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Background/Aim. In menopausal women lipid and lipoprotein values are important predictors of development of cardiovascular diseases (CVD). The use of estrogens reduces levels of low density lipoprotein cholesterol (LDLC) and lipoprotein A [Lp(a)], and increases levels of triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) depending on the dose and route of administration. Simultaneous administration of progesterone, depending on the type, can have different effects on lipids. The aim of the study was to examine the effect of estroprogestagen therapy on the lipid metabolism of women in menopause, depending on the administration route. Methods. A study was conducted as prospective clinical interventional study with controlled parallel groups. It included 64 women in menopause, divided into three groups: the group 1 (n = 22) on oral therapy with estroprogestagens, the group 2 (n = 17) on transdermal patch therapy with estroprogestagens and the group 3 (n = 25) treated with estroprogestagens given intramuscularly. The following biochemical parameters in the serum were determined: total cholesterol (TC), HDL-C, LDL-C, TG, Lp(a), apoprotein A (Apo-A), apoprotein B (Apo-B), follicle- stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, testosterone, sex hormonebinding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-SO4), prolactin and thyroid-stimulating hormone (TSH), prior to administration of the menopausal hormonal therapy (MHT), as well as after sixth months and 2–5 years from the beginning of the therapy. The statistical significance of the difference in values obtained was examined independently and depending on the route of MHT application. Results. MHT, regardless of the administration route, led to a statistically significant continuous decrease of TC, LDL-C and Apo-B levels and the continuous increase of HDL-C and Apo-A levels. Serum levels of TC, LDL-C, HDL-C, Lp(a), Apo-A and Apo-B did not show a statistically significant differences among groups of women given MHT by different routes. It was found that the serum level of Apo-A increased significantly with the rise of estradiol, and the values of LDL and Apo-B decreased regardless of the route of the MHT application. Conclusion. MHT introduced in time, regardless of the route of administration, has beneficial effects on the lipid status of menopausal women and consequently might prevent numerous cardiovascular diseases that are the leading cause of mortality.

Introduction/Objective. Hot flashes are one of the first clinical symptoms of menopause. The mechanism of hot flashes is still not fully understood. Changes in concentrations of the circulating follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, and other hormones can lead to thermoregulatory dysfunction. The aim of this study was to examine the association between dynamic changes in concentrations of sex hormones and the presence of vasomotor symptoms in menopausal women. Methods. The study involved 36 women divided into two groups: in the first group there were 24 women with hot flashes, BMI 26.16 ± 3.42 kg/m2; the control group comprised 12 women, BMI 26.82 ± 3.89 kg/m2. Data on the presence of hot flashes were based on medical history data. Venous blood samples were collected for the analyses of FSH, LH, prolactin, estradiol, progesterone, testosterone, sex hormone binding globulin, dehidroepiandrosteron sulfate, thyroid-stimulating hormone, and thyroxin. During the subjective feeling of hot flashes, three blood samples during the day and night were collected to determine the mean levels of FSH, LH, and estradiol in women with hot flashes. Results. Women with hot flashes had significantly higher prolactin (389.58 ± 123.69 mIU/L to 258.19 ± 122 mIU/L, p < 0.01) and dehydroepiandrosterone sulfate (3.60 ± 2.49 nmol/L vs. 1.88 ± 1.27 nmol/L, p < 0.05) levels, as well as lower mean values of FSH during hot flashes during the day (69.08 ± 28.84 IU/L vs. 107.18 ± 39.11 IU/L, p < 0.01) and night (60.72 ± 21.89 IU/L vs. 104.57 ± 38.06 IU/L, p < 0.01). Conclusion. .Women with hot flashes had significantly lower mean FSH levels during hot flashes during the day and night than the control group.

The species and ecology of sandflies present in the coastal district of Bar, which lies in Montenegro, an endemic focus of visceral leishmaniasis (VL), were investigated in 1996-1999. A mean of 10 cases of VL and a greater number of viral infections (some of which are attributed to pathogens transmitted by sandflies) are diagnosed each year in this district. Phlebotomus papatasi, P. perfiliewi, P. tobbi, P. neglectus and Sergentomyia minuta were collected, P. perfiliewi being recorded for the first time in Montenegro. The ecology and distribution of each of these five species are described and their role, if any, in the transmission of Leishmania to humans is discussed. [ABSTRACT FROM AUTHOR]

Female pseudohermaphroditism represents discrepancy between karyotype and gonadal features on one side and a psychogenic phenotype on the other. Congenital adrenal hyperplasia is the part of the spectrum of female pseudohaermaofroditism and is due to an enzyme deficiency in steroidogenesis. More than 95% of patients have 21 hydroxylase deficiency which leads to a lack of cortisol and ACTH hypersecretion of pituitary, overproduction of 17 hydroxy progesterone (17OHP) and androgens and adrenal cortex hyperplasia. The clinical phenotype is classified as classical and nonclassical (aka. 'Late onset' form). The classic form is represented as salt-waisting and simply virilizing, depending on the degree of lack of aldosterone. Pathophysiology of CAH due to the lack of 21α hydroxylase is closely associated with the degree of enzyme deficiency. Overproduction of androgens is leading to accelerated virilisation. Classical form is manifested in childhood and is characterized by the overproduction of cortisol precursors and adrenal androgens. In the most severe form, co-aldosterone deficiency leads to loss of salt with all the complications. Girls with the classical form of CAH typically have am ambiguous genitals at birth due to high concentrations of androgens in utero. CAH due to 21OH deficiency is the most common cause of ambiguous genitals in 46XX newborns. Characteristically, the clitoris is enlarged, partially fused labia maiora and a common urogenital sinus at the site of the urethra and vagina. The uterus, Fallopian tubes and ovaries are present and normal, a structures of Wolfian duct are absent. When diagnosed in childhood 46XX CAH patients has been assigned female gender so far, even in fully expressed in virilised external genitalia. This dogmatic approach is based on preserving fertility, and if there was at least uterus, opting for female sex was considered justified. Only about 5% of 46 patients with XX KAH has a psychogenic male gender, as described patient. In addition to mutations of CYP21A2 and effects of high concentration of androgen in the CAH, in the phenotypic expression of CAH different length of sequence of CAG androgen receptor could have an impact, which modulates the effect of androgens on the periphery. Also, while the cases of adaptation of sexual identity and the external genitalia from female to male were documented, not a single case of questionable male sexual identity is noted. In the presented patient testosterone levels are at the upper limit for men, which may be due to enzymatic block and synthesis of cortisol precursor, which is further metabolized to the active androgen: testosterone and dihydrotestosterone. High concentrations of T prenatally and in infancy has led to premature fusion epiphysis and low growth, and high concentrations of DHT to clitoromegaly. The LHRH test showed no stimulatory response of LH, which is probably suppressed by high concentrations of testosterone , but there still needs to be done endocraniaol MNR to rule out other possible etiologies of gonadotroph suppression. Dexamethasone suppression test with measurement of testosterone could give an answer. The treatment of adult patients is based on hydrocortisone in dosages that provide permanent substitution of cortisol and suppress ACTH hypersecretion. In 46 XX patients who are phenotypically male, and whose full identity is male, reconstructive surgical procedures are needed to enable adequate quality of life.

Introduction. Androgen insensitivity syndrome (AIS) belongs to disorders of sex development, resulting from complete or partial resistance to the biological actions of androgens in persons who are genetically males (XY) with normally developed testes and age-appropriate for males of serum testosterone concentration. Case Outline. A 21-year-old female patient was admitted at our Clinic further evaluation and treatment of testicular feminization syndrome, which was diagnosed at the age of 16 years. The patient had never menstruated. On physical examination, her external genitalia and breast development appeared as completely normal feminine structures but pubic and axillary hair was absent. Cytogenetic analysis showed a 46 XY karyotype. The values of sex hormones were as in adult males. The multisliced computed tomography (MSCT) showed structures on both sides of the pelvic region, suggestive of testes. Bilateral orchiectomy was performed. Hormone replacement therapy was prescribed after gonadectomy. Vaginal dilatation was advised to avoid dyspareunia. Conclusion. The diagnosis of complete androgen insensitivity is based on clinical findigs, hormonal analysis karyotype, visualization methods and genetic analysis. Bilateral gonadectomy is generally recommended in early adulthood to avoid the risk of testicular malignancy. Vaginal length may be short requiring dilatation in an effort to avoid dyspareunia. Vaginal surgery is rarely indicated for the creation of a functional vagina. [Projekat Ministarstva nauke Republike Srbije, br. 175067]

Introduction. Menopause leads to the development of central adiposity, a more atherogenic lipid profile and increased incidence of metabolic syndrome independent of age and other factors. Objective. The aim of the study was to investigate the relationships between anthropometric characteristics, sex hormones, lipids and fasting glucose in menopausal women. Methods. The study included 87 menopausal women, who where divided into groups according to two criteria: BMI≥26.7 kg/m2 and BMI≥25 kg/m2. Anthropometric characteristics and blood pressure were measured. Blood was taken at 08.00 h for fasting glucose, triglycerides, cholesterol, HDL, LDL, apolipoprotein A, apolipoprotein B, lipoprotein(a) (Lp(a)), C-reactive protein, fibrinogen, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol, progesterone, testosterone and sex hormone binding globulin (SHBG). Results. Significant differences between groups were found for weight, BMI, waist, hips circumference, waist/hip ratio (WHR), systolic and diastolic blood pressure, Lp(a), FSH, LH, PRL (for systolic blood pressure p

Introduction. Premature ovarian failure (POF) is characterized by amenorrhea, hypergonadotropism and hypoestrogenism in women bellow 40 years. Osteoporosis is one of the late complications of POF. Objective. To correlate collagen type I alpha1 (COLIA1) gene polymorphism with bone mineral density (BMD) in women with POF. Methods. We determined the COLIA1 genotypes SS, Ss, ss in 66 women with POF. Single nucleotide polymorphism (G to T substitution) within the Sp 1-binding site in the first intron of the COLIA1 gene was assessed by polymerase chain reaction (PCR) followed by single-stranded conformation polymorphism (SSCP) analysis. Bone mineral density (BMD) was measured at the lumbar spine region by dual X-ray absorptiometry. Statistics: Kruskal-Wallis ANOVA, Chisquare test, Spearman correlation test. Results. The relative distribution of COLIA1 genotype alleles was SS - 54.4%, Ss - 41.0% and ss - 4.5%. No significant differences were found between genotype groups in body mass index, age, duration of amenorrhea or BMD. A significant positive correlation was observed between BMI and parity. Conclusion. The COLIA1 gene is just one of many genes influencing bone characteristics. It may act as a marker for differences in bone quantity and quality, bone fragility and accelerated bone loss in older women. However, in young women with POF, COLIA1 cannot identify those at higher risk for osteoporosis. [Projekat Ministarstva nauke Republike Srbije, br. ON 173056]

Introduction. Adenocarcinoma of the small bowel is a rare gastrointestinal neoplasm usually affecting the distal duodenum and proximal jejunum. Because of their rarity and poorly defined abdominal symptoms, a correct diagnosis is often delayed. Case Outline. We present a 43-year-old woman admitted at the Clinic for Endocrinology due to a large tumor (over 7 cm) of the left adrenal gland. The tumor was detected by ultrasound and confirmed by CT scan. The patient complained of abdominal pain in the left upper quadrant, fatigue and septic fever. Normal urinary catecholamines excluded pheochromocytoma. The endocrine evaluations revealed laboratory signs of subclinical hypercorticism: midnight cortisol 235 nmol/L, post 1 mg - overnight Dexamethasone suppression test for cortisol 95.5 nmol/L and basal ACTH 4.2 pg/mL. Plasma rennin activity and aldosterone were within the normal range. Surgery was performed. Intraoperative findings showed signs of acute peritonitis and a small ulceration of the jejunum below at 70 cm on the anal side from the Treitz’s ligament. Adrenal glands were not enlarged. Patohistology and immunochemistry identified adenocarcinoma of the jejunum without infiltration of the lymphatic nodules. The extensive jejunal resection and lavage of the peritoneum were performed. Due to complications of massive peritonitis, the patient died seven days after surgery. Conclusion. Poorly defined symptoms and a low incidence make the diagnosis of small bowel carcinoma, particularly of the jejunal region, very difficult in spite of the new endoscopic techniques.

Introduction. Cushing’s syndrome results from inappropriate exposure to excessive glucocorticoids. Untreated, it has significant morbidity and mortality. Case Outline. A 38-year-old woman with a typical appearance of Cushing’s syndrome was admitted for further evaluation of hypercortisolism. The serum cortisol level was elevated without diurnal rhythm, without adequate suppression of cortisol after 1 mg dexamethasone suppression test. 24-hour urinaryfree cortisol level was elevated. Differential diagnostic testing indicated adrenocorticotrophin (ACTH)- dependent lesion of the pituitary origin. Pituitary abnormalities were not observed during repeated MRI scanning. Inferior petrosal sinus sampling (IPSS) was performed: 1) Baseline ratio ACTH inferior petrosal sinus/peripheral was 1.7. Transsphenoidal exploration and removal of the pituitary tumor was performed inducing iatrogenic hypopituitarism. Postoperative morning serum cortisol level was less than 50 nmol/l on adequate replacement therapy with hydrocortisone, levothyroxine and estro-progestagen. Conclusion. No single test provides absolute distinction, but the combined results of several tests generally provide a correct diagnosis of Cushing’s syndrome.

Premature ovarian failure (POF) is the occurrence of hypergonadotropic hypoestrogenic amenorrhea in women under the age of forty years. It is idiopathic in 74-90% patients. Known cases can be divided into primary and secondary POF. In primary POF genetic aberrations can involve the X chromosome (monosomy, trisomy, translocations, deletions) or autosomes. Genetic mechanisms include reduced gene dosage and non-specific chromosome effects impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation. Autoimmune ovarian damage is caused by alteration of T-cell subsets and T-cell mediated injury, increase of autoantibody producing B-cells, a low number of effector/cytotoxic lymphocyte, which decreases the number and activity of natural killer cells. Bilateral oophorectomy, chemotherapy, radiotherapy and infections cause the secondary POF. Symptoms of POF include irritability, nervousness, loss of libido, depression, lack of concentration, hot flushes, weight gaining, dry skin, vaginal dryness, frequent infections etc. The diagnosis is confirmed by the level of FSH of over 40 IU/L and estradiol below 50 pmol/L in women aged below 40 years. Biochemical and other hormonal analysis (free thyroxin, TSH, prolactin, testosterone), karyotype (

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.

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 hormonebinding 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

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 100μg 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.

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.

INTRODUCTION Tissue expose to excessive levels of circulating thyroid hormones results in thyrotoxicosis. In most cases, thyrotoxicosis is due to hyper-activity 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 hyperthyreoidism 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 euthyreoid state is established [3]. Three treatment modalities are available in hyperthyreodism, 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 agranu locytosis 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 dehidrogenase and mildly elevated aspartate transaminase 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 secession 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 thyreotoxicosis [9]. Patients with coronary arteriosclerosis can develop angina pectoris during thyreotoxic 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 hyperthyro-idism [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. Errosions 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.

Although increased hip fracture risk is noted in patients with alcoholic liver disease (ALD), their femoral microstructural and mechanical properties were not investigated previously. The present study aimed to analyze the associations between subregional deteriorations in femoral mechano-structural properties and clinical imaging findings to explain increased femoral fracture risk among ALD patients. This study analyzed proximal femora of 33 male cadaveric donors, divided into ALD (n = 13, 57 ± 13 years) and age-matched control group (n = 20, 54 ± 13 years). After pathohistological verification of ALD stage, DXA and HSA measurements of the proximal femora were performed, followed by micro-CT and Vickers microindentation of the superolateral neck, inferomedial neck, and intertrochanteric region. Bone mineral density and cross sectional area of the femoral neck were deteriorated in ALD donors, compared with healthy controls (p < 0.05). Significant ALD-induced degradation of trabecular and cortical microstructure and Vickers microhardness reduction were noted in the analyzed femoral regions (p < 0.05). Still, the most prominent ALD-induced mechano-structural deterioration was noted in intertrochanteric region. Additionally, more severe bone alterations were observed in individuals with an irreversible stage of ALD, alcoholic liver cirrhosis (ALC), than in those with an initial ALD stage, fatty liver disease. Observed osteodensitometric and mechano-structural changes illuminate the basis for increased femoral fracture risk in ALD patients. Additionally, our data suggest bone strength reduction that may result in increased susceptibility to intertrochanteric femoral fracture in men with ALD. Thus, femoral fracture risk assessment should be advised for all ALD patients, especially in those with ALC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC., Methods: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU., Findings: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2-23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9-82·0] vs 64·0% [61·4-66.4]) while maintaining sensitivity (99·0% [94·4-100·0] vs 100·0% [96·3-100·0]; PPV 19·7%, 16·3-23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6-41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2-84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4-100·0)., Interpretation: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours., Funding: European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aim: to test effects of estradiol (E2) 1 mg and drospirenone (DRSP) 2 mg in treatment of normal weight menopausal women with typical menopausal symptoms, hyperinsulinism, and grade I hypertension. Material and methods: The participants were 133 menopausal women, mean age 51.82 ± 3.25 years, body mass index (BMI) 24.9 ± 2.6 kg/m 2 , waist/hip 0.80 ± 0.05, amenorrhoeic period 2.12 ± 2.10 years. All patients were treated with E2 1 mg and DRSP 2 mg during 12 months period. Blood samples were taken at 8 am before and during 12 months of therapy for: glycemia, lipids, hormonal analysis, follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, testosterone (T), prolactin (PRL), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG). Oral glucose tolerance test (OGTT) was performed with 75 g glucose in order to assess insulin secretion. All had grade I hypertension 24 h blood pressure monitoring was performed before and after 12 months of therapy. Results: E2/DRSP significantly decreased total cholesterol, low-density lipoprotein (LDL), apolipoprotein B (ApoB), and increased high-density lipoprotein cholesterol (HDL) and apolipoprotein A (ApoA). Insulin area under the curve (AUC) significantly decreased (6586.1 ± 4194.2 vs. 5315.3 ± 2895.0, p  < .05) and homeostatic model assessment (HOMA) (3.53 ± 2.18 vs. 3.0 ± 1.8, p  < .05). FSH, LH decreased, E2 increased significantly. Of 24 h day blood pressure decreased significantly. Conclusions: E2/DRSP represents suitable therapy for hyperinsulinemic, grade I hypertensive menopausal women with typical symptoms and normal weight.

More empathized approach is required and is obligatory to women with premature ovarian insufficiency (POI) interested for pregnancy. In order to improve fertility rate in POI patients our suggestions would be: (1) To decrease FSH value to 10-15 IU/L by increasing estrogen. Oocyte donation can be suggested after a minimum of six month interval from FSH between 10-15 IU/L and when no dominant follicles are found. (2) To perform oral glucose tolerance test (OGTT). Insulin sensitizing agents has to be included, when indicated, 3-6 month before pregnancy. (3) TSH has to be 1-2.5 mM/L during 3-6 months before pregnancy. (4) Tests for thrombophyllia (Leiden V, FII, MTHFR, PAI) have to be obligatory. They are less expensive than those repeated in vitro fertilizations. Therapy has to be included according to the indications. (5) In order to regulate disturbed immune response in POI patients with endometriosis oral contraceptive therapy is needed for atleast six months prior to the pregnancy. (5) Encourage the patients and advice them about healthy life style and eating habits. (6) Add other drugs, when they are indicated. Complex interplay between endocrine, immunological, haematological, and psychological factors are very often underdetected in POI patients. It is very important to find out the real time for oocyte donation after correcting all the disturbances, improving endometrium receptivity and reaching women's acceptable psychological status. Untreated disturbances induce cardiovascular diseases, diabetes mellitus, thyroid diseases, coagulopathioes etc.

To improve our understanding of hyperostosis frontalis interna (HFI), we investigated whether HFI was accompanied by changes in the postcranial skeleton. Based on head CT scan analyses, 103 postmenopausal women were divided into controls without HFI and those with HFI, in whom we measured the thickness of frontal, occipital, and parietal bones. Women in the study underwent dual energy x-ray absorptiometry to analyze the bone density of the hip and vertebral region and external geometry of the proximal femora. Additionally, all of the women completed a questionnaire about symptoms and conditions that could be related to HFI. Women with HFI had a significantly higher prevalence of headaches, neurological and psychiatric disorders, and a significantly lower prevalence of having given birth. Increased bone thickness and altered bone structure in women with HFI was localized only on the skull, particularly on the frontal bone, probably due to specific properties of its underlying dura. Bone loss in the postcranial skeleton showed the same pattern in postmenopausal women with HFI as in those without HFI. Recording of HFI in medical records can be helpful in distinguishing whether reported disorders occur as a consequence of HFI or are related to other diseases, but does not appear helpful in identifying women at risk of bone loss.

Objective: To investigate whether gene variants of SOHLH1 exist in Chinese and Serbian patients with primary ovarian insufficiency (POI)., Design: Case-control genetic study., Setting: University hospitals., Patient(s): A total of 364 Han Chinese and 197 Serbian women with nonsyndromic POI and ethnically matched controls., Intervention(s): None., Main Outcome Measure(s): SOHLH1 gene sequencing., Result(s): We found 10 novel heterozygous variants in our cohorts of 561 women with POI but none in the 600 ethnically matched controls. Statistical and bioinformatic analyses indicated that three of the eight variants in Chinese POI cases are potentially disease causing. They comprise two missense variants (p.Ser317Phe and p.Glu376Lys) that might each change activity of the SOHLH1 protein as a transcription factor and one variant (c.*118C>T) located in the 3' untranslated region of the SOHLH1 gene, which might generate a new binding site for the microRNA hsa-miR-888-5p. Of the two variants in the Serbian POI cases, both were synonymous, and no missense variant was identified. The allele frequencies of some known single-nucleotide polymorphisms were statistically significantly different between patients and controls in both the Chinese and Serbian groups., Conclusion(s): Our results suggest that SOHLH1 may be regarded as a new candidate gene for POI., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To identify whether variants found in a large Han Chinese cohort - 8q22.3 SNPs rs3847153 and rs3108910; and one SNP each in HK3 (rs2278493), ESR1 (rs2234693) and BRSK1 (rs12611091) - are associated with premature ovarian failure (POF) in a different ethnic group (Serbian)., Design: Case-control genetic association study in 197 Serbian POF cases and 552 matched controls., Results: None of the SNPs found associated with POF in Chinese cohort were found to be associated in the Serbian sample., Conclusions: In contrast to Han Chinese, no association was found between POF in Serbian women and any of the four tested loci: 8q22.3, HK3, ESR1 and BRSK1. This indicates that ethnically distinct populations may show differences in gene-regulating pathways and genes causing POF., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Glucocorticoid (GC) sensitivity depends on glucocorticoid receptor (GR) and heat shock proteins (Hsps). We investigated whether common GR genes (ER22/23EK, N363S, Bcl I, and 9β) and adrenocorticotropin receptor promoter polymorphisms influence susceptibility for unilateral adrenal incidentaloma (AI), plus GR and Hsp expression in tumorous (n = 19), peritumorous (n = 13) and normal adrenocortical (n = 11) tissues. Patients (n = 112), population-matched controls (n = 100) and tumor tissues (n = 32) were genotyped for these polymorphisms. Postdexamethasone serum cortisol was higher in patients (p < 0.001). GR gene variants, larger allele of Bcl I (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.7-5.1; p < 0.001] and minor allele of 9β (OR 3.0; 95% CI 1.6-5.7; p < 0.001) were independent predictors of AI. In patients, the first allele is linked with larger tumors (p = 0.002) and the latter with higher postdexamethasone cortisol levels (p = 0.025). Both allele carriers had lesser waist circumference (p = 0.02), similar adrenocorticotropin and higher basal (p = 0.024) and postdexamethasone cortisol concentrations (p < 0.001). Tumorous and constitutional genotypes were similar. GR-D is the major receptor isoform in normal adrenal cortex by Western blotting. Loss of other receptor isoforms, decrease in immunostaining for GR (p < 0.0001), underexpression of chaperones (p ≤ 0.01) and the presence of inducible Hsp70 were found in adenomas. In conclusion, GR gene variants, C allele of Bcl I and minor allele of 9β, are associated with AIs. Their concurrent presence in patients reduces GC sensitivity. Normal adrenal cortex preferentially expresses GR-D. In adenomas, the lack of other GR isoforms and underexpression of heat shock proteins perhaps permanently impair GC signaling, which could promote dysregulated cortisol production and tumor growth. The innate GC sensitivity probably modifies these effects.

In this paper we examined age-related and sex-specific deterioration in bone strength of the proximal femur reflected in mechanical properties from dual energy X-ray absorptiometry (DXA)-based hip structural analysis (HSA) on a cadaveric sample from the Balkans. Cadaveric studies permit more precise measurement of HSA parameters and allow further analyses by micromorphometric methods. DXA and HSA analysis was performed on a total of 138 cadaveric proximal femora (63 female, 75 male, age range 20-101 years) from Belgrade. HSA parameters are reported for three standard regions of the proximal femur (narrow neck, intertrochanteric, and shaft). Major age-related findings include an increase in the radius of gyration (first reported in this study), a decline in the cross-sectional area (CSA), a shift in the centroid towards the medial cortex, higher buckling ratios and lower section moduli. Whereas age appears to affect mostly the neck region in men, weakening is also evident in the intertrochanteric region in women, particularly after the age of 80. Aging femoral neck declines in bending strength and increases in buckling susceptibility. The reduced bone mass tends to be distributed farther from the centroidal axis (increase in radius of gyration with decline in CSA). Bone mass is preferentially lost from the lateral part of the cross-section shifting the centroid towards the medial cortex which may increase fragility of the lateral part during fall impact. Results of this study contribute to the epidemiologic data on gender differences and age trends in aging male and female femora.