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OBJECTIVES: Salivary cortisol and cortisone at late night and after dexamethasone suppression test (DST) are increasingly used for screening of Cushing's syndrome (CS). We aimed to establish reference intervals for salivary cortisol and cortisone with three liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques and for salivary cortisol with three immunoassays (IAs), and evaluate their diagnostic accuracy for CS. METHODS: Salivary samples at 08:00 h, 23:00 h and 08:00 h after a 1-mg DST were collected from a reference population (n=155) and patients with CS (n=22). Sample aliquots were analyzed by three LC-MS/MS and three IA methods. After establishing reference intervals, the upper reference limit (URL) for each method was used to calculate sensitivity and specificity for CS. Diagnostic accuracy was evaluated by comparing ROC curves. RESULTS: URLs for salivary cortisol at 23:00 h were similar for the LC-MS/MS methods (3.4-3.9 nmol/L), but varied between IAs: Roche (5.8 nmol/L), Salimetrics (4.3 nmol/L), Cisbio (21.6 nmol/L). Corresponding URLs after DST were 0.7-1.0, and 2.4, 4.0 and 5.4 nmol/L, respectively. Salivary cortisone URLs were 13.5-16.6 nmol/L at 23:00 h and 3.0-3.5 nmol/L at 08:00 h after DST. All methods had ROC AUCs ≥0.96. CONCLUSIONS: We present robust reference intervals for salivary cortisol and cortisone at 08:00 h, 23:00 h and 08:00 h after DST for several clinically used methods. The similarities between LC-MS/MS methods allows for direct comparison of absolute values. Diagnostic accuracy for CS was high for all salivary cortisol and cortisone LC-MS/MS methods and salivary cortisol IAs evaluated.
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Cortisona , Síndrome de Cushing , Humanos , Cromatografia Líquida/métodos , Cortisona/análise , Síndrome de Cushing/diagnóstico , Hidrocortisona , Saliva/química , Espectrometria de Massas em Tandem/métodosRESUMO
OBJECTIVE: Rathke's cleft cysts are benign, embryological remnants in the pituitary gland. The majority of them are small and asymptomatic but a few may become large, and cause mass effects, pituitary hormone deficiencies and visual impairment. Recommendations for the follow-up of Rathke's cleft cysts vary since data on the natural history are sparse. PATIENTS AND DESIGN: Data at diagnosis and at 1, 5 and 10 years for patients with a Rathke's cleft cyst (434 at diagnosis, 317 females) were retrieved from the Swedish Pituitary Registry. Cysts ≤3 mm in diameter were excluded from the study. MEASUREMENTS: Data included demographics, cyst size, pituitary function, visual defects and surgery. RESULTS: The mean age at diagnosis was 45 years. In patients with cysts <10 mm in diameter (n = 204) 2.9% had pituitary hormone deficiencies and 2% had visual field impairments. Cyst size did not progress during the 5 years. Cysts with a diameter of ≥10 mm that were not operated (n = 174) decreased in size over the years (p < .01). Pituitary hormone deficiencies and visual impairments were more frequent (18% and 5.7%, respectively) but were stable over time. Transphenoidal surgery was performed in 56 patients of whom 51 underwent surgery before the 1-year follow-up. The mean cyst diameter at diagnosis was 18 mm (range: 9â30 mm), 36% had pituitary hormone deficiency, 45% had visual field defects and 20% had impaired visual acuity. One year after surgery 60% had no cyst remnants, 50% had a pituitary deficiency, 26% had visual field defects and 12% had impaired visual acuity. No major changes were observed after 5 years. Twelve of the operated patients had a follow-up at 10 years, in eight the cyst remnants or recurrences increased in size over time (p < .05). CONCLUSIONS: Rathke's cleft cysts with a size less than 10 mm rarely grow and our results indicate that radiological follow-up can be restricted to 5 years. In contrast, progression of postoperative remnants or recurrent cysts is more likely and require long-term follow-up.
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Cistos do Sistema Nervoso Central , Neoplasias Hipofisárias , Cistos do Sistema Nervoso Central/cirurgia , Feminino , Humanos , Recidiva Local de Neoplasia , Hipófise/cirurgia , Neoplasias Hipofisárias/cirurgia , Sistema de Registros , Suécia , Resultado do TratamentoRESUMO
BACKGROUND: Studies on the incidence of Cushing's disease (CD) are few and usually limited by a small number of patients. The aim of this study was to assess the annual incidence in a nationwide cohort of patients with presumed CD in Sweden. METHODS: Patients registered with a diagnostic code for Cushing's syndrome (CS) or CD, between 1987 and 2013 were identified in the Swedish National Patient Registry. The CD diagnosis was validated by reviewing clinical, biochemical, imaging, and histopathological data. RESULTS: Of 1317 patients identified, 534 (41%) had confirmed CD. One-hundred-and-fifty-six (12%) patients had other forms of CS, 41 (3%) had probable but unconfirmed CD, and 334 (25%) had diagnoses unrelated to CS. The mean (95% confidence interval) annual incidence between 1987 and 2013 of confirmed CD was 1.6 (1.4-1.8) cases per million. 1987-1995, 1996-2004, and 2005-2013, the mean annual incidence was 1.5 (1.1-1.8), 1.4 (1.0-1.7) and 2.0 (1.7-2.3) cases per million, respectively. During the last time period the incidence was higher than during the first and second time periods (P < 0.05). CONCLUSION: The incidence of CD in Sweden (1.6 cases per million) is in agreement with most previous reports. A higher incidence between 2005 and 2013 compared to 1987-2004 was noticed. Whether this reflects a truly increased incidence of the disease, or simply an increased awareness, earlier recognition, and earlier diagnosis can, however, not be answered. This study also illustrates the importance of validation of the diagnosis of CD in epidemiological research.
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Síndrome de Cushing/epidemiologia , Hipersecreção Hipofisária de ACTH/epidemiologia , Hormônio Adrenocorticotrópico/sangue , Estudos de Coortes , Síndrome de Cushing/sangue , Humanos , Hidrocortisona/sangue , Incidência , Hipersecreção Hipofisária de ACTH/sangue , Suécia/epidemiologiaRESUMO
OBJECTIVE: Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to 5 years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA). DESIGN AND METHODS: Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded. RESULTS: Preoperative ACTH, TSH, LH/FSH, and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742), and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm3. Among patients with preoperative, 1 year and 5 years postoperative data on the HPA axis (n = 428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, 1 year postoperatively, 163 (38%) patients were ACTH-deficient (P < .001 vs. preoperatively). No further increase was seen 5 years postoperatively (36%, P = .096). At 1 year postoperatively, recoveries in the TSH and LH/FSH axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively. CONCLUSIONS: Adrenocorticotrophic hormone deficiency increased significantly at 1 year postoperatively. Even though not significant, some patients recovered from or developed new deficiency between 1 and 5 years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA.
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Neoplasias Hipofisárias , Humanos , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/patologia , Sistema Hipotálamo-Hipofisário , Suécia/epidemiologia , Sistema Hipófise-Suprarrenal , Hormônio Foliculoestimulante , Hormônio Adrenocorticotrópico , TireotropinaRESUMO
Context: Whether biochemical remission normalizes life expectancy in Cushing's disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls. Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort. Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (nâ =â 1484) matched at the diagnosis date by age, sex, and residential area were included. Main outcome measures: Mortality and causes of death. Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)]. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up (nâ =â 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery (nâ =â 177), and 5.6 (2.7-11.6) for those not in remission (nâ =â 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death. Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.
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OBJECTIVE: To describe the treatment and long-term outcomes of patients with acromegaly from all healthcare regions in Sweden. DESIGN AND METHODS: Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991 to 2011. The latest clinical follow-up date was December 2012, while mortality data were collected for 28.5 years until June 2019. RESULTS: The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy, and 39% medical treatment. At the 5- and 10-year follow-ups, insulin-like growth factor 1 levels were within the reference range in 69 and 78% of patients, respectively. In linear regression, the proportion of patients with biochemical control including adjuvant therapy at 10 years follow-up increased over time by 1.23% per year. The standardized mortality ratio (SMR) (95% CI) for all patients was 1.29 (1.11-1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed between 1991 and 2000, SMR: 1.06 (0.85-1.33) nor between 2001 and2011, SMR: 0.87 (0.61-1.24). In contrast, non-controlled patients at the latest follow-up from both decades had elevated SMR, 1.90 (1.33-2.72) and 1.98 (1.24-3.14), respectively. CONCLUSIONS: The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy, while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.
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Acromegalia/terapia , Adenoma/terapia , Antineoplásicos Hormonais/uso terapêutico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia , Procedimentos Neurocirúrgicos , Somatostatina/análogos & derivados , Transtornos da Visão/fisiopatologia , Acromegalia/metabolismo , Adenoma/complicações , Adenoma/metabolismo , Adenoma/patologia , Adulto , Idoso , Causas de Morte , Quimioterapia Adjuvante , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Mortalidade , Modelos de Riscos Proporcionais , Radiocirurgia , Radioterapia , Radioterapia Adjuvante , Sistema de Registros , Suécia , Carga Tumoral , Transtornos da Visão/etiologia , Campos VisuaisRESUMO
Pituitary neuroendocrine tumors (PitNETs) are common, generally benign tumors with complex clinical characteristics related to hormone hypersecretion and/or growing sellar tumor mass. PitNETs can be classified based on the expression pattern of anterior pituitary hormones and three main transcriptions factors (TF), SF1, PIT1 and TPIT that regulate differentiation of adenohypophysial cells. Here, we have extended this classification based on the global transcriptomics landscape using tumor tissue from a well-defined cohort comprising 51 PitNETs of different clinical and histological types. The molecular profiles were compared with current classification schemes based on immunohistochemistry. Our results identified three main clusters of PitNETs that were aligned with the main pituitary TFs expression patterns. Our analyses enabled further identification of specific genes and expression patterns, including both known and unknown genes, that could distinguish the three different classes of PitNETs. We conclude that the current classification of PitNETs based on the expression of SF1, PIT1 and TPIT reflects three distinct subtypes of PitNETs with different underlying biology and partly independent from the expression of corresponding hormones. The transcriptomic analysis reveals several potentially targetable tumor-driving genes with previously unknown role in pituitary tumorigenesis.
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Adenoma/genética , Estudo de Associação Genômica Ampla , Tumores Neuroendócrinos/genética , Neoplasias Hipofisárias/genética , Adenoma/metabolismo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Tumores Neuroendócrinos/metabolismo , Adeno-Hipófise/metabolismo , Hormônios Adeno-Hipofisários/metabolismo , Neoplasias Hipofisárias/metabolismo , TranscriptomaRESUMO
CONTEXT: Psychiatric symptoms are common in Cushing's disease (CD) and seem only partly reversible following treatment. OBJECTIVE: To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up. DESIGN: Nationwide longitudinal register-based study. SETTING: University Hospitals in Sweden. SUBJECTS: CD patients diagnosed between 1990 and 2018 (N = 372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis, and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed. MAIN OUTCOME MEASURES: Data from the Swedish Prescribed Drug Register and the Patient Register. RESULTS: In the 5-year period before and at diagnosis, use of antidepressants (odds ratio [OR] 2.2 [95% confidence interval (CI) 1.3-3.7]) and 2.3 [1.6-3.5]), anxiolytics [2.9 (1.6-5.3) and 3.9 (2.3-6.6)], and sleeping pills [2.1 (1.2-3.7) and 3.8 (2.4-5.9)] was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants [2.4 (1.5-3.9)] and sleeping pills [3.1 (1.9-5.3)]. Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (interquartile range 8.1-10.4) had higher use of antidepressants [OR 2.0 (1.1-3.8)] and sleeping pills [2.4 (1.3-4.7)], but not of drugs for hypertension. CONCLUSIONS: Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.
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Transtornos Mentais/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/epidemiologia , Psicotrópicos/uso terapêutico , Adulto , Estudos Transversais , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Morbidade , Hipersecreção Hipofisária de ACTH/complicações , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Estudos Retrospectivos , Suécia/epidemiologiaRESUMO
IgG4-related hypophysitis (IgG4-RH) is increasingly being reported as an isolated entity or, less frequently, as a manifestation of a multiorgan IgG4-related disease (IgG4-RD), in which typical histopathology is a cornerstone for the diagnosis. We aimed to describe the histopathological changes in the surgical specimens from patients with clinical signs of pituitary disease that fulfilled the current diagnostic criteria for IgG4-RH. Histopathological features were correlated with clinical and radiological findings. Of 19 patients with pituitary dysfunction and inflammatory changes in the surgical pituitary specimen operated on during 2011-2019, we identified five patients with typical IgG4-related pathology (lymphoplasmacytic infiltration with more than 10 IgG4-positive plasma cells per one high power microscopic field, representing at least 40% of all plasma cells and at least focal storiform fibrosis). One patient with diabetes insipidus and pachymeningitis with IgG4-related changes in a biopsy from the dura was also included. Additional histopathological changes that typically are not part of the IgG4-RH were observed: Rathke's cleft cyst in four and granulomatous changes in two patients. One patient had an elevated serum IgG4 level and systemic manifestations that could be associated with the systemic IgG4-RD. Our findings indicate that pure IgG4-RH is uncommon. All patients with pituitary dysfunction, beyond typical IgG4-related pathology, had other pathological findings that could trigger the secondary IgG4-response. Both primary pathology and secondary IgG4-related features should be reported in patients with pituitary dysfunction because their co-occurrence may cause atypical clinical and imaging features, and unexpected response to surgical and pharmacological treatment. The current criteria for the diagnosis of IgG4-RH can lead to overdiagnosis of IgG4-RH if additional pathological changes are not taken into consideration. The classification criteria of IgG4-RD proposed by the American College of Rheumatology/European League Against Rheumatism could help classify patients more properly as IgG4-RH if applied to the pituitary gland.
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Hipofisite Autoimune/patologia , Imunoglobulina G/imunologia , Adulto , Idoso , Hipofisite Autoimune/tratamento farmacológico , Hipofisite Autoimune/cirurgia , Cistos do Sistema Nervoso Central/patologia , Diabetes Insípido/patologia , Feminino , Cefaleia/complicações , Terapia de Reposição Hormonal , Humanos , Inflamação/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hipófise/patologia , Plasmócitos/patologia , Resultado do TratamentoRESUMO
CONTEXT: Whether multisystem morbidity in Cushing's disease (CD) remains elevated during long-term remission is still undetermined. OBJECTIVE: To investigate comorbidities in patients with CD. DESIGN, SETTING, AND PATIENTS: A retrospective, nationwide study of patients with CD identified in the Swedish National Patient Register between 1987 and 2013. Individual medical records were reviewed to verify diagnosis and remission status. MAIN OUTCOMES: Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by using the Swedish general population as reference. Comorbidities were investigated during three different time periods: (i) during the 3 years before diagnosis, (ii) from diagnosis to 1 year after remission, and (iii) during long-term remission. RESULTS: We included 502 patients with confirmed CD, of whom 419 were in remission for a median of 10 (interquartile range 4 to 21) years. SIRs (95% CI) for myocardial infarction (4.4; 1.2 to 11.4), fractures (4.9; 2.7 to 8.3), and deep vein thrombosis (13.8; 3.8 to 35.3) were increased during the 3-year period before diagnosis. From diagnosis until 1 year after remission, SIRs (95% CI were increased for thromboembolism (18.3; 7.9 to 36.0), stroke (4.9; 1.3 to 12.5), and sepsis (13.6; 3.7 to 34.8). SIRs for thromboembolism (4.9; 2.6 to 8.4), stroke (3.1; 1.8 to 4.9), and sepsis (6.0; 3.1 to 10.6) remained increased during long-term remission. CONCLUSION: Patients with CD have an increased incidence of stroke, thromboembolism, and sepsis even after remission, emphasizing the importance of early identification and management of risk factors for these comorbidities during long-term follow-up.
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Hipersecreção Hipofisária de ACTH/epidemiologia , Sepse/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Tromboembolia/epidemiologia , Adulto , Idoso , Comorbidade , Feminino , Seguimentos , Fraturas Ósseas/epidemiologia , Glucocorticoides/uso terapêutico , Humanos , Incidência , Masculino , Prontuários Médicos/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Suécia/epidemiologiaRESUMO
OBJECTIVE: The challenge of diagnosing Cushing's syndrome (CS) calls for high precision biochemical screening. This study aimed to establish robust reference intervals for, and compare the diagnostic accuracy of, salivary cortisol and cortisone in late-night samples and after a low-dose (1 mg) dexamethasone suppression test (DST). DESIGN AND METHODS: Saliva samples were collected at 08:00 and 23:00 h, and at 08:00 h, after a DST, from 22 patients with CS and from 155 adult reference subjects. We also collected samples at 20:00 and 22:00 h from 78 of the reference subjects. Salivary cortisol and cortisone were analysed with liquid chromatography-tandem mass spectrometry. The reference intervals were calculated as the 2.5th and 97.5th percentiles of the reference population measurements. Diagnostic accuracies of different tests were compared, based on areas under the receiver-operating characteristic curves. RESULTS: The upper reference limits of salivary cortisol and cortisone at 23:00 h were 3.6 nmol/L and 13.5 nmol/L, respectively. Using these reference limits, CS was detected with a sensitivity (95% CI) of 90% (70-99%) and specificity of 96% (91-98%) for cortisol, and a 100% (84-100%) sensitivity and 95% (90-98%) specificity for cortisone. After DST, cortisol and cortisone upper reference limits were 0.79 nmol/L and 3.5 nmol/L, respectively. CS was detected with 95% (75-100%) sensitivity and 96% (92-99%) specificity with cortisol, and 100% (83-100%) sensitivity and 94% (89-97%) specificity with cortisone. No differences in salivary cortisol or cortisone levels were found between samples collected at 22:00 and 23:00 h. CONCLUSION: Salivary cortisol and cortisone in late-night samples and after DST showed high accuracy for diagnosing CS, salivary cortisone being slightly, but significantly better.
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Cortisona/análise , Síndrome de Cushing/diagnóstico , Hidrocortisona/análise , Programas de Rastreamento/estatística & dados numéricos , Saliva/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Ritmo Circadiano , Dexametasona , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Curva ROC , Valores de Referência , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem , Fatores de Tempo , Adulto JovemRESUMO
CONTEXT: Whether patients with Cushing disease (CD) in remission have increased mortality is still debatable. OBJECTIVE: To study overall and disease-specific mortality and predictive factors in an unselected nationwide cohort of patients with CD. DESIGN, PATIENTS, AND METHODS: A retrospective study of patients diagnosed with CD, identified in the Swedish National Patient Registry between 1987 and 2013. Medical records were systematically reviewed to verify the diagnosis. Standardized mortality ratios (SMRs) with 95% CIs were calculated and Cox regression models were used to identify predictors of mortality. RESULTS: Of 502 identified patients with CD (n = 387 women; 77%), 419 (83%) were confirmed to be in remission. Mean age at diagnosis was 43 (SD, 16) years and median follow-up was 13 (interquartile range, 6 to 23) years. The observed number of deaths was 133 vs 54 expected, resulting in an overall SMR of 2.5 (95% CI, 2.1 to 2.9). The commonest cause of death was cardiovascular diseases (SMR, 3.3; 95% CI, 2.6 to 4.3). Excess mortality was also found associated with infections and suicide. For patients in remission, the SMR was 1.9 (95% CI, 1.5 to 2.3); bilateral adrenalectomy and glucocorticoid replacement therapy were independently associated with increased mortality, whereas GH replacement was associated with improved outcome. CONCLUSION: Findings from this large nationwide study indicate that patients with CD have excess mortality. The findings illustrate the importance of achieving remission and continued active surveillance, along with adequate hormone replacement and evaluation of cardiovascular risk and mental health.
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Hipersecreção Hipofisária de ACTH/mortalidade , Adulto , Doenças Cardiovasculares/mortalidade , Feminino , Terapia de Reposição Hormonal , Humanos , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/terapia , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
OBJECTIVE: To investigate the contemporary presentation of pituitary metastases. PATIENTS: Thirty-eight patients diagnosed with pituitary metastases from 1996 to 2018 in Sweden. METHODS: Pituitary metastases were confirmed by histopathology (n = 27) or considered highly likely according to radiological findings, including rapid tumor progression (n = 11). Medical records were reviewed and sellar images reexamined centrally. RESULTS: Breast and lung cancers were the most common primary tumors, in 45% and 21% of patients, respectively. Sixty-seven percent of breast cancers overexpressed human epidermal growth factor receptor 2 (HER2); 53% of pituitary metastases from breast cancers appeared ≥10 years after diagnosis of the primary tumor. At presentation, 71% appeared to have ACTH deficiency, 65% had TSH deficiency, and 26% had diabetes insipidus. Fatigue, nausea/vomiting, loss of appetite, weight loss, myalgia, and/or arthralgia were reported in 47% of patients with morning cortisol <100 nmol/L vs 23% with cortisol ≥200 nmol/L. Sixteen patients had visual field defects, and eight had diplopia. Intrasellar and suprasellar tumor growth was the most frequent finding. Initially, a pituitary adenoma was considered the etiology in 18% of patients.Radiotherapy, pituitary surgery, and chemotherapy were used in 68%, 68%, and 11% of patients, respectively. One and 2 years after diagnosis of pituitary metastases, 50% and 26% of patients were alive. CONCLUSION: Pituitary metastases may be mistaken for pituitary adenomas and can appear late, especially in breast cancer. Breast cancers overexpressing HER2 seem prone to metastasize to the pituitary. Hypocortisolism may be misdiagnosed as cancer-related malaise. An increased awareness of pituitary metastases and undiagnosed pituitary failure can improve management in these patients.
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Adenoma/patologia , Neoplasias da Mama/patologia , Neoplasias Pulmonares/patologia , Neoplasias Hipofisárias/secundário , Adenoma/epidemiologia , Adulto , Neoplasias da Mama/epidemiologia , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Pessoa de Meia-Idade , Suécia/epidemiologiaRESUMO
CONTEXT: The impact of long-term GH replacement on cerebrovascular and cardiovascular diseases and diabetes mellitus in hypopituitary patients is unknown. OBJECTIVE: The incidence of nonfatal stroke and cardiac events, and prevalence of type 2 diabetes mellitus (T2D) and cardioprotective medication were compared between cohorts of GH-deficient (GHD) patients and population controls. DESIGN AND PARTICIPANTS: The incidence of nonfatal stroke and cardiac events was estimated retrospectively from questionnaires in 750 GHD patients and 2314 matched population controls. A prevalence of T2D and cardioprotective medication was recorded at the distribution of questionnaires. Time since first pituitary deficiency to start of GH therapy was 4 and 2 yr, and time on GH therapy was 6 yr for GHD women and men, respectively. RESULTS: Lifelong incidence of nonfatal stroke was tripled in GHD women and doubled in GHD men, but a decline was seen in both genders during periods after first pituitary hormone deficiency and GHD, during which most patients had GH therapy. The lifelong incidence of nonfatal cardiac events declined in GHD men during first pituitary hormone deficiency and GHD periods. GHD women had a higher prevalence of T2D and lipid-lowering medication, whereas GHD men had a higher prevalence of antihypertensive medication. CONCLUSIONS: The declined risks of nonfatal stroke in both genders and of nonfatal cardiac events in GHD men during periods on GH replacement may be caused by prescription of cardioprotective drugs and 6-yr GH replacement. GHD women had an increased prevalence of T2D, partly attributed to higher body mass index and lower physical activity.
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Diabetes Mellitus Tipo 2/epidemiologia , Cardiopatias/epidemiologia , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Hipopituitarismo/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Adulto , Idoso , Cardiotônicos/uso terapêutico , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/epidemiologia , Feminino , Cardiopatias/complicações , Cardiopatias/prevenção & controle , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Hipopituitarismo/epidemiologia , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicaçõesAssuntos
Lesões Encefálicas/complicações , Hipopituitarismo/etiologia , Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/reabilitação , Humanos , Hidrocortisona/sangue , Hipopituitarismo/diagnóstico , Sistema Hipotálamo-Hipofisário/fisiopatologia , Testes de Função Hipofisária , Hormônios Hipofisários/sangue , Guias de Prática Clínica como AssuntoRESUMO
OBJECTIVE: Overfeeding suppresses GH secretion and makes evaluation of a suspected GH deficiency (GHD) difficult. In normal weight subjects, gender is known to influence GH concentrations, which is most apparent in the ambulatory, morning-fasted state. In this study, we examined the GH/IGF-I axis in obese men and women and the effect of surgically induced weight loss. DESIGN: Sixty-three subjects (body mass index (BMI) 45 +/- 6 kg/m2; 54 women, 9 men) were studied prior to, and 6 and 12 months following Roux-en-Y gastric bypass (RYGBP) surgery. Fifty-four patients with classic GHD (BMI 27 +/- 6 kg/m2; 35 men, 19 women) were included for comparison. METHODS: Hormones were analysed in fasting morning serum samples. RESULTS: RYGBP resulted in a decreased BMI to 35 +/- kg/m2 at 6 months and 32 +/- 6 kg/m2 at 12 months. GH and IGF-I increased at 6 months in the women and at 12 months in both sexes by > or = 300 and 11% respectively. Prior to RYGBP, GH concentrations were low in the obese men and similar to those of GHD men (mean 0.09 mU/l). Obese women had tenfold higher values than obese men and sevenfold higher than GHD women. IGF-I levels were in the low reference range in the obese and below -2 S.D. for age in 13%. CONCLUSIONS: Surgically induced weight loss partially restores GH secretion. Despite a marked suppression of GH values, a gender influence is maintained in severe obesity. In obese women, single morning GH and IGF-I values seem sufficient to exclude a suspicion of classic GHD.
Assuntos
Derivação Gástrica , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Obesidade/fisiopatologia , Obesidade/cirurgia , Adulto , Índice de Massa Corporal , Feminino , Glucose/metabolismo , Homeostase , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
CONTEXT AND OBJECTIVE: The role of cabergoline in Cushing's disease (CD) remains controversial. The experience is limited to case reports and few open studies that report the effects determined after ≥1 month of treatment. In prolactinomas and dopamine-responsive GH-secreting tumours, effects of cabergoline are seen within days or weeks. Here, we searched for short-term effects of cabergoline in CD. DESIGN: Twenty patients (19 naïve and one recurrent) were included in a prospective study. Cabergoline was administered in increasing doses of 0.5-5 mg/week over 6 weeks. METHODS: Urinary free cortisol (UFC) 24 h, morning cortisol and ACTH, and salivary cortisol at 0800, 1600 and 2300 h were determined once weekly throughout. Diurnal curves (six samples) of serum cortisol were measured at start and end. RESULTS: At study end, the median cabergoline dose was 5 mg, range 2.5-5 mg/week. The prolactin levels, markers of compliance, were suppressed in all patients. During the treatment, hypercortisolism varied, gradual and dose-dependent reductions were not seen. Five patients had a >50% decrease of UFC, three had a >50% rise of UFC. Salivary cortisol at 2300 h showed a congruent >50% change with UFC in two of the five cases with decreased UFC, and in one of the three cases with increased UFC. One patient with decreases in both UFC and 2300 h salivary cortisol also had a reduction in diurnal serum cortisol during the course of the study. CONCLUSIONS: Cabergoline seems to be of little value in the management of CD. Only one patient had a response-like pattern. Given the known variability of disease activity in CD, this might represent a chance finding.
Assuntos
Agonistas de Dopamina/uso terapêutico , Ergolinas/uso terapêutico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Cabergolina , Ritmo Circadiano , Ergolinas/administração & dosagem , Feminino , Humanos , Hidrocortisona/análise , Hidrocortisona/sangue , Hidrocortisona/urina , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Saliva/químicaRESUMO
DESIGN: Gastric bypass (GBP) and duodenal switch (DS) in morbid obesity are accompanied by marked metabolic improvements, particularly in glucose control. In recent years, episodes of severe late postprandial hypoglycemia have been increasingly described in GBP patients; data in DS patients are scarce. We recruited three groups of subjects; 15 GBP, 15 DS, and 15 non-operated overweight controls to examine to what extent hypoglycemia occurs in daily life. METHODS: Continuous glucose monitoring (CGM) was used during 3 days of normal activity. The glycemic variability was measured by mean amplitude of glycemic excursion and continuous overall net glycemic action. Fasting blood samples were drawn, and the patients kept a food and symptom log throughout the study. RESULTS: The GBP group displayed highly variable CGM curves, and 2.9% of their time was spent in hypoglycemia (<3.3 âmmol/l, or 60 âmg/dl). The DS group had twice as much time in hypoglycemia (5.9%) and displayed CGM curves with little variation as well as lower HbA1c levels (29.3 vs 35.9âmmol/mol, P<0.05). Out of a total of 72 hypoglycemic episodes registered over the 3-day period, 70 (97%) occurred in the postprandial state and only about one-fifth of the hypoglycemic episodes in the GBP and DS groups were accompanied by symptoms. No hypoglycemias were seen in controls during the 3-day period. CONCLUSION: Both types of bariatric surgery induce marked, but different, changes in glucose balance accompanied by frequent, but mainly unnoticed, hypoglycemic episodes. The impact and mechanism of hypoglycemic unawareness after weight-reduction surgery deserves to be clarified.
Assuntos
Duodeno/cirurgia , Endoscopia Gastrointestinal , Derivação Gástrica , Hipoglicemia/cirurgia , Adulto , Idoso , Glicemia/metabolismo , Monitorização Ambulatorial da Pressão Arterial , Registros de Dieta , Ingestão de Alimentos , Feminino , Homeostase , Humanos , Hipoglicemia/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Adulto JovemRESUMO
Ghrelin is a recently discovered gastric peptide that increases appetite, glucose oxidation, and lipogenesis and stimulates the secretion of GH. In contrast to ghrelin, GH promotes lipolysis, glucose production, and insulin secretion. Both ghrelin and GH are suppressed by intake of nutrients, especially glucose. The role of GH in the regulation of ghrelin has not yet been established. We investigated the effect of GH on circulating levels of ghrelin in relation to its effects on glucose, insulin, body composition, and the adipocyte-derived peptides leptin and adiponectin. Thirty-six patients with adult-onset GH deficiency received recombinant human GH for 9 months in a placebo-controlled study. Body composition and fasting serum analytes were assessed at baseline and at the end of the study. The GH treatment was accompanied by increased serum levels of IGF-I, reduced body weight (-2%) and body fat (-27%), and increased serum concentrations of glucose (+10%) and insulin (+48%). Ghrelin levels decreased in 30 of 36 subjects by a mean of -29%, and leptin decreased by a mean of -24%. Adiponectin increased in the women only. The decreases in ghrelin and leptin correlated with changes in fat mass, fat-free mass, and IGF-I. The reductions in ghrelin were predicted independently of the changes in IGF-I and fat mass. It is likely that the reductions in ghrelin and leptin reflect the metabolic effects of GH on lipid mobilization and glucose production. Possibly, a suppression of ghrelin promotes loss of body fat in GH-deficient patients receiving treatment. The observed correlation between the changes in ghrelin and IGF-I may suggest that the GH/IGF-I axis has a negative feedback on ghrelin secretion.
Assuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Peptídeos e Proteínas de Sinalização Intercelular , Leptina/sangue , Hormônios Peptídicos/sangue , Adiponectina , Adulto , Glicemia/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Feminino , Grelina , Transtornos do Crescimento/sangue , Humanos , Insulina/sangue , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas/metabolismo , Análise de RegressãoRESUMO
OBJECTIVE: The aim of this trial was to evaluate the effect on insulin sensitivity and body composition of combination therapy with GH and IGF1 in adults with GH deficiency (GHD) and diabetes. DESIGN, PATIENTS AND METHODS: A 6-month randomised placebo-controlled pilot study. Fourteen adults with GHD and type 2 diabetes were included. All received rhGH (0.15 mg/day for 1 month and 0.3 mg/day for 5 months) and were randomised to rhIGF1 (15 µg/kg per day for 1 month and 30 µg/kg per day for 5 months) or placebo. Insulin sensitivity was evaluated with euglycaemic hyperinsulinaemic clamp and body composition by computed tomography of abdominal and thigh fat, as well as bioimpedance. RESULTS: Twelve patients completed the study. They were overweight and obese; at baseline, insulin sensitivity (M-value) was low. IGF1 and IGF1 SDS increased in both groups, with the highest increase in the GH and IGF1 group. Positive changes in M-value by +1.4 mg/kg per min, in subcutaneous abdominal fat by -60.5 ml and in fat-free mass by +4.4% were seen in the GH and IGF1 group. Corresponding values in the GH and placebo-treated group were -1.5 mg/kg per min, +23 ml and -0.04% respectively (P=0.02, P=0.04 and P=0.03 for delta values between groups). No safety issues occurred. CONCLUSIONS: Combined GH and IGF1 treatment resulted in positive, but rather small effects, and might be a treatment option in a few selected patients.