (17 boys) with cyst diagnosed at 4.3 ± 1 years were routinely evaluated at 5.4 ± 1 years; 24 of them had one or multiple cyst derivations. Some 23 cases had an abnormal height, weight or puberty: short (<−2SD, 5 cases) or tall (>2SD, 10 cases) stature, overweight (body mass index, BMI, >2SD, 6 cases), central precocious puberty (10 cases) and/or no progression of pubertal development (3 cases). The growth hormone (GH) peaks after pharmacological stimulation test were low (<10 μg/l) in 16 patients, confirmed by a second evaluation in 8/11 of them. The plasma free thyroxine was low in five patients, prolactin was high in two and the cortisol and concomitant plasma and urinary osmolalities were normal. BMI was correlated negatively with the GH peaks (r=−0.37, P < 0.01) and positively with the plasma leptin concentrations (r=0.55, P < 0.01). The plasma fasting insulin concentrations were also correlated negatively with the GH peaks (r=−0.55, P < 0.02) and positively with the plasma insulin-like growth factor I concentrations (r=0.64, P < 0.002). The adult height (12 cases) was at 4SD in 1 and <−2SD in 4 patients, two of whom had precocious puberty untreated with gonadotropin releasing hormone (GnRH) analogue, and two had untreated GH deficiency. The adult height of those treated was normal. One girl had primary amenorrhoea and two boys had low plasma testosterone, despite a normal gonadotropin response to a GnRH test. Conclusion Suprasellar arachnoid cysts may cause deficiencies of growth hormone and thyrotropin, stimulation of the hypothalamic-pituitary-gonadal axis, tall stature and/or overweight. These last two disorders may be due to hyperinsulinism, itself due to suprasellar arachnoid cyst. Received: 5 May 1999 / Accepted: 28 October 1999     

The endocrine spectrum of arachnoid cysts in childhood

BACKGROUND: On clinical grounds, arachnoid cysts are usually associated with neurological dysfunction. There is little information concerning their involvement in endocrinological disorders. PATIENTS: The experience in 6 children (birth to 12 years) with hypothalamic-pituitary disturbances secondary to the presence of intracranial arachnoid cysts is reported and the literature is reviewed. RESULTS: Three of our children were diagnosed with isolated hormone abnormalities (2 children with precocious puberty and 1 child with growth hormone, GH deficiency). One child presented the unusual combination of GH deficiency and precocious puberty. The remaining 2 children developed panhypopituitarism associated with diabetes insipidus. CONCLUSION: Arachnoid cysts may cause a wide spectrum of endocrinological disorders. Periodical and complete follow-up of every patient is recommended.     

Growth and pubertal disorders in neurofibromatosis type 1

The first textbook of Pediatric Endocrinology in the early 1950s reported an association of neurofibromatosis type 1 (NF1) and precocious puberty (PP) and/or short stature. Recent studies have indicated that children with NF1 grow normally until puberty; thereafter height velocity and relative height (SDS or percentiles) decreases with respect to healthy peers, reaching a mean adult height close to the 25th percentile for the general population. Moreover, the percentage of patients with true short stature (<3rd percentile) increases from childhood (5%) to late puberty (20-30% in literature, 18% in our study), and final height is significantly below the genetic target and predicted adult height calculated just before or at the beginning of puberty. Finally, among the shortest patients (<10th percentile) there is a high incidence of severe complications, such as CNS tumors, huge plexiform neurofibromas and severe scoliosis. Precocious puberty is a frequent complication of NF1, and occurs mainly in association with optic pathway tumors (OPT); however, occasionally it has been reported in the absence of optic gliomas, probably with a similar incidence as in the general population. GnRH agonist therapy must be decided individually as in some patients further growth could be normal and/or treatment would not improve final height. In the presence of early pubertal signs, an OPT must be ruled out. In addition to PP, delayed puberty has been frequently reported in NF1. In a study of 123 girls with NF1, we found that the mean age at menarche (13.0 +/- 1.9 yr) was later than in their mothers (12.7 +/- 1.4 yr) and in the general population (12.4 +/- 1.2 yr; p <0.05), with a very high incidence of delayed menarche (>2 SD): 16% vs 6.8% (mothers) vs 3.4% (controls) (p <0.01). In conclusion, growth and puberty present unusual patterns in NF1, often with true pathological findings increasing medical and psychological problems.     

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     

When and how to combine growth hormone with a luteinizing hormone-releasing hormone analogue

The effect of combined treatment with growth hormone (GH) and a luteinizing hormone-releasing hormone (LHRH) analogue, or GH alone, on pubertal height gain was assessed in an uncontrolled study in 15 boys and 10 girls with GH deficiency (GHD). Seven boys and six girls were treated with GH alone (group 1), and eight boys and four girls were treated with a combination of GH and an LHRH analogue during puberty (group 2). Mean ages (+/- SD) at the start of GH treatment and at the onset of puberty were significantly lower in group 2 (8.0 +/- 3.3 years and 11.2 +/- 0.8 years, respectively, in boys, and 6.3 +/- 1.6 years and 10.8 +/- 0.7 years in girls) than in group 1 (12.8 +/- 1.9 years and 13.7 +/- 1.4 years in boys, and 11.2 +/- 1.0 years and 12.5 +/- 1.2 years in girls). Height at the onset of puberty was less in group 2 than in group 1, but the difference was significant only for the boys. Combination treatment was started at a mean age of 11.7 +/- 1.2 years in boys and 11.5 +/- 1.0 years in girls. The duration of the combination treatment was 5.1 +/- 1.5 years in boys and 2.3 +/- 0.7 years in girls. The duration of the period between the onset of puberty and the end of GH treatment was significantly longer in group 2 (6.8 +/- 1.2 years in boys and 5.5 +/- 1.0 years in girls) than in group 1 (4.3 +/- 1.6 years in boys and 3.6 +/- 1.4 years in girls). The pubertal height gain was also significantly greater in group 2 (36.7 +/- 6.5 cm in boys and 29.0 +/- 8.3 cm in girls) than in group 1 (21.9 +/- 4.1 cm in boys and 18.6 +/- 4.1 cm in girls). Final height was significantly greater in group 2 than in group 1 in boys. Although there was no significant difference in final height between groups in the girls, the change in height SDS from the start of GH treatment until final height was significantly greater in group 2 (2.7 +/- 1.6 in boys and 4.5 +/- 0.5 SD in girls) than in group 1 (1.0 +/- 0.8 in boys and 1.8 +/- 0.9 SD in girls), in both boys and girls. In conclusion, it appears that combination of an LHRH analogue and GH may increase the pubertal height gain and the final height of children with GHD. The improvement is attributed to the prolongation of the treatment period, permitting slow bone maturation, and to the maintenance of height velocity. This combination treatment appears to be more effective in boys than girls. To fully assess this therapeutic approach, prospective controlled studies are needed.     

Growth and endocrine disorders secondary to cranial irradiation

External cranial radiation for the treatment of malignant diseases has become a frequent cause of growth hormone deficiency (GHD). The timing of occurrence and the frequency of GHD were related to the hypothalamic-pituitary radiation dose. Frequency varied from 50% in leukemia (2400 cGy) to 75% in face and neck tumors or medulloblastoma (2500-4500 cGy) and up to 100% in optic glioma (greater than 4500 cGy). The significantly more severe growth deficit in patients with GHD given higher radiation doses suggests different levels of residual GH secretion according to radiation dosage. The minimum harmful radiation dose is probably close to 1800-2000 cGy. Our data show that stimulation tests remain a useful means of defining GHD and predicting growth. A fair agreement between GH secretion and growth was found in most cases, regardless of the radiation dose. The only exception was a group of leukemic children (2400 cGy) who achieved normal prepubertal growth despite a low GH response. The 24-h spontaneous plasma GH profiles and IGF-I measurements may add information if growth is retarded despite a normal GH response. We showed that growth retardation occurring after some schedules of total body irradiation was not due to GH deficiency but rather to radiation-induced skeletal lesions. Early or true precocious puberty, generally associated with GHD, was another cause of height loss. As the role of GH deficiency in the final height reduction was demonstrated in all groups of patients after cranial radiation, we suggest that hGH therapy should be considered in any child with proven GH deficiency and significant growth retardation after such radiation.     

Disorders of growth and puberty in children with non-tumoral hydrocephalus

Hydrocephalus may cause disorders of growth and puberty. 31 patients (25 girls) with non-tumoral hydrocephalus were seen at 8.5 +/- 3.1 (SD) years for short stature (8 patients), overweight (8 patients), central early puberty (onset before 9 years, 21 patients), premature pubarche (1 patient) and/or delayed puberty (2 patients). Among the patients with short stature, 4 had meningomyelocele and one had untreated early puberty. Only 1/11 patients evaluated had growth hormone deficiency. Among the overweight patients, 5 had early puberty. The plasma leptin concentrations were positively correlated with the body mass index (r = 0.65, p < 0.01, n = 14). Free thyroxin, cortisol, prolactin and concomitant plasma and urinary osmolalities were normal in all cases evaluated, except one who had low free thyroxin. The 7 patients with early puberty and who were given gonadotropin releasing hormone analog for over 2 years had mean predicted adult height of -2.45 +/- 1.9 SD before treatment and -2.46 +/- 1.4 SD afterwards. Ventriculocisternostomy performed on 2 girls seen for delayed puberty was followed by breast development and menarche. In conclusion, in children with hydrocephalus, short stature is frequently due to meningomyelocele and rarely to GH deficiency. Central early puberty is the most frequent endocrine disorder.     

Growth hormone secretory dynamics in children with precocious puberty

We investigated whether an increase in growth hormone secretion contributed to the growth spurt in children with precocious puberty by measuring the 24-hour profile of serum growth hormone in 51 patients with central precocious puberty. Girls with central precocious puberty had significantly greater mean 24-hour levels of growth hormone in comparison with normal prepubertal girls (5.1 +/- 0.5 SEM vs 3.4 +/- 0.3 ng/mL, P less than 0.005). Mean 24-hour growth hormone levels did not differ significantly between boys with central precocious puberty and normal prepubertal boys (4.4 +/- 1.2 vs 3.0 +/- 0.4 ng/mL). Serum somatomedin C levels were significantly correlated with mean 24-hour growth hormone levels in the girls only. Height age advancement (expressed as height age/chronologic age) was significantly correlated with mean 24-hour growth hormone levels in both boys and girls with central precocious puberty. We conclude that spontaneous 24-hour growth hormone secretion in girls with precocious puberty is greater than that of normal prepubertal girls and may mediate at least in part the increased growth rate in this disorder.     

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.     

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.     

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.     

Hypothalamic-pituitary gonadal axis in boys with primary hypothyroidism and macroorchidism

Nine of 15 boys with severe long-standing primary hypothyroidism were found to have macroorchidism. All 15 patients had elevated thyroid-stimulating hormone levels. However, only those patients with testicular enlargement had striking elevations of serum prolactin and gonadotropin values. The response to gonadotropin-releasing hormone in our patients was blunted, in contradistinction to that of children with true precocious puberty. In spite of the elevated levels of luteinizing hormone, the serum testosterone levels were in the prepubertal range, explaining the lack of peripheral manifestations of androgenic effect. Improvement of testosterone secretion followed decreasing prolactin levels with bromocriptine administration, suggesting an inhibitory effect of prolactin on luteinizing hormone action at the Leydig cell. We conclude that testicular enlargement is the result of continuous follicle-stimulating hormone stimulation and that the term "true precocious puberty" is not appropriate in children with hypothyroidism and macroorchidism unless the hypothalamic-pituitary gonadal axis is shown to be at the pubertal stage.