ABSTRACT
Adrenal Cortical Carcinoma (ACC) is a rare malignancy with an incidence of 1.0 per million per year in the Netherlands. Median survival varies according to the European Network for the Study of Adrenal Tumours (ENS@T) tumour stage. It is unknown whether time until development of metastases is of influence on prognosis. To asses this, data were retrospectively obtained from centres of the Dutch Adrenal Network. Patients who presented with ACC between January 1, 2004 and October 31, 2013 were included. Date of detection of metastases, number of metastases and affected organs were registered. One hundred sixty patients were included in the analysis. Synchronous metastases were defined as diagnosis of metastasis ≤6 months after the initial diagnosis of ACC. Overall survival rate was calculated from the date of diagnosis of metastasis until death from any cause. At first presentation, 50 patients (31 %) had ACC with metastases (ENS@T stage IV). Another 67 (42 %) developed metastases during follow-up. Amongst the 117 patients with metastases, 84 (72 %) patients had synchronous metastases and 33 (28 %) developed metachronous metastases. Diagnosis of synchronous metastases (p = 0.046), more than one affected organ (p < 0.001) and four or more metastases (p < 0.001) were found to be associated with reduced overall survival. Limitations included retrospective design and limited details regarding pathological data. We conclude that synchronous metastases of ACC are associated with a poorer prognosis compared to metachronous metastases of ACC. The clinical characteristics associated with prognosis in this study support the view to refine the prognostic classification for patients with stage IV ACC.
Subject(s)
Adrenal Gland Neoplasms/pathology , Adrenocortical Carcinoma/pathology , Neoplasms, Multiple Primary/epidemiology , Neoplasms, Second Primary/epidemiology , Adrenal Gland Neoplasms/mortality , Adrenocortical Carcinoma/mortality , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Neoplasm Staging , Neoplasms, Multiple Primary/secondary , Neoplasms, Second Primary/secondary , Netherlands , Prognosis , Retrospective Studies , Survival Analysis , Young AdultABSTRACT
OBJECTIVE: In the last decade, pre-operative medical cortisol suppression therapy has frequently been used in Cushing's disease to normalize cortisol concentrations pre-operatively. Our aim was to assess the efficacy of presurgical medical cortisol suppression therapy in Cushing's disease. DESIGN AND METHODS: We retrospectively assessed the medical files of all patients with Cushing's disease that received presurgical cortisol suppression therapy with ketoconazole or metyrapone and underwent subsequent transsphenoidal surgery between 1990 and 2010 at our centre. We retrieved the pretreatment regimen, adequacy of pretreatment, early postoperative serum cortisol levels, adverse effects and long-term remission status. RESULTS: Nineteen of 33 patients (58%) obtained long-term remission after pituitary surgery without additional postoperative therapy. Thirteen of 16 patients with adequate presurgical cortisol suppression therapy had postoperative cortisol concentrations <50 nmol/l. The 16 patients with adequate presurgical cortisol suppression had a higher long-term remission rate after primary surgery compared with the 13 patients with borderline or inadequate pretreatment (81% vs 38%; P < 0·05). CONCLUSIONS: Adequate presurgical cortisol suppression treatment with ketoconazole or metyrapone in Cushing's disease seems to be associated with suppressed postoperative cortisol concentrations and an increased long-term remission rate.
Subject(s)
Hydrocortisone/analysis , Ketoconazole/therapeutic use , Metyrapone/therapeutic use , Pituitary ACTH Hypersecretion/drug therapy , Adolescent , Adrenocorticotropic Hormone/blood , Adult , Aged , Enzyme Inhibitors/therapeutic use , Female , Humans , Hydrocortisone/blood , Hydrocortisone/urine , Male , Middle Aged , Pituitary ACTH Hypersecretion/surgery , Preoperative Period , Remission Induction , Retrospective Studies , Time Factors , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE/METHODS: Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone. RESULTS: Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction. CONCLUSIONS: The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS-parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering.
Subject(s)
Hypertension/drug therapy , Pituitary ACTH Hypersecretion/drug therapy , Renin-Angiotensin System/physiology , Adult , Aged , Aldosterone/blood , Angiotensinogen/blood , Angiotensinogen/pharmacology , Animals , Cabergoline , Ergolines/therapeutic use , Female , Humans , Hypertension/blood , Iliac Artery/drug effects , In Vitro Techniques , Male , Middle Aged , Pituitary ACTH Hypersecretion/blood , Rats , Renin/blood , Somatostatin/analogs & derivatives , Somatostatin/therapeutic use , Vasoconstriction/drug effectsABSTRACT
Cushing's disease (CD) is associated with severely impaired quality of life (QoL). Moreover, the physiological cortisol diurnal rhythm (CDR) is disturbed in CD. QoL can improve after successful surgery, the primary treatment for CD. We evaluated the effects of medical treatment on QoL and CDR. In 17 patients, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline and the adrenal-blocking agent ketoconazole. After 80 days, 15/17 (88%) patients had reached normal urinary free cortisol excretion (UFC). Subsequently, patients continued medical therapy or underwent surgery. UFC, plasma and salivary CDR and QoL-related parameters (assessed using 5 questionnaires: Nottingham Health Profile, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index-20, RAND-36, CushingQoL) were measured. At baseline, 5/17 patients had preserved CDR. In 6/12 patients with disturbed baseline CDR, recovery was observed, but without any correlation with QoL. QoL was significantly impaired according to 18/20 subscales in CD patients compared to literature-derived controls. According to the RAND-36 questionnaire, patients reported more pain at day 80 (p < 0.05), which might reflect steroid-withdrawal. Generally, QoL did not improve or deteriorate after 80 days. CushingQoL scores seemed to improve after 1 year of remission in three patients that continued medical therapy (p = 0.11). CDR can recover during successful pituitary- and adrenal-targeted medical therapy. Patients with CD have impaired QoL compared to controls. Despite the occurrence of side-effects, QoL does not deteriorate after short-term biochemical remission induced by medical therapy, but might improve after sustained control of hypercortisolism.
Subject(s)
Circadian Rhythm , Hydrocortisone/blood , Pituitary ACTH Hypersecretion/blood , Pituitary ACTH Hypersecretion/drug therapy , Quality of Life , Adult , Aged , Cabergoline , Dopamine Agonists/therapeutic use , Ergolines/therapeutic use , Female , Humans , Hydrocortisone/metabolism , Ketoconazole/therapeutic use , Male , Middle Aged , Pituitary ACTH Hypersecretion/metabolism , Somatostatin/analogs & derivatives , Somatostatin/therapeutic use , Surveys and Questionnaires , Young AdultABSTRACT
CONTEXT: Cushing's disease (CD) is accompanied by an increased risk of venous thromboembolism. Surgery is the primary treatment of CD. OBJECTIVE: The aim of the study was to compare hemostatic parameters between patients with CD and controls and to evaluate the effect of medical treatment of CD on hemostasis. DESIGN AND SETTING: During 80 d, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline, and ketoconazole, which suppresses adrenocortical steroidogenesis, at four university medical centers in The Netherlands. PATIENTS: Seventeen patients with de novo, residual, or recurrent CD were included. MAIN OUTCOME MEASURES: We measured urinary free cortisol and parameters of coagulation and fibrinolysis. RESULTS: Patients with CD had significantly higher body mass index (P < 0.001), shortened activated partial thromboplastin time (P < 0.01), and higher levels of fibrinogen, Factor VIII, and protein S activity (P < 0.05) compared to healthy control subjects. In addition, fibrinolytic capacity was impaired in patients with CD as reflected by prolonged clot lysis time (P < 0.001) and higher levels of plasminogen activator inhibitor type 1, thrombin-activatable fibrinolysis inhibitor, and α2-antiplasmin (P < 0.01). There were no statistically significant differences in von Willebrand factor:antigen, antithrombin, and protein C activity. After 80 d, 15 of 17 patients had normalized urinary free cortisol excretion. Despite biochemical remission, only slight decreases in antithrombin (P < 0.01) and thrombin-activatable fibrinolysis inhibitor (P < 0.05) levels were observed. Other parameters of coagulation and fibrinolysis did not change significantly. CONCLUSIONS: The hypercoagulable state in patients with CD, which is explained by both increased production of procoagulant factors and impaired fibrinolysis, is not reversible upon short-term biochemical remission after successful medical therapy. This may have implications for the duration of anticoagulant prophylaxis in patients with (cured) CD.
Subject(s)
Blood Coagulation Factors/analysis , Blood Coagulation/drug effects , Fibrinolysis/drug effects , Pituitary ACTH Hypersecretion/drug therapy , Pituitary ACTH Hypersecretion/physiopathology , Pituitary Hormones, Anterior/antagonists & inhibitors , Thrombophilia/etiology , Adult , Aged , Cabergoline , Dopamine Agonists/administration & dosage , Dopamine Agonists/therapeutic use , Drug Monitoring , Drug Resistance , Drug Therapy, Combination/adverse effects , Ergolines/administration & dosage , Ergolines/therapeutic use , Humans , Hydrocortisone/blood , Hydrocortisone/urine , Ketoconazole/administration & dosage , Ketoconazole/therapeutic use , Male , Middle Aged , Pituitary ACTH Hypersecretion/blood , Pituitary ACTH Hypersecretion/urine , Remission Induction , Somatostatin/administration & dosage , Somatostatin/adverse effects , Somatostatin/analogs & derivatives , Somatostatin/therapeutic use , Thrombophilia/chemically induced , Thrombophilia/prevention & control , Young AdultSubject(s)
Neoplasms, Second Primary/diagnostic imaging , Ovarian Neoplasms/diagnostic imaging , Radiopharmaceuticals , Teratoma/diagnostic imaging , Adult , Cobalt Radioisotopes , Female , Humans , Iodine Radioisotopes/therapeutic use , Neoplasms, Second Primary/surgery , Ovarian Neoplasms/surgery , Radionuclide Imaging , Radiopharmaceuticals/therapeutic use , Teratoma/surgery , Thyroid Neoplasms/physiopathology , Thyroid Neoplasms/radiotherapy , Thyroid Neoplasms/surgery , Thyroid Nodule/physiopathology , Thyroid Nodule/radiotherapy , Thyroid Nodule/surgery , Thyroidectomy , Treatment OutcomeABSTRACT
OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by parathyroid, gastroenteropancreatic, pituitary and adrenal tumours. Cardiovascular disease has been identified as an important cause of death in MEN1 patients. Menin, the product of the MEN1 gene, is a co-activator for peroxisome proliferator-activated receptor-γ and the vitamin D receptor, which are involved in glucose metabolism. We aimed to compare insulin sensitivity and prevalence of impaired fasting glucose and diabetes mellitus between MEN1 patients and controls. DESIGN: Cross-sectional study. PATIENTS: Sixty-three MEN1 gene mutation carriers (44% men, mean age 41 years) from 22 kindreds and 126 unrelated controls matched for gender, age and BMI. MEASUREMENTS: Fasting glucose levels were categorized and compared using WHO criteria. Homeostasis model assessment (HOMA) was used as a measure of insulin resistance. RESULTS: Homeostasis model assessment was significantly increased in MEN1 patients compared with controls (3·0 ± 2·0 vs 2·0 ± 1·0, P < 0·05). In MEN1 patients, HOMA was associated with BMI, but not with age, calcium and gastrin levels. Using logistic regression analysis, the presence of hyperparathyroidism, pancreatic lesions and various other manifestations was not associated with HOMA. Impaired fasting glucose was more prevalent in MEN1 compared with controls (17%vs 6%, P < 0·05). Three MEN1 patients (5%) compared with four controls (3%) were diabetic (not significant). CONCLUSIONS: Multiple endocrine neoplasia type 1 patients had decreased insulin sensitivity and higher prevalence of impaired fasting glucose compared with controls, which was unrelated to MEN1 manifestations. Impaired glucose metabolism may result in increased risk of cardiovascular disease in MEN1 patients.
Subject(s)
Blood Glucose/genetics , Blood Glucose/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Adult , Female , Genetic Predisposition to Disease , Homeostasis , Humans , Insulin Resistance/genetics , Male , MutationABSTRACT
CONTEXT: Venous thrombosis has frequently been reported in patients with endogenous Cushing's syndrome (CS). OBJECTIVE: The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with CS prior to treatment and after surgery. DESIGN AND SETTING: We conducted a multicenter cohort study at all university medical centers in The Netherlands. PATIENTS: Consecutive patients diagnosed with endogenous CS of benign origin between January 1990 and June 2010 were eligible for inclusion. Patients surgically treated for nonfunctioning pituitary adenoma served as controls for the incidence of postoperative VTE in ACTH-dependent CS. MAIN OUTCOME MEASURES: We documented all objectively confirmed VTE during 3 yr prior to, and 3 yr after treatment onset. The incidences of VTE were expressed as incidence rates. RESULTS: A total of 473 patients (mean age 42 yr, 363 women) were included (360 ACTH-dependent pituitary CS). The total number of person-years was 2526. Thirty-seven patients experienced VTE during the study period, resulting in an incidence rate of 14.6 [95% confidence interval (CI) 10.3-20.1] per 1000 person-years. The incidence rate for first-ever VTE prior to treatment was 12.9 (95% CI 7.5-12.6) per 1000 person-years (17 events). The risk of postoperative VTE, defined as risk within 3 months after surgery, was 0% for ACTH-independent and 3.4% (95% CI 2.0-5.9) for ACTH-dependent CS (12 events in 350 patients); most events occurred between 1 wk and 2 months after surgery. Compared with the controls, the risk of postoperative VTE in patients undergoing transsphenoidal surgery was significantly greater (P = 0.01). CONCLUSIONS: Patients with CS are at high risk of VTE, especially during active disease and after pituitary surgery. Guidelines on thromboprophylaxis are urgently needed.
Subject(s)
Cushing Syndrome/epidemiology , Postoperative Complications/epidemiology , Venous Thromboembolism/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Cohort Studies , Cushing Syndrome/surgery , Female , Humans , Incidence , Male , Middle Aged , Netherlands/epidemiology , Postoperative PeriodABSTRACT
BACKGROUND: Cabergoline, a dopamine agonist used to treat hyperprolactinemia, is associated with an increased risk of fibrotic adverse reactions, e.g. cardiac valvular fibrosis, pleuropulmonary, and retroperitoneal fibrosis. OBJECTIVE: This study evaluated the prevalence and risk of fibrotic adverse reactions during cabergoline therapy in hyperprolactinemic and acromegalic patients. DESIGN: A cross-sectional study was conducted in a University Hospital. PATIENTS: A total of 119 patients with hyperprolactinemia and acromegaly who were on cabergoline therapy participated in the study. METHODS: All patients were requested to undergo a cardiac assessment, pulmonary function test, chest X-ray, and blood tests as recommended by the European Medicine Agency. Matched controls were recruited to compare the prevalence of valvular regurgitation. Cardiac valvular fibrosis was evaluated by assessing valvular regurgitation and the mitral valve tenting area (MVTa). The risk of pleuropulmonary fibrosis was assessed by a pulmonary function test, a chest X-ray, and if indicated, by additional imaging studies. RESULTS: The prevalence of clinically relevant valvular regurgitation was not significantly different between cases (11.3%) and controls (6.1%; P=0.16). The mean MVTa was 1.27+/-0.17 and 1.24+/-0.21 cm(2) respectively (P=0.54). Both valvular regurgitation and the MVTa were not related to the cumulative dose of cabergoline. A significantly decreased pulmonary function required additional imaging in seven patients. In one patient, possible early interstitial fibrotic changes were seen. Lung function impairment was not related to the cumulative cabergoline dose. CONCLUSION: Cabergoline, typically dosed for the long-term treatment of hyperprolactinemia or acromegaly, appears not to be associated with an increased risk of fibrotic adverse events.
Subject(s)
Acromegaly/drug therapy , Dopamine Agonists/administration & dosage , Ergolines/adverse effects , Heart Valve Diseases/chemically induced , Hyperprolactinemia/drug therapy , Lung Diseases/chemically induced , Retroperitoneal Fibrosis/chemically induced , Acromegaly/blood , Blood Sedimentation , C-Reactive Protein/metabolism , Cabergoline , Creatinine/blood , Cross-Sectional Studies , Dopamine Agonists/therapeutic use , Echocardiography , Electrocardiography , Ergolines/therapeutic use , Female , Fibrosis , Glomerular Filtration Rate , Heart Valve Diseases/blood , Heart Valve Diseases/pathology , Heart Valves/pathology , Humans , Hyperprolactinemia/blood , Lung/pathology , Lung Diseases/blood , Lung Diseases/pathology , Male , Middle Aged , Respiratory Function Tests , Retroperitoneal Fibrosis/blood , Retroperitoneal Fibrosis/pathology , Statistics, NonparametricABSTRACT
We report on a 73-year-old man with a toxic multinodular goitre, which was treated with radioiodine therapy (I-131) without pretreatment with an antithyroid drug. Four weeks later he presented with rapidly progressive dyspnoea and a significant increase in free thyroxin. The electrocardiogram showed ST -segment elevation, and echocardiography demonstrated apical akinesia and a left ventricular ejection fraction of only 25%. However, direct coronary catheterisation showed no evidence of coronary artery disease. Left ventricular angiography showed apical ballooning consistent with the diagnosis of takotsubo cardiomyopathy. Following treatment of the cardiomyopathy and thyrotoxicosis, he experienced a complete recovery. To the best of our knowledge, this is the first report of a takotsubo cardiomyopathy associated with thyrotoxicosis resulting from radiation thyroiditis induced by radioiodine. Three other cases of takotsubo cardiomyopathy associated with Graves' disease have been described in literature.
Subject(s)
Goiter, Nodular/radiotherapy , Iodine Radioisotopes/adverse effects , Radiation Injuries/etiology , Takotsubo Cardiomyopathy/etiology , Thyrotoxicosis/etiology , Aged , Dyspnea , Humans , Iodine Radioisotopes/therapeutic use , Male , Radiation Injuries/complications , Risk Factors , Stroke Volume , Thyrotoxicosis/complications , Thyroxine/metabolism , Ventricular Function, LeftABSTRACT
OBJECTIVE: To our knowledge, no case of remission in autoimmune Addison's disease has previously been reported. We describe a patient with primary adrenal insufficiency caused by autoimmune adrenalitis in whom partial remission was observed after 7 yr. CASE: A 39-yr-old male was referred because of extreme fatigue, weight loss, anorexia, nausea, and bouts of fever. During physical examination hyperpigmentation was seen. Laboratory tests showed a plasma cortisol of 0.02 micromol/l (08:30 h). Cortisol failed to increase during the ACTH stimulation test (0.02 to 0.03 micromol/l) and ACTH was markedly elevated (920 pmol/l). Adrenal auto-antibodies were weakly positive. A CT-scan showed no evidence of calcifications or other abnormalities of the adrenal glands. The diagnosis of autoimmune Addison's disease was made and replacement therapy with hydrocortisone and fludrocortisone was started. During the following years the dose of hydrocortisone was gradually decreased. Eventually, the patient decided to stop his medication completely. A repeated ACTH-stimulation test revealed a basal cortisol of 0.25 micromol/l and a peak cortisol of 0.30 micromol/l with a basal ACTH of 178 pmol/l. The patient did not have any complaints. CONCLUSION: Recovery of adrenal insufficiency, due to causes other than autoimmune adrenalitis, has been reported in the past. If our case of partial recovery of autoimmune adrenalitis is not unique this could have profound effects on treatment and follow-up of Addison's disease.
Subject(s)
Addison Disease/immunology , Adrenal Glands/physiology , Autoimmune Diseases/immunology , Addison Disease/blood , Addison Disease/diagnosis , Adrenal Glands/immunology , Adrenocorticotropic Hormone/blood , Adult , Autoimmune Diseases/blood , Humans , Hydrocortisone/blood , Hydrocortisone/immunology , MaleABSTRACT
AIM: The aim of this study was to evaluate the effect on body weight and safety of subcutaneously administered recombinant leptin in obese adults and to evaluate whether the timing of recombinant leptin administration influences efficacy. METHODS: A randomized, double-blind, placebo-controlled, multicentre study was designed, comprising of a 3-week dietary lead-in followed by a 12-week leptin or placebo treatment period. A total of 284 overweight and obese (body mass index 27-37.0 kg/m(2)) predominantly white (98%) women (66%) and men (34%) with a mean (+/-s.d.) 46.8+/-10.4 years of age were randomized into three treatment groups with three matching placebo groups. Recombinant leptin was administered by subcutaneous injection [10 mg/morning, 10 mg/evening or 20 mg/day (10 mg twice daily)]. Patients were counselled at baseline to reduce dietary intake by 2,100 kJ/day (500 kcal/day), and dietary advice was reinforced every 2-4 weeks. RESULTS: No statistically significant change in body weight occurred with recombinant leptin treatment compared with placebo treatment in any treatment group. No clinically significant adverse effects were observed with the exception of an increase in injection-site reactions in patients treated with recombinant leptin (83%) vs. placebo (36%). CONCLUSIONS: Administration of recombinant leptin to an overweight and obese population, in addition to a mildly energy-restricted diet, was not efficacious in terms of weight loss at the doses and schedules studied. The hypothesis that nocturnal administration of recombinant leptin might have a specific effect on weight loss was not supported.
Subject(s)
Anti-Obesity Agents/administration & dosage , Leptin/analogs & derivatives , Obesity/drug therapy , Adult , Anti-Obesity Agents/adverse effects , Anti-Obesity Agents/therapeutic use , Double-Blind Method , Drug Administration Schedule , Energy Intake/drug effects , Female , Humans , Hunger/drug effects , Injections, Subcutaneous , Leptin/administration & dosage , Leptin/adverse effects , Leptin/blood , Leptin/therapeutic use , Lipids/blood , Male , Middle Aged , Obesity/blood , Obesity/physiopathology , Weight Loss/drug effectsABSTRACT
Overweight and obesity are rapidly increasing health problems, leading to considerable co-morbidity and increased mortality. In this article a Dutch guideline is proposed for the management of overweight and obesity, which in part is based on North American and European treatment proposals. After having assessed the degree of overweight and associated health risks, based on medical history, physical examination and laboratory investigations, a decision to start treatment can be made. First, consensus with regard to treatment goals has to be reached between doctor and patient, who has to be motivated to change his or her lifestyle. A modest (5-15% of pre-treatment weight) weight loss, which has to be sustained in the long term, is a desirable, realistic and achievable treatment goal for the majority of patients. Dietary management, an increased level of physical activity and behavioural advice are the most important basic treatment options in obesity. This advice is best provided as a multidisciplinary approach. In selected patients pharmacotherapy and in severe obesity bariatric surgery can be a useful addition to basic obesity management.
Subject(s)
Exercise/physiology , Obesity/therapy , Practice Guidelines as Topic , Adult , Body Mass Index , Female , Health Promotion , Humans , Life Style , Male , Motivation , Netherlands , Obesity/diet therapy , Obesity/drug therapy , Obesity/surgery , Patient Care TeamABSTRACT
Prasterone (dehydroepiandrosterone; DHEA) is a steroid hormone from the adrenal cortex with weak androgenic properties. It can be converted into stronger acting steroids with both androgenic and oestrogenic properties. DHEA also appears to have an affinity with certain receptors in the brain and can act as a neurosteroid. Patients with primary or secondary adrenocortical insufficiency exhibit a marked decrease in DHEA production and the added value of DHEA replacement in these patients has been investigated in three recently published trials. With a daily dose of 50 mg DHEA, the plasma levels of DHEAS (the sulphate of DHEA) increase to levels within the normal range and beneficial effects have been demonstrated for several psychological parameters such as mood, fatigue, general well-being and sexual function. The androgenic side effects on skin and hair appear to be both moderate and acceptable. For patients with adrenocortical insufficiency who function suboptimally despite adequate replacement therapy with glucocorticosteroids and (if indicated) mineralocorticosteroids, these results would seem to justify treatment with a replacement dose of DHEA.
Subject(s)
Adrenal Insufficiency/drug therapy , Dehydroepiandrosterone Sulfate/therapeutic use , Hormone Replacement Therapy/methods , Humans , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
OBJECTIVE: We studied the validity and reproducibility of a new abdominal ultrasound protocol for the assessment of intra-abdominal adipose tissue. MEASUREMENTS: Intra-abdominal adipose tissue was assessed by CT, MRI, anthropometry and ultrasonography on a single day. By ultrasonography the distance between peritoneum and lumbar spine was measured using a strict protocol, including the location of the measurements, pressure on the transducer and respiration. All measurements were repeated after 3 months. RESULTS: The study population consisted of 19 overweight patients with a body mass index (BMI) of 32.9 kg/m(2) (s.d. 3.7), intra-abdominal adipose tissue on CT 140.1 cm(2) (s.d. 55.9), and a mean ultrasound distance of 9.8 cm (s.d. 2.5). There was a strong association between the CT and ultrasonographic measures: Pearson correlation coefficient was 0.81 (P<0.001). The correlation between ultrasound and waist circumference was 0.74 (P<0.001), the correlation between CT and waist circumference was 0.57 (P=0.01). Ultrasound appeared a good method to diagnose intra-abdominal obesity: the area under the ROC curve was 0.98. During the follow-up period of 3 months, the patients lost on average almost 3 kg of body weight. The correlation coefficient between changes in intra-abdominal adipose tissue assessed by CT and ultrasound was 0.74 (P<0.001). The correlation coefficient of the mean ultrasound distance assessed by two different sonographers at baseline was 0.94 (P<0.001), the mean difference 0.4 cm (s.d. 0.9), and the coefficient of variation 5.4%, indicating good reproducibility of the ultrasound measurements. CONCLUSIONS: The results of this validation study show that abdominal ultrasound, using a strict protocol, is a reliable and reproducible method to assess the amount of intra-abdominal adipose tissue and to diagnose intra-abdominal obesity.
Subject(s)
Abdomen/diagnostic imaging , Adipose Tissue/diagnostic imaging , Obesity/diagnosis , Adipose Tissue/anatomy & histology , Adult , Anthropometry/methods , Body Composition , Body Constitution , Female , Humans , Magnetic Resonance Imaging/methods , Male , Reproducibility of Results , Sensitivity and Specificity , Tomography, X-Ray Computed/methods , UltrasonographyABSTRACT
BACKGROUND: Premature atherosclerosis is a clinical feature in untreated acromegaly. Increased postprandial lipoprotein remnant levels are associated with premature atherosclerosis. In most studies, remnants have been measured indirectly using retinyl esters (RE) as a chylomicron core label. Remnants can also be directly quantified by immunoseparation using monoclonal antibodies to apolipoprotein (apo) AI and apo B100 to remove nonremnant lipoproteins. Cholesterol is quantified in the remaining apo E-rich remnant fraction (RLP-C). OBJECTIVE: The aim of the present study was to investigate the role of postprandial lipaemia in patients with acromegaly to further define abnormalities leading to increased susceptibility for atherosclerosis. PATIENTS: In a case-control study, the plasma postprandial lipoprotein remnant fraction (RLP-C and RE) were analysed in six patients with active acromegaly [two females, four males; aged 53 +/- 9 years; body mass index (BMI), 29 +/- 4 kg/m2] and in six normolipidaemic control subjects (matched for age, gender, BMI and apo E genotype). They underwent an oral vitamin A fat loading test. RESULTS: Baseline plasma triglycerides (TG) were not significantly different in patients (1.75 +/- 0.71 mM) and controls (1.15 +/- 0.46 mM). Lipoprotein lipase activity was significantly lower in patients than in controls (108 +/- 21 vs. 141 +/- 19 U/l, respectively; P < 0.05). Baseline plasma apo E levels were higher in patients (60.8 +/- 7.9 mg/l) than in controls (48.3 +/- 5.9 mg/l; P < 0.05). No differences were found in the area under the postprandial TG curve (AUC-TG), the incremental AUC-TG (DeltaAUC-TG) and AUC-RE in the Sf < 1000 remnant fraction. However, fasting plasma RLP-C concentrations, isolated by immunoseparation, were increased in patients with active acromegaly (0.41 +/- 0.13 mM) compared to control subjects (0.20 +/- 0.07 mM; P < 0.05). Incremental postprandial RLP-C response (corrected for fasting values) was also significantly elevated in patients (2.14 +/- 1.19 mM/h/l) compared to controls (0.86 +/- 0.34 mM/h/l; P < 0.05). In both groups, the maximal RLP-C concentration was reached between 2 and 4 h. CONCLUSIONS: In conclusion, the atherogenic postprandial remnants, represented by RLP-C, were significantly elevated at baseline and in the postprandial period, whereas the larger-sized remnants, represented by retinyl esters (Sf < 1000), were not different from controls. The disturbances in the postprandial RLP-C response increased the susceptibility for premature atherosclerosis as observed in patients with acromegaly.
Subject(s)
Acromegaly/blood , Apolipoproteins/blood , Lipoproteins/blood , Postprandial Period/physiology , Triglycerides/blood , Acromegaly/complications , Adult , Arteriosclerosis/etiology , Case-Control Studies , Cholesterol/blood , Dietary Fats , Disease Susceptibility , Fasting/blood , Female , Humans , Male , Middle AgedABSTRACT
Serum thyroglobulin (Tg) is usually the best marker of residual or metastatic disease after treatment of differentiated thyroid cancer. We evaluated the effect of so-called blind therapeutic doses of iodine-131 in patients with detectable Tg during suppressive levothyroxine treatment (Tg-on), and in patients with a negative diagnostic scintigram but detectable Tg during the hypothyroid phase (Tg-off). Twenty-two patients with differentiated thyroid carcinoma underwent total thyroidectomy and radioiodine ablation. During the follow-up, six patients with detectable Tg-on and 16 patients with detectable Tg-off were identified. All patients were treated with a blind therapeutic dose of 7,400 MBq iodine-131. Diagnostic scintigrams were compared with post-treatment scintigrams. Tg-off was measured in 16 cases, 1 year after the administration of the blind therapeutic dose, at the time of the follow-up diagnostic scintigram. Six patients were followed up by Tg-on only. Post-therapy scintigrams revealed previously undiagnosed local recurrence or distant metastases in 13/22 cases (59%); the remaining nine post-therapy scintigrams were negative. At the time of the blind therapeutic doses, Tg-off values ranged from 8 to 608 microg/l. After 1 year of follow-up, Tg-off decreased in 14/16 (88%) patients. In all patients who were followed by Tg-on only (n=6), a decrease in Tg values was measured. It is concluded that blind therapeutic doses resulted in a decrease in Tg levels in the majority of patients with suspected recurrence or metastases. The post-treatment scintigrams revealed pathological uptake in 59% of patients.
Subject(s)
Carcinoma, Papillary, Follicular/radiotherapy , Iodine Radioisotopes/therapeutic use , Thyroglobulin/metabolism , Thyroid Neoplasms/radiotherapy , Adult , Aged , Carcinoma, Papillary, Follicular/metabolism , Female , Follow-Up Studies , Humans , Male , Middle Aged , Thyroid Neoplasms/metabolism , Thyroidectomy , Thyroxine/therapeutic use , Whole-Body CountingABSTRACT
Differentiated thyroid cancer is treated by (near) total thyroidectomy followed by radioiodine (131I) ablation of the residual active tissue in the thyroid bed. Controversy remains concerning the use and the dose of pre-ablative diagnostic 131I scintigraphy. This study was designed to assess the efficacy of thyroid ablation by high-dose 131I without pre-ablative diagnostic 131I scintigraphy. Ninety-three patients were treated with (near) total thyroidectomy and with a high ablative dose of 131I (3700-7400 MBq). A preablative 131I diagnostic scintigram was not performed. To assess the efficacy of the treatment, all patients were studied with a diagnostic 131I scintigram and with thyroglobulin plasma assays 1 year later after withdrawal of L-thyroxine for 4-6 weeks. The main criterion for a successful ablation was the absence of thyroid bed activity. An additional criterion was a thyroglobulin value of <10 microg x l(-1). Successful ablation according to the main criterion was obtained in 88% of patients. Forty patients (43%) showed no neck uptake and had undetectable serum thyroglobulin. Twenty-two patients (25%) had serum thyroglobulin concentrations between 1 and 10 microg x l(-1). Twenty-six patients (27%) had thyroglobulin >10 microg x l(-1), 19 patients showing residual thyroid uptake or metastatic lesions. We conclude that high-dose radioiodine ablation without prior diagnostic scintigraphy results in a high rate of successful ablation, preventing repeat 131I treatment.
Subject(s)
Iodine Radioisotopes/therapeutic use , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/radiotherapy , Adult , Aged , Combined Modality Therapy , Follow-Up Studies , Humans , Iodine Radioisotopes/pharmacokinetics , Lymphatic Metastasis , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Radionuclide Imaging , Radiotherapy Dosage , Thyroglobulin/blood , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/pathology , Thyroidectomy , Time Factors , Tissue DistributionABSTRACT
ACTH-independent Cushing's syndrome may be due to the development of ectopic hormone receptors in adrenal tissue. Thus, in food-dependent Cushing's syndrome the adrenals aberrantly express receptors for gastric inhibitory polypeptide (GIP). We present the case of a 60-year-old woman with food-dependent Cushing's syndrome whose cortisol levels increased after stimulation with CRH. In this patient with Cushing's syndrome the finding of low basal plasma cortisol levels in the late night and early morning as well as a paradoxical rise of plasma cortisol during a 7-h infusion with dexamethasone (carried out without any restriction in food intake), suggested that cortisol production was stimulated at times of food intake. Hourly measurements of plasma cortisol for 48 h revealed prominent meal-related peaks. A plasma cortisol response, elicited by oral glucose administration, could be prevented by octreotide. Plasma ACTH was low or undetectable. CRH administration was followed by a ACTH response from 3 to 16 ng/l and a plasma cortisol response from 230 to 680 nmol/l. Octreotide treatment for nearly five months induced a partial clinical and biochemical remission. Total bilateral adrenalectomy was performed. The left adrenal was grossly enlarged (7 x 5.5 x 4 cm) and the right adrenal was slightly enlarged (6 x 4 x 1.8 cm). Microscopy revealed bilateral nodular hyperplasia. Cell suspensions of adrenal tissue from the patient did respond in a dose-dependent fashion to stimulation with GIP and were very sensitive to stimulation with synthetic ACTH1-24. However, CRH had no significant effect on cortisol production in vitro. Using RT-PCR amplification and cDNA hybridization, GIP receptor was found to be overexpressed in the left and right adrenal tissues from this patient as compared to adrenal tissues from a normal individual or from non GIP-dependent adrenal Cushing's syndrome. There was no evidence of presence of adrenal CRH receptors. Thus, in this patient with food-dependent Cushing's syndrome, the CRH-induced plasma ACTH and cortisol response is probably mediated by an incomplete suppression of the HPA axis as a result of the intermittent food-dependent nature of Cushing's syndrome.
Subject(s)
Adrenal Cortex/pathology , Adrenocorticotropic Hormone/blood , Corticotropin-Releasing Hormone , Cushing Syndrome/pathology , Gastric Inhibitory Polypeptide/metabolism , Hydrocortisone/blood , Adrenal Cortex/chemistry , Cells, Cultured , Cushing Syndrome/metabolism , Eating , Female , Humans , Hyperplasia , Middle Aged , Receptors, Gastrointestinal Hormone/analysis , Receptors, Gastrointestinal Hormone/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Stimulation, ChemicalABSTRACT
The syndrome of resistance to thyroid hormone is associated with diverse mutations in the ligand-binding domain of the thyroid hormone beta receptor, localizing to three clusters around the hormone binding cavity. Here, we report three novel resistance to thyroid hormone mutations (S314C, S314F, and S314Y), due to different nucleotide substitutions in the same codon, occurring in six separate families. Functional characterization of these mutant receptors showed marked differences in their properties. S314F and S314Y receptor mutants exhibited significant transcriptional impairment in keeping with negligible ligand binding and were potent dominant negative inhibitors of wild-type receptor action. In contrast, the S314C mutant bound ligand with reduced affinity, such that its functional impairment and dominant negative activity manifest at low concentrations of thyroid hormone, but are more reversible at higher T3 concentrations. The degree of functional impairment of mutant receptors in vitro may correlate with the magnitude of thyroid dysfunction in vivo. Modelling these mutations using the crystal structure of thyroid hormone receptor beta shows why ligand binding is perturbed and why the phenylalanine/tyrosine mutations are more deleterious than cysteine.