Sazi Imamoglu

TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction

The timely secretion of gonadal sex steroids is essential for the initiation of puberty, the postpubertal maintenance of secondary sexual characteristics and the normal perinatal development of male external genitalia. Normal gonadal steroid production requires the actions of the pituitary-derived gonadotropins, luteinizing hormone and follicle-stimulating hormone. We report four human pedigrees with severe congenital gonadotropin deficiency and pubertal failure in which all affected individuals are homozygous for loss-of-function mutations in TAC3 (encoding Neurokinin B) or its receptor TACR3 (encoding NK3R). Neurokinin B, a member of the substance P–related tachykinin family, is known to be highly expressed in hypothalamic neurons that also express kisspeptin, a recently identified regulator of gonadotropin-releasing hormone secretion. These findings implicate Neurokinin B as a critical central regulator of human gonadal function and suggest new approaches to the pharmacological control of human reproduction and sex hormone-related diseases.

The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome

Insulin resistance (IR) is one of the common features of the polycystic ovary syndrome (PCOS), and recent studies indicate the possible role of vitamin D in the pathogenesis of IR and glucose metabolism. Aim of this study was aimed to determine the effect of vitamin D replacement therapy on glucose metabolism, insulin, and androgen levels in obese, insulin-resistant women with PCOS. Eleven women with PCOS were included in the study. Mean age of the patients was 23.6±5.7 yr, body mass index 33.9±5.1 kg/m2. Six patients (54.5%) had acantosis nigricans and 10 (90.9%) oligoamenorrhea. The mean Ferriman Gallwey score was 14.1 ±4.6. Only 2 women were within the normal limits of vitamin D levels as >20 ng/ml. Three weeks after the administration of the single dose of 300,000 units of vitamin D3 orally, 25-hydroxyvitamin D3 significantly increased from 16.9±16 ng/ml to 37.1 ±14.6 ng/ml (p: 0.027) and only 2 women were detected to have vitamin D3 levels <20 ng/ml. Although glucose and insulin levels were decreased non-significantly, homeostasis model assesment (HOMA)-IR significantly decreased from 4.41 ±1.38 to 3.67±1.48 (p: 0.043). No significant alterations were witnessed at the levels of DHEAS, total and free testosterone, androstenedione. No correlation was found between vitamin D with HOMA and other hormonal parameters. In conclusion, women with PCOS have mostly insufficient vitamin D levels, and vitamin D replacement therapy may have a benefical effect on IR in obese women with PCOS.

Effect of rosiglitazone, metformin and medical nutrition treatment on arterial stiffness, serum MMP-9 and MCP-1 levels in drug naive type 2 diabetic patients.

The aim of the study was to evaluate the long-term effect of rosiglitazone and metformin monotherapy with medical nutrition treatment (MNT) and of MNT alone on arterial stiffness, serum monocyte chemoattractant protein (MCP)-1 and matrix metalloproteinase (MMP)-9 in drug naive patients with type 2 diabetes mellitus. Fifty type 2 diabetic patients were randomized to receive rosiglitazone 4 mg/day (n=19) or metformin 850 mg/day (n=16) with MNT or MNT alone (n=15), for 52 weeks. Arterial stiffness was assessed by using large and small artery elasticity index (SAEI and LAEI, respectively). SAEI, LAEI, serum MCP-1 and MMP-9 levels were measured at baseline and following 52 weeks of treatment. SAEI was improved only in the rosiglitazone group, and the difference was still statistically significant when the three groups were compared (p=0.024). There were no differences in LAEI in inter- and intragroup comparisons at the end of the study. Serum MMP-9 levels were decreased in the metformin (-13.5+/-34.8%, p=0.02) and rosiglitazone (-27.2+/-51.0%, p=0.023) groups compared with baseline values, whereas no significant change was seen in serum MCP-1 levels. These results suggest that rosiglitazone monotherapy has favorable effects on arterial stiffness compared with metformin monotherapy independent of glycemic control.

Comparative effects of pioglitazone and rosiglitazone on plasma levels of soluble receptor for advanced glycation end products in type 2 diabetes mellitus patients

Low levels of soluble receptor for advanced glycation end products (sRAGE) have been associated with the occurrence of vascular complications in patients with type 2 diabetes mellitus. Preliminary evidence has suggested that thiazolidinediones have the ability to modulate circulating levels of this molecule in the hyperglycemic milieu. The aim of this pilot study was to assess the differential effect of 2 different thiazolidinediones-pioglitazone and rosiglitazone-on plasma levels of sRAGE in type 2 diabetes mellitus patients. Sixty type 2 diabetes mellitus subjects were randomly assigned to receive pioglitazone (30 mg/d, n = 19), rosiglitazone (4 mg/d, n = 20), or placebo (medical nutrition therapy, n = 21) for 12 weeks. Changes in plasma glucose, glycosylated hemoglobin, insulin resistance (homeostasis model assessment), total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and sRAGE were evaluated at baseline and after 12 weeks. At 12 weeks, the pioglitazone (P < .001) group had a significant increase from baseline in sRAGE values that was not seen in the medical nutrition therapy and rosiglitazone groups. We conclude that, in type 2 diabetes mellitus patients, pioglitazone-but not rosiglitazone-significantly raised sRAGE, which may contribute to its antiatherogenic effects.

Effect of levothyroxine treatment on QT dispersion in patients with subclinical hypothyroidism.

OBJECTIVE To examine the effect of levothyroxine treatment in patients with subclinical hypothyroidism on electrocardiographic variables, especially on ventricular repolarization-related factors. METHODS Sixteen women (mean age, 48.2 years) with subclinical hypothyroidism were treated with levothyroxine for 16 weeks. All standard 12-lead electrocardiographic recordings were scanned and transferred to a computer, and the QT intervals were measured on 300 times magnified recordings. QT dispersion, which reflects the heterogeneity of the ventricular repolarization, was calculated by the difference between the QT maximum and the QT minimum. RESULTS We found that, after 16 weeks of levothyroxine treatment, the QT interval decreased from 387.2 +/- 10.8 ms to 345.6 +/- 13.0 ms (P<0.0001). The study patients exhibited a significant reduction of QT dispersion from 46.5 +/- 5.3 ms to 30.7 +/- 5.8 ms (P<0.0001). On linear regression analysis, a positive relationship was found between QT dispersion and logarithmic serum TSH levels (r = 0.492; P<0.0001). CONCLUSION We conclude that serum TSH concentration has a role in ventricular inhomogeneity and, therefore, that subclinical hypothyroidism may predispose to ventricular arrhythmias. A large-scale, multicenter, randomized trial should be undertaken to address the benefit-to-risk ratio of levothyroxine treatment on cardiac inhomogeneity in patients with subclinical hypothyroidism.

Metacarpal brown tumor in secondary hyperparathyroidism due to vitamin-D deficiency. A case report.

B rown tumors are locally destructive bone lesions caused by rapid osteoclastic bone resorption due to severe hyperparathyroidism1. For years, brown tumors have been considered to be characteristic of primary hyperparathyroidism. However, brown tumors also have been reported to occur in patients with severe hyperparathyroidism secondary to chronic renal failure2-4, especially those on long-term hemo-dialysis. Hypocalcemia, hyperphosphatemia, and vitamin-D deficiency are the basic characteristics of chronic renal failure associated with secondary hyperparathyroidism. Fig. 1 Photograph of the lesion at presentation. The appearance of brown tumor lesions in a patient with secondary hyperparathyroidism due to malabsorption has been reported5; but, to our knowledge, there are no reported cases of a patient in whom brown tumor developed secondary to osteomalacia due to inadequate sunlight exposure and dietary vitamin-D deficiency. Our patient was informed that data concerning the case would be submitted for publication. A twenty-eight-year-old woman who had been in purdah (no skin exposed in public except the hands and face) since she was thirteen years old presented with a 4 × 3-cm painful mass in the region of the fourth metacarpal of the right hand without redness or warmth (Fig. 1). Her hand movement was extremely restricted. Radiographs revealed an expansile lytic lesion …

Total and acylated ghrelin levels in type 2 diabetic patients: similar levels observed after treatment with metformin, pioglitazone or diet therapy.

Ghrelin, a potent gut-brain orexigenic peptide, has a role in stimulation of food intake and long-term regulation of body weight. Metformin and pioglitazone treatment have different effects on body weight. This discrepancy might be related with the effect of these two drugs on plasma ghrelin levels. We investigated the effect of these two drugs on post-prandial acylated and total ghrelin levels in patients with type 2 diabetes. Eleven patients treated with diet, 12 patients treated with 850 mg/day metformin monotherapy and 12 patients treated with 30 mg/day pioglitazone monotherapy for at least 6 months were enrolled in the study. Plasma acylated and total ghrelin levels were investigated at baseline and at the 60 (th), 120 (th), 180 (th), 240 (th) minutes after a mixed meal test. There were no differences between groups in any of baseline metabolic and anthropometric parameters, including acylated and total ghrelin levels. Acylated and total ghrelin concentrations were suppressed similarly after food consumption, and we could not determine any significant difference between the groups at any time interval. A prolonged postprandial suppression of acylated ghrelin concentrations was observed in the pioglitazone treatment group compared with baseline values. In conclusion, total and acylated ghrelin levels after a mixed meal test were similar in type 2 diabetic patients treated with metformin, pioglitazone or diet therapy alone. These results suggest that changes in body weight during metformin and pioglitazone treatment are not associated with plasma ghrelin levels.

The investigation of the efficacy of insulin glargine on glycemic control when combined with either repaglinide or acarbose in obese Type 2 diabetic patients

Combinations of insulin and oral antidiabetic drugs (OAD) are often prescribed instead of insulin alone. In this study, the effects of insulin glargine (IG) in combination with repaglinide or acarbose on glycemic parameters were investigated. Obese Type 2 diabetic patients with fasting blood glucose (FBG) levels ≥ mmol/l and hemoglobin glycated (A1C) ≥9% under maximal OAD combination therapy were enrolled. Previous therapies were discontinued, and patients were randomized into 2 groups. The combinations of IG and repaglinide were administered to group 1, and of IG and acarbose to group 2 for 13 weeks. Twenty patients in group 1 and 18 patients in group 2 completed the study. A1C levels were significantly decreased from 10.9±1.4% to 7.7±1.1% in group 1 and 11.0±1.4% to 8.1±1.4% in group 2. FBG levels were significantly decreased from 11.9±2.7 to 7.1 ±2.3 mmol/l in group 1 and 11.1 ±2.5 to 6.8±1.4 mmol/l in group 2. Post-prandial glucose levels were significantly decreased from 15.3±3.8 to 10.3±3.0 mmol/l in group 1 and 14.0±3.1 to 8.9±2.2 mmol/l in group 2. Intergroup comparisons indicated no significant differences. More weight gain was detected in group 1, compared to the baseline. Syptomatic hypoglycemia incidence was similar in both groups. Severe hypoglycemic attacks were seen in two patients in group 1. Flatulance incidence was higher in acarbose group. Conclusively, repaglinide and acarbose were equally effective when combined with IG for obese Type 2 diabetic patients controlled inadequately with OAD alone. Furthermore, acarbose seems to have advantages over repaglinide concerning weight gain and severe hypoglycemic attacks.

Prostate cancer metastasis to thyroid gland.

Metastases to the thyroid gland are rarely encountered in clinical practice. They may originate from various primary sites, mainly kidney, lung, breast, esophagus and uterus. Prostate cancer is one of the most frequent malignancies in men. It generally has a favorable course, and autopsy series have shown occult prostate cancer in many subjects, especially in aged males. However, prostate cancer sometimes exhibits an aggressive behavior and cases with a poor prognosis have been reported. Occasional reports of metastasis from prostate cancer to the thyroid gland have been documented. We describe the case of a 73-year-old patient presenting with thyroid metastasis from long-standing prostate cancer.

Body fat distribution has no effect on serum visfatin levels in healthy female subjects.

Obesity is the presence of either abnormal absolute amount or relative proportion of body fat. Contrary to gluteal obesity, visceral obesity is associated with different metabolic alterations including insulin resistance (IR). A relatively new adipocytokine visfatin is shown to be expressed predominantly in visceral fat and exhibit insulin-mimicking effects in rodents. It is still unclear whether serum visfatin levels are associated with increased total or visceral fat mass in humans. The aim of our study was to investigate the relation between visfatin and obesity parameters namely body mass index (BMI) and waist circumference (WaC) and IR in healthy female subjects. Eighty one female subjects 20 years of age, having no diagnosis of glucose intolerance or diabetes, hypertension and dyslipidemia were chosen. The patients were divided into four groups according to their BMI and WaC values. Serum visfatin and HOMA-IR levels did not differ among groups. No correlation was detected between serum visfatin levels and obesity and metabolic parameters. In conclusion, we demonstrated that body fat distribution did not affect serum visfatin levels in healthy female subjects. Further studies are needed to clarify the exact factors influencing and determining serum visfatin levels and its clinical reflections.