Effects of alternate fasting or very low calorie diet and low calorie diet on metabolic syndrome in severely obese patients.

BACKGROUND AND AIM: Weight loss improves the metabolic syndrome (MetS) features and related clinical abnormalities in obese subjects. The aim of this study was to assess the effects of a non-surgical therapeutic program on the MetS in severely obese patients. PATIENTS AND METHODS: Sixty-four extremely obese patients were involved in the therapeutic program, which consisted of two alternating phases: the three-week therapeutic fasting or semi-fasting in hospital conditions and the low calorie diet with dosed physical activity in outpatient conditions. At the baseline we measured: anthropometric parameters, blood pressure and lipid profile. Subjects underwent an oral glucose tolerance test and insulin resistance/sensitivity was evaluated by the homeostasis model assessment and the oral glucose insulin sensitivity. After weight reduction by at least 10%, all mentioned assessments were repeated. RESULTS: None of the patients had significant adverse effects. Forty-one patients aged 43.0±11.5 years completed the study. The mean weight loss was 27 kg or 18% of the initial weight (p<0.01), which was followed by a significant decrease of the insulin resistance, the overall prevalence of MetS (32%) and all MetS parameters, without the significant change in high-density lipoprotein. This weight loss pogram substantially improves the MetS in extremely obese patients. CONCLUSION: The tailored alternating either fasting or semi- fasting should be considered as an optional approach to manage extreme obesity and related metabolic abnormality.

Glucocorticoid effect on insulin sensitivity: a time frame.

It is well known that glucocorticoids induce insulin resistance, but the exact time scale in humans is not well known. The aim of the study was to determine the time scale of effects of pharmacologic doses of glucocorticoids on insulin sensitivity. Subjects were treated with repeated methylprednisolone infusions and oral prednisone for Graves' orbitopathy. Insulin sensitivity was determined using euglycemic hyperinsulinemic clamp (EHGC) before, during the first glucocorticoid infusion and after 2 months of treatment. EHGC started 2 h after the start of the glucocorticoid infusion, and lasted for 2 h. In another group of patients, insulin sensitivity was determined by short insulin tolerance test (SITT) before and during the first glucocorticoid infusion. SITT started 15 min after the start of the glucocorticoid infusion and lasted for 15 min. Ten subjects were included in each protocol. All were euthyroid during the study period. Four hours after the start of the glucocorticoid infusion significant reduction of insulin sensitivity was observed, which did not change for a further 2 months of glucocorticoid treatment [before 7.82 (95% confidence interval (CI) 5.35-10.29), first infusion, 4.93 (95% CI 2.99-6.87), after 2 months 5.36 (95%CI 3.91-6.81) mg/kg/min]. No significant change in insulin sensitivity occurred during the first 30 min of glucocorticoid infusion [before 139.7 (95%CI 94.1-185.3), during 146.7 (95%CI 106.3-187.1) mumol/l/min]. In humans, glucocorticoid- induced insulin resistance develops quickly, in about 4 h, and does not change during further glucocorticoid treatment.

Effect of hormone replacement therapy on lipids and left ventricular function in postmenopausal smokers.

OBJECTIVE: Menopause and smoking have negative effects on the cardiovascular system. The study was planned to investigate the influence of oral hormone replacement therapy (HRT) on heart function and lipids in postmenopausal smokers. METHODS: Lipid levels and left ventricular systolic and diastolic function by means of echocardiography were assessed before entering the study and at 6-month intervals during the 12 months of oral HRT in 62 postmenopausal women, 30 of whom were smokers and 32 were non-smokers. RESULTS: Oral HRT caused a significant decrease in levels of total cholesterol and low density lipoprotein (LDL) cholesterol and a significant increase in high density lipoprotein (HDL) cholesterol in non-smokers. This effect was not evident in smokers. Echocardiography revealed a significant improvement of systolic function (ejection fraction, left ventricular outflow tract velocity, forward velocity integral, acceleration time and mean systolic acceleration) and diastolic function (diastolic time, duration of the early filling phase, peak velocity of early mitral flow, and the ratio of late to early peak mitral flow) in non-smokers. In smokers, a significant increase in some parameters of systolic function (ejection fraction, acceleration time and mean systolic acceleration) and an insignificant change in diastolic function were observed. Oral HRT of 12 months' duration has very limited beneficial effects on CONCLUSION: lipids and left ventricular heart function in postmenopausal women who smoke.

Temporal coupling of luteinizing hormone and follicle stimulating hormone secretion in polycystic ovary syndrome.

The aim of this study was to assess the luteinizing hormone (LH) and follicle stimulating hormone (FSH) pulsatile secretion and their temporal relation (concordance) in subjects with polycystic ovary syndrome (PCOS). Fifteen subjects were included in the study (age 17-30 years, body mass index (BMI) 19.38-33.46 kg/m2). For the LH and FSH determinations, blood sampling started at 23.00 and lasted for 6 h with an intersample interval of 10 min. Pulse analysis was carried out using the PulsDetekt program. LH/FSH pulse concordance was calculated using the specific concordance index. Gonadotropin co-pulsatility was found in six subjects who were significantly younger than the others (median 18.5 vs. 22.5 years, p = 0.036). BMI, hirsutism grade, insulin sensitivity, estradiol, progesterone, testosterone, prolactin, cortisol and results obtained from the pulsatility analysis did not significantly differ between the groups. A serum cortisol concentration was correlated with the increased LH/FSH lag time (p = 0.851, p = 0.036) all subjects were included. In conclusion, two distinct LH/FSH secretory patterns were found in PCOS patients, manifested by the presence or absence of the concordance of gonadotropin secretion. In the group where LH/FSH co-pulsatility was present, correlation was found between the serum cortisol and the LH/FSH lag. We also confirmed the finding of previous studies that LH and FSH secretion are regulated by two different mechanisms.

[Why aren't Leydig cell tumors of the ovary diagnosed in time?]. / Zasto se tumor Leydigovih celija ovarijuma ne dijagnostikuje na vreme?

INTRODUCTION: Leydig cell tumor is a rare sex-cord tumor with sex steroid secretion (mostly testosterone). All clinical symptoms and signs are the consequence of extremely high testosterone level. The diagnosis is confirmed using hormone analysis. CASE DESCRIPTION: A 46-year-old woman with previously normal reproductive function was admitted to the hospital due to hirsutism, temporal hair loss, hoarse voice, increased libido, amenorrhea and clitoromegaly. The examination revealed hirsutism score 36 and signs of defeminization and virilisation. Basal testosterone levels were extremely high before operation, while follicle stimulating hormone and luteinizing hormone were suppressed. Androstenedione was above normal level, while other hormones were normal. Testosterone increased twice in response to Pregnyl. In regard to dexamethasone test there was no response of testosterone, indicating a virilizing ovary tumor. The ultrasound of pelvis was normal. Intraoperatively, a solid 2.3 cm Leydig cell tumor was diagnosed. Testosterone decreased promptly. CONCLUSION: This study points to a long-term diagnostic procedure in Leydig cell tumor detection and effects of endogenous testosterone secretion on hypothalamic-pituitary-ovarian axis.

[Treatment of Grave's ophthalmopathy with high doses of corticosteroids]. / Lecenje Grejvsove oftalmopatije visokim dozama kortikosteroidnih lekova.

UNLABELLED: Severe ophthalmopathy with sight impairment and double vision due to a compressive optic neuropathy, extraocular muscle thickness and corneal exposure occurs in 3-5% of all patients with Graves' hyperthyroidism [1]. Steroids are the choice of treatment for ophthalmopathy in more than 50%, and with orbital radiotherapy or surgical decompression in more than 70% of cases [2]. In severe ophthalmopathy steroids are effective in more than 60% of patients [1, 3], but to be effective high dosage is necessary [1, 4-6]. High-dose intravenous steroid pulse therapy is probably preferable to oral steroids giving a better response with fewer adverse effects [6]. The aim of the study was to evaluate the efficacy of high-dose intravenous methylprednisolone pulse therapy followed by oral steroids in the treatment of patients with severe Graves' ophthalmopathy. PATIENTS AND METHODS: Fourteen euthyroid patients with severe Graves' ophthalmopathy were treated with high-dose intravenous methylprednisolone during 6 months and followed-up for 24-48 months by clinical and ophthalmological assessment. During three days two doses of methylprednisolone were given as 500 mg in 500 ml isotonic saline infusion. The treatment was followed by oral prednisone 40 mg daily and tapered off to 10 mg in four weeks when next course of therapy started. There were no contraindications for steroid treatment. Characteristics of the group are presented in Table 1. Ophthalmological assessment relating to the status of cornea, extraocular muscles, eyelids, proptosis and optic nerve function was done during the study. It provides the measurement of visual acuity, intraocular pressure, visual evoked potentials, palpebral apertures and proptosis, fundoscopy, the assessment of ocular motility, visual fields, color vision, lagophthalmos and corneal changes. For better evaluation of eye disease clinical activity score and patients self-assessment were used. Thyroid hormones and thyroid microsomal antibodies were measured during the study. All patients were photographed before and after treatment. Orbital computed tomograms were performed before and after treatment for extraocular muscles assessment. Data were analyzed by Wilcoxon test. RESULTS: Clinical activity score fell significantly within the first week of therapy in all patients and remained stable during the follow-up period (before treatment: mediana 5, min 3, max 7 and after: mediana 2, min 1, max 4, p < 0.01). Proptosis (Table 2, Figure 1) was significantly reduced (mean values before and after treatment were 24.15 mm and 22.75 mm respectively, the difference was 1.40 mm; p = 0.014). Visual acuity was improved in 2 of 5 patients (Table 3). Ophthalmological assessment of color vision, fundal changes, visual fields and intraocular pressure is presented in Table 4. Five of 9 patients experienced loss or amelioration of diplopia after a 3-6 month treatment. The ocular motility was normalized or improved in 9 of 10 patients. The extraocular muscle enlargement on orbital CT scans decreased in 10 patients (mean score before and after treatment was 6.9 and 3.8 respectively). Minimal and transient side effects were observed during treatment. DISCUSSION: The best parameters of severity of the disease and of response to treatment are those related to assessment of optic nerve function, ocular motility and corneal status [6, 10]. In this series of 14 patients treated with high-dose steroids we found an improvement in visual acuity and color vision and normalization of visual fields, intraocular pressure, visual evoked potentials and fundal changes within a few days of treatment. Clinical activity score (CAS) was significantly and promptly reduced by therapy as most reports revealed [3, 5, 8]. CAS has a high predictive value for the outcome of treatment since it is based on signs of inflammation. The low score level, however, does not preclude a therapeutic success [9]. A mean value of proptosis was significantly reduced by thera

Effect of weight loss on the pulsatile insulin secretion.

The aim of the study was to assess whether pulsatile insulin secretion is variable in the same individual and is related to changes in insulin sensitivity. Insulin sensitivity and pulsatility were measured before and after weight reduction in nine obese subjects. A pulsatility analysis was done using the PulsDetekt program. Blood was sampled every 2 min over a period of 90 min. The secretion randomness was quantified using approximate entropy (ApEn), and ApEn normalized by SD of the insulin time series (nApEn). Lower values indicate more regular secretion. Insulin sensitivity was measured using the homeostasis model assessment. Data are presented as median, minimum-maximum. After weight loss insulin sensitivity was increased (12.16, 7.60-76.70 vs. 38.96, 19.88-74.96%), the number of insulin pulses was reduced (11, 8-16 vs. 9,6-12), and they were more regular (ApEn, 0.92, 0.53-133 vs. 0.69,0,40-1.27; nApEn, 1.07, 0.74-1.33 vs. 0.97, 0.54-1.42). Before and after the weight loss there was a correlation between ApEn and nApEn and insulin sensitivity. Therefore, insulin secretion regularity is variable in the same individual and is related to insulin sensitivity.

[Ovarian Leydig cell tumor]. / Tumor Leydigovih celija ovarijuma.

INTRODUCTION: Leydig cell tumors are sex cord-stromal tumors with sexual steroid production (predominantly testosterone). They account for less than 0.6% of ovarian neoplasms and mostly appear at the age of 28. HISTOPATHOLOGY: It is a solid yellowish nodular tumor, less than 5 cm in diameter. It consists of polygonal Leydig cells, eosinophillic cytoplasm with lipid vacuole and lipochrome pigments. Nuclei are oval, pleomorphic with rare nucleoli. Hyperthecosis is around the tumor. CASE DESCRIPTION: Signs and symptoms depend on age of women and testosterone levels. Women complain about hirsutism, hoarseness, muscular hypertrophy, increased libido, clitoromegaly, temporal hair loss and menstrual disturbances. DIAGNOSIS: Basal hormone analysis reveals extremely high testosterone levels, mildly high androstenedione and 17 OH progesterone, and suppressed follicle stimulating hormone and luteinizing hormone. Estradiol, dehydroepiandrosterone sulfate and other hormones are normal. Dexamethasone screening test decreases dehydroepioandrosterone sulfate and androstenedion, whereas testosterone levels are only partly suppressed. Human choriogonadotropin test is clearly stimulatory for testosterone. Suppressed gonadotropin levels do not respond to luteinizing hormone releasing hormone stimulation. Ultrasonography, nuclear magnetic imaging, Doppler sonography, ovarian vein catheterization can be used for visualization. The removal of tumor is followed by normalization of testosterone levels, increase of gonadotropins and gradual disappearance of all symptoms and signs. THERAPY: The only effective therapy is operative.

Optimizing the diagnostic criteria for standard (250-microg) and low dose (1-microg) adrenocorticotropin tests in the assessment of adrenal function.

ACTH stimulation is the standard test for assessment of adrenal function. It was suggested that the low dose (1 microg) would be more sensitive for detecting mild secondary adrenal insufficiency than the usual dose of 250 microg. The aim of this study was to find the optimal diagnostic criteria and to compare standard dose test (SDT) with the low dose test (LDT). A group of patients treated with corticosteroids for the 6 months was considered to have hypothalamo-pituitary-adrenal impairment. Studies were performed in 14 corticosteroid-treated and 28 control subjects in random order on 2 consecutive days. Tests were analyzed using the receiver operating characteristic curve method. The best test was cortisol increment at 15 min of the LDT. It was significantly better than the cortisol concentration at 15 min of the SDT, the best test during the SDT (receiver operating characteristic curve area and 95% confidence interval: LDT, 0.997 and 0.956-0.999; SDT, 0.827 and 0.662-0.929; P = 0.0113). For the cortisol increment at 15 min of the LDT at 100% sensitivity, the diagnostic value was 100 mmol/L, and the specificity was 96%. Therefore, the LDT is superior to the standard dose test in the assessment of secondary adrenal insufficiency.

Influence of three-week fasting on gonadotropin pulsatility in obese menstruating women.

OBJECTIVE: To evaluate the influence of three-week fasting on gonadotropin pulsatility in extremely obese women of reproductive age. DESIGN: Prospective study of 21-day fasting (400 kcal/day), under medical supervision. SUBJECTS: 20 females, average age of 35.1 +/- 5.9 y, and average BMI of 41.19 +/- 8.39 kg/m2, with regular menstrual cycles (26-34 days). The mean weight loss was 12.5 +/- 3.23 kg. MEASUREMENTS: Blood samples for LH and FSH were taken between 4th and 7th day of the menstrual cycle, before and in the first cycle immediately after weight reduction, for 6 h, starting at 09.00 with 10 min intersample intervals. Pulsatility analysis was done using Pulsar program. Statistical analysis was done using Wilcoxon's matched pairs signed ranking test and McNemar's test. RESULTS: There was no statistically significant difference (p > 0.05) in LH and FSH pulsatile secretion before and after diet including the number of pulses, amplitudes, interpulse intervals and peak lengths. There were no disturbances of menstrual cycle during or after the diet. CONCLUSION: These results suggest that a 21-day fast, accompanied with significant weight loss, does not affect gonadotropin pulse pattern in follicular phase and normal menstrual cycle length in extremely obese females of reproductive age, compared with the pattern before diet.

[Intraarterial perfusion of inoperable adrenocortical carcinoma with emulsion of lipiodol and cytostatics in a patient with Cushing syndrome]. / Intraarterijska perfuzija inoperabilnog karcinoma nadbubrezne zlezde emulzijom lipiodola i citostatskih sredstava kod bolesnika s floridnim sindromom Kusing.

The therapy of adrenocortical carcinoma has not yet been standardized, and a palliative treatment with embolization of hormonally active metastases or adrenocortical tumour, could be a method of choice. We report on a case of adrenocortical carcinoma which was diagnosed as S. Cushing. In the time of diagnosis the tumour was unresectable, and the therapy with mitotane and aminoglutethimide began. When medical treatment was unsuccessful, and side effects aggravated the disease, embolization of the tumour was performed. Superselective angiography of the artery adrenalis mediae sinistrae allowed parfusion of the malignant tissue by emulsion of Streptozotocin (2 g), 5-fluorouracil (17.5 ml) and Lipiodol (15 ccm). There was no adverse reaction after this administration. Plasma cortisol levels were on the same levels three months after this therapy, and improvement of the disease was evident.