Metin Guclu

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.

Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome.

CONTEXT Gordon Holmes syndrome (GHS) is characterized by cerebellar ataxia/atrophy and normosmic hypogonadotropic hypogonadism (nHH). The underlying pathophysiology of this combined neurodegeneration and nHH remains unknown. OBJECTIVE We aimed to provide insight into the disease mechanism in GHS. METHODS We studied a cohort of 6 multiplex families with GHS through autozygosity mapping and whole-exome sequencing. RESULTS We identified 6 patients from 3 independent families carrying loss-of-function mutations in PNPLA6, which encodes neuropathy target esterase (NTE), a lysophospholipase that maintains intracellular phospholipid homeostasis by converting lysophosphatidylcholine to glycerophosphocholine. Wild-type PNPLA6, but not PNPLA6 bearing these mutations, rescued a well-established Drosophila neurodegenerative phenotype caused by the absence of sws, the fly ortholog of mammalian PNPLA6. Inhibition of NTE activity in the LβT2 gonadotrope cell line diminished LH response to GnRH by reducing GnRH-stimulated LH exocytosis, without affecting GnRH receptor signaling or LHβ synthesis. CONCLUSION These results suggest that NTE-dependent alteration of phospholipid homeostasis in GHS causes both neurodegeneration and impaired LH release from pituitary gonadotropes, leading to nHH.

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.

Puberty, stress, and sudden death

In September, 2008, a 22-year-old man was referred for investigation of delayed puberty. He was thin (BMI 17·1 kg/m²) but had no history of anorexia nervosa. Neurological examination and sense of smell were normal; testes volumes were 2 mL and 3 mL [normal, 15–25 mL]. Concentrations of gonadotropins were not elevated (FSH 4·1 IU/L [normal 1·3–13·5], LH 0·77 IU/L [1·2–10]) and testosterone was 0·9 nmol/L [9–30], consistent with a central form of hypogonadism; prolactin concentration was normal. During a gonadotropin stimulation test, he became weak and dizzy; blood pressure was 90/40 mm Hg, sodium119 mmol/L, and potassium 5·4 mmol/L. At this time, we noticed that he was pigmented, and on further questioning we found that he had had previous episodes of weakness, especially during concurrent illnesses. We suspected adrenal insuffi ciency and treated him with intravenous hydrocortisone, which led to a rapid improvement in symptoms. Basal cortisol con centration before treatment was 290 nmol/L (180–500), but corticotropin was 297 pmol/L (0–11) (fi gure). On more detailed questioning we found that his older brother had presented at 18 years of age with features of hypogonadism that had been treated with testosterone. He also had a normal basal cortisol concentration, but a poor response to co-syntropin stimulation on two occasions, and slightly raised concentrations of corticotropin (20–47 pmol/L; fi gure). Although further review of adrenal function had been planned, our patient’s brother died suddenly during intensive physical activity.Impaired puberty in males can be due to testicular failure (hypergonadotropic hypogonadism) or to a central cause that aff ects pulsatile LH and FSH release (hypogonadotropic hypogonadism). The presence of adrenal insuffi ciency and central hypogonadism could refl ect a multiple pituitary defi ciency aff ecting both corticotropin and gonadotropin

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.

Serum Levels of sRAGE Are Associated with Body Measurements, but Not Glycemic Parameters in Patients with Prediabetes.

BACKGROUND Our aim was to assess serum levels of the soluble receptor for advanced glycation end products (sRAGE) and to examine their association with anthropometric and metabolic parameters in patients with prediabetes and obese controls. METHODS The two study groups were composed of 42 patients with prediabetes and diabetic neuropathy and 42 age-, gender-, body weight (BW)-, and body mass index (BMI)-matched obese adults as the control group. Prediabetes was diagnosed by the following criteria issued by the American Diabetes Association: impaired fasting glucose [fasting plasma glucose (FPG) level of 100-125 mg/dL], impaired glucose tolerance (2 hr plasma glucose level of 140-199 mg/dL after a 75 grams oral glucose challenge), or a glycated hemoglobin (HbA1C) level of 5.7%-6.4%. RESULTS There were no differences between the groups in terms of age, gender distribution, BW, or BMI. Despite these similarities, patients with prediabetes had higher FPG, HbA1c, and 2-hr postchallenge glucose levels, higher systolic and diastolic blood pressure, and larger waist and hip circumferences compared with the obese controls. Lipid measurements, complete blood counts, kidney and liver function tests, high-sensitivity C-reactive protein, and sRAGE levels were similar between the two groups. We found significant negative correlations between sRAGE levels and BW, BMI, waist and hip circumferences, waist-to-hip ratios, and low-density lipoprotein (LDL) cholesterol levels. There were no significant correlations with other parameters, including demographic, metabolic, and blood pressure measurements. CONCLUSIONS In contrast to glycemic parameters, serum levels of sRAGE were negatively correlated with body measurements indicative of obesity in the prediabetic state. In addition, the negative correlation with LDL cholesterol levels suggests that sRAGE has a more robust association with metabolic syndrome than with prediabetes.

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.

Evaluation of serum Spondin 2 levels in the different stages of Type 2 diabetic nephropathy

We aimed to determine whether serum SPON2 is a useful biomarker in the detection of Diabetic Nephropathy (DN) and to compare serum SPON2 levels with 24‐hour urinary albumin excretion rate (UAER) in patients with DN at different stages.