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.

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.

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.

Effect of insulin sensitivity on pulsatile insulin secretion.

OBJECTIVE: The aim of the study was to determine whether derangements in insulin pulsatility are related to the presence of insulin resistance or whether these changes occur only in non-insulin-dependent diabetes mellitus (NIDDM). DESIGN AND METHODS: The study included 26 obese, 11 NIDDM and 10 control subjects. The obese group was divided into a low insulin (plasma insulin <20 mU/l, OLI, 14 subjects) and a high insulin (OHI, 12 subjects) group. For pulsatility analysis blood was sampled every 2 min for 90 min. Pulsatility analysis was carried out using the PulsDetekt program. The insulin secretion randomness was quantified using interpulse interval deviation (IpID) and approximate entropy (ApEn). ApEn and ApEn normalized by s.d. of the individual insulin time series (nApEn) were calculated. Lower values of ApEn and IpID indicate more regular secretion. Homeostasis model assessment (HOMA) was used to quantify insulin sensitivity. RESULTS: Insulin pulses were significantly less regular in the OHI and the NIDDM groups compared with the control and the OLI groups (control: ApEn 0.54+/-0.16, nApEn 0.69+/-0.19, IpID 2.53+/-0.99; OLI: ApEn 0.64+/-0.12, nApEn 0. 79+/-0.15, IpID 2.92+/-1.09; OHI: ApEn 0.88+/-0.07, nApEn 0.92+/-0. 07, IpID 3.95+/-0.84; NIDDM: ApEn 0.92+/-0.16, nApEn 0.99+/-0.09, IpID 4.41+/-0.53; means +/- s.d.). There was no difference in the pulse regularity between the OHI and the NIDDM groups. CONCLUSIONS: Decrease in insulin sensitivity was correlated with the reduction of insulin secretion regularity. Therefore irregular insulin secretion is related to a reduction in insulin sensitivity, and it is not unique to NIDDM.

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.

Increased incidence of neoplasia in patients with pituitary adenomas. The Pituitary Study Group.

OBJECTIVE: The goal of our study was to determine the rate of neoplasms in patients with other pituitary adenomas (non-functioning and prolactinomas) in comparison with acromegaly which is known to favour the development of neoplasia. DESIGN AND PATIENTS: We reviewed clinical records for 220 patients with acromegaly, 151 patients with non-functioning pituitary adenoma (NF) and 98 patients with prolactinomas. Incidence rates of cancer for patients with pituitary tumours were calculated per person-years of follow-up study. These rates were then compared with sex and age adjusted incidence rates reported by National Tumour Registry. An internal control group of 163 subjects with a non-neoplastic condition, i.e. Graves' disease followed chronically in the same clinic was also studied. The ratios observed to expected were expressed as standardized incidence rates (SIR). The only significant difference between the acromegalic and other pituitary tumours patients was in hypopituitarism, present in 18.2% (acromegaly) 47% (NF) and 18.6% (prolactinomas). RESULTS: Twenty-three malignant tumours were registered in 19 acromegalics (1 Hodgkin disease, 1 myelogenous leukaemia, 1 lymphocytic leukaemia, 3 papillary thyroid carcinomas, 1 ovarian carcinoma, 2 colorectal carcinoma, 1 renal cell carcinoma, 4 cervical carcinoma, 2 skin cancers, 2 pancreatic carcinoma, 4 breast carcinoma, 1 bladder carcinoma). Three acromegalics harboured two malignancies. Patients with acromegaly had a 3.39-fold increased rate of malignant tumours compared with the general population and a 3.21-fold increased rate compared with our internal control group. Eleven malignant tumours were found in patients with NF-pituitary adenomas and 2 in prolactinoma patients (1 lymphoma, 1 multiple myeloma, 1 colonic cancer, 1 renal cell cancer, 1 stomach cancer, 2 lung cancers, 1 cervix carcinoma, 1 breast cancer, 1 testicular carcinoma and 3 melanoma). Patients with NF pituitary adenomas had a 3.91-fold increased rate of malignant tumours compared with the general population and 4.07-fold increase compared with the internal control group. Patients harbouring prolactinomas did not have an increased incidence rate of malignancy compared with the general population or our internal controls. Female patients with acromegaly and male patients with NF-pituitary adenoma had higher incidences of neoplasia. CONCLUSION: We have demonstrated that the overall incidence of malignant tumours in patients with non-functioning pituitary adenomas and acromegaly is significantly higher than expected for general population and for our internal control group.

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.