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Changes in intracranial pressure associated with delayed cerebral radionecrosis.

Continuous recording of intracranial pressure (ICP) from one lateral ventricle in a case of histologically proven delayed temporal radionecrosis due to previous irradiation of the pituitary gland for the treatment of an adiposity of the Cushing type has revealed the occurrence of B-waves and ramplike waves despite the absence of raised intracranial pressure. Ventriculo-atrial shunting failed to relieve the severe psychic symptomatology, which was due to direct tissue damage. These observations indicate that B-waves may have a neurogenic origin.

Brain↗

Hyperprolactinemia and hypogonadism in the human female.

Prolactin is a mammotropic hormone essential for the initiation of lactation. It also influences ovarian function; during hyperprolactinemia hypogonadism occurs. This is true for pathological forms of hyperprolactinemia but also for the early puerperium when there is physiological hyperprolactinemia. Amenorrhea is a better parameter of hyperprolactinemia than galactorrhea. The mechanisms by which prolactin disrupts ovarian function are not as yet fully understood; it probably alters hypothalamic neurotransmitter content through a direct feedback mechanism resulting in a decrease of Gn-RH. However, the direct effect of prolactin-producing pituitary tumors on the capacity of the gonadotrophs or a direct interference of prolactin at the gonadal level are also possibilities. Hyperprolactinemia can be treated very effectively with bromocriptine and this drug appears to have become the favorite form of treatment. In the case of obvious tumors hypophysectomy is indicated. When there are smaller tumors irradiation of the pituitary gland previous to bromocriptine treatment may prevent expansion of the gland during subsequent pregnancy.

Amenorrhea↗

Hypothalamic, pituitary and thyroid dysfunction after radiotherapy to the head and neck.

One hundred-ten patients who had nasopharyngeal cancer and paranasal sinus tumors and were free of the primary disease were studied one to 26 years following radiotherapy. There were 70 males and 40 females ranging in age from 4 to 75 years, with a mean age of 36.5 years. During therapy both the hypothalamus and the anterior pituitary gland were in the field of irradiation. The radiation dose to the hypothalamus and the anterior pituitary gland was estimated to be 400 to 7500 rad with a median dose of 5618 rad to the anterior pituitary gland and a median dose of 5000 rad to the hypothalamus. We found evidence of endocrine deficiencies in 91 of the 110 patients studied. Seventy-six patients showed evidence of one or more hypothalamic lesions and 43 patients showed evidence of primary pituitary deficiency. Forty of the 66 patients who received radiotherapy to the neck for treatment or prevention of lymph node metastasis showed evidence of primary hypothyroidism. The range of the dose to the thyroid area was 3000 to 8800 rad with a median of 5000 rad. One young adult woman who developed galactorrhea and amenorrhea 2 years following radiotherapy showed a high serum prolactin level, but had normal anterior pituitary function and sella turcica. She regained her menses and had a normal pregnancy and delivery following bromocriptine therapy. These results indicate that endocrine deficiencies after radiotherapy for tumors of the head and neck are common and should be detected early and treated. Long-term follow-up of these patients is indicated since complications may appear after the completion of radiotherapy.

Adolescent↗

A follow-up study of childhood nasopharyngeal radium irradiation in Washington County, Maryland.

In 1978 an epidemiologic study exploring the health consequences of nasopharyngeal radium irradiation among individuals treated for adenoid enlargement in Washington County, Maryland, found an excess risk of brain tumors and a deficit of female breast cancers. The study population included all persons first seen at the Washington County Clinic for the Prevention of Deafness in Children from 1940 to January 1, 1960. We will continue the follow-up of irradiated and nonirradiated patients to (1) assess the risk of brain tumors and other neoplasms of the head and neck developing during a 40-year period, (2) assess hormone-related disorders resulting from irradiation of the pituitary gland, and (3) compare cancer incidence and mortality rates among exposed and nonexposed groups. Of the 2135 persons eligible for this study, 93.5% have been traced, and 90% have replied to a mailed questionnaire that elicits information on demographic characteristics, reproductive and medical history, infertility, and other sources of radiation exposure. Information on cancer incidence and mortality is being obtained from the Washington County Cancer Registry and death certificate files from Washington County and the Social Security Administration. Statistical methods to be used in the data analysis include standardized mortality ratios, standardized cancer incidence ratios, and Kaplan-Meier survival analysis.

Brain Neoplasms↗

Serum testosterone levels in women with Cushing's disease.

Serum testosterone was measured pre- and post-operatively in 31 women who obtained remission of Cushing's disease following treatment by interstitial irradiation of the pituitary gland. The mean serum testosterone was initially elevated at 3.35 nmol/l, with values ranging from 0.7 to 14.4 nmol/l. Following treatment the mean serum testosterone fell to 1.42 nmol/l (i.e. normal) and all but one of the 15 patients with initially elevated pre-treatment values obtained normal levels. The pretreatment testosterone concentrations correlated significantly (r = 0.47; p = 0.019) with the midnight ACTH concentration. The likely determinant of the raised serum testosterone would appear to be the intensity of the ACTH drive, although an individual's inherent sensitivity to ACTH may also be a factor.

Adolescent↗

[The effect of proton therapy on the protein-amino acid metabolism in Itsenko-Cushing disease].

The composition and blood concentration of free aminoacids and other aminocompounds were investigated using automatic aminoacid analysis by a physiological program in 12 patients with diagnosed corticotropin secreting hypophyseal disease (Itsenko-Cushing disease) before and 1-3 years after proton "hypophysectomy". Imbalance of components of the glucose-alanine cycle, expressed in hypoalaninemia and raised concentration of aminoacids with a bifurcated lateral chain, was detected against a background of marked hypercorticotropinemia and hypercorticolism. Single irradiation of the pituitary gland with a proton beam at absorbed doses of 100-120 Gy in the maximum of a deep field resulted in remission and normalization of aminograms of blood plasma (suggesting pathogenicity of proton-beam therapy) for 6-12 mos. The authors discussed probable mechanisms of the interrelationship of protein-amino-acid and carbohydrate metabolic derangements and their correlation with a type of changes in the hormonal balance.

Adult↗

[Immunohistochemical detection of hormones in hypophyseal adenomas of the rat after fractionated irradiation].

BACKGROUND: The aim of this study was to determine the hormones produced in pituitary gland tumours (TM) following fractionated external irradiation in rats. The TM arose in the course of studies on other questions of radiation effects. METHODS: The left neck and skull base of sixty female Wistar rats, 3 to 4 months of age at the beginning of the external irradiation, were subjected to roentgen rays exposure, fractionated to 2 Grays daily, either up to 20, 40 or 60 Gy. The midline of the neck and skull was always inside the radiation field. The animals were sacrificed either 6 months or 12 months after completion of the randomly assigned irradiation protocol. Five non-irradiated rats served as controls. RESULTS: No TM developed in the non-irradiated animals. Out of 60 irradiated rats 9 developed a pituitary TM (15%). In remnants of the normal adenohypophysis we revealed immunohistochemical reactivity for growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin (PRL), thyroid stimulating hormone (TSH), and follicle stimulating hormone (FSH). In the radiation-induced adenomas, 4 TM were immuno-reactive for TSH, 4 for GH, 2 for PRL, and 2 for FSH. The TM did not react with anti-ACTH and anti-LH (luteinizing hormone) anti-sera. CONCLUSIONS: Obviously, irradiation accelerates the development of pituitary gland adenomas. In this series the TM were predominantly incidental findings at necropsies after pretermed follow-up intervals with a variety of hormone-producing cells. On the other hand, four of nine TM were null adenomas. Necropsies of the brain should be carried out routinely in irradiation studies of the skull.

Adenoma↗

Hormone production in pituitary adenomas following external irradiation: an experimental study in rats.

INTRODUCTION: The aim of this study was to investigate the hormone production in pituitary gland tumors following fractionated external irradiation in rats. MATERIALS AND METHODS: Sixty female Wistar rats 3 to 4 month of age at the beginning of the experiments, were subjected to fractionated roentgen-rays exposure, 2 Grays (Gy) daily, either up to 20, 40 or 60 Gy. The animals were sacrificed either 6 month or 1 year after completion of the randomly assigned irradiation protocol. RESULTS: We found 9 pituitary tumors in 60 irradiated rats (15%). All tumors proved to be adenomas. Immunohistochemical analysis of hormone production in remnants of the normal adenohypophysis revealed immunoreactivity for growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin (PRL), thyroid-stimulating hormone (TSH), and follicle-stimulating hormone (FSH). In adenomas, 4 cases were immunoreactive for TSH, 4 for GH, 2 for PRL, and 2 for FSH. The tumors were not reactive with anti-ACTH and anti-LH (luteinizing hormone). DISCUSSION: We concluded that irradiation accelerates the development of pituitary gland adenomas. In our series these tumors were predominantly incidental findings at necropsies after pre-termed follow-up, with a variety of hormone producing tumor cells. However, 4 of 9 tumors in our study were not producing hormones.

Animals↗

Malignant pituitary tumors.

Pituitary malignancies are rare. The definition of pituitary malignancy is still subject to debate. Three types of malignancy with the description of clinical course and complete autopsy were presented; i) true carcinosarcoma, ii) ectopic sphenoid invasive tumor, and iii) post-irradiation sarcoma. The first true carcinosarcoma had a long natural tumor history of 46 years, ending in malignant transformation with extracranial metastasis from a pituitary adenoma. The second ectopic sphenoid tumor was prolactin-producing, locally invasive, with the intact pituitary gland. The third post-irradiation sarcoma was followed by chromophobe pituitary adenoma. The interval between irradiation to the adenoma and malignant transformation to fibrosarcoma was about 14 years.

Adenoma↗

Radiation-induced tumorigenesis of mammary glands in pituitary transplanted rats ovariectomized before onset of estrous cycle.

The role of prolactin in the initiation of mammary tumorigenesis by radiation was evaluated in ovarian hormone-free rats. Rats were bilaterally ovariectomized at 23 days of age, and then, at 2.5 months of age, two pituitaries obtained from mature rats of the same strain were transplanted underneath the kidney capsule as a means of increasing the serum prolactin level to provide stimulation of development of mammary glands. After 2 weeks, the ovariectomized rats with ectopic pituitary glands were exposed to whole body irradiation of 2.6 Gy of gamma-rays from a 60Co source and then treated with diethylstilbestrol as a tumor promoter. For the control, ovariectomized rats without ectopic pituitary glands were exposed and treated in the same way as the experimental group. A significant increase of serum prolactin level was observed at the time of irradiation by the pituitary transplanted rats, and intense immunohistochemical reaction with a specific anti-prolactin antiserum was detected in the ectopic pituitary glands. Also, mammary glands in the pituitary transplanted rats, ovariectomized before puberty, showed lactiferous ducts without alveolar buds at the time of tumor initiation. The pituitary transplanted rats showed a significantly increased incidence of adenocarcinoma and fibroadenoma compared with the control. Many of the mammary tumors induced in the pituitary transplanted rats given radiation were estrogen receptor (ER)(+) progesterone receptor (PgR)(+) and ER(+)PgR(-) tumors, whereas ER(-)PgR(-) tumors were mainly obtained in the control rats. In the experimental group, many of the fibroadenomas had low concentrations of ER and no PgR, while the adenocarcinomas had moderate concentrations of ER and high PgR. These results suggest that hypersecretion of prolactin from the pituitary transplants developed lactiferous ducts and accelerated the tumorigenesis of mammary glands initiated by radiation in the absence of synergism with ovarian hormones.

Animals↗

Endocrine complications after radiotherapy for tumors of the head and neck.

One hundred sixty-six patients 6 to 80 years of age with nasopharyngeal cancer and paranasal sinus tumors who were free of the primary disease were studied from 1 to 26 years after radiotherapy. Studies in 65 of these patients were performed prospectively. Both the hypothalamus and the anterior pituitary gland were in the field of irradiation. The median radiation dose was estimated to be 5700 rad to the anterior pituitary gland and 5000 rad to the hypothalamus. We found evidence of endocrine deficiencies in 134 of the 166 patients observed. One hundred eleven patients showed evidence suggestive of hypothalamic lesions and 67 patients showed evidence of primary pituitary deficiency. Forty-eight of the 110 patients who received radiotherapy to the neck for treatment or prevention of lymph node metastasis showed evidence of primary hypothyroidism. The median dose to the thyroid area was 5000 rad. Adolescents younger than 15 years of age had a higher incidence of growth hormone deficiency soon after radiotherapy, but the older group showed adrenocortical and luteinizing hormone deficiency. These results indicate that endocrine deficiencies after radiotherapy for tumors of the head and neck are common. The highest incidence of complications occurred 1 to 5 years after radiotherapy, but long-term follow-up is indicated because complications may appear years after radiotherapy.

Adolescent↗

Treatment of Cushing's disease in juveniles with interstitial pituitary irradiation.

Nine juvenile patients (five boys and four girls aged 10--18 with Cushing's disease were treated with pituitary implantation of 198Au and/or 90Y. No patient had any surgical complication from the procedure. At the latest assessment, 3 months to 17 years after operation, Cushing's disease was in remission in all the patients; the response time following operation was a few days to 3 months. Radiology of the pituitary fossa at time of pituitary implantation was normal in all patients and remains so. The final height in six patients is 149--172 cm (59--67.5 inches) and three patients who continue to grow have increased by 13, 6 and 3 cm since implantation. Only one patient required full pituitary hormone replacement therapy, and he had been previously treated by external irradiation, and one other patient failed to complete puberty. In all the other seven sexual maturation is normal and one has fathered two children. We conclude that pituitary implantation with interstitial irradiation is a satisfactory form of treatment for Cushing's disease in juveniles.

Adolescent↗

Conventional pituitary irradiation in acromegaly. Effect on growth hormone and TSH secretion.

Thirty-one patients who had been treated for acromegaly for 1-21 years with conventional pituitary irradiation were re-examined. Immunoreactive growth hormone (GH) was measured in connection with an oral glucose load. Adrenal and gonadal functions were assessed on the basis of plasma cortisol and the urinary excretion of 17-ketogenic steroids, 17-ketosteroids and gonadotrophins. In evaluating the thyroid-pituitary axis the thyrotrophin-releasing hormone stimulation test (TRH) was used. Initially 30 patients had experienced definite benefit from the treatment but at the time of re-examination 10 still had clinically active disease and required another type of treatment. Normal GH levels (less than 5 ng/ml/1) were seen in only 12 patients. Skin thickness was normal in 15 out of 30. Thus the remission rate can be evaluated as being 67% as regards clinical activity, 50% with regard to skin thickness and 39% in terms of GH levels. Hypogonadism occurred in 12 patients (39%) and adrenal and thyroid failure in 5 patients each (16%). The response to TRH was within the normal range in 2 of the hypothyroid patients. In 22 euthyroid patients the mean increment in serum TSH in response to 200 mug of synthetic TRH was only 5.8 mU/1 which was significantly below the normal mean 12.5 mU/1. Furthermore, in 7 of these patients (32%) the response was absent or subnormal (less than 3.0 mU/1). This indicated that the pituitary is capable of secreting enough TSH for maintenance of an euthyroid state but that its capacity is limited. Conventional pituitary irradiation is not a very effective treatment in acromegaly but may still be recommended in selected cases.

Acromegaly↗