[Influence of duration of menopause, anthropometric and hormonal parameters on metabolic syndrome].

INTRODUCTION: Hypoestrogenic status in the menopausal women shows a shift to a central android fat distribution and metabolic syndrome (MIS). Related metabolic changes and hypertension increase the risk for cardiovascular (CV) diseases. The aim of this study was to investigate the influence of duration of menopause, anthropometric and hormonal parameters on metabolic syndrome. MATERIAL AND METHODS: 50 obese women were examined with BMI = 31.92 = 5.83 kg/m2, age 54.40 +/- 3.64, time since menopause 5.90 +/- 5.46 years. Control group consisted of 37 normal weight women with BMI = 23.50 +/- 2.13 kg/m2, age 53.92 +/- 3.95, time since menopause 5.96 +/- 4.92 years. Anthropometric characteristics and blood pressure were measured. Blood was taken at 8 am for: fasting glucose, triglycerides, cholesterol, HDL, LDL, apolipoprotein A (ApoA), apolipoprotein B (ApoB), lipoprotein(a) (Lp(a)), C-reactive protein (CRP), fibrinogen, FSH, LH, prolactin, estradiol, progesterone, testosterone and sex hormone binding globulin (SHBG). RESULTS: In obese women significant negative correlations were found for: BMI anid HDL (p < 0.05), waist and HDL (p < 0.05), FSII and systolic blood pressure (p < 0.01), FSH and fasting glucose (p < 0.05), LH and waist (p < 0.05), SHBG and fasting glucose (p < 0.05). A positive correlation was found for time since menopause and waist/hip ratio (p < 0.05). In controls positive correlations were found for: waist/hip ratio and systolic and diastolic blood pressure (p < 0.05), LH and HDL (p < 0.05). estradiol and diastolic blood pressure (p < 0.05). Negative correlations were detected for estradiol and waist (p < 0.05), time since menopause and HDL (p < 0.05). CONCLUSION: Gaining weight together with menopausal endocrine changes cause metabolic and hemodynamic imbalances, which contribute to risk for cardiovascular diseases.

[Gaining weight and components of metabolic syndrome in the period of menopause].

INTRODUCTION: Menopause induces redistribution of fat mass and development of abdominal obesity, increasing risk for metabolic syndrome (MS) by 60%. Related cardiovascular diseases become a leading cause of morbidity and mortality in women after fifty years of age. OBJECTIVE: The aim of this study was to investigate the influence of gaining weight on components of MS in the menopause. METHOD: The study included 50 obese women, BMI=31.92 +/- 5.83 kg/m2, age 54.40 +/- 3.64, time since menopause 5.90 +/- 5.46 years, and 37 normal weight women, BMI = 23.50 +/- 2.13 kg/m2, age 53.92 +/- 3.95, time since menopause 5.96 +/- 4.92 years. Both groups were divided according to the presence of MS into two subgroups. Anthropometric characteristics and blood pressure were measured. Blood was taken at 8 am for the following: fasting glucose, triglycerides, cholesterol, HDL, LDL, apolipoprotein A (ApoA), apolipoprotein B (ApoB), lipoprotein(a) (Lp(a)), C-reactive protein (CRP), fibrinogen, FSH, LH, prolactin, oestrogen, progesterone, testosterone and sex hormone-binding globulin (SHBG). RESULTS: 66% of obese women had MS compared with 22% normal weight women. Significant differences between groups were found for the following: weight, BMI, waist, hip circumference, waist/hip ratio, diastolic blood pressure, Lp(a), FSH, LH, prolactin (all p < 0.01) and fasting glucose (p < 0.05). Obese women with and without MS were significantly diverse for the following: waist/hip ratio, systolic blood pressure and fasting glucose (all p < 0.01); age, BMI, waist circumference, triglycerides, HDL, Lp(a) and SHBG (all p < 0.05). Normal weight women with and without MS had significantly different values of waist/hip ratio, systolic, diastolic blood pressure, triglycerides (all p < 0.01); HDL and testosterone (p < 0.05). Significant differences were found between obese and normal weight women with MS in anthropometric characteristics, ApoA, Lp(a), fibrinogen (all p < 0.01) and FSH (p < 0.05). CONCLUSION: Abdominal obesity significantly increases incidence of MS as a cluster of cardiovascular risk factors in the menopause.

[Adrenal incidentaloma in neurofibromatosis type 1].

INTRODUCTION: Neurofibromatosis type 1 is one of the most common genetically transmitted diseases with a high index of spontaneous mutations and extremely varied and unpredictable clinical manifestations. It is diagnosed by the existence of certain clinical criteria. The presence of numerous localised cutaneous neurofibromas or a plexiform neurofibroma is virtually pathognomonic of neurofibromatosis type 1. The incidence of pheochromocytoma in neurofibromatosis type 1 is 0.1-5.7%. CASE OUTLINE: A 56-year old female patient was admitted for further evaluation of incidental adrenal tumour previously diagnosed on computerized tomography (CT). She had previously unrecognized neurofibromatosis type 1 and a clinical picture which could remind of pheochromocytoma. None of the catecholamine samples in 24 hr urine indicated functionally active pheochromocytoma. Chromogranin A was moderately increased. Decision for operation was made after performing the image techniques. Adrenal incidentaloma had features of pheochromocytoma on abdominal magnetic resonance imaging (MRI), with positive 131I-MIBG (iodine 131-labelled metaiodobenzylguanidine scintigraphy). After being treated with phenoxybenzamine and propranolol, she was operated on. The pathohistological finding showed the case of left adrenal pheochromocytoma. CONCLUSION: Detailed diagnostic procedure for pheochromocytoma should be performed with patients having neurofibromatosis type 1 and adrenal incidentaloma. Pheochromocytomas are rare tumours with fatal outcome if not duly recognized and cured.

[The effects of three-week fasting diet on blood pressure, lipid profile and glucoregulation in extremely obese patients].

INTRODUCTION: Obesity is often accompanied by a number of complications including diabetes mellitus and cardiovascular diseases. Elevated blood pressure and lipids, as well as deterioration of glucoregulation are attributed, as the most significant factors, to development of diabetes mellitus and cardiovascular complications in obese patients. OBJECTIVE: The aim of our study was to evaluate the effects of a fasting diet on blood pressure, lipid profile and glucoregulatory parameters. METHOD: We included 110 patients (33 male and 77 female; mean age 35 +/- 1 years, body weight 131.7 +/- 2.6 kg, body mass index 45.4 +/- 0.8 kg/m2) who were hospitalized for three weeks for the treatment of extreme obesity with the fasting diet. At the beginning, during, and at the end of this period, we evaluated changes in blood pressure, lipid profile, as well as parameters of glucoregulation including glycaemia, insulinaemia, and insulin sensitivity by HOMA. Oral glucose tolerance test (OGTT) was performed in all patients at the beginning and at the end of the fasting diet. RESULTS: During the fasting diet, the body weight decreased from 131.7 +/- 2.6 kg to 117.7 +/- 2.4 kg (p < 0.001), the body mass index decreased from 45.4 +/- 0.8 kg/m2 to 40.8 +/- 0.8 kg/m2 (p < 0.001), and both systolic and diastolic blood pressure significantly declined (143 +/- 2 vs. 132 +/- 2 mm Hg, p < 0.001; 92 +/- 2 vs. 85 +/- 2 mm Hg, p < 0.001). In addition, the fasting diet produced a significant decrease in total cholesterol, LDL cholesterol, triglycerides, as well as basal glycaemia and insulinaemia (p < 0.001) Before the fasting diet, OGTT was normal in 76% of patients, whereas 21% of patients showed glucose intolerance, and 4% of patients diabetes mellitus. After the fasting diet, OGTT was normal in 88% of patients, whereas 12% of patients still had signs of glucose intolerance (p < 0.05). In addition, insulin resistance significantly (p < 0.05) increased from 54 +/- 6% to 89 +/- 13% after the fasting diet. CONCLUSION: The three-week fasting diet in extremely obese patients produced a significant decrease and normalization of blood pressure, decrease in lipids, and improvement in glucoregulation including the increase in insulin sensitivity.

[The value of corticotropin-releasing hormone (CRH) test for differential diagnosis of Cushing's syndrome].

INTRODUCTION: Diagnosis and differential diagnosis of Cushing's syndrome (CS) remain considerable challenge in endocrinology. For more than 20 years, CRH has been widely used as differential diagnostic test. Following the CRH administration, the majority of patients with ACTH secreting pituitary adenoma show a significant rise of plasma cortisol and ACTH, whereas those with ectopic ACTH secretion characteristically do not. OBJECTIVE: The aim of our study was to assess the value of CRF test for differential diagnosis of CS using the ROC (receiver operating characteristic) curve method. METHOD: A total of 30 patients with CS verified by pathological examination and postoperative testing were evaluated. CRH test was performed within diagnostic procedures. ACTH secreting pituitary adenoma was found in 18, ectopic ACTH secretion in 3 and cortisol secreting adrenal adenoma in 9 of all patients with CS. Cortisol and ACTH were determined -15.0, 15, 30, 45, 60, 90 and 120 min. after i.v. administration of 100 microg of ovine CRH. Cortisol and ACTH were determined by commercial RIA. Statistical data processing was done by ROC curve analysis. Due to small number, the patients with ectopic ACTH secretion were excluded from test evaluation by ROC curve method. RESULTS: In evaluated subgroups, basal cortisol was (1147.3 +/- 464.3 vs. 1589.8 +/- 296.3 vs. 839.2 +/- 405.6 nmol/L); maximal stimulated cortisol (1680.3 +/- 735.5 vs. 1749.0 +/- 386.6 vs. 906.1 +/- 335.0 nmol/L); and maximal increase as a percent of basal cortisol (49.1 +/- 36.9 vs. 9.0 +/- 7.6 vs. 16.7 +/- 37.3%). Consequently, basal ACTH was (100.9 +/- 85.0 vs. 138.0 +/- 123.7 vs. 4.8 +/- 4.3 pg/mL) and maximal stimulated ACTH (203.8 +/- 160.1 vs. 288.0 +/- 189.5 vs. 7.4 +/- 9.2 pg/mL). For cortisol, determination area under ROC curve was 0.815 +/- 0.083 (CI 95% 0.652-0.978). For cortisol increase cut-off level of 20%, test sensitivity was 83%, with specificity of 78%. For ACTH, determination area under ROC curve was 0.637 +/- 0.142 (CI 95% 0.359-0.916). For ACTH increase cut-off level of 30%, test sensitivity was 70%, with specificity of 57%. CONCLUSION: Determination of cortisol and ACTH levels in CRH test remains reliable tool in differential diagnosis of Cushing's syndrome.

[Insulin sensitivity in patients with adrenal incidentaloma].

INTRODUCTION: Frequent use of modern imaging methods (such as ultrasound, CT and MRI) results in high incidence of accidentally discovered adrenal mass. Adrenal incidentalomas are accidentally discovered adrenal tumors by imaging methods without any prior suspicion of adrenal disease. Some studies have shown decreased insulin sensitivity in patients with adrenal incidentaloma. OBJECTIVE: The objective of our study was to assess the insulin sensitivity in patients with adrenal incidentalom a. METHOD: A total of 22 patients with accidentally discovered adrenal mass confirmed by CT/MRI were evaluated in our study. Average age was 53.31 +/- 26.5 years and average BMI 25.84 +/- 3.65 kg/m2. Control group consisted of 33 healthy subjects. Insulin sensitivity was assessed by short ITT (insulin tolerance test). Blood samples were taken before, 3, 6, 9, 12, 15, 20 and 30 minutes after i.v. bolus of regular insulin (0.05 IU/kg BW). Glycemia was determined by glucose oxidase method. Statistical analysis was done by ANCOVA, using BMI as covariate. RESULTS: Our results showed significantly lower insulin sensitivity in patients with adrenal incidentalomas comparing to the control group (4.95 +/- 0.58 vs. 6.62 +/- 0.47, p=0.015). CONCLUSION: Our patients with adrenal incidentalomas manifested lower insulin sensitivity what suggested further follow up and assessment of insulin sensitivity during endocrine evaluation of these patients.

[Diagnosis and differential diagnosis of Cushing's syndrome].

Endogenous Cushing's syndrome is a clinical state resulting from prolonged, inappropriate exposure to excessive endogenous secretion of cortisol and hence excess circulating free cortisol, characterized by loss of normal feedback mechanisms of the hypothalamo-pituitary-adrenal axis and normal circadian rhythm of cortisol secretion. The etiology of Cushing's syndrome may be excessive ACTH secretion from the pituitary gland, ectopic ACTH/CRH secretion by non-pituitary tumor, or excessive autonomous secretion of cortisol from hyperfunctioning adrenal adenoma or carcinoma, PPNAD and MAH. Other than these broad ACTH-dependent and ACTH-independent categories, there are some unclassified variants as cyclical Cushing's syndrome, pituitary hyperplasia and subclinical Cushing's syndrome. In addition, variants of hypercorticism secondary to ectopic or aberrant expression of several G-protein-coupled receptors have been identified. Diagnosis of Cushing's syndrome must be made before any attempt at differential diagnosis, and key biochemical characteristics are: excess endogenous cortisol secretion; loss of normal feedback of hypothalamic-pituitary-adrenal axis; and disturbance of normal circadian rhythm of cortisol secretion. Biochemical diagnosis of Cushing's syndrome includes: urinary free cortisol determination, low-dose dexamethasone testing, circadian rhythm assessment, insulin tolerance test, and LDDST/CRH test. Differential diagnosis of Cushing's syndrome involves: plasma ACTH level determination, high dose dexamethasone testing, metyrapone testing, testing with CRH, testing with vasopressin or combination, and finally, bilateral simultaneous petrosal sinus sampling with CRH stimulation.

Drospirenone in the treatment of severe premenstrual cerebral edema in a woman with antiphospholipid syndrome, lateral sinus thrombosis, situs inversus and epileptic seizures.

We report herein the case of 32-year-old woman with situs inversus, thrombophilia, antiphospholipid syndrome and severe premenstrual syndrome (PMS) with cerebral edema and epileptic seizures prior to menstruation. Seven days prior to regular menstruation she developed severe PMS, including headache, blurred vision, epileptic seizures, urinary incontinence, craving for food, depression and irritability. Papilledema was detected. Daily hormone analyses prior to and during menstruation confirmed an ovulatory cycle with extremely high progesterone, prolactin and insulin levels in the late luteal phase. From day 29 to day 31, progesterone and insulin decreased sharply and the estradiol/progesterone ratio changed, leading to epileptic seizures and the peak of her symptoms. Diuretic treatment was administered. All symptoms disappeared during the first few days of menstruation. A novel oral contraceptive, containing ethinyl estradiol and drospirenone, an antimineralocorticoid progestogen, was given during the next cycle and hormone analyses were repeated. All symptoms were reduced significantly and no cerebral edema and epileptic seizures occurred. This is the first report of a woman with severe PMS and cerebral edema being treated successfully with an oral contraceptive containing drospirenone.

Gonadotropin pulsatility in Cushing's syndrome compared with polycystic ovary syndrome.

Many of the presenting features in women with Cushing's syndrome (CS) are similar to those observed for patients with polycystic ovary syndrome (PCOS). The aim of this study was to compare gonadotropin pulsatility characteristics in CS and PCOS. We evaluated 32 females divided into three groups. The first group comprised 12 females with clinically and biochemically proven CS, subsequently confirmed by histology (seven with Cushing's syndrome, five with adrenal adenoma). The second group comprised ten females with clinical, endocrine and ultrasonographic parameters for PCOS, while the third group comprised ten healthy females with regular menstrual cycles to serve as controls. Blood samples were taken at 15-min intervals for 6 h in the follicular phase, for determination of luteinizing hormone (LH) and follicle-stimulation hormone (FSH). Pulse analysis was carried out using the PulsDetekt program, and statistical analysis was done using the Kruskal-Wallis test. The following data, presented as median (minimum-maximum), were found for the three groups respectively. Number of LH pulses: 0 (0-5), 7 (3-8) and 3 (2-7); LH pulse amplitude: 2.29 (1.98-3.49), 2.27 (1.15-5.90) and 2.03 (1.02-4.46) mU/l; LH pulse mass: 17.81 (14.82-26.20), 29.85 (8.59-185.82) and 27.57 (7.63-66.69) mU/l x min. Number of FSH pulses: 3 (0-3), 2 (0-5) and 3 (1-5); FSH pulse amplitude: 1.62 (1.29-1.94), 1.49 (1.19-4.40) and 2.02 (1.37-2.52) mU/l; FSH pulse mass: 12.17 (9.64-41.69), 11.18 (8.92-33.02) and 15.16 (10.31-18.93) mU/l x min. Only the number of pulses was compared because other parameters of pulsatile secretion cannot be estimated when no pulses are detected. The difference in number of LH pulses between groups was statistically significant (p < 0.05); however, there was no difference in the number of detected FSH pulses between groups (p > 0.05). Attenuation of pulsatile LH secretion indicating gonadotropin deficiency in the majority of women with CS is mostly due to alterations in serum cortisol levels. Our data also suggest that different mechanisms alter LH pulsatile secretion in CS and PCOS.

[Effects of estro-progestagens on lipid and hormonal profiles in women with premature primary ovarian failure].

INTRODUCTION: Premature primary ovarian failure (PPOF) is defined as cessation of menstruation before the age of 40. Women with PPOF have hypergonadotropic amenorrhea and hypoestrogenia. The incidence of PPOF is 0.9-3%, and its etiology is multifactorial (genetic, enzyme deficit, virus infections, autoimmune diseases and idiopathic). PPOF is an independent risk factor for cardiovascular diseases. Untreated women are at higher risk for coronary disease, due to increase of total cholesterol, LDL, triglycerides and decrease of HDL. The aim of this investigation was to study effects of estro-progestagens on lipid and hormonal profiles in PPOF.: MATERIAL AND METHODS: This tudy included: 30 healthy women aged 41+/-2.3 years; body mass index 25+/-3.2 kg; hip/waist ratio 0.76+/-0.04; amenorrheic for three years on average. Blood samples were taken for glycemia, cholesterol, HDL, LDL, FSH, LH, prolactin, estradiol, and progesterone measurement at 8 am, before and during the therapy with Trisequens. Hormone analysis: radioimmunoassay (RIA) (INEP, Zemun). Statistics. T-test and linear correlation. RESULTS: Total cholesterol, IIDL and LDL have decreased, while prolactin, estradiol and progesterone have increased significantly. DISCUSSION: Women receiving hormone replacement therapy (HRT) have reported reduced mortality and morbidity (30% to 50%) and risk for coronary diseases (61%). Neither has Gaspard's study, nor has ours, found changes in concentrations of triglycerides due to higher synthesis of insulin and higher insulin sensitivity. However, 19-nor-testosterone, in some studies, decreases HDL significantly. In our study, the decrease of HDL was not significant, because subjects were younger, with normal BMI. Women with PPOF have to start hormone therapy immediately, in order to prevent cardiovascular diseases, osteoporosis, depression, etc. and to improve their quality of life.

Value of assessing adrenocorticotropic hormone (ACTH) levels in differential diagnosis of hypercorticism.

Diagnosis and differential diagnosis of Cushing's syndrome remains a challenge in clinical endocrinology. The aim of this study was to establish the value of assessing adrenocorticotropic hormone (ACTH) levels in differential diagnosis of hypercorticism using receiver operating characteristic (ROC) curve. We have evaluated 114 patients with Cushing's syndrome testing the value of pathohistological examination and postoperative testing. The control group consisted of 53 obese healthy persons. ACTH level was determined using a commercial RIA (CIS, France). ACTH secreting pituitary adenoma was found in 56.14% examinees, ectopic secretion in 6.14%, cortisol secreting adrenal adenoma in 37.57%, and adrenal carcinoma in 6.14% of all patients with Cushing's syndrome. Basal ACTH level for pituitary adenoma was 107.29 +/- 75.69 pg/mL; for ectopic secretion 181.63 +/- 149.84 pg/mL; for adrenal adenoma 4.22 +/- 2.32 pg/mL; for adrenal carcinoma 5.50 +/- 7.72 pg/mL; and 34.76 = 10.07 pg/mL in control group. Testing the value of assessing ACTH the area under ROC curve was 0.9965 +/- 0.0071. Test sensitivity was 99.89% and test specificity was 97%. For ACTH cut-off level of 8 pg/mL, test sensitivity was 88.50%, with specificity of 99%. For ACTH cut-off level of 22 pg/mL, test sensitivity was 99.30%, with specificity of 98%. Our intermediate zone from 8 to 22 pg/mL confirms that assessment of ACTH level is a reliable tool in differential diagnosis of Cushing's syndrome.

[Agranulocytosis and acute coronary syndrome in apathetic hyperthyroidism]. / Agranulocitoza i akutni koronarni sindrom u apaticnoj hipertireozi.

INTRODUCTION: Tissue expose to excessive levels of circulating thyroid hormones results in thyrotoxicosis. In most cases, thyrotoxicosis is due to hyperactivity of the thyroid gland. Cardiovascular and myopathic manifestations are predominant clinical features in most hyperthyroid patients, aged 60 years and older. Some of patients have apathetic hyperthyroidism which presents with weight loss, small goiter, severe depression and without clinical features of increased sympathetic activity [3, 6]. About 50% of patients with cardiovascular manifestations have no evidence of underlying heart disease. Cardiac problems resolve when euthyroid state is established [3]. Three treatment modalities are available in hyperthyroidism, namely medicament therapy, surgery and radioactive iodine. Antithyroid drug therapy complications, can be mild such as rash, which is managed without cessation of therapy by antihistamines administration. On the other hand, very serious complications such as agranulocytosis, necessitate immediate discontinuation of the medication and appropriate treatment. Although extremely rear, it is life-threatening with highly variable recovery time. CASE REPORT: A 62-year-old woman with recurrent hyperthyroidism was admitted after treatment of agranulocytosis due to antithyroid drugs in another institution with G-CSF. The patient presented with clinical features of apathetic hyperthyroidism with extremely elevated thyroid hormone levels (total and free T4) and suppressed TSH. Radioactive iodine (5 mCi) was administered after increased thyroid uptake was confirmed. Echocardiography on admission was normal. ECG revealed moderately inverted T waves in standard and V1, V2 precordial leads. Laboratory analysis revealed mild normocytic anemia with normal white blood cell count, hypokaliemia and normal concentration of creatine phosphokinase, lactic dehydrogenase and mildly elevated aspartate transminase in sera. Chest X-ray was consistent with pulmonary emphysema. Because the worsening of ECG changes she was transferred to Coronary unit. The diagnosis of non-Q myocardial infarction was confirmed and treatment with nitrates and beta-adrenergic antagonists was instituted. Four weeks later she became euthyroid and coronarography was performed. Subepicardial coronary arteries were normal (Figure 1). She was dismissed, and still euthyroid three months later. DISCUSSION: Agranulocytosis is very rare but very serious complication of antithyroid drug therapy. It can be detected in about 0.1-1% patients during the first three months of treatment. Sudden appearance, heralded by sore throat and fever, prompt physicians to seek white blood cell and differential count [1-3]. Confirmation of diagnosis urges cessation of drug therapy and appropriate antibiotic treatment. Recently, it was reported that recombinant human granulocyte colony-stimulating factor (rhG-CSF) is to be effective in shortening the recovery time in the neutropenic patients undergoing chemotherapy and also in patients with other types of neutropenia [5]. Tamai at al. [7] confirmed positive outcome in 34 patients treated with rhG-CSF compared to corticosteroid treatment. Hematologic laboratory abnormalities disappear 7-10 days after session of therapy. Patients completely recover two to three weeks later. Fatal outcome was also described [1-5]. Thyroid hormones have profound effects on cardiovascular physiology, especially on heart rate, cardiac output and systemic vascular resistance. In patients with hyperthyroidism, cardiac output is much higher than in normal persons. This is the result of direct effect of thyroid hormones on cardiac muscle contractility, heart rate and decrease in systemic vascular resistance. Excessive thyroid hormone secretion increases cardiac Na-K-activated plasma membrane ATP-ase and sarcoplasmic reticulum Ca-activated ATP-ase with resultant in increase myocardial contractility [6, 9]. Sinus tachycardia is the most common rhythm disorder in hyperthyroidism, but paroxysmal tachycardia and atrial fibrillation are not rare. This can be explained by increased heart rate, cardiac output, blood volume, coronary artery flow and peripheral oxygen consumption in thyrotoxicosis [9]. Patients with coronary arteriosclerosis can develop angina pectoris during thyrotoxic stage, which can be explained by imbalance between cardiac demand and supply. Myocardial damage is often in thyrotoxic patients with chronic hart failure, together with myocardial infarction in patients without coronary disease [2,6]. Congestive heart failure and atrial fibrillation are relatively resistant to digitalis treatment because of high metabolic turn over of medication and excessive myocardial irritability in hyperthyroidism [6]. Cardiovascular and myopathic manifestations predominate in older hyperthyroid patients (over 60 years) and some of them can have only few symptoms of hyperthyroidism [1-3]. Thyrotoxic state characterized by fatigue, apathy, extreme weakness, low-grade fever and sometimes congestive heart failure are designated as apathetic hyperthyroidism. Such patients have small goiters, mild tachycardia and often cool and dry skin with few eye signs [6]. Patients with subclinical hyperthyroidism are at increased risk for atrial fibrillation [9]. Unstable angina and non-Q myocardial infarction (non ST elevation) are acute manifestation of coronary artery disease. The acute coronary syndrome of unstable angina, non-Q myocardial infarction and Q-wave myocardial infarction have atherosclerotic lesions of the coronary arteries as a common pathogenic substrate. Erosions or ruptures of unstable atherosclerotic plaque triggered pathophysiologic processes, resulted in thrombus formation at the site of arterial injury. This leads to abrupt reduction or cessation through the affected vessel. Clinical manifestations of unstable angina and non-Q myocardial infarction are similar and diagnosis of non-Q myocardial infarction is made on the basis of elevated serum markers indicative of cardiac necrosis, detected in peripheral circulation. Acute coronary syndrome ranging from unstable angina to myocardial infarction an non-Q myocardial infarction represents increasingly severe manifestations of the same pathophysiologic processes [10,11]. In conclusion, these 62-year-old woman presented with apathetic form of recurrent hyperthyroidism associated with two serious complications, life-threatening agranulocytosis and acute coronary syndrome.

[Disorder of adrenal gland function in chronic fatigue syndrome]. / Poremecaj funkcije nadbubrega u sindromu hronicnog zamora.

Chronic fatigue syndrome (CFS) is defined as constellation of the prolonged fatigue and several somatic symptoms, in the absence of organic or severe psychiatric disease. However, this is an operational definition and conclusive biomedical explanation remains elusive. Similarities between the signs and symptoms of CFS and adrenal insufficiency prompted the research of the hypothalamo-pituitary-adrenal axis (HPA) derangement in the pathogenesis of the CFS. Early studies showed mild glucocorticoid deficiency, probably of central origin that was compensated by enhanced adrenal sensitivity to ACTH. Further studies showed reduced ACTH response to vasopressin infusion. The response to CRH was either blunted or unchanged. Cortisol response to insulin induced hypoglycaemia was same as in the control subjects while ACTH response was reported to be same or enhanced. However, results of direct stimulation of the adrenal cortex using ACTH were conflicting. Cortisol and DHEA responses were found to be the same or reduced compared to control subjects. Scott et al found that maximal cortisol increment from baseline is significantly lower in CFS subjects. The same group also found small adrenal glands in some CFS subjects. These varied and inconsistent results could be explained by the heterogeneous study population due to multifactorial causes of the disease and by methodological differences. The aim of our study was to assess cortisol response to low dose (1 microgram) ACTH using previously validated methodology. We compared cortisol response in the CFS subjects with the response in control and in subjects with suppressed HPA axis due to prolonged corticosteroid use. Cortisol responses were analysed in three subject groups: control (C), secondary adrenal insufficiency (AI), and in CFS. The C group consisted of 39 subjects, AI group of 22, and CFS group of nine subjects. Subject data are presented in table 1. Low dose ACTH test was started at 0800 h with the i.v. injection of 1 microgram ACTH (Galenika, Belgrade, Serbia). Blood samples for cortisol determination were taken from the i.v. cannula at 0, 15, 30, and 60 min. Data are presented as mean +/- standard error (SE). Statistical analysis was done using ANOVA with the Games-Howell post-hoc test to determine group differences. ACTH dose per kg or per square meter of body surface was not different between the groups. Baseline cortisol was not different between the groups. However, cortisol concentrations after 15 and 30 minutes were significantly higher in the C group than in the AI group. Cortisol concentration in the CFS group was not significantly different from any other group (Graph 1). Cortisol increment at 15 and 30 minutes from basal value was significantly higher in C group than in other two groups. However, there was no significant difference in cortisol increment between the AI and CFS groups at any time of the test. On the contrary, maximal cortisol increment was not different between CFS and other two groups, although it was significantly higher in C group than in the AI group. Maximal cortisol response to the ACTH stimulation and area under the cortisol response curve was significantly larger in C group compared to AI group, but there was no difference between CFS and other two groups. Several previous studies assessed cortisol response to ACTH stimulation. Hudson and Cleare analysed cortisol response to 1 microgram ACTH in CFS and control subjects. They compared maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve. There was no difference between the groups in any of the analysed parameters. However, authors commented that responses were generally low. On the contrary Scott et al found that cortisol increment at 30 min is significantly lower in the CFS than in the control group. Taking into account our data it seems that the differences found in previous studies papers are caused by the methodological differences. We have shown that cortisol increment at 15 and 30 min is significantly lower in CFS group than in C group. Nevertheless, maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve were not different between the C and CFS groups. This is in agreement with our previous findings that cortisol increment at 15 minutes has the best diagnostic value of all parameters obtained during of low dose ACTH test. However, there was no difference between CFS and AI group in any of the parameters, although AI group had significantly lower cortisol concentrations at 15 and 30 minutes, maximal cortisol response, area under the cortisol curve, maximal cortisol increment, and maximal cortisol change velocity than C group. Consequently, reduced adrenal responsiveness to ACTH exists in CFS. In conclusion, we find that regarding the adrenal response to ACTH stimulation CFS subjects present heterogeneous group. In some subjects cortisol response is preserved, while in the others it is similar to one found in secondary adrenal insufficiency.

[Effect of postmenopausal hormone substitution on the lipid profile and coagulation factors in female smokers]. / Efekat supstitucije postmenopauze hormonima na lipidogram i faktore koagulacije kod zena pusaca cigareta.

Postmenopause and smoking impair lipid profile, induce hypercoagulability and reduce fibrinolytic capacity [1, 2]. Postmenopause induced lipid changes can be reversed by oestrogen replacement [3]. Oestrogens also reduce fibrinogen level [4] and have beneficial effects on endothelium [5]. Although several studies showed that hormone replacement therapy may increase the risk of thromboembolic diseases, procoagulant oestrogen activity has not clearly been demonstrated. It is well known that smoking accelerates oestrogen metabolism [6, 7], which may attenuate its beneficial effects. The present study was undertaken to determine if there is difference in beneficial effects of oestrogens between smokers and non-smokers in terms of coagulation process and lipids. The examination was a longitudinal, one-year, before/after therapeutic study, which included healthy postmenopausal women (FSH levels at least 40 U/l), 30 smokers and 32 non-smokers who were under 55 years of age and postmenopausal period shorter than 5 years. Women with surgically induced menopause received unopposed oral oestrogens, while those with spontaneous menopause were treated with combined oral oestrogen/progestogen therapy. Before entering the study and in three-months intervals total LDL, HDL cholesterol, triglycerides and VLDL were determined, as well as plasma fibrinogen, prothrombin time, and activated partial thromboplastin time. Neither beneficial nor adverse effects of oestrogens on lipids and coagulation were observed during one-year follow-up in smokers, although subjects with longer smoking history had higher triglycerides levels after 12 months of therapy. On the contrary, oestrogen replacement reduced total and LDL cholesterol, and increased HDL cholesterol in non-smokers, with no change in triglycerides and VLDL level. A decrease in fibrinogen levels and coagulation activity, expressed by prothrombin time and partial thromboplastin time, were also observed in hormone replacement therapy in postmenopausal women who did not smoke. Peroral hormone replacement therapy does not induce favorable lipid changes in smokers. Higher triglycerides levels observed after one-year therapy in women with a longer smoking history indicate that transdermal replacement maybe more suitable in this group. Peroral oestrogen replacement has no anticoagulant or procoagulant activity in smokers during the early postmenopausal period.