Original Article
Hypothalamic-Pituitary Dysfunction after Radiation for Brain Tumors
N Engl J Med 1993; 328:87-94January 14, 1993
- Abstract
Background
Patients with brain tumors who are treated with radiation frequently have growth hormone deficiency, but other neuroendocrine abnormalities are presumed to be uncommon.
Methods
We studied endocrine function in 32 patients (age, 6 to 65 years) 2 to 13 years after they had received cranial radiotherapy for brain tumors. The doses of radiation to the hypothalamic-pituitary region ranged from 3960 to 7020 rad (39.6 to 70.2 Gy). Nine patients also received 1800 to 3960 rad (18.0 to 39.6 Gy) to the craniospinal axis. Serum concentrations of thyroid, gonadal, and pituitary hormones were measured at base line and after stimulation.
Results
Nine patients (28 percent) had symptoms of thyroid deficiency, and 20 patients (62 percent) had low serum total or free thyroxine or total triiodothyronine concentrations. Of the 23 patients treated only with cranial radiation, 15 (65 percent) had hypothalamic or pituitary hypothyroidism. Of the nine patients who also received spinal (and thus direct thyroid) radiation, three (33 percent) had evidence of primary thyroid injury.
Seven of the 10 postpubertal, premenopausal women (70 percent) had oligomenorrhea, and 5 (50 percent) had low serum estradiol concentrations. Three of the 10 men (30 percent) had low serum testosterone concentrations. Overall, 14 of the 23 postpubertal patients (61 percent) had evidence of hypogonadism. Mild hyperprolactinemia was present in 50 percent of the patients. Responses to stimulation with corticotropin-releasing hormone and corticotropin were normal in all patients except one, who had panhypothalamic dysfunction. However, serum 11-deoxycortisol responses to the administration of metyrapone were low in 11 of the 31 patients (35 percent) tested.
Three of the 32 patients (9 percent) had no endocrine abnormalities, 9 (28 percent) had an abnormal result on tests of thyroid, gonadal, prolactin, or adrenal function, 8 (25 percent) had abnormalities in two axes, 8 (25 percent) in three axes, and 4 (12 percent) in all four axes.
Conclusions
Cranial radiotherapy in children and adults with brain tumors frequently causes abnormal hypothalamic-pituitary function. The most frequent changes are hypothyroidism and gonadal dysfunction, although subtle abnormalities in adrenal function may also be present.
Media in This Article
Figure 1
Serum Free T Concentrations in Patients with Brain Tumors Treated with Cranial Radiation (Open Circles) or Craniospinal Radiation (Solid Circles) as a Function of the Time after Radiation and the Dose of Radiation.Figure 2
Relation of the Serum Prolactin Concentration to the Dose of Radiation in Female Patients and Male Patients.Article Activity
- Article
Children and adults with brain tumors who are treated with cranial radiation may subsequently have deficits in neuroendocrine function1-13. Although deficiency of growth hormone is common, hypothyroidism and gonadal disturbances are seldom reported and are presumed to occur only after particularly high doses of radiation14-18. This underestimation of the threshold doses of radiation capable of damaging the hypothalamic-pituitary axis results from the lack of dose-related studies of patients evaluated at intervals sufficiently long for the sequelae of radiation to become evident.
With respect to the secretion of growth hormone, 65 percent of children with acute lymphoblastic leukemia treated with 2000 to 3000 rad (20 to 30 Gy) of cranial radiation have impaired serum growth hormone responses to provocative stimulation,12 and children with brain tumors who receive higher doses are even more likely to have abnormal secretion of growth hormone and abnormal growth1,3,7,11,13. The site of the injury is apparently the hypothalamus, since growth hormone-releasing hormone appropriately stimulates the secretion of growth hormone in these patients19.
Most studies of other neuroendocrine sequelae of cranial radiation have been done in children who received relatively low doses of radiation. For example, less than 5 percent of children treated for medulloblastoma with craniospinal radiation have hypothalamic or pituitary hypothyroidism,3,11 but the dose of radiation to the hypothalamus and pituitary is generally 3600 rad (36 Gy) or less. Conversely, about 30 percent of patients treated for other head or neck (generally nasopharyngeal) tumors with high doses of radiation that include the hypothalamic-pituitary axis have hypothyroidism, and about 80 percent have some type of hypothalamic-pituitary dysfunction20-23.
We began to appreciate that neuroendocrine abnormalities were more frequent than generally presumed when we evaluated a group of children and adults with brain tumors who had received radiation therapy24. Therefore, we examined these patients more thoroughly to determine the frequency and severity of clinical and chemical abnormalities of thyroid, gonadal, and adrenal function; the site of the abnormalities; and their relation to demographic or therapeutic factors.
Methods
Patients
The study group consisted of patients treated at the University of Rochester Cancer Center for a brain tumor not involving any portion of the hypothalamic-pituitary axis. Patients were considered eligible if they had no evidence of tumor recurrence, had not received radiation or chemotherapy for at least two years, and had been seizure-free for at least one year. All patients receiving care in the radiation-oncology follow-up clinic who met these criteria were asked to participate in the study, and informed consent was obtained from the patients or their parents. Patients who were taking anticonvulsant agents or hormones discontinued their medications at least one month (two months in the case of estrogen and progesterone preparations) before testing began.
The study group contained 32 patients (16 female and 16 male) who had been treated since 1973. Twenty-one patients had gliomas, five medulloblastomas, two ependymomas, and four other types of tumors. Their mean age at the time of radiation therapy was 19 years (range, 2 to 57), and at the time of the study, it was 26 years (range, 6 to 65). The mean interval between therapy and testing was 7 years (range, 2 to 13). Twenty patients (10 girls and 10 boys) were children ( ≤ 18 years of age) at the time of radiation therapy, and 16 were children (6 to 18 years) when tested.
Radiation Therapy
All patients had received radiation therapy, with a cobalt-60 unit or linear accelerators of 10 or 18 MV, to all or part of the hypothalamus and pituitary gland. Simulation or beam films were available for all patients and used to estimate the dose of radiation received by the two areas. Some patients had received whole-brain radiation, whereas in others treatment was localized. The calculated doses delivered to the hypothalamus and pituitary ranged from 3960 to 7020 rad (39.6 to 70.2 Gy), with a mean of 5360 rad (53.6 Gy). Nine patients had also received radiation to the spinal axis (1800 to 3960 rad [18.0 to 39.6 Gy]; mean, 3100 rad [31.0 Gy]). The dose of radiation to the thyroid gland, measured by thermoluminescent dosimetry, was 1.4 percent of the midline cranial dose. For the patients who received spinal-axis radiation, the dose to the thyroid averaged 92 percent of that prescribed.
Chemotherapy
Six adult patients received carmustine chemotherapy (80 mg per square meter of body-surface area intravenously for three days every two months for one to two years) concurrently with radiation therapy. One adult received six intravenous doses of methotrexate before undergoing any radiation therapy, and one child received vincristine, prednisone, and lomustine during and after radiation therapy.
Endocrinologic Evaluation
The patients were admitted to the University of Rochester Clinical Research Center early on the morning of study, at which time a history was obtained and a complete physical examination performed. Patients were considered postpubertal if they had mature secondary sexual characteristics (Tanner stage 5). Height was measured in the 20 patients who were irradiated during childhood, 19 of whom were 2 to 13 years of age when treated, and 6 of whom were 18 years or older when their height was measured.
All patients received thyrotropin-releasing hormone (TRH, 7 μg per kilogram of body weight; maximal dose, 200 μg), gonadotropin-releasing hormone (GnRH, 100 μg), and corticotropin (0.25 mg) intravenously in a single injection between 8 and 10 a.m. Fifteen adults also received corticotropin-releasing hormone (1 μg per kilogram) intravenously between 5 and 8 p.m. Blood samples were obtained for measurements of serum pituitary hormones and cortisol 20 minutes before the injection, at the time of the injection, and 15, 30, 45, 60, 90, and 150 minutes after the injection. Serum concentrations of free and total thyroxine (T4), total triiodothyronine (T3), estradiol, and testosterone were measured 20 minutes before the injection and at the time of the injection. Metyrapone was given orally (adults, 1.5 g; children, 30 mg per kilogram) between 11:30 p.m. and midnight; blood samples were obtained for measurements of serum 11-deoxycortisol, cortisol, and corticotropin at 8 a.m. the next morning. Serum concentrations of growth hormone or insulin-like growth factor I were not measured. Patients were not tested for posterior pituitary function, but no patient had symptoms of diabetes insipidus, excessive urinary output, or increased serum electrolyte concentrations.
Hormonal Assays
All hormones were measured by radioimmunoassay with commercial kits. The sensitivity and intraassay and interassay coefficients of variation were as follows: free T4: 0.085 ng per deciliter, 5.3 percent and 4.9 percent (Dade-Baxter Travenol Diagnostics, Cambridge, Mass.); total T4: 0.35 μg per deciliter, 5.0 percent and 5.3 percent (Dade-Baxter Travenol); total T3: 9.0 ng per deciliter, 3.6 percent and 4.8 percent (Clinical Assays, Stillwater, Minn.); thyrotropin: 0.3 mU per liter, 3.7 percent and 5.1 percent (Hybritech, San Diego, Calif.); cortisol: 0.20 μg per deciliter, 6.5 percent and 6.0 percent (Diagnostic Products, Los Angeles); testosterone: 4.03 ng per deciliter, 6.6 percent and 10.4 percent (Diagnostic Products); estradiol: 7.9 pg per milliliter, 4.3 percent and 6.8 percent (Diagnostic Products); prolactin: 3.7 ng per milliliter, 4.8 percent and 12.9 percent (Diagnostic Products); corticotropin: 15 ng per liter, 6.3 percent and 6.0 percent (Incstar, Stillwater, Minn.); luteinizing hormone (LH): 0.4 IU per liter, 3.4 percent and 4.0 percent (Clinetics, Tustin, Calif.); and follicle-stimulating hormone (FSH): 0.7 IU per liter, 3.3 percent and 3.9 percent (Clinetics). The basal values reported are the mean of the values in the samples obtained 20 minutes before the injection and at the time of injection.
The reference ranges (mean ±2 SD) for serum total and free T4 and total T3 concentrations were obtained by determining the levels in 80 normal subjects (31 men and 49 women), ranging from 19 to 67 years of age (median, 29). The reference ranges for the remaining hormones were obtained from the Laboratory Medicine Division of Strong Memorial Hospital, with the exception of the peak serum cortisol concentration in response to corticotropin-releasing hormone, which was from the literature25.
Statistical Analysis
The results are expressed as the mean ±SD. The serum total T4, free T4, total T3, and thyrotropin concentrations were compared between groups with the Mann-Whitney test26. Associations between endocrine measures and the dose of radiation to the hypothalamic-pituitary region, the age at treatment, and the interval between treatment and the study were assessed with Kendall's tau test27. The frequency of abnormalities in different groups was compared by Fisher's exact test28. The P values for all tests are two-sided. A patient's hormonal secretion was considered abnormal if he or she had a value outside the reference range, either basally or after provocative testing. In the summary analysis of data, patients were considered to have abnormal hormonal secretion if their basal serum hormone concentrations were low (high for prolactin only) or if they had a blunted response to provocative testing.
Results
Thyroid Function
Nine of the 32 patients had symptoms or signs of hypothyroidism, including lethargy (7 patients); intolerance to the cold (5 patients); dry hair, dry skin, and pronounced weight gain (2 patients each); and constipation (1 patient). These patients and nine others who were asymptomatic had low serum free T4 concentrations. All clinical abnormalities were ameliorated by thyroxine therapy.
The mean serum free T4, total T4, and total T3 concentrations in the 23 patients in the cranial-radiation group were significantly lower than those in the normal subjects (P<0.001 for each comparison) (Table 1Table 1
Hypothalamic-Pituitary-Thyroid Function in 32 Patients Who Received Cranial or Craniospinal Radiation.). Fifteen (65 percent), seven (30 percent), and five (22 percent) patients had serum free T4, total T4, and total T3 concentrations below normal, respectively, and all patients with low serum total T4 concentrations had low serum free T4 concentrations. The mean basal and peak serum thyrotropin concentrations in response to stimulation with TRH were within the respective normal ranges, and no patient had a supranormal response. Twelve of the 15 patients with below-normal concentrations of serum free T4 (80 percent) were thought to have hypothalamic hypothyroidism, as defined by a low serum free T4 concentration and normal basal and peak serum thyrotropin concentrations in response to stimulation with TRH. Three patients with a low serum free T4 concentration and a blunted response of serum thyrotropin (<5.0 mU per liter) to TRH were considered to have either hypothalamic or pituitary hypothyroidism.The mean serum free T4 concentration in the nine patients who received craniospinal radiation (and thus direct radiation to the thyroid) was lower than that in the normal subjects (P<0.001) (Table 1). Three of these patients had low serum free T4 concentrations, but none had low serum total T4 or T3 concentrations. The mean basal and peak serum thyrotropin concentrations in the group that received craniospinal radiation were normal. Two and three patients, respectively, had supranormal basal and supranormal peak serum thyrotropin concentrations after stimulation with TRH, a response reflecting injury to the thyroid gland. The group that received craniospinal radiation had higher basal (P = 0.05) and peak (P = 0.004) serum thyrotropin concentrations than the patients who received only cranial radiation.
There was a significant negative relation between the serum free T4 concentration and the interval between radiation and testing (P = 0.02) (Figure 1AFigure 1
Serum Free T Concentrations in Patients with Brain Tumors Treated with Cranial Radiation (Open Circles) or Craniospinal Radiation (Solid Circles) as a Function of the Time after Radiation and the Dose of Radiation.), but not between serum total T4 or T3 concentrations and this interval. Five of the 12 patients tested less than five years after receiving radiation had low serum free T4 concentrations, as compared with 13 of the 20 patients tested later.There was no significant correlation between the serum free T4 concentration and the dose of radiation in either group (Figure 1B). However, an increasing dose was associated with decreasing serum total T4 and T3 concentrations for both the entire study group (P<0.001 and P = 0.002, respectively) and the 23 patients who received cranial radiation (P = 0.03 and P = 0.006, respectively). Only patients treated with 5000 rad (50 Gy) or more to the hypothalamus and pituitary had serum total T4 concentrations of less than 4.5 μg per deciliter (57.9 nmol per liter) or free T4 concentrations of less than 0.6 ng per deciliter (7.7 pmol per liter). The three patients with the lowest values for each test received at least 5500 rad (55 Gy). The basal, but not the peak, serum thyrotropin concentrations after stimulation with TRH were lower among the patients in the cranial-radiation group who received higher doses (P = 0.04 and P = 0.12, respectively).
Both the basal and peak serum thyrotropin concentrations after stimulation with TRH were negatively correlated with age in the patients treated with cranial radiation (P = 0.007 and P = 0.032, respectively). Serum total T4 and T3 but not free T4 concentrations also were negatively correlated with age in the combined study group (P = 0.007 and P = 0.003, respectively) and in the 23 patients who received cranial radiation (P = 0.02 and P = 0.021, respectively).
Prolactin Secretion
The basal serum prolactin concentration was elevated in 16 of the 32 patients (50 percent) (Table 2Table 2
Hypothalamic-Pituitary-Gonadal Function in 32 Patients Who Received Cranial or Craniospinal Radiation. and Figure 2Figure 2Relation of the Serum Prolactin Concentration to the Dose of Radiation in Female Patients and Male Patients.). Two of the six women and one of the seven men with hyperprolactinemia reported decreased libido. On the basis of the patients' ages at the time of radiation therapy, hyperprolactinemia was more common in adults (75 percent) than in children (30 percent). One of the three patients with primary hypothyroidism had hyperprolactinemia.There was no relation between the serum prolactin concentration and the interval between radiation therapy and testing (P = 0.38) or the radiation dose (P = 0.17). However, the two women with mild hyperprolactinemia had received 4500 and 5000 rad (45 and 50 Gy), whereas the four women with the highest concentrations (26 to 39 ng per milliliter) had received more than 5500 rad (55 Gy) (Figure 2A). Only one male patient had a serum prolactin concentration of more than 20 ng per milliliter.
Gonadal Function
Of the 10 female patients who were postpubertal and premenopausal when studied, 3 had primary oligomenorrhea and 4 had secondary oligomenorrhea. Serum estradiol concentrations were undetectable in four, low in one, normal in four (including two with normal menstruation), and elevated in a sexually mature 13-year-old girl (bone age, 16 years) who was menstruating (Table 2). Four of the seven patients with oligomenorrhea as well as one normally menstruating woman had hyperprolactinemia. The basal serum FSH and LH concentrations were low in 0 and 4 of the 10 postpubertal, premenopausal women, respectively. The 13-year-old sexually mature girl had an elevated basal serum FSH concentration (28.2 IU per liter) and elevated peak serum FSH and LH responses to stimulation with GnRH. Both postmenopausal women had low basal serum FSH and LH concentrations. The peak serum FSH and LH responses to GnRH were low in only 3 and 1 of 11 postpubertal women, respectively (Figure 3Figure 3
Basal and GnRH-Stimulated Serum FSH and LH Concentrations in Postpubertal Patients with Brain Tumors Treated with Radiation.), despite the high frequency of oligomenorrhea.Serum testosterone concentrations were low in 3 of the 10 postpubertal men (30 percent) in whom it was measured. Two of the three had hyperprolactinemia, as did five of the seven men with normal serum testosterone concentrations. No man had symptoms clearly attributable to his low serum testosterone concentration; semen analyses were not performed. No postpubertal man had a low basal serum FSH concentration, although the peak concentrations after the administration of GnRH were low in nine. The basal LH concentrations after stimulation with GnRH were low in two men; the peak concentrations were low in none (Figure 3).
Seven children (four boys and three girls) were prepubertal, and two children (one boy and one girl) were pubertal when studied. The pubertal girl, who was 15 years of age (and who was irradiated at the age of 11), had no menstrual cycles, partial sexual development (Tanner stage 2 to 3), an undetectable serum estradiol concentration, and basal serum FSH and LH concentrations of 7.3 and 1.1 IU per liter, respectively. Of the prepubertal girls, one who was 11 years old (and who was irradiated at the age of 5) had an accelerated bone age (16 years) but no sexual development. The remaining two girls, who were 6 and 10 years of age when studied (2 and 6 years of age, respectively, when treated) were developmentally normal for their age. Among the six female patients who were treated before puberty (age, 5 to 11 years) and studied after the expected age of puberty, all but one had Tanner stage 4 or 5 sexual characteristics. The pubertal boy was 15 years of age (irradiated at the age of 12) and had Tanner stage 3 development and a normal serum testosterone concentration. Of the prepubertal boys, one who was 14 years old (irradiated at the age of 7) had no sexual development (Tanner stage 1), a low serum testosterone concentration, and a normal serum prolactin concentration. The remaining three boys, who were 8 to 11 years old when studied (4 to 7 years of age when treated), were developmentally normal for their age. Four other male patients who were treated before puberty (age, 3 to 13 years) attained full sexual maturation. The mean (±SD) basal serum LH and FSH concentrations for all seven prepubertal children were 3.5 ±1.7 and 4.9 ±1.8 IU per liter, respectively. The two pubertal children had normal serum FSH and LH responses to stimulation with GnRH29,30. The gonadotropin responses to GnRH in the prepubertal children are not included in Table 2 and Figure 3 because values for normal children were not available and the values reported in the literature vary widely29-32.
Adrenal Function
No patient had symptoms or signs of adrenal insufficiency, but three patients had low basal serum cortisol concentrations, and one patient had a low serum cortisol response to stimulation with corticotropin (Table 3Table 3
Hypothalamic-Pituitary-Adrenal Function in 32 Patients Who Received Cranial or Craniospinal Radiation.). This patient had panhypothalamic dysfunction, including hypothyroidism and hyperprolactinemia.The mean peak serum corticotropin response to corticotropin-releasing hormone was within the normal range in all 15 adults tested, and no patient had a subnormal response. The serum cortisol responses to corticotropin-releasing hormone were also normal or slightly exaggerated in all patients tested.
Eleven of the 31 patients tested (35 percent) had a subnormal serum 11-deoxycortisol response to the administration of metyrapone. There was an inverse correlation between the intensity of the serum 11-deoxycortisol response and the dose of radiation (P<0.001), and all patients with subnormal responses had received more than 5000 rad (50 Gy) (Figure 4Figure 4
Serum 11-Deoxycortisol Concentrations after the Administration of Metyrapone in Patients with Brain Tumors as a Function of the Dose of Radiation.).Growth
Only 4 of the 11 children who received cranial radiation and 2 of the 8 children who received craniospinal radiation attained a height above the third percentile. One patient was fully grown when treated at the age of 18 years. However, formal testing of growth hormone secretion was not performed.
Chemotherapy
Eight of the 32 patients received chemotherapy. There was no significant difference in the frequency of abnormal hormonal test results between these 8 patients and the 24 patients who did not receive chemotherapy, with the exception of elevated basal serum prolactin concentrations (P = 0.037). Of the eight patients who received chemotherapy, seven had hyperprolactinemia, two had primary and three had hypothalamic hypothyroidism, three had low gonadal test results, and three had low adrenal test results.
Summary of Findings
The pattern of hormonal (i.e., thyroid, gonadal, prolactin, and adrenal) abnormalities varied (Table 4Table 4
Type and Frequency of Hormonal Abnormalities in 32 Patients Who Received Cranial or Craniospinal Radiation.). There was no discernible predominance of any combination of hormonal deficits.Discussion
The reported frequency of pituitary or hypothalamic hypothyroidism and hypoadrenalism in patients with brain tumors not involving the pituitary gland who are treated with radiation is generally less than 5 percent, whereas that for hypogonadism is less than 20 percent1-13,33,34. In patients treated for other head or neck tumors with high doses of radiation to the hypothalamus and pituitary, the frequency of hormonal abnormalities ranges from 8 to 50 percent20-23. Possible explanations for this apparent inconsistency include the previous focus on children with medulloblastoma, who generally receive relatively low doses of radiation; the short interval between treatment and testing in some reports; the unreliability of clinical evaluations of endocrine deficiency; and the less sensitive and specific laboratory assessments used in the past. Because the results of our study are similar to those reported in patients with head or neck tumors, we suggest that endocrine dysfunction will occur frequently when patients with brain tumors are aggressively treated with large doses of radiation to a region that encompasses the hypothalamus and pituitary gland.
The most striking abnormality was the substantial frequency of pituitary or hypothalamic hypothyroidism in the patients who received cranial radiation alone. The greater number of patients found to have low serum free T4 concentrations, as compared with low serum total T4 or total T3 concentrations, presumably reflects the sensitivity of the free T4 measurement in the assessment of thyroid function. The most common pattern of abnormality was low concentrations of serum free or total T4 or T3 and normal basal and TRH-stimulated serum thyrotropin concentrations, findings suggestive of TRH deficiency35,36. Although the mechanism of radiation damage to the hypothalamus or pituitary is not known, it must involve a direct injury to the cells responsible for hormonal secretion, an injury to the stroma or its microvasculature, or an injury to the vascular channels that transfer the hypothalamic hormones to the pituitary. The correlation between the frequency of hypothyroidism and the interval between treatment and evaluation is compatible with both vascular injury and damage to parenchymal cells, which have a slow rate of turnover37. Since tissue injury caused by radiation is generally related to the dose of radiation, an increase in the frequency or severity of dysfunction with an increasing dose might be expected. Children treated with radiation therapy for leukemia or brain tumors are known to have growth hormone deficiency, with the onset dependent on the dose of radiation,38 and adults with pituitary tumors treated with radiation therapy have endocrine deficiencies more commonly after higher doses of radiation39. We found a clear inverse relation between the dose of radiation and serum total T4 and T3 concentrations, as well as basal and stimulated serum thyrotropin concentrations. The absence of an association between the dose of radiation and serum free T4 concentration is unexplained. The influence of age on the propensity for hypothalamic-pituitary injury also remains unclear. Although older age did appear to be associated with hypothyroidism, the interpretation of this association is complicated, because most of the children received lower doses of radiation.
The occurrence of primary hypothyroidism in patients who received craniospinal radiation was expected, because their thyroid gland was irradiated directly. Primary hypothyroidism resulting from direct radiation to the thyroid gland is well recognized; up to 80 percent of patients with Hodgkin's disease treated with mantle radiation have primary hypothyroidism, and the effect is dose-dependent40-43. The hypothyroidism that occurs in these patients could be due to radiation damage to the thyroid follicular cells, the thyroid vasculature, or the supporting stroma37.
The 50 percent frequency of hyperprolactinemia in our patients is best explained by an injury to the hypothalamus that disrupts its normal inhibition of prolactin secretion by the pituitary lactotrophs. The extent to which hyperprolactinemia contributed to gonadal dysfunction is uncertain, since the hyperprolactinemia was slight.
Seventy percent of the women and one of the pubertal girls had oligomenorrhea. The presence of low serum estradiol concentrations and low or normal basal and GnRH-stimulated serum LH and FSH concentrations is compatible with GnRH deficiency. Similarly, the decreased serum testosterone concentrations in some of the men may have resulted from GnRH deficiency, since their serum LH and FSH concentrations were normal or slightly low. The documented capability of the pituitary to respond to GnRH argues against pituitary, as opposed to hypothalamic, hypogonadism.
Basal pituitary-adrenal function was normal, or nearly so, in most patients. Thirty-five percent of the patients, however, had a low serum 11-deoxycortisol response to the administration of metyrapone, and the degree of the abnormality correlated inversely with the dose of radiation. Yet the results of corticotropin-releasing hormone and corticotropin stimulation were normal or slightly increased. This apparent inconsistency may be due to the fact that metyrapone stimulates the release of corticotropin by lowering cortisol secretion, whereas corticotropin and to a lesser extent corticotropin-releasing hormone were administered in pharmacologic doses.
In conclusion, both children and adults with brain tumors are at risk for hypothalamic and pituitary injury after radiation therapy. The spectrum of endocrinologic abnormalities that occurs suggests that hypothalamic dysfunction is more common than pituitary dysfunction. The clinical consequences of these abnormalities are most apparent in the thyroid and gonadal axes. Evaluating patients after radiation therapy for brain tumors for neuroendocrine sequelae, and treating them when necessary, should enhance the quality of their lives.
Presented in part at the 33rd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Washington, D.C., November 4-8, 1991.
Supported in part by a general Clinical Research Center grant (RR00044) from the Division of Research Resources, National Institutes of Health.
We are indebted to Mrs. Ann G. Muhs for assistance in the preparation of the manuscript.
Source Information
From the Department of Radiation Oncology (L.S.C., P.R.), Pediatric Oncology Division, Department of Pediatrics (L.S.C.), Endocrinology Division, Department of Medicine (P.D.W.), and the Department of Biostatistics (R.F.R.), University of Rochester Medical Center, Rochester, N.Y.; the Department of Radiation Oncology, Dover General Hospital, Dover, N.J. (D.C.); and the Endocrinology Division, Department of Pediatrics, State University of New York Health Science Center, Syracuse (G.M., K.M.).
Address reprint requests to Dr. Constine at the Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14642-8647.
- References
References
1
Duffner PK ,Cohen ME ,Voorhess ML , et al. Long-term effects of cranial irradiation on endocrine function in children with brain tumors: a prospective study. Cancer 1985;56:2189-2193
CrossRef | Web of Science | Medline2
Harrop JS ,Davies TJ ,Capra LG ,Marks V . Hypothalamic-pituitary function following successful treatment of intracranial tumours. Clin Endocrinol (Oxf) 1976;5:313-321
CrossRef | Web of Science | Medline3
Oberfield SE ,Allen JC ,Pollack J ,New MI ,Levine LS . Long-term endocrine sequelae after treatment of medulloblastoma: prospective study of growth and thyroid function. J Pediatr 1986;108:219-223
CrossRef | Web of Science | Medline4
Livesey EA ,Brook CGD . Thyroid dysfunction after radiotherapy and chemotherapy of brain tumours. Arch Dis Child 1989;64:593-595
CrossRef | Web of Science | Medline5
Livesey EA ,Brook CGD . Gonadal dysfunction after treatment of intracranial tumours. Arch Dis Child 1988;63:495-500
CrossRef | Web of Science | Medline6
Shalet SM ,Beardwell CG ,Morris-Jones PH ,Pearson D . Pituitary function after treatment of intracranial tumours in children. Lancet 1975;2:104-107
CrossRef | Web of Science | Medline7
Shalet SM ,Beardwell CG ,Pearson D ,Jones PH . The effect of varying doses of cerebral irradiation on growth hormone production in childhood. Clin Endocrinol (Oxf) 1976;5:287-290
CrossRef | Web of Science | Medline8
Perry-Keene DA ,Connelly JF ,Young RA ,Wettenhall HN ,Martin FI . Hypothalamic hypopituitarism following external radiotherapy for tumours distant from the adenohypophysis. Clin Endocrinol (Oxf) 1976;5:373-380
CrossRef | Web of Science | Medline9
Danoff BF ,Cowchock FS ,Marquette C ,Mulgrew L ,Kramer S . Assessment of the long-term effects of primary radiation therapy for brain tumors in children. Cancer 1982;49:1580-1586
CrossRef | Medline10
Wara WM ,Richards GE ,Grumbach MM ,Kaplan SL ,Sheline GE ,Conte FA . Hypopituitarism after irradiation in children. Int J Radiat Oncol Biol Phys 1977;2:549-552
CrossRef | Web of Science | Medline11
Abayomi OK ,Sadeghi-Nejad A . The incidence of late endocrine dysfunction following irradiation for childhood medulloblastoma. Int J Radiat Oncol Biol Phys 1986;12:945-948
CrossRef | Web of Science | Medline12
Rappaport R ,Brauner R . Growth and endocrine disorders secondary to cranial irradiation. Pediatr Res 1989;25:561-567
CrossRef | Web of Science | Medline13
Brauner R ,Rappaport R ,Prevot C , et al. A prospective study of the development of growth hormone deficiency in children given cranial irradiation, and its relation to statural growth. J Clin Endocrinol Metab 1989;68:346-351
CrossRef | Web of Science | Medline14
Brunner H . Ueber den Einfluss der Rontgenstrahlen auf das Gehirn. Arch Klin Chir 1920;114:332-37215
Kelly KH ,Feldsted ET ,Brown RF , et al. Irradiation of the normal human hypophysis in malignancy: report of three cases receiving 8,100-10,000 r tissue dose to the pituitary gland. J Natl Cancer Inst 1951;11:967-983
Web of Science | Medline16
Crompton MR ,Layton DD . Delayed radionecrosis of the brain following therapeutic X-radiation of the pituitary. Brain 1961;84:85-101
CrossRef | Web of Science | Medline17
Almquist S ,Dahlgren S ,Notter G ,Sundbom L . Brain necrosis after irradiation of the hypophysis in Cushing's disease: report of a case. Acta Radiol Ther Phys Biol 1964;2:179-188
Medline18
Wigg DR ,Murray RML ,Koschel K . Tolerance of the central nervous system to photon irradiation: endocrine complications. Acta Radiol [Oncol] 1982;21:49-60
CrossRef | Medline19
Lannering B ,Albertsson-Wikland K . Growth hormone release in children after cranial irradiation. Horm Res 1987;27:13-22
CrossRef | Web of Science | Medline20
Samaan NA ,Vieto R ,Schultz PN , et al. Hypothalamic, pituitary and thyroid dysfunction after radiotherapy to the head and neck. Int J Radiat Oncol Biol Phys 1982;8:1857-1867
CrossRef | Web of Science | Medline21
Samaan NA ,Schultz PN ,Yang KP , et al. Endocrine complications after radiotherapy for tumors of the head and neck. J Lab Clin Med 1987;109:364-372
Medline22
Lam KSL ,Tse VK ,Wang C ,Yeung RTT ,Ho JHC . Effects of cranial irradiation on hypothalamic-pituitary function -- a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q J Med 1991;78:165-176
Web of Science | Medline23
Bajorunas DR ,Ghavimi F ,Jereb B ,Sonenberg M . Endocrine sequelae of antineoplastic therapy in childhood head and neck malignancies. J Clin Endocrinol Metab 1980;50:329-335
CrossRef | Web of Science | Medline24
Constine LS ,Rubin P ,Woolf PD ,Doane K ,Lush CM . Hyperprolactinemia and hypothyroidism following cytotoxic therapy for central nervous system malignancies. J Clin Oncol 1987;5:1841-1851
Web of Science | Medline25
Schurmeyer TH ,Avgerinos PC ,Gold PW , et al. Human corticotropin-releasing factor in man: pharmacokinetic properties and dose-response of plasma adrenocorticotropin and cortisol secretion. J Clin Endocrinol Metab 1984;59:1103-1108
CrossRef | Web of Science | Medline26
Some methods based on ranks. In: Conover WJ. Practical nonparametric statistics. 2nd ed. New York: John Wiley, 1980:215-8.
27
Measures of association for ordinal variables. In: Agresti A. Analysis of ordinal categorical data. New York: John Wiley, 1984:161-3.
28
Assessing significance in a fourfold table. In: Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York: John Wiley, 1981:24-6.
29
Quigley C ,Cowell C ,Jimenez M , et al. Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia. N Engl J Med 1989;321:143-151
Full Text | Web of Science | Medline30
Dickerman Z ,Prager-Lewin R ,Laron Z . Response of plasma LH and FSH to synthetic LH-RH in children at various pubertal stages. Am J Dis Child 1976;130:634-638
Web of Science | Medline31
Garnier PE ,Chaussain J-L ,Binet E ,Schlumberger A ,Job J-C . Effect of synthetic luteinizing hormone-releasing hormone (LH-RH) on the release of gonadotrophins in children and adolescents. VI. Relations to age, sex and puberty. Acta Endocrinol (Copenh) 1974;77:422-434
Medline32
Reiter EO ,Kaplan SL ,Conte FA ,Grumbach MM . Responsivity of pituitary gonadotropes to luteinizing hormone-releasing factor in idiopathic precocious puberty, precocious thelarche, precocious adrenarche, and in patients treated with medroxyprogesterone acetate. Pediatr Res 1975;9:111-116
Web of Science | Medline33
Sklar CA . Growth and pubertal development in survivors of childhood cancer. Pediatrician 1991;18:53-60
Medline34
Deutsch M. Late effects of craniospinal radiotherapy for medulloblastoma. In: Zeltzer PM, Pochedly C, eds. Medulloblastomas in children: new concepts in tumor biology, diagnosis and treatment. New York: Praeger, 1986: 213-36.
35
Hajjar RA ,Anderson MS ,Samaan NA . Thyrotropin-releasing hormone as a pituitary-function indicator: a comparison with other tests. Arch Intern Med 1973;132:836-839
CrossRef | Web of Science | Medline36
Snyder PJ ,Jacobs LS ,Rabello MM , et al. Diagnostic value of thyrotrophin-releasing hormone in pituitary and hypothalamic diseases: assessment of thyrotrophin and prolactin secretion in 100 patients. Ann Intern Med 1974;81:751-757
Web of Science | Medline37
Rubin P, Casarett G. Clinical radiation pathology. Philadelphia: W.B. Saunders, 1968.
38
Clayton PE ,Shalet SM . Dose dependency of time of onset of radiation-induced growth hormone deficiency. J Pediatr 1991;118:226-228
CrossRef | Web of Science | Medline39
Littley MD ,Shalet SM ,Beardwell CG ,Robinson EL ,Sutton ML . Radiation-induced hypopituitarism is dose-dependent. Clin Endocrinol (Oxf) 1989;31:363-373
CrossRef | Web of Science | Medline40
Constine LS ,Donaldson SS ,McDougall IR ,Cox RS ,Link MP ,Kaplan HS . Thyroid dysfunction after radiotherapy in children with Hodgkin's disease. Cancer 1984;53:878-883
CrossRef | Web of Science | Medline41
Slanina J ,Musshoff K ,Rahner T ,Stiasny R . Long-term side effects in irradiated patients with Hodgkin's disease. Int J Radiat Oncol Biol Phys 1977;2:1-19
Web of Science | Medline42
Ramsay N ,Kim T ,Coccia P ,Ulstrom R ,Krivit W ,Nesbit M . Thyroid dysfunction in pediatric patients after mantle field radiation therapy for Hodgkin's disease. Proc Am Assoc Cancer Res Proc Am Soc Clin Oncol 1978;19:389-389 abstract.
Web of Science43
Glatstein E ,McHardy-Young S ,Brast N ,Eltringham JR ,Kriss JP . Alterations in serum thyrotropin (TSH) and thyroid function following radiotherapy in patients with malignant lymphoma. J Clin Endocrinol Metab 1971;32:833-841
CrossRef | Web of Science | Medline
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CrossRef12
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CrossRef15
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CrossRef16
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CrossRef17
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CrossRef18
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CrossRef29
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CrossRef32
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CrossRef46
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CrossRef48
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CrossRef49
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CrossRef50
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CrossRef51
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CrossRef52
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CrossRef53
C. Kretschmar, L. Kleinberg, M. Greenberg, P. Burger, Emi Holmes, M. Wharam. (2007) Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: A report from the Children's Oncology Group. Pediatric Blood & Cancer 48:3, 285-291
CrossRef54
Jorge A Alvarez, Rebecca E Scully, Tracie L Miller, F Daniel Armstrong, Louis S Constine, Debra L Friedman, Steven E Lipshultz. (2007) Long-term effects of treatments for childhood cancers. Current Opinion in Pediatrics 19:1, 23-31
CrossRef55
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CrossRef56
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CrossRef57
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CrossRef58
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CrossRef59
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CrossRef60
Mark Sherlock, Andrew A Toogood. (2006) Sensitivity of anterior pituitary hormones to irradiation. Expert Review of Endocrinology & Metabolism 1:5, 633-649
CrossRef61
F. Borson-Chazot, T. Brue. (2006) Pituitary deficiency after brain radiation therapy. Annales d'Endocrinologie 67:4, 303-309
CrossRef62
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CrossRef63
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CrossRef64
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CrossRef65
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CrossRef66
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CrossRef67
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CrossRef68
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CrossRef69
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CrossRef70
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CrossRef71
Laurie E. Cohen. (2005) Endocrine Late Effects of Cancer Treatment. Endocrinology & Metabolism Clinics of North America 34:3, 769-789
CrossRef72
R Hameed, MR Zacharin. (2005) Long-term endocrine effects of cancer treatment: Experience of the Royal Children's Hospital, Melbourne. Journal of Paediatrics and Child Health 41:1-2, 36-42
CrossRef73
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CrossRef74
Patricia K. Duffner. (2004) Long-Term Effects of Radiation Therapy on Cognitive and Endocrine Function in Children With Leukemia and Brain Tumors. The Neurologist 10:6, 293-310
CrossRef75
MK Garg. (2004) Target gland dysfunction following external cranial radiation for extrasellar tumours. Medical Journal Armed Forces India 60:4, 342-347
CrossRef76
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CrossRef77
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CrossRef78
Claire Phillips, David Willis, Jim Cramb, Franc Chicas-Angulo, Maree Sexton. (2004) A modified technique for craniospinal irradiation in children designed to reduce acute and late radiation toxicity. Australasian Radiology 48:2, 188-194
CrossRef79
Barbara A Jereczek-Fossa, Daniela Alterio, Jacek Jassem, Bianca Gibelli, Nicoletta Tradati, Roberto Orecchia. (2004) Radiotherapy-induced thyroid disorders. Cancer Treatment Reviews 30:4, 369-384
CrossRef80
Stephen A Sands. (2004) Central Nervous System Germ Cell Tumors. American Journal of Cancer 3:1, 41-46
CrossRef81
M. Pugeat. (2004) Advances in Growth Hormone Therapy: A New Registry Tool. Hormone Research 62:Suppl. 4, 2-7
CrossRef82
Lorna Zadravec Zaletel, Nevenka Bratanič, Berta Jereb. (2004) Gonadal Function in Patients Treated for Leukemia in Childhood. Leukemia & Lymphoma 45:9, 1797-1802
CrossRef83
MK Garg. (2004) Growth hormone and prolactin secretion after external cranial irradiation for extrasellar tumours. Medical Journal Armed Forces India 60:1, 35-38
CrossRef84
Annice Mukherjee, Robert D. Murray, Breeda Columb, Helena K. Gleeson, Stephen M. Shalet. (2003) Acquired prolactin deficiency indicates severe hypopituitarism in patients with disease of the hypothalamic-pituitary axis. Clinical Endocrinology 59:6, 743-748
CrossRef85
Bruce E. Pollock, Paul C. Carpenter. (2003) Stereotactic Radiosurgery as an Alternative to Fractionated Radiotherapy for Patients with Recurrent or Residual Nonfunctioning Pituitary Adenomas. Neurosurgery 53:5, 1086-1094
CrossRef86
Michelle P Warren, Caroline Vu. (2003) Central causes of hypogonadism—functional and organic. Endocrinology & Metabolism Clinics of North America 32:3, 593-612
CrossRef87
Bruce E. Pollock. (2003) Radiosurgery for Intracranial Meningiomas. Neurosurgery Quarterly 13:2, 77-86
CrossRef88
Bruce E. Pollock. (2003) Stereotactic radiosurgery for intracranial meningiomas: indications and results. Neurosurgical FOCUS 14:5, 1-7
CrossRef89
Costas G. Hadjipanayis, Douglas Kondziolka, John C. Flickinger, L. Dade Lunsford. (2003) The role of stereotactic radiosurgery for low-grade astrocytomas. Neurosurgical FOCUS 14:5, 1-7
CrossRef90
Massimo Gerosa, Antonio Nicolato, Roberto Foroni. (2003) The role of gamma knife radiosurgery in the treatment of primary and metastatic brain tumors. Current Opinion in Oncology 15:3, 188-196
CrossRef91
S Kanumakala, GL Warne, MR Zacharin. (2003) Evolving hypopituitarism following cranial irradiation. Journal of Paediatrics and Child Health 39:3, 232-235
CrossRef92
H.A. Spoudeas, E. Charmandari, C.G.D. Brook. (2003) Hypothalamo-pituitary-adrenal axis integrity after cranial irradiation for childhood posterior fossa tumours. Medical and Pediatric Oncology 40:4, 224-229
CrossRef93
M. Degerblad, K. Brismar, T. Rahn, M. Thoren. (2003) The hypothalamus-pituitary function after pituitary stereotactic radiosurgery: evaluation of growth hormone deficiency. Journal of Internal Medicine 253:4, 454-462
CrossRef94
Laurie E. Cohen. (2003) Endocrine late effects of cancer treatment. Current Opinion in Pediatrics 15:1, 3-9
CrossRef95
Nicole E Cross, Michael J Glantz. (2003) Neurologic complications of radiation therapy. Neurologic Clinics 21:1, 249-277
CrossRef96
Edward J. Dropcho. 2003. Neurologic Complications of Radiation Therapy. , 1140-1146.
CrossRef97
Z PETROVICH, G JOZSEF, C YU, M APUZZO. (2003) Radiotherapy and stereotactic radiosurgery for pituitary tumors. Neurosurgery Clinics of North America 14:1, 147-166
CrossRef98
Helen A. Spoudeas. (2002) Growth following malignancy. Best Practice & Research Clinical Endocrinology & Metabolism 16:3, 561-590
CrossRef99
Bruce E. Pollock, Todd B. Nippoldt, Scott L. Stafford, Robert L. Foote, Charles F. Abboud. (2002) Results of stereotactic radiosurgery in patients with hormone-producing pituitary adenomas: factors associated with endocrine normalization. Journal of Neurosurgery 97:3, 525-530
CrossRef100
Constantinos G. Hadjipanayis, Douglas Kondziolka, Paul Gardner, Ajay Niranjan, Shekhar Dagam, John C. Flickinger, L. Dade Lunsford. (2002) Stereotactic radiosurgery for pilocytic astrocytomas when multimodality therapy is necessary. Journal of Neurosurgery 97:1, 56-64
CrossRef101
A. Gudmundsdottir, J. A. Schlechte. (2002) Central Hypothyroidism. The Endocrinologist 12:3, 218-223
CrossRef102
Arnold C. Paulino, B.-Chen Wen, John M. Buatti, David H. Hussey, Weining K. Zhen, Nina A. Mayr, Arnold H. Menezes. (2002) Intracranial Ependymomas. American Journal of Clinical Oncology 25:2, 117-122
CrossRef103
Jørn Müller. (2002) Disturbance of pubertal development after cancer treatment. Best Practice & Research Clinical Endocrinology & Metabolism 16:1, 91-103
CrossRef104
Ajay Sandhu, Jacqueline Williams, Louis Constine. 2002. Late Effects of Radiation Therapy. , 7-19.
CrossRef105
Daniel M. Anderson, Kimberly M. Rennie, Richard S. Ziegler, Joseph P. Neglia, Leslie R. Robison, James G. Gurney. (2001) Medical and neurocognitive late effects among survivors of childhood central nervous system tumors. Cancer 92:10, 2709-2719
CrossRef106
Scott L. Stafford, Bruce E. Pollock, Robert L. Foote, Michael J. Link, Deborah A. Gorman, Paula J. Schomberg, Jacqueline A. Leavitt. (2001) Meningioma Radiosurgery: Tumor Control, Outcomes, and Complications among 190 Consecutive Patients. Neurosurgery 49:5, 1029-1038
CrossRef107
Charlotte Höybye, Eva Grenbäck, Tiit Rähn, Marie Degerblad, Marja Thorén, Anna-Lena Hulting. (2001) Adrenocorticotropic Hormone-producing Pituitary Tumors: 12- to 22-year Follow-up after Treatment with Stereotactic Radiosurgery. Neurosurgery 49:2, 284-292
CrossRef108
Charlotte H??ybye, Eva Grenb??ck, Tiit R??hn, Marie Degerblad, Marja Thor??n, Anna-Lena Hulting. (2001) Adrenocorticotropic Hormone-producing Pituitary Tumors: 12- to 22-year Follow-up after Treatment with Stereotactic Radiosurgery. Neurosurgery 49:2, 284-292
CrossRef109
Takeshi Nakajima, Toshihiro Kumabe, Hidefumi Jokura, Takashi Yoshimoto. (2001) Recurrent Germinoma in the Optic Nerve: Report of Two Cases. Neurosurgery 48:1, 214-218
CrossRef110
Jonas M. Sheehan, Mary L. Vance, Jason P. Sheehan, Dilantha B. Ellegala, Edward R. Laws. (2000) Radiosurgery for Cushing's disease after failed transsphenoidal surgery. Journal of Neurosurgery 93:5, 738-742
CrossRef111
Schmiegelow, Lassen, Poulsen, Feldt-Rasmussen, Schmiegelow, Hertz, Muller. (2000) Cranial radiotherapy of childhood brain tumours: Growth hormone deficiency and its relation to the biological effective dose of irradiation in a large population based study. Clinical Endocrinology 53:2, 191-197
CrossRef112
Andrew W. Walter, Amar Gajjar, David A. Reardon, Stephen J. Thompson, James W. Langston, Dana Jones-Wallace, Larry E. Kun, Richard L. Heideman. (2000) Tamoxifen and Carboplatin for Children With Low-Grade Gliomas: A Pilot Study at St. Jude Children's Research Hospital. Journal of Pediatric Hematology/Oncology 22:3, 247-251
CrossRef113
Janneke Heikens, Mathilde C. Ubbink, Heleen P. J. van der Pal, Piet J. M. Bakker, Eric Fliers, Tineke J. Smilde, John J. P. Kastelein, Mieke D. Trip. (2000) Long term survivors of childhood brain cancer have an increased risk for cardiovascular disease. Cancer 88:9, 2116-2121
CrossRef114
Marianne Schmiegelow, Soren Lassen, Lars Weber, Hans Skovgaard Poulsen, Henrik Hertz, Joern M
CrossRef115
Daniel Arbaiza, Kathy Noriega, Julio Marcial, Antonio Wachtel, Clara Perez, Carlos F. Torres. (1999) Ectopic production of prolactin in an infant with non-Hodgkin lymphoma. Medical and Pediatric Oncology 32:4, 311-312
CrossRef116
Thomas Moshang. (1998) Use of growth hormone in children surviving cancer. Medical and Pediatric Oncology 31:3, 170-172
CrossRef117
R. Jeffrey Lee, Sharon H. Smith, Wesley L. Hicks, Vaseem Iqbal, Daniel M. Green. (1998) Management of extraosseous Ewing sarcoma of the infratemporal fossa. Medical and Pediatric Oncology 31:1, 31-35
CrossRef118
David Schiff, Tracy Batchelor, Patrick Y. Wen. (1998) NEUROLOGIC EMERGENCIES IN CANCER PATIENTS. Neurologic Clinics 16:2, 449-483
CrossRef119
A MONNIER. (1997) Effets tardifs de la radioth
CrossRef120
Lillian R. Meacham, Thad T. Ghim, Ian R. Crocker, Mark S. O'Brien, Joseph Petronio, Patricia Davis, Beth C. Vogel, Nicolas S. Krawiecki. (1997) Systematic approach for detection of endocrine disorders in children treated for brain tumors. Medical and Pediatric Oncology 29:2, 86-91
CrossRef121
Sadhna M. Shankar, Nancy J. Bunin, Thomas Moshang. (1996) Growth in Children Undergoing Bone Marrow Transplantation After Busulfan and Cyclophosphamide Conditioning. Journal of Pediatric Hematology/Oncology 18:4, 362-366
CrossRef122
Thomas Moshang, Adda Grimberg. (1996) THE EFFECTS OF IRRADIATION AND CHEMOTHERAPY ON GROWTH. Endocrinology & Metabolism Clinics of North America 25:3, 731-741
CrossRef123
J. J. Groot-Loonen, B. J. Otten, M. A. van't Hof, R. J. J. Lippens, G. B. A. Stoelinga. (1996) Influence of treatment modalities on body weight in acute lymphoblastic leukemia. Medical and Pediatric Oncology 27:2, 92-97
CrossRef124
Juan Román, Carmen J. Villaizán, Jesús García-Foncillas, Cristina Azcona, Javier Salvador, Luis Sierrasesúmaga. (1995) Chemotherapy-induced growth hormone deficiency in children with cancer. Medical and Pediatric Oncology 25:2, 90-95
CrossRef125
Andrew A. Toogood, W. David, J. Ryder, Colin G. Beardwell, Stephen M. Shalet. (1995) The evolution of radiation-induced growth hormone deficiency in adults is determined by the baseline growth hormone status. Clinical Endocrinology 43:1, 97-103
CrossRef126
M. J. B. Taphoorn, J. J. Heimans, E. A. Veen, A. B. M. F. Karim. (1995) Endocrine functions in long-term survivors of low-grade supratentorial glioma treated with radiation therapy. Journal of Neuro-Oncology 25:2, 97-102
CrossRef127
Willemina M Molenaar, John Q. Trojanowski. (1994) Primitive neuroectodermal tumors of the central nervous system in childhood: tumor biological aspects. Critical Reviews in Oncology/Hematology 17:1, 1-25
CrossRef128
S. J. KELLIE, H. SOMERVILLE, C. T. COWELL. (1994) CURING CNS GERMINOMAS IN ADOLESCENTS: IS CRANIOSPINAL IRRADIATION NECESSARY?. Journal of Paediatrics and Child Health 30:4, 372a-372
CrossRef129
Vance, Mary Lee. (1994) Hypopituitarism. New England Journal of Medicine 330:23, 1651-1662
Full Text130
Ryszard M. Pluta, Zvi Ram, Nicholas J. Patronas, Harry Keiser. (1994) Long-term effects of radiation therapy for a catecholamine-producing glomus jugulare tumor. Journal of Neurosurgery 80:6, 1091-1094
CrossRef131
Berta Jereb, Roman Korenjak, Ciril Kržišnik, Gabrtjela Petrič-Grabnar, Lorna Zadravec-Zaletel, Jožica Anzic, Janez Stare. (1994) Late Sequelae in Children Treated for Brain Tumors and Luekemia. Acta Oncologica 33:2, 159-164
CrossRef132
Shalet, Steven M., . (1993) Radiation and Pituitary Dysfunction. New England Journal of Medicine 328:2, 131-133
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