RESUMO
PURPOSE: This study was undertaken to show whether the rate of expression of radiation injury in the rat pituitary gland could be accelerated by the use of growth stimulants. METHODS AND MATERIALS: Rat pituitary glands were irradiated in situ with a range of single doses up to 20 Gy. The rats were then given subcutaneous slow-release implants containing 17beta-estradiol (E2) and sulpiride (S) to stimulate lactotroph proliferation. Two sequential cycles were used, each consisting of stimulation (3 weeks) and withdrawal (2 weeks). Measurements were made of gland weight; BrdU-labeled, giant, and apoptotic cells; lactotrophs; as well as pituitary prolactin content, in response to exogenous thyroid-releasing hormone (TRH). RESULTS: The two cycles of stimulation/withdrawal resulted in marked changes in gland weight, BrdU-labeling index, and serum prolactin (PRL) levels in unirradiated rats. The proportion of immunopositive growth-hormone-producing (GH) cells increased after irradiation. Radiation inhibited the hypertrophic response to E2 + S and also inhibited increases in BrdU-labeling index and serum PRL levels. Also, giant lactotrophs were observed in the irradiated pituitaries. However, they were not seen in the unirradiated rats or in the irradiated rats treated with E2 + S. TRH promoted PRL secretion in the unirradiated rat. In contrast, TRH inhibited PRL secretion in the irradiated rat and in all treatment groups receiving E2 + S. Apoptosis was induced by irradiation and was substantially increased in lactotrophs and in other cell types by withdrawal of the E2 and S stimulus, although the highest observed incidence was only 7 per 10,000 cells. CONCLUSION: Both irradiation and E2 + S treatment removed the hypothalamic control of PRL secretion, which reveals this important inhibitory action of TRH upon PRL secretion. This suggests that it is not suitable as a dynamic test of pituitary PRL reserves in such abnormal situations, where there may also be damage to the hypothalamic-pituitary vasculature. The increasing proportion of GH cells after irradiation indicates that lactotrophs respond more rapidly to irradiation. The stimulation by E2 + S somehow prevented the radiation-damaged lactotrophs from becoming giant cells. Also, the ratio of apoptotic cells to BrdU-labeled cells was increased by the E2 + S treatment, indicating that the E2 + S did enhance radiation-induced cell death relative to cell renewal. However, overall, the E2 + S stimulus protocol did not promote a dramatic increase in cell death (apoptosis) nor a marked decrease in residual gland weight after irradiation. Hence, its use would probably not be beneficial in the treatment of slow-responding prolactinomas, if malignant lactotrophs respond similarly to the normal pituitary lactotrophs. However, the observation of induced apoptosis after hormone and drug withdrawal suggests that agents which promote tumor shrinkage may be effective by causing rapid apoptosis of tumor cells in vivo.
Assuntos
Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Divisão Celular/efeitos dos fármacos , Divisão Celular/efeitos da radiação , Estradiol/farmacologia , Substâncias de Crescimento/farmacologia , Hipófise/efeitos dos fármacos , Hipófise/efeitos da radiação , Sulpirida/farmacologia , Animais , Masculino , Tamanho do Órgão/efeitos dos fármacos , Hipófise/patologia , Prolactina/sangue , Ratos , Ratos WistarRESUMO
A radioimmunoassay method for the measurement of arginine-vasopressin (AVP) in human plasma has been developed which requires 5 ml of plasma and has a lower limit of detection of 1-8 pg/ml plasma. Arginine-vasopressin was found to be stable in whole blood for up to 1 h at room temperature and for at least 4 h at 4 degrees C, while in plasma stored at -20 degrees C no loss was seen over 10 days. Dehydration and rehydration in normal subjects produced appropriate changes in AVP concentration but there was considerable variability in the levels attained by individual subjects and no obvious correlation with plasma osmolality. No consistent increase in plasma AVP concentration was seen on change of posture from the recumbent to the upright position. Vigorous exercise produced a marked rise in plasma AVP concentrations in most subjects which could not be attributed simply to an increase in plasma osmolality. In fusion studies with Pitressin in normal subjects showed a mean half-life of 6-4 min with an overall plasma clearance rate of 8-5 ml/min/kg body weight and a mean volume of distribution of 5-33 l. In patients with a biochemical picture suggestive of inappropriate antidiuretic hormone secretion, markedly raised plasma AVP concentrations were found only in patients with bronchial carcinoma.
Assuntos
Arginina Vasopressina/sangue , Radioimunoensaio , Vasopressinas/análogos & derivados , Arginina Vasopressina/metabolismo , Preservação de Sangue , Neoplasias Brônquicas/sangue , Desidratação/sangue , Furosemida , Hormônio do Crescimento/sangue , Humanos , Hidrocortisona/sangue , Hiponatremia/sangue , Leucemia/sangue , Concentração Osmolar , Esforço Físico , Postura , Tireotropina/sangue , Urina , Vasopressinas/farmacologiaRESUMO
The lectin-binding properties of serum alpha subunit were studied by lectin affinity chromatography. Normal individuals and most patients with pituitary tumours produced alpha subunit which bound specifically to Concanavalin A-Sepharose (Con A). Some patients with pituitary tumours produced both Con A-reactive alpha subunit and alpha subunit which did not bind to Con A. Concanavalin A-Sepharose-binding alpha subunit from all sources bound strongly to Ricinus communis agglutinin-Sepharose after treatment with neuraminidase. Serum alpha subunit from those patients with pituitary tumours, which did not bind to Con A, bound to wheat germ agglutinin-Sepharose, exhibiting both weakly binding and strongly binding forms. Serum alpha subunit from both patients and controls, which did bind to Con A, showed only weak affinity for wheat germ agglutinin-Sepharose. Neither the low affinity nor the high affinity of serum alpha subunit from any source for wheat germ agglutinin-Sepharose was affected by neuraminidase. These findings show that (a) the predominant pattern of glycosylation of serum alpha subunit from normal controls is a Con A-reactive, biantennate complex oligosaccharide and (b) that the structural alteration which results in serum alpha subunit which does not bind to Con A in some patients with pituitary tumours is not an absence of carbohydrate, rather the alpha subunit contains highly branched, either complex or hybrid oligosaccharides.
Assuntos
Concanavalina A/metabolismo , Fragmentos de Peptídeos/metabolismo , Hormônios Adeno-Hipofisários/metabolismo , Lectinas de Plantas , Adulto , Cromatografia de Afinidade , Cromatografia em Gel , Cromatografia por Troca Iônica , Feminino , Subunidade alfa de Hormônios Glicoproteicos , Humanos , Lectinas/metabolismo , Masculino , Pessoa de Meia-Idade , Oligossacarídeos/metabolismo , Neoplasias Hipofisárias/análise , Ligação Proteica , Sefarose/metabolismo , Aglutininas do Germe de TrigoRESUMO
Serum alpha subunits from patients with pituitary tumours and from normal controls were studied for their ability to bind to Lens culinaris agglutinin-Sepharose (LCA), L-phytohaemagglutinin-agarose (L-PHA) and soybean agglutinin-Sepharose (SBA). Serum alpha subunits from normal controls which had previously been shown to bind to Concanavalin A-Sepharose (Con A) were not retained by LCA. In contrast, Con A-reactive alpha subunits from patients with pituitary tumours bound specifically to LCA. Non-Con A-reactive alpha subunits from patients with pituitary tumours were also largely not bound to LCA, but were retained by L-PHA. No alpha subunits from any source bound to SBA. These results indicate that the structural alterations resulting in non-Con A-reactive serum alpha subunits include highly branched complex oligosaccharides in addition to the hybrid-type glycans previously described. The increased branching appears to be associated with fucosylation in the core region of the oligosaccharides. Serum alpha subunit from any source appears to be devoid of terminal N-acetylgalactosamine residues. These structural modifications may be related to the variable biological activity of alpha subunit which has been reported.
Assuntos
Fragmentos de Peptídeos , Hormônios Adeno-Hipofisários , Sequência de Carboidratos , Cromatografia de Afinidade , Feminino , Subunidade alfa de Hormônios Glicoproteicos , Humanos , Lectinas , Pessoa de Meia-Idade , Oligossacarídeos/metabolismo , Fragmentos de Peptídeos/metabolismo , Hormônios Adeno-Hipofisários/metabolismo , Neoplasias Hipofisárias/análise , Ligação ProteicaRESUMO
A case of Cushing's syndrome due to micronodular adrenal disease in a 17-year-old girl is presented. The adrenals showed both black and yellow nodules. Histologically the cells contained lipofuschin and either had a clear cytoplasm or an eosinophilic cytoplasm with a prominent nucleus. Lymphocytes were a prominent feature. No cells of the zona reticularis were identified. The cell of origin of these nodules appeared to be from the inner layer of the zona fasciculata. We postulate that the disease is caused by an abnormality in the migration and ultimate destruction of cells from the zona fasciculata to the zona reticularis with a build up of cells at the interface zone.
Assuntos
Doenças do Córtex Suprarrenal/patologia , Adolescente , Córtex Suprarrenal/ultraestrutura , Doenças do Córtex Suprarrenal/complicações , Síndrome de Cushing/etiologia , Feminino , Humanos , Lisossomos/ultraestrutura , Microscopia Eletrônica , Mitocôndrias/ultraestrutura , Tamanho do ÓrgãoRESUMO
The combination of trilostane 960 mg daily and either dexamethasone 0.5 mg b.d. or hydrocortisone 10 mg b.d. has been used to treat advanced metastatic breast cancer in post-menopausal women. Twenty-three patients had assessable disease and received treatment for a minimum of 8 weeks. Six (26%) showed an objective response and three (13%), stabilisation of previously progressive disease, sustained for at least 3 months. Side-effects were mainly gastrointestinal. Biochemical studies suggest that the mechanism of action may be inhibition of conversion of androstenedione to oestrone.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Di-Hidrotestosterona/análogos & derivados , Antineoplásicos/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Di-Hidrotestosterona/administração & dosagem , Di-Hidrotestosterona/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Hidrocortisona/administração & dosagem , Hidrocortisona/efeitos adversos , Pessoa de Meia-Idade , Metástase NeoplásicaAssuntos
Radioimunoensaio , Vasopressinas/sangue , Sequência de Aminoácidos , Arginina , Carcinoma Broncogênico/sangue , Cromatografia em Gel , Hormônios Ectópicos , Humanos , Hiponatremia/sangue , Isótopos de Iodo , Lisina , Métodos , Nicotina/farmacologia , Concentração Osmolar , Plasma , Urina , Vasopressinas/metabolismo , Privação de ÁguaAssuntos
Glândulas Endócrinas/efeitos da radiação , Neoplasias/radioterapia , Adolescente , Neoplasias Encefálicas/radioterapia , Criança , Pré-Escolar , Feminino , Gônadas/efeitos da radiação , Hormônio do Crescimento/deficiência , Humanos , Sistema Hipotálamo-Hipofisário/efeitos da radiação , Masculino , Radioterapia/efeitos adversos , Glândula Tireoide/efeitos da radiação , Tireotropina/metabolismoAssuntos
Doenças da Glândula Tireoide/terapia , Antagonistas Adrenérgicos beta/uso terapêutico , Carbimazol/uso terapêutico , Quimioterapia Combinada , Feminino , Bócio/diagnóstico , Bócio/terapia , Doença de Graves/terapia , Humanos , Hipertireoidismo/congênito , Hipertireoidismo/tratamento farmacológico , Hipotireoidismo/tratamento farmacológico , Radioisótopos do Iodo , Gravidez , Complicações na Gravidez , Propranolol/uso terapêutico , Doenças da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/diagnóstico , Tireoidectomia , Tireotropina/sangue , Tiroxina/uso terapêuticoAssuntos
Abdome Agudo/etiologia , Hipertireoidismo/diagnóstico , Abdome Agudo/tratamento farmacológico , Adulto , Antiácidos/uso terapêutico , Peso Corporal , Carbimazol/uso terapêutico , Cólica/diagnóstico , Diarreia/etiologia , Feminino , Bócio/cirurgia , Hematemese/complicações , Humanos , Radioisótopos do Iodo , Masculino , Metoclopramida/uso terapêutico , Náusea/etiologia , Propranolol/uso terapêutico , Pulso Arterial , Sudorese , Taquicardia/etiologia , Trombocitopenia/complicações , Glândula Tireoide/fisiopatologia , Vômito/etiologiaRESUMO
A 31-year-old acromegalic was normoprolactinaemic after partial removal of her pituitary tumour. The post-operative external pituitary irradiation lowered the mean growth hormone (GH) level from 75 mU/1 to less than 1 mU/1 within 2 years. However, at the same time hyperprolactinaemia developed. These changes in the GH and prolactin levels were confirmed 3 and 4 years after irradiation. The cause of the hyperprolactinaemia was radiation-induced hypothalamic damage. Therefore it is suggested that similar damage may occur in patients receiving external pituitary irradiation for 'prolactinomas' and that this mechanism may contribute to the persistent hyperprolactinaemia observed in such patients.
Assuntos
Acromegalia/radioterapia , Hipotálamo/efeitos da radiação , Neoplasias Hipofisárias/radioterapia , Prolactina/sangue , Radioterapia/efeitos adversos , Acromegalia/etiologia , Adulto , Feminino , Hormônio do Crescimento/sangue , Hormônio do Crescimento/metabolismo , Humanos , Hipófise/efeitos da radiação , Neoplasias Hipofisárias/complicações , Prolactina/metabolismo , Taxa Secretória/efeitos da radiaçãoRESUMO
In adults, hypopituitarism is a common consequence of external radiotherapy. The clinical manifestations may be subtle and develop insidiously many years after radiotherapy. Anterior pituitary deficiencies can therefore only be detected by regular testing, including dynamic tests of GH and ACTH reserve. Although the deficiencies most commonly develop in the order GH, gonadotrophins, ACTH then TSH, this sequence may not be predictable in an individual patient and comprehensive testing is therefore required. The tests should ideally be performed annually for at least 10 years after treatment or until deficiency has been detected and treated. It is not only the patients with pituitary disease who are at risk of developing hypopituitarism after radiotherapy. Any patient who receives a total dose of irradiation of 20 Gy or more to the hypothalamic-pituitary axis is at risk of hypopituitarism, although the threshold dose may be lower than this. This is particularly important in the long-term survivors of malignant disease in whom endocrine morbidity may be relatively common and in whom this can be easily treated, with consequent improvement in quality of life. Whilst patients who receive a high total dose of irradiation are at increased risk of developing multiple deficiencies, a higher fraction size also increases the risk of anterior pituitary failure. There is good evidence that the earliest damage to the hypothalamic-pituitary axis after external radiotherapy is at the level of the hypothalamus. However, patients who undergo pituitary ablation with interstitial radiotherapy or heavy particle beams are likely to sustain direct damage to the pituitary. In these patients, the sequence in which individual pituitary hormone deficiencies develop is generally the same as that observed with the hypothalamic damage after conventional external radiotherapy. The increasing use of radiotherapy as a means of treatment for malignant disease means that new groups of patients with potential for endocrine dysfunction are emerging. Whole body irradiation in the preparation for bone marrow transplant is one such treatment and although hypothalamic-pituitary damage appears to be confined to GH deficiency in children, longitudinal experience is limited to date, particularly in adults. The treatment of malignant disease in childhood is of particular importance in terms of the delayed endocrine sequelae. The hypothalamic-pituitary axis may not be the only endocrine tissue damaged by treatment in these patients and management is therefore more complicated. In the growing child, the potential association of growth hormone deficiency, gonadal failure or premature puberty and thyroid dysfunction mean that expert endocrine supervision is essential for optimum long-term outcome.
Assuntos
Sistema Hipotálamo-Hipofisário/efeitos da radiação , Radioterapia/efeitos adversos , Relação Dose-Resposta à Radiação , Feminino , Gonadotropinas/deficiência , Hormônio do Crescimento/deficiência , Humanos , Hipotálamo/efeitos da radiação , Masculino , Hipófise/efeitos da radiação , Puberdade/efeitos da radiaçãoRESUMO
OBJECTIVE: A number of studies of the effect of GH replacement therapy in adult patients with GH deficiency have been published, but the definition of GH deficiency has varied considerably. In order to define severe GH deficiency more critically we have determined GH status in the context of gonadotrophin, ACTH and TSH secretion in adult patients with pituitary disease. DESIGN: Analysis of peak GH response to an insulin tolerance test performed during comprehensive assessment of pituitary function. PATIENTS: One hundred and ninety non-acromegalic patients (96 male) with pituitary disease whose ages ranged from 16 to 72 (mean 39.4) years. MEASUREMENTS: The patients were divided into four groups according to the number of anterior pituitary hormone deficiencies demonstrated; isolated GH deficiency (GHD0), or GH deficiency plus an additional one, two or three pituitary hormone deficits (GHD1, GHD2, GHD3). RESULTS: The four groups were matched for age and blood glucose nadir during the ITT. The median (interquartile range) GH peaks were GHD0, 10.0 (5.4-16); GHD1, 4.0 (2.7-7.7); GHD2, 2.0 (1-2.9); GHD3, 1.8 (1-3.2) mU/l. There was a significant downward trend in the medians (P < 0.0001). The differences between GHD0 and GHD1, and GHD1 and GHD2, were highly significant (P < 0.0001); however, there was no difference between GHD2 and GHD3. Ninety-one per cent of patients in combined groups GHD2 and GHD3, 55% in GHD1 and 24% in GHD0 had a peak GH < 5 mU/l. CONCLUSIONS: Our study has shown that GH deficiency is variable according to the degree of hypopituitarism present and that the greater the number of pituitary hormone deficits the more severe the GH deficiency. These observations will help to clarify the diagnosis of GH deficiency in adult life.
Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Gonadotropinas Hipofisárias/metabolismo , Hormônio do Crescimento/deficiência , Doenças da Hipófise/fisiopatologia , Hipófise/fisiopatologia , Tireotropina/metabolismo , Adolescente , Adulto , Idoso , Feminino , Hormônio do Crescimento/metabolismo , Humanos , Insulina , Masculino , Pessoa de Meia-Idade , Hormônios Hipofisários/deficiênciaRESUMO
Growth hormone (GH) secretion has been studied under physiological conditions and in response to standard pharmacological stimuli in 14 children, who had previously received cranial irradiation between two and fourteen years earlier. All fourteen showed a blunted GH response to insulin hypoglycaemia and, in twelve, the GH response to arginine stimulation was also subnormal. Physiological GH secretion was studied by measuring integrated GH concentrations in 30 min blood samples collected over a 24 hour period by a continuous withdrawal pump. Compared to normal controls (n = 5), the irradiated patients showed a significant reduction in the mean integrated GH concentration (2.2: 8.8 mU/l; p less than 0.002), the total 24 hour GH output (mean 105.7 mU vs. 391.7 mU; p less than 0.002) and the mean GH output during the first six hours of sleep (mean 48.2 mU vs. 226 mU; p less than 0.002). There was no significant correlation between the maximum peak GH response to either pharmacological test and the total 24 hour GH output. Conventionally most short children undergo two provocative tests of GH release and if the GH response to one of the two tests is normal, it is usually assumed that GH production is adequate. Adopting these criteria in this study it would have been assumed incorrectly that GH production was normal in two children. Nonetheless all 14 children showed a blunted GH response to an ITT as well as a reduced total 24 hour GH output.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Encéfalo/efeitos da radiação , Hormônio do Crescimento/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos da radiação , Adolescente , Arginina/farmacologia , Neoplasias Encefálicas/radioterapia , Criança , Pré-Escolar , Feminino , Seguimentos , Hormônio do Crescimento/sangue , Humanos , Leucemia Linfoide/radioterapia , MasculinoRESUMO
Familial dysalbuminaemic hyperthyroxinaemia (FDH) can be confused with thyrotoxicosis if clinical signs and laboratory tests are misinterpreted. We describe three members of the same family with FDH who were erroneously treated for thyrotoxicosis. Screening of other family members resulted in the discovery of a further six patients at risk of being misdiagnosed as thyrotoxic. Clinical and biochemical findings relevant to the diagnosis of FDH are discussed.
Assuntos
Hipertireoxinemia/genética , Adulto , Criança , Humanos , Hipertireoxinemia/diagnóstico , Masculino , Pessoa de Meia-Idade , Albumina Sérica/análise , Tireotropina/sangue , Tri-Iodotironina/sangueRESUMO
Two patients presenting with diabetes mellitus and hypokalaemia resulting from markedly increased ACTH and cortisol secretion are described. Neither patient showed any evidence of a tumour and both responded dramatically to treatment with metyrapone in that all abnormal clinical features disappeared, ACTH concentrations returned to normal and both patients showed prolonged remission after metyrapone treatment was stopped. One patient relapsed after a severe viral illness and the administration of dexamethasone and cortisone. It is suggested that these cases may represent an unusual form of Cushing's syndrome in which ACTH secretion is stimulated by increasing concentrations of cortisol. When these are reduced by metyrapone administration ACTH secretion falls in parallel and prolonged remission of disease may result.
Assuntos
Síndrome de Cushing/tratamento farmacológico , Metirapona/uso terapêutico , Hormônio Adrenocorticotrópico/metabolismo , Idoso , Síndrome de Cushing/fisiopatologia , Feminino , Humanos , Hidrocortisona/metabolismo , Masculino , Testes de Função Adreno-HipofisáriaRESUMO
We have studied the relationship between abnormalities of the growth hormone-somatomedin axis and growth in 26 children previously treated for acute lymphatic leukemia. Each child had previously received cranial irradiation, was in complete clinical and hematologic remission, and off all drugs. The mean standing height SDS of the 26 children was significantly less than normal. There was no significant difference between the mean standing height SDS, height velocity SDS, somatomedin activities, and degree of bone age retardation between the 17 children who received the higher dose of cranial irradiation (Group 1) and the nine who had the lower dose of cranial irradiation (Group II). Furthermore, there was no significant reduction in mean height velocity SDS, somatomedin activity, or bone age in either group when compared to normal age-matched controls. The peak GH responses to both insulin hypoglycemia and an arginine test were significantly lowered in Groups I and II when compared to a control group of children. We conclude that only a minority of children, who previously received cranial irradiation for ALL were clinically GH deficient and, therefore, likely to benefit from GH therapy despite the finding that the majority of these children had reduced GH responses to pharmacologic stimuli.
Assuntos
Hormônio do Crescimento/metabolismo , Crescimento , Leucemia Linfoide/fisiopatologia , Somatomedinas/metabolismo , Determinação da Idade pelo Esqueleto , Antineoplásicos/uso terapêutico , Arginina , Glicemia/metabolismo , Estatura , Encéfalo/efeitos da radiação , Feminino , Humanos , Insulina , Leucemia Linfoide/tratamento farmacológico , Leucemia Linfoide/radioterapia , Masculino , Dosagem RadioterapêuticaRESUMO
Testicular function was studied in ten men, aged between 17 and 36 years, who had received irradiation for a nephroblastoma during childhood. The dose of scattered irradiation to the testes ranged from 268 to 983 rad. Eight subjects had either oligo- or azoospermia (0 to 5.6 million/ml), seven of whom had an elevated serum follicle-stimulating hormone (FSH) level. One subject showed evidence of Leydig cell dysfunction with a raised serum luteinizing hormone level (LH) and a low plasma testosterone concentration. A second group of eight prepubertal males, aged between 8 and 14 years, were studied. These had also been irradiated for abdominal malignancies during childhood and received a similar dose of irradiation to the testis as the first group studied. The plasma testosterone levels were within the normal range for prepubertal boys in all eight. The mean gonadotrophin levels were not significantly different from the mean levels of normal prepubertal males. Thus irradiation-induced damage to the germinal epithelium in prepubertal boys produces raised FSH levels after puberty but not before it. We conclude, therefore, that inhibition has a minor role in the control of the prepubertal hypothalamic-pituitary testicular axis and its contribution to gonadal control of gonadotrophin secretion changes with sexual maturation.