Oxidative stress status in congenital hypogonadism: an appraisal.

Patients with hypogonadism are at increased risk of cardiac and metabolic diseases. However, the pathogenesis of increased cardiometabolic risk in patients with hypogonadism is not clear. Oxidative stress plays an important role in the pathogenesis of cardiometabolic diseases. This study aimed to investigate possible differences in oxidative stress conditions between patients with hypogonadism and healthy controls. In this study, 38 male patients with congenital hypogonadotropic hypogonadism (CHH) (mean age: 21.7 ± 1.6 years) and 44 healthy male controls (mean age: 22.3 ± 1.4 years) with almost equal body mass index were enrolled. The demographic parameters, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total and free testosterone, homeostatic model assessment of insulin resistance (HOMA-IR) and oxidative stress parameters, such as superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx) and malondialdehyde (MDA), were compared between both groups. Compared to the healthy controls, triglycerides (p = .02), insulin levels, HOMA-IR values, CAT activities and MDA levels (p < .001 for all) were significantly higher and HDL cholesterol (p = .04), total and free testosterone, FSH, LH levels and GPx activity were significantly lower (p < .001 for all) in patients with CHH. There were significant correlations between total testosterone levels and CAT activity (r = -.33 p = .01), GPx activity (r = .36 p = .007) and MDA (r = -.47 p < .001) levels. The results of this study showed that young and treatment-naïve patients with congenital hypogonadism had an increased status of oxidative stress.

Trace Element Levels in Congenital Hypogonadotrophic Hypogonadism.

Cardiometabolic diseases are prevalent in hypogonadism. The pathophysiologic mechanism of increased cardiometabolic risk in hypogonadal patients is not clear. Recently, trace elements have been linked to the development of chronic disease especially cardiovascular disease. We investigated the trace element levels in an unconfounded population of congenital hypogonadotrophic hypogonadism (CHH) and also searched for the relationship with metabolic risk factors. A total of 89 patients with CHH (mean age 21.8 ± 2.0 years) and 80 healthy control subjects (mean age 21.3 ± 1.1 years) were enrolled. The demographic parameters, homeostatic model assessment of insulin resistance (HOMA-IR) levels and plasma zinc, copper, and selenium levels, were measured in patients and healthy controls. The patients had higher waist circumferences (p = 0.014), triglyceride (p = 0.04), insulin (p = 0.004), HOMA-IR levels (p = 0.001), and lower selenium (p = 0.049), zinc (p = 0.004), and copper (p = 0.012) levels when compared to the healthy controls. There was a significant relationship between zinc levels and HOMA-IR levels (p = 0.015). In the regression analysis, zinc levels were independently associated with the calculated HOMA-IR levels (p = 0.015). The results of the present study show that plasma selenium, zinc, and copper levels are decreased in patients with CHH. Also, plasma zinc levels are independently associated with insulin resistance in patients with hypogonadism. Long-term follow-up studies are warranted to investigate the effect of trace elements on the increased cardiometabolic risk in hypogonadism.

Osteoprotegerin, fibroblast growth factor 23, and vitamin D3 levels in male patients with hypogonadism.

Cardiometabolic disorders and osteoporosis are prevalent in patients with hypogonadism. Osteoprotegerin (OPG) and fibroblast growth factor-23 (FGF-23), are co-secreted from bones and vascular endothelium, regulating bone mineral metabolism and vascular functions. Vitamin D is another hormone with dual effects on bone and vascular metabolism. The aim of this study was to search for any difference between the serum levels of OPG, FGF-23, and vitamin D in patients with hypogonadism and the healthy controls. We also aimed to search for any relationship between these parameters and endothelial dysfunction or insulin resistance. Forty-nine male patients with congenital hypogonadotropic hypogonadism (CHH) (mean age 20.71 ± 1.75 years) and 43 BMI matched healthy male subjects (mean age 21.37 ± 1.04 years) were enrolled. OPG, FGF-23, vitamin D, and asymmetric dimethylarginine (ADMA) levels were measured from the fasting serum samples. The insulin sensitivity was estimated by homeostatic model assessment-insulin resistance (HOMA-IR) formula. Triglycerides, insulin, HOMA-IR, and ADMA levels in the patient group were significantly higher than the values of the control group (p = 0.014, p = 0.002, p = 0.003, p < 0.001, respectively). The OPG, FGF-23, and vitamin D levels of the patients were not significantly different from the healthy controls. In addition, these markers were not correlated to ADMA or HOMA-IR levels. The results show that young and treatment naive subjects with CHH have endothelial dysfunction and insulin resistance when compared to their healthy counterparts. However, the OPG, FGF-23, and vitamin D levels were similar in the 2 groups. In addition, these parameters are not significantly related to the endothelial functions or insulin resistance in these subjects.

HDL cholesterol subfractions and the effect of testosterone replacement in hypogonadism.

Metabolic disorders and cardiovascular events are increased in hypogonadism. Serum HDL composition is a better cardiovascular predictor than the HDL counts. However, there is no information about the HDL subfractions in patients with hypogonadism. We designed a prospective study to investigate the HDL subfractions in treatment naïve subjects with hypogonadism and the effects of 2 different testosterone replacement regimens on the HDL subfractions. Seventy young male patients with congenital hypogonadotropic hypogonadism (CHH) and 70 age and BMI-matched healthy males were enrolled in the present study. The patients were assigned to receive intramuscular injections of testosterone esters 250 mg every 3 weeks and transdermal testosterone applications 50 mg daily. Biochemical investigations including HDL subfractions and insulin resistance were done. Patients with CHH had higher levels of insulin, HOMA-IR, WC, triglyceride, and diastolic blood pressure. Although, the HDL cholesterol concentrations were similar in both groups, hypogonadal patients had lower HDL2 and higher HDL3 levels. The total testosterone levels were independent determinants of the HDL2 subfractions. During the follow-up, a significant increase in the BMI and WC values and a significant decrease in the levels of total cholesterol, HDL cholesterol, and HDL3 were observed. No difference was present between the 2 treatment arms. These results show that patients with hypogonadism have unfavorable HDL compositions in addition to the other dysmetabolic features. However, testosterone replacement for about six months neither improves the metabolic problems nor the HDL composition. Mechanistic studies are warranted to better understand the cardiovascular effects of unfavorable HDL compositions in hypogonadism.

Women with polycystic ovary syndrome have increased plasma chitotriosidase activity: a pathophysiological link between inflammation and impaired insulin sensitivity?

Polycystic ovary syndrome (PCOS) is characterized by insulin resistance. Chronic low grade inflammation has been reported to participate in the pathogenesis of insulin resistance. Chitotriosidase (ChT), a protein secreted by activated macrophages, has been shown to be involved in chronic inflammatory responses. In the present study, serum chitotriosidase activity and its relationship with insulin resistance were determined in patients with PCOS.34 patients with PCOS and 44 age and body mass index (BMI) matched healthy controls were enrolled in the study. ChT activity was measured by the fluorescence method. High sensitivity C reactive protein (hs-CRP) and adiponectin levels were determined by enzyme immunoassay (EIA). Insulin resistance was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) formula.Plasma ChT activity, hs-CRP level and HOMA-IR score were significantly higher (p=0.024, p=0.002, p=0.001, respectively) while plasma adiponectin concentration was significantly lower (p=0.018) in women with PCOS compared to healthy controls. Blood ChT activity correlated positively with age, waist-to-hip ratio (WHR), BMI, hs-CRP, HOMA-IR and negatively with blood adiponectin level. After adjustment for age and BMI, ChT activity, total testosterone level and WHR remained as the independent predictors of HOMA-IR score in logistic regression analysis.ChT activity is increased in patients with PCOS in concordance with insulin resistance. These findings may reflect the pronounced risk for metabolic syndrome and atherosclerotic diseases in this particular patient group.

Non-operative management of isolated solid organ injuries due to blunt abdominal trauma in children: a fifteen-year experience.

The purpose of this study was to evaluate essential prerequisites for a selective non-operative approach in children with solid organ injuries due to blunt abdominal trauma, and to determine the predictive value of two different trauma scoring systems: the Injury Severity Score (ISS) and the Paediatric Trauma Score (PTS). A retrospective review of children who were admitted with blunt abdominal solid organ injuries to a paediatric trauma centre between January 1986 and September 2001 was performed. Hepatic, splenic, and renal injuries were graded, based on the American Association for the Surgery of Trauma (AAST) Organ Injury Scale (ranged from grade I to IV). The patients were treated non-operatively or operatively and the two groups were compared for variables such as age, blood transfusion, ISS, PTS, length of hospitalisation, morbidity and mortality rate. Two hundred and five patients (147 boys and 58 girls) entered in this study. Median age was 7 years (1 - 15 yrs). The most common cause of trauma was falls (50%). Abdominal organ injuries were present in all patients with the spleen as the most commonly injured organ (111 patients). Fifty-one patients (32%) had additional extra-abdominal organ injuries. Thirty-five (17%) patients were treated operatively, while 170 (83%) were treated non-operatively. Post-traumatic complications developed in 10 patients treated operatively versus 4 patients treated non-operatively. Four patients died due to multiple organ failure (2 non-operative, 2 operative). When compared to the non-operative group, higher transfusion requirements (p < 0.05), a higher ISS (p < 0.01), lower PTS values (p = 0.0001), a longer hospitalisation period (p = 0.0001), and a higher complication rate (p < 0.05) were observed in the operative group. In addition, the non-operative treatment approach was more common in the last five years compared to the previous ten years (p = 0.002). In conclusion, the appropriate non-operative management of injured children reduces the risks of blood transfusion and decreases the length of hospital stay compared with a surgical approach. The use of physiological parameters and radiological findings may be sufficient criteria for observing haemodynamically stable patients with isolated abdominal organ injuries, and thus intensive care unit costs may be avoided. In addition, a careful and close follow-up is essential in injured patients with a low PTS or high ISS.

Effects of aminoguanidine and tolrestat on the development of ocular and renal structural changes in experimental diabetic rats.

Studies that researched the role of aminoguanidine and tolestat in the prevention of diabetic retinopathy and nephropathy resulted in conflicting data. We investigated the effects of these agents in the prevention of ocular and renal changes in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by intravenous injection of STZ in 30 rats. Ten rats that were not given STZ served as non-diabetic control (Group 1). Ten STZ-diabetic rats that were not given any treatment served as diabetic control (Group 2). Groups 3 and 4 were composed of STZ-induced diabetic rats (10 each) that were given tolrestat and aminoguanidine respectively. Eyes and kidneys were examined at the 24th week under electronmicroscopy. Cataract was observed in all six of the surviving rats in Groups 2 and 4, and in one of 6 surviving rats in group 3. Cataract development was lower in Group 3 than Groups 2 and 4. All retinal samples obtained from group 2 demonstrated a number of structural abnormalities, whereas there were no significant ultrastructural changes in groups 3 and 4. Groups 2 and 3 demonstrated mesangial proliferation and expansion, diffuse glomerular basement membrane (GBM) thickening, and focal GBM thickening in the bulb form. Group 4 demonstrated a normally appearing mesangial space, minimal diffuse but no focal GBM thickening. The urinary albumin excretion (UAE) was lower in Group 4 than the other groups. In conclusion, our results suggest that aminoguanidine may be an important agent for the prevention of renal changes, whereas tolrestat may be effective for the prevention of ocular changes in diabetes mellitus.

Effects of granulocyte-colony stimulating factor in the treatment of diabetic foot infection.

AIMS: Foot infections and the subsequent amputation of a lower extremity are the most common cause of hospitalization among patients with diabetes mellitus. Although there are several reasons for susceptibility to infection in diabetic patients, white blood cell dysfunction is considered to be an important cause for this tendency. Granulocyte-colony stimulating factor (G-CSF) increases the release of neutrophils from the bone marrow and improves neutrophil functions. Based on this knowledge, the aim of the present study was to investigate the effects of addition of G-CSF to the treatment of foot infections in diabetic patients. METHODS: Thirty diabetic patients with foot infection were included in the study. Fifteen of the patients received standard treatment consisting of local wound care and antibiotics (standard group), and the other 15 patients received G-CSF besides standard treatment (G-CSF group). The objectives of this study were to determine the time to resolution of infection, time to hospital discharge, need for surgical intervention, and the effects of G-CSF on phagocytosis and respiratory burst of neutrophils. RESULTS: Treatment with G-CSF led to significantly higher neutrophil counts on the 5th and 10th days, and at the end of treatment in the G-CSF treated group compared to the standard group. Respiratory burst of neutrophils increased significantly in both the G-CSF group (from 1.6 +/- 0.3 to 2.3 +/- 0.5, p = 0.001) and the standard group (from 2.0 +/- 0.4 to 2.3 +/- 0.4, p = 0.02) with treatment. But, while phagocytosis of neutrophils increased significantly in the G-CSF group (from 70.4 +/- 2.0 to 74.5 +/- 1.9, p = 0.004), it did not change significantly in the standard group (from 68.1 +/- 0.2 to 69.4 +/- 1.9, p = 0.3) with treatment. Duration of hospitalization (26.9 +/- 2.0 vs. 28.3 days, p < 0.05), duration of parenteral antibiotic administration (22.9 +/- 2.0 vs. 23.3 +/- 1.9 days, p < 0.05), time to resolution of infection (23.6 +/- 1.8 vs. 22.3 +/- 1.7 days, p < 0.05), and need for amputation (13.3% vs. 20%, p > 0.05) were similar between the G-CSF and the standard groups. CONCLUSIONS: Although G-CSF improves neutrophil function as well as increasing the absolute numbers, this improvement is not associated with shortening of duration of antibiotic administration, duration of hospital stay or need for amputation in diabetic foot infection.

Colon injuries in children.

BACKGROUND/PURPOSE: Colonic injuries are rare in childhood, but when they do occur, they are mostly associated with penetrating abdominal injuries. The primary repair of colon injuries without stoma is still controversial within surgical experience, and the potential risk factors affecting morbidity and mortality is not sufficiently known. METHODS: Between 1985 and 1997, 34 children presenting with traumatic colonic perforations were reevaluated by analyzing the relationship between the overall morbidity and mortality and the potential risk factors. RESULTS: Of the 34 children in the case study, 27 boys and 7 girls, there were 7 (21%) isolated colonic injuries. The remaining 27 (79%) patients showed colonic injuries most frequently associated with the small bowel, the liver, and the bladder. Localization of injury was distributed thus: 21% in the right colon, 29% in the transverse colon, and 50% in the left colon. Primary repair, with or without intestinal resection, was performed in 27 (79%) of the patients. In total, postoperative complications occurred in 10 (29%) of the patients. Risk factors such as age, abdominal contamination, and associated abdominal organ injuries were found significant in these complications, however, the mechanism of injury, shock, blood transfusion, and localization of injury were not correlated significantly to postoperative complications. "'Flint's Colon Grading System" was used to ascertain the sensitivity of trauma scoring systems for postoperative complications. CONCLUSION: Colonic wounds can be repaired primarily without the need of colostomy in the majority of cases in children when the required selections are established.

Zenker's diverticulum in childhood: a new case.

Zenker's diverticulum (ZD) is a very rare pathology in childhood and to date only few pediatric cases have been reported in literature. Herein we report on a case of ZD with cervical abscess formation and oral purulent drainage in a 6-year old girl with severe malnutrition. Diverticulectomy was performed as surgical treatment. The patient is free of symptoms after two years' follow-up.

Effect of octreotide acetate on thyrotropin-secreting adenoma: report of two cases and review of the literature.

OBJECTIVE: To present two cases with thyrotropin-secreting adenoma and the effectiveness of octreotide acetate treatment on their tumor size as well as on thyroid stimulating hormone (TSH) and thyroid hormone levels. CASE REPORTS: The first case presented with tremor, palpitations and sweating as suggestive of hyperthyroidism, but the other one presented with predominantly headache, while the other symptoms such as palpitation and nervousness were less prominent and he also did not have any thyroid enlargement at physical examination. Thyroid hormone levels in both cases were increased. However, TSH levels were not suppressed thus indicating an inappropriate secretion of TSH. Moreover, TSH levels did not change after T3 and TRH administration, which also contributed to the assumption of an inappropriate TSH secretion. One case had no increase in the TSH alpha subunit level, while this was increased in the other one. Both magnetic resonance imaging and somatostatin receptor scintigraphy revealed that there was a microadenoma (the first case; 6 x 7 mm in diameter)and a macroadenoma (the second case; 14 x 18 mm in diameter). Both patients were placed on a therapy with somatostatin analog octreotide (Sandostatin, Sandoz). Octreotide was initially given at a dose of 300 microg daily and then increased gradually up to 600 microg per day. There was some decrease in the levels of TSH and thyroid hormones at first. However, such decreases did not persist with ongoing therapy for 6 months. In addition, there was no change in the tumor size with this therapy at the end. CONCLUSIONS: We conclude that the treatment by somatostatin analogue octreotide may not be an effective means of reducing the pituitary tumor size, though it may be used to reduce TSH and thyroid hormones temporarily.

A case of thyrotropin-secreting pituitary microadenoma with normal thyrotropin alpha-subunit level.

We present a 32-year-old male with a thyrotropin (TSH)-secreting pituitary microadenoma with normal alpha-subunit (SU) and/or alpha-SU/TSH molar ratio. An interesting feature of this patient is that the size of the pituitary tumor remained unchanged during a 6-year follow-up without treatment. The tumor was clearly visualized with somatostatin receptor imaging, indicating that it was somatostatin receptor-positive. Subcutaneous injection of 100 microg octreotide acetate three times daily resulted in significant reduction of TSH and free thyroid hormones 6 weeks after initiation of treatment. However, tumor size was not changed 3 months after initiation of octreotide therapy and thyroid hormones, but not TSH level, eventually increased in spite of increasing the octreotide dosage up to 600 microg/day. This led to discontinuation of treatment. The patient responded only temporarily to octreotide in spite of somatostatin receptors. This case further demonstrates that a normal alpha-SU and/or alpha-SU/TSH molar ratio cannot exclude the possibility of a TSH-secreting pituitary adenoma.

Gingival Langerhans' cells in type I diabetes mellitus.

Langerhans' cells (LCs) are intraepithelial immunocompetent cells. Changes in the number of LCs occur in inflammatory and autoimmune diseases. In this study, the number of gingival LCs in patients with type I diabetes mellitus was compared with those of normal individuals using immunohistochemical methods. Gingival biopsies were obtained from 20 type I diabetics and 10 healthy individuals. Anti-CD1 positive LCs formed an intraepithelial network and showed a marked increase in type I diabetics. This increase was not related to diabetic age. The number of LCs was proportional to the density of subepithelial inflammatory cells. Our findings suggest that LCs may play a role in the development of diabetic gingivitis.

Can we use plasma fibronectin levels as a marker for early diabetic nephropathy.

Although increased plasma fibronectin (PF) levels have been found in diabetic patients with microalbuminuria, there is still controversy about its clinical implication for detecting early diabetic nephropathy. To evaluate the PF concentration as a possible marker for early diabetic nephropathy, three groups of sex-and age-matched patients were studied I) 22 insulin dependent diabetic (IDDM) patients with microalbuminuria (mean age +/- SEM: 23.3 +/- 3.6 years, mean urinary albumin excretion rate (AER) +/- SEM: 47.1 +/- 39.5 micrograms/min); II) 17 IDDM patients with normoalbuminuria (mean age: 23.4 +/- 4.4 years, mean AER: 7.8 +/- 2.1 micrograms/min) and III) 20 healthy control subjects (mean age: 22.6 +/- 4.1 years, mean AER: 6.7 +/- 2.1 micrograms/min). PF and urinary excretion of albumin were measured by an immunoturbidimetric method using commercially available kits (Boehringer Mannheim GMBH FRG, and Miles Lab., UK). The mean PF was significantly higher in the group with microalbuminuria (406.5 +/- 122.9 micrograms/ml) than in the group with normoalbuminuria (295.6 +/- 96.9 micrograms/ml, P < 0.01) or in the control group (299.54 +/- 105.5 micrograms/ml, P < 0.01). A weak positive correlation was found between PF and urinary albumin values (r = 0.35, P < 0.05). There were no significant correlations between PF and the other variables such as age, duration of diabetes, body mass index, arterial blood pressure, fasting blood glucose, fructosamine and HbA1 in the diabetic patients or in the control group. Our results suggest that the PF concentration could be a weak marker for early diabetic nephropathy. We cannot therefore use PF instead of microalbuminuria because there is only a weak correlation between PF and microalbuminuria.