In-ovo monochromatic green light photostimulation enhances embryonic somatotropic axis activity.

Previous studies demonstrated that in ovo photostimulation with monochromatic green light increases body weight and accelerates muscle development in broilers. The mechanism in which in ovo photostimulation accelerates growth and muscle development is not clearly understood. The objective of the current study was to define development of the somatotropic axis in the broiler embryo associated with in ovo green light photostimulation. Two-hundred-forty fertile broiler eggs were divided into 2 groups. The first group was incubated under intermittent monochromatic green light using light-emitting diode (LED) lamps with an intensity of 0.1 W\m2 at shell level, and the second group was incubated under dark conditions and served as control. In ovo green light photostimulation increased plasma growth hormone (GH) and prolactin (PRL) levels, as well as hypothalamic growth hormone releasing hormone (GHRH), liver growth hormone receptor (GHR), and insulin-like growth factor-1 (IGF-1) mRNA levels. The in ovo photostimulation did not, however, increase embryo's body weight, breast muscle weight, or liver weight. The results of this study suggest that stimulation with monochromatic green light during incubation increases somatotropic axis expression, as well as plasma prolactin levels, during embryonic development.

Effect of cancer treatment on hypothalamic-pituitary function.

The past 30 years have seen a great improvement in survival of children and young adults treated for cancer. Cancer treatment can put patients at risk of health problems that can develop many years later, most commonly affecting the endocrine system. Patients treated with cranial radiotherapy often develop dysfunction of the hypothalamic-pituitary axis. A characteristic pattern of hormone deficiencies develops over several years. Growth hormone is disrupted most often, followed by gonadal, adrenal, and thyroid hormones, leading to abnormal growth and puberty in children, and affecting general wellbeing and fertility in adults. The severity and rate of development of hypopituitarism is determined by the dose of radiotherapy delivered to the hypothalamic-pituitary axis. Individual growth hormone deficiencies can develop after a dose as low as 10 Gy, whereas multiple hormone deficiencies are common after 60 Gy. New techniques in radiotherapy aim to reduce the effect on the hypothalamic-pituitary axis by minimising the dose received. Patients taking cytotoxic drugs do not often develop overt hypopituitarism, although the effect of radiotherapy might be enhanced. The exception is adrenal insufficiency caused by glucocorticosteroids which, although transient, can be life-threatening. New biological drugs to treat cancer can cause autoimmune hypophysitis and hypopituitarism; therefore, oncologists and endocrinologists should be vigilant and work together to optimise patient outcomes.

Seqüelas endócrinas da radioterapia no tratamento do câncer na infância e adolescência / Endocrine sequelae after radiotherapy in childhood and adolescence

A radioterapia resulta em endocrinopatias, osteoporose, obesidade e seqüelas neurológicas em pacientes tratados por câncer. A deficiência de GH é a complicação mais freqüente no eixo hipotálamo-hipofisário. A freqüência, prazo de surgimento e gravidade da deficiência de GH dependem da dose recebida durante a irradiação craniana, mas idade à radioterapia e fracionamento da dose também são variáveis importantes. Outras anormalidades do eixo hipotálamo-hipofisário são igualmente dose-dependentes. Baixas doses de irradiação induzem puberdade precoce ou avançada, enquanto altas doses provocam deficiência gonadotrópica. Complicações endócrinas secundárias à irradiação periférica, como distúrbios gonadais ou tireoidianos são descritos. Mesmo com secreção normal de GH, o crescimento pode ser comprometido por lesões ósseas após irradiação corporal total ou crânio-espinhal. Resultados melhores sobre a estatura final têm sido obtidos com reposição de GH em associação com o tratamento da puberdade precoce ou avançada. O objetivo desta revisão é a abordagem das seqüelas endócrinas tardias da radioterapia.

[Endocrine sequelae after radiotherapy in childhood and adolescence]. / Seqüelas endócrinas da radioterapia no tratamento do câncer na infância e adolescência.

Radiotherapy may result in endocrine abnormalities, osteoporosis, obesity and neurological sequelae in patients treated for cancer. In the hypothalamo-pituitary area, GH deficiency is the most frequent complication. The frequency, delay of appearance and severity of GH deficiency depend most on the dose delivered during cranial irradiation but variables as age at treatment and fractionation schedule may play an important role as well. Other hypothalamo-pituitary dysfunctions are also dose-dependent. Low dose cranial irradiation may induce precocious or early puberty, while high doses are related to gonadotropin deficiency. Endocrine complications due to extracranial irradiation such as gonadal or thyroid abnormalities are described. In spite of normal GH secretion, linear growth may be impaired by bone lesions secondary to craniospinal or total body irradiation. Results on final height have been optimized by better indicators of GH therapy associated with adequate treatment of early or precocious puberty. The purpose of this review is to explore the late endocrine sequelae of radiotherapy.

[Growth hormone deficiency after treatment of medulloblastoma with radiotherapy in childhood: case report]. / Deficiência de hormônio do crescimento após radioterapia por meduloblastoma na infância: relato de caso.

Craniospinal radiation therapy for treatment of brain tumors may result in growth hormone (GH) insufficiency with resultant linear growth retardation, one of the most common complications. We report the case of a 10-year-old boy presenting headache associated to vertigo, nausea and vomiting. A CT scan showed an homogeneous mass in the left cerebelar hemisphere, that was surgically removed. The histopathological examination revealed medulloblastoma and the patient was submitted to craniospinal radiation. He did not present tumor recurrence nor neurological or cognitive deficits during 4 years, but evolved to short stature due to GH deficiency. Nowadays, he is being receiving GH 0,1 U/kg/day and has presented 4cm stature increment after 6 months. The present case highlights the importance in carefully monitoring of children after cranial radiation for oncologic treatment, because they may develop hormonal deficiencies, that can be successfully replaced.

Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma.

PURPOSE: To examine the long-term effects of treatment in children receiving radiotherapy for head and neck rhabdomyosarcoma. METHODS: From 1967 to 1994, a total of 30 children with head and neck rhabdomyosarcoma received megavoltage radiotherapy at one institution. Seventeen patients (57%) have survived and have at least a 5-year follow-up. There were 11 males and 6 females, with a median age of 5.7 years (range 2.2-11.6) at the time of radiotherapy. Tumor location was orbit in 6 patients, infratemporal fossa in 4, paranasal sinuses in 2, and supraglottic larynx in 2; the nasopharynx, pterygopalatine fossa, and parotid gland were sites for the remaining children. All but 2 patients had tumors of embryonal histology. The Intergroup Rhabdomyosarcoma Study (IRS) Group was I in 2, II in 3, and III in 11 children; 1 patient had a recurrent tumor after surgery alone. Radiotherapy volume was the primary tumor or tumor bed in 13, tumor and whole brain in 3, and tumor and craniospinal axis in 1. Median radiotherapy dose to the primary site was 5,040 cGy (range 4,140-6,500) and to the whole brain was 3,000 cGy. All but 1 were treated with 150-200-cGy fractions; 1 patient received 250-cGy fractions for a tumor in the larynx. Chemotherapy was vincristine (V), actinomycin-D (A), and cyclophosphamide (C) in 10 patients, VAC + adriamycin in 2, VA in 1, VA + ifosfamide in 1, VC + adriamycin in 1, and none in 2. One patient had salvage chemotherapy consisting of cisplatin and etoposide. Median follow-up time was 20 years (range 7.5-33). RESULTS: Late effects of treatment were seen in all patients and included facial growth retardation in 11, neuroendocrine dysfunction in 9, visual/orbital problems in 9, dental abnormalities in 7, hearing loss in 6, and hypothyroidism in 3. Intellectual and academic delays were documented in 3 patients who had received whole brain radiotherapy. While neuroendocrine, thyroid, dental, and cognitive sequelae were primarily attributed to radiotherapy, hearing loss was thought to be a direct result of tumor destruction and, in 1 case, cisplatin chemotherapy. Late effects at or beyond 10 years from radiotherapy were few, but severe, and included chondronecrosis, esophageal stenosis, second malignancy, and brain hemorrhage. CONCLUSION: Late effects of treatment in children receiving radiotherapy for head and neck rhabdomyosarcoma are frequent. Although radiotherapy is a significant contributor of neuroendocrine, dental, thyroid, and cognitive toxicity, it is not usually implicated with hearing loss. Late toxicity of treatment beyond 10 years is not as frequent as those occurring within 10 years of therapy.

Growth and growth hormone secretion after treatment for acute lymphoblastic leukemia in childhood. 18-Gy versus 24-Gy cranial irradiation.

PURPOSE: Cranial irradiation (CI) given during the first phase of treatment of childhood acute lymphoblastic leukemia (ALL) has been associated with significant long-term morbidity. As a result, the dose of radiotherapy has been reduced from 24 to 18 Gy to reduce the severity of these late effects. To compare the effects of 24 and 18 Gy CI on growth, puberty, and growth hormone (GH) secretion, a cohort of survivors of childhood ALL were studied. PATIENTS AND METHODS: Of a total of 48 children, 28 (14 boys, 14 girls) had received 24 Gy and 20 (eight boys, 12 girls) had received 18 Gy. Similar chemotherapy regimens had been used in both groups, and age at diagnosis (5.2 +/- 2.7 vs. 5.1 +/- 2.8 years, 18 Gy vs. 24 Gy) and mean height at diagnosis [standard deviation score (SDS) 0.17 +/- 0.17 vs. 0.05 +/- 0.17, 18 Gy vs. 24 Gy] were comparable. RESULTS: Growth rates in both groups did not differ for the first 5 years after diagnosis. After this time, however, a significant height decrease was observed in children who had received 24 Gy but not in children who had received 18 Gy (at 8 years the change in SDS from diagnosis was -0.32 +/- 0.14 vs. -0.73 +/- 0.16, 18 Gy vs. 24 Gy, p < 0.05). Menarche occurred earlier in the girls in the 24-Gy group (at 12.9 +/- 0.3 vs. 11.7 +/- 0.4 years of age, 18 Gy vs. 24 Gy, p < 0.02). Overnight GH concentrations (12-h sampling every 20 min) were reduced in both groups compared with healthy age-matched control children but were even lower in the 24-Gy group (12.7 +/- 0.7 mU/L vs. 7.9 +/- 0.6 vs. 6.1 +/- 0.5 [6.4 +/- 0.4 ng/ml vs. 3.9-0.3 vs. 3.1 +/- 0.3]; control vs. 18 Gy and 24 Gy, p < 0.001; 18 Gy vs. 24 Gy, p < 0.025). CONCLUSIONS: Although both doses of CI impair GH secretion, 24 Gy has a greater impact on growth in the long term. This effect may be exaggerated by the induction of early puberty in some children.

Safety of growth hormone after treatment of a childhood malignancy.

The use of growth hormone therapy in children with radiation-induced growth hormone (GH) deficiency is widely accepted, but the safety of this mitogenic hormone, particularly in children previously treated for cancer, continues to cause concern. A variety of malignant tumours have been induced in animals exposed to supraphysiological doses of GH, whereas hypophysectomised animals appear protected from carcinogen-induced neoplasms. Growth hormone and insulin-like growth factor-1 have been shown to stimulate both proliferation and transformation of normal and leukaemic human lymphocytes in vitro when used in supraphysiological doses. Despite the theoretical arguments, there is no evidence of an increased risk of tumour recurrence following GH therapy in replacement dosage in children previously treated for a malignancy.

Longitudinal growth and final height in long-term survivors of childhood leukaemia.

Survival of children with acute lymphoblastic leukaemia (ALL) has increased considerably in recent years and data on the spontaneous growth and final height of these children are conflicting. Therefore, we analysed the longitudinal growth and final height in 52 survivors (33 females, 19 males) of childhood ALL. These children were diagnosed and treated in a single institution, all remained in first remission and were submitted to cranial irradiation with either 2400 or 1800 cGy. None of the patients received testicular or spinal irradiation. Median age at diagnosis was 4.2 (range 1.3-9.6) years in the first group (2400 cGy) and 3.9 (0.8-10.5) years in the second (1800 cGy). Standing height was measured at diagnosis, at the end of treatment (median 3.1 years after diagnosis), 6, 12, 24 months after the end of treatment, and finally at the completion of growth. In girls a significant decrease of mean height standard deviation score (SDS) during treatment and a catch up in growth after the end of therapy was followed by a second period of reduced growth. Mean final height SDS was significantly lower than the value at diagnosis in both groups of girls, but only in males treated with 2400 cGy. Mean overall loss in height SDS from diagnosis to final height was higher in females (-1.24) than in males (-0.40) (P = 0.009). Females < or = 4 years of age at diagnosis showed a higher loss in final height than females > 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnetic resonance imaging of the pituitary area in children treated for acute lymphoblastic leukemia with low-dose (18-Gy) cranial irradiation. Relationships to growth and growth hormone secretion.

OBJECTIVE: To determine the effects of 18-Gy cranial irradiation on growth, growth hormone (GH) secretion, and pituitary magnetic resonance imaging in children who underwent previous irradiation for treatment of acute lymphoblastic leukemia. DESIGN: Clinical survey. SETTING: Department of Pediatrics of the University of Bologna (Italy). PATIENTS: Ten boys and 18 girls who were treated for acute lymphoblastic leukemia; median age at diagnosis was 3.1 years and at the end of follow-up was 11.5 years. MEASUREMENTS AND RESULTS: Height was periodically measured from diagnosis until the end of follow-up, when GH secretion study and magnetic resonance imaging were performed. The mean height SD score was significantly lower than at diagnosis only at the end of treatment. Nocturnal mean GH concentration and GH response to pharmacological tests (arginine and levodopa [L-dopa]) were pathological in 22 cases (81.5%) and 18 cases (64.3%), respectively. Sixteen cases (59.2%) had a blunted GH release to the three tests. Mean pituitary anterior lobe height was reduced and seven subjects (25%) showed an empty sella. CONCLUSIONS: Cranial irradiation with 18 Gy does not seem to influence the growth pattern of most children who are treated for acute lymphoblastic leukemia, despite severe impairment of GH secretion and morphological abnormalities of the sellar area. However, a follow-up until final height is necessary.

Persistent or recurrent acromegaly. Long-term endocrinologic efficacy and neurologic safety of postsurgical radiation therapy.

As in other clinics, pituitary surgery was definitive treatment in less than 50% of cases of acromegaly treated at one institution over several decades. From 1965 to 1989, 24 acromegalic patients who had noncurative pituitary surgery received radiation therapy at the National Institutes of Health, with a basal human growth hormone level of greater than 5 ng/ml as the criterion for active disease. Using megavoltage irradiation, more than 60% of these patients stabilized at a normal hormonal range, and the overwhelming majority had decreasing growth hormone levels with time. No major side effects of irradiation were encountered except panhypopituitarism of varying degrees. The authors evolved a policy of surgery as the first option, followed by irradiation for patients with postoperative growth hormone levels more than 5 ng/ml.

Dose dependency of time of onset of radiation-induced growth hormone deficiency.

Growth hormone (GH) secretion during insulin-induced hypoglycemia was assessed on 133 occasions in 82 survivors of childhood malignant disease. All had received cranial irradiation with a dose range to the hypothalamic-pituitary axis of 27 to 47.5 Gy (estimated by a schedule of 16 fractions over 3 weeks) and had been tested on one or more occasions between 0.2 and 18.9 years after treatment. Results of one third of the GH tests were defined as normal (GH peak response, greater than 15 mU/L) within the first 5 years, in comparison with 16% after 5 years. Stepwise multiple linear regression analysis showed that dose (p = 0.007) and time from irradiation (p = 0.03), but not age at therapy, had a significant influence on peak GH responses. The late incidence of GH deficiency was similar over the whole dose range (4 of 26 GH test results normal for less than 30 Gy and 4 of 25 normal for greater than or equal to 30 Gy after 5 years), but the speed of onset over the first years was dependent on dose. We conclude that the requirement for GH replacement therapy and the timing of its introduction will be influenced by the dose of irradiation received by the hypothalamic-pituitary axis.

Polygraphic sleep patterns and growth hormone secretion in children after cranial irradiation.

The effects of radiotherapy on subsequent growth hormone (GH) secretion and sleep organization was studied by simultaneous evaluation of spontaneous sleep-related GH secretion (SSRGHS), arginine-insulin tolerance test (AITT) and polygraphic sleep recording in a follow up of 19 children who underwent surgical removal of an intracranial tumour and cranial radiotherapy 1-7 years previously. Electrophysiological patterns of sleep phases, the amount and distribution of sleep stages were normal, suggesting that the procedure utilized should not entail modifications of SSRGHS per se. Long-term after radiotherapy SSRGHS and AITT GH responses were lower than those of the medium-term group. The lack of correlation between SSRGHS and AITT GH secretion suggests that SSRGHS and AITT measure different aspects of GH secretion. The highest value of GH plasma level (peak) corresponded to slow wave sleep, mainly during the first non-rapid eye movement-rapid eye movement (NREM-REM) cycle, in practically all the patients. Although the SSRGHS synchronization with SWS of the first NREM-REM cycle was preserved, no sleep measure was correlated with the SSRGHS. The usefulness of polygraphic monitoring of sleep patterns was confirmed.

Long-term effects of radiotherapy for acromegaly on circulating prolactin.

In 61 acromegalic patients, serum PRL was assessed (off medical treatment) before and 2 to 12 (mean 6.4) years after external beam radiotherapy. Before radiotherapy elevated PRL levels were present in 22 of 35 males (63%) and 12 of 26 females (46%) and were above 1000 mU/l in 11 males and 5 females. When studied for up to 5 years after radiotherapy, 22 of 23 (96%) patients who had not had surgery and who had normal PRL pre-radiotherapy showed an increased PRL level and this was also seen in 17 of 27 (63%) who had been hyperprolactinaemic initially. In contrast, 10 of 27 patients (37%) who had elevated pre-radiotherapy levels (all greater than 1000 mU/l) had a reduction in PRL values after radiotherapy. In all 11 patients who underwent surgery before radiotherapy, an increase in PRL was seen after radiotherapy. In the 21 patients followed for 10-12 years, the peak PRL value occurred 1-6 years after radiotherapy. After this, a progressive reduction of PRL to normal was seen. Normal levels were reached 4 to 10 years after radiotherapy. No correlation was found between pretreatment PRL values and final GH values in the whole group, nor between changes in PRL and the development of impaired ACTH or TSH secretion. Thus, different patterns of PRL behaviour suggest that radiotherapy treatment may either produce hyperprolactinemia from mild hypothalamic damage or ablate PRL secreting cells if they were present in the tumour before treatment. These changes do not predict final GH results or the development of hypopituitarism after radiotherapy.

Growth in children treated for acute lymphoblastic leukemia with and without prophylactic cranial irradiation.

Growth and weight gain were studied longitudinally over a period of four years in thirty-nine children treated for acute lymphoblastic leukemia. The children were divided into two groups according to treatment. Twenty-eight children were given prophylactic cranial irradiation and eleven children were treated without such irradiation. The duration of cytostatic treatment was three years in all cases. Average growth during the first two years was similar in the two groups, and the standard deviation scores (SDS) were below average. The rate of growth (in height) during the fourth year was significantly higher among those children who had not received cranial irradiation (p less than 0.01). After four years the average attained height had declined 0.5 SD for children treated with cranial irradiation and 0.2 SD for children without such treatment. Weight velocity was significantly greater than the expected mean in the non-irradiated group during the first year and in the irradiated group during the fourth year of the study. Attained weight after four years had increased 0.4 SD more among those children who had not received irradiation. The results suggest that prophylactic cranial irradiation is responsible for the greater part of the prepubertal growth inhibition in these children.