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Purpose: Neuroendocrine neoplasms of the appendix (aNET) are rare tumors that are often diagnosed by pathology as an incidental finding after appendectomy for acute appendicitis. Several guidelines proposed risk criteria to indicate oncological completion surgery after appendectomy. The aim of this study was to evaluate the reliability of proposed criteria for completion surgery of aNET. Methods: Patients with aNET treated at ENETS center of excellence Marburg between 2002 and 2022 were retrieved from a prospective data base. Demographic data, histopathological findings, including formerly proposed criteria to indicate oncological completion surgery, histological results of the completion resection and disease-free survival were evaluated. Results: 82 patients with a median age of 35 (range 8–82) years were analysed. 72 (88%) patients underwent an emergency appendectomy because of acute appendicitis. 11 (13%) patients received an ileocecal resection or right hemicolectomy. Seven (8.5%) patients had lymph node metastases and three (3.6%) patients had distant metastases at the initial operation. 27 (33%) patients underwent completion surgery by right hemicolectomy according to guideline criteria, but postoperative histology detected lymph node and distant metastases in only six (22%) and zero patients resulting in an overtreatment of 21 (75%) patients. A tumor size of > 2 cm was the only significant criterion which was associated with lymph node metastases (p < 0.05). After a median follow-up of 62 months (range 2-264) 76 (96%) of the patients in stages I to III were alive with no evidence of disease. Conclusion: aNET have an excellent prognosis in stages I-III and distant metastases are rare. Formerly proposed criteria for oncological completion surgery have to be adopted and discussed for every patient, as they might result in an overtreatment in at least 75% of patients. [ABSTRACT FROM AUTHOR]

Objectives: To highlight a possible association of Calpain (CAPN 10) gene UCSNP-43 polymorphism with hormonal and metabolic traits of young women with different phenotypes of polycystic ovary syndrome (PCOS). Design: PCOS women were genotyped for the CAPN 10 gene UCSNP-43 polymorphism. A comparison of clinical and biochemical features of women with PCOS stratified on the basis of the CAPN 10 gene UCSNP-43 variants was assessed. Methods: Anthropometric, hormonal and biochemical measurements were carried out in 668 PCOS women and 200 healthy controls. Subjects were also genotyped for the CAPN 10 gene UCSNP-43 polymorphism. The genotype frequency distributions between groups and controls were compared using the chi-square test. The association of the polymorphism with the clinical and biochemical features of the study cohort was estimated as well. Results: No association of the frequency of CAPN 10 gene UCSNP-43 polymorphism with PCOS was detected. No association of the polymorphism with the anthropometric, biochemical and hormonal features was detected both in PCOS and control women. The polymorphism was associated with serum Δ4 androstenedione (p = 0.018), as well as with 17-OH progesterone (17-hydroxyprogesterone) among women with PCOS phenotype A (p = 0.012). Conclusions: CAPN 10 gene polymorphism UCSNP-43 is deprived of a metabolic contribution to cardiovascular disease (CVD). However, due to its association with androgen excess in phenotype A, CAPN 10 gene polymorphism UCSNP-43 could be used as a genetic marker for CVD in young PCOS women. 目的：探究不同分型的多囊卵巢综合症（PCOS）年轻女性患者中，钙蛋白酶（CAPN 10）基因UCSNP-43的多态性与她们激素和代谢特征间可能的关系。 实验设计：检测PCOS女性CAPN 10基因UCSNP-43的多态性。依据CAPN 10基因UCSNP-43的变异型对PCOS患者进行分层，比较评估不同分层间的临床和生化特性。 方法：对668名PCOS女性和200名健康对照组女性进行人体测量学指标、激素和生化指标的检测。受试者均检测其CAPN 10基因UCSNP-43的基因型。实验组和对照组间基因型频率分布的比较采用卡方检验。同时对基因多态性与该队列研究中临床和生化特征间的相关性也进行了评估。 结果：未发现CAPN 10基因UCSNP-43多态性频率与PCOS有相关性。PCOS组和对照组均未检测到基因多态性与人体测量学指标、生化和激素指标有相关性。该基因多态性在表型A的PCOS女性中与血清Δ4雄烯二酮和17-OH孕酮（17-羟孕酮）相关（分别为p=0.018和p=0.012） 结论：CAPN 10多态基因UCSNP-43来源于其在心血管疾病（CVD）发展进程中对代谢方面的影响。但是，由于其与表型A中雄激素过多相关，CAPN 10多态基因UCSNP-43可作为年轻PCOS女性发生CVD的基因标记物。 [ABSTRACT FROM PUBLISHER]

Background: Polycystic ovary syndrome (PCOS) represents a moving spectrum of hormonal to metabolic abnormalities, as women with the syndrome are aging. Hormonal abnormalities, anovulation, and hyperandrogenic signs were predominant during the early years of PCOS and fade away with the years. Metabolic abnormalities and insulin resistance (IR) remain throughout the PCOS life cycle; however, it is unclear as to how they change, as women with the syndrome are aging. Objective: To evaluate the changes in IR and its associations with clinical, biochemical, hormonal, and ultrasound findings in a large cohort of women with PCOS and controls, as they are aging. Design: A cross-sectional study was carried out to evaluate the diverse impacts of aging on IR. Setting: An outpatient clinic was chosen for the study. Participants: A total of 1345 women with PCOS (Rotterdam criteria) and 302 controls of Caucasian origin and Greek ethnicity comprised the study group. Main outcome and measures: The impact of age on IR, as calculated using homeostasis model assessment of IR (HOMA-IR) index, and several PCOS characteristics were evaluated. Conclusions: Aging increases IR in obese but not in lean and overweight women with PCOS. As BMI and androgens are positively associated with HOMA-IR and androgens decline through time, it appears that if women with PCOS do not become obese they may exhibit a better metabolic profile during their reproductive years. [ABSTRACT FROM AUTHOR]

Background: Serotonin exhibits a vast repertoire of actions including cell proliferation and differentiation. The effect of serotonin, as an incomplete mitogen, on liver regeneration has recently been unveiled and is mediated through 5-HT2 receptor. The aim of the present study was to investigate the effect of 5-HT7 receptor blockade on liver regeneration after partial hepatectomy. Methods: Male Wistar rats were subjected to 60-70% partial hepatectomy. 5-HT7 receptor blockade was applied by intraperitoneal administration of SB-269970 hydrochloride two hours prior to and sixteen hours after partial hepatectomy and by intraperitoneal administration of SB-258719 sixteen hours after partial hepatectomy. Animals were sacrificed at different time points until 72 h after partial hepatectomy. Liver regeneration was evaluated by [3H]-thymidine incorporation into hepatic DNA, the mitotic index in hematoxylin-eosin (HE) sections and by immunochemical detection of Ki67 nuclear antigen. Reversion of 5-HT7 blockade was performed by intraperitoneal administration of AS-19. Serum and liver tissue lipids were also quantified. Results: Liver regeneration peaked at 24 h ([3H]-thymidine incorporation into hepatic DNA and mitotic index by immunochemical detection of Ki67) and at 32 h (mitotic index in HE sections) in the control group of rats. 5-HT7 receptor blockade had no effect on liver regeneration when applied 2 h prior to partial hepatectomy. Liver regeneration was greatly attenuated when blockade of 5-HT7 receptor was applied (by SB-258719 and SB-269970) at 16 h after partial hepatectomy and peaked at 32 h ([3H]-thymidine incorporation into hepatic DNA and mitotic index by immunochemical detection of Ki67) and 40 h (mitotic index in HE sections) after partial hepatectomy. AS-19 administration totally reversed the observed attenuation of liver regeneration. Conclusions: In conclusion, 5-HT7 receptor is a novel type of serotonin receptor implicated in hepatocyte proliferation. [ABSTRACT FROM AUTHOR]

Objective Obesity is frequently present in women with the polycystic ovary syndrome ( PCOS) and aggravates insulin resistance ( IR) and hyperandrogenemia. We aimed to assess the effects of orlistat combined with lifestyle changes in overweight and obese women with PCOS and body mass index ( BMI)-matched controls. Design Prospective study. Patients We studied 101 women with PCOS (age 26·1 ± 6·4 years, BMI 34·5 ± 5·9 kg/m2) and 29 BMI-matched women with normal ovulating cycles. All women were instructed to follow a low-calorie diet to exercise and were treated with orlistat 120 mg tid for 6 months. Measurements Metabolic and endocrine characteristics of PCOS, blood pressure ( BP) and lipid profile. Results A significant and comparable reduction in BMI was observed in women with PCOS and controls. Systolic and diastolic BP decreased only in women with PCOS. Serum low-density lipoprotein cholesterol levels decreased in both women with PCOS and controls; however, this reduction was greater in controls. In contrast, serum high-density lipoprotein cholesterol levels did not change in women with PCOS and decreased in controls. Serum triglyceride levels decreased significantly and to a comparable degree in the two groups. Similarly, markers of IR improved significantly and to a comparable degree in women with PCOS and controls. Serum testosterone levels and the free androgen index decreased significantly in women with PCOS and did not change in controls. Conclusions Orlistat combined with lifestyle changes induces substantial weight loss in women with PCOS, resulting in improvements in IR, hyperandrogenemia and cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Obesity is frequently present in patients with polycystic ovary syndrome (PCOS) and plays an important role in the pathogenesis of the metabolic, endocrine, and reproductive abnormalities associated with this syndrome. We aimed to summarize the effects of lifestyle changes and anti-obesity pharmacotherapy in patients with PCOS. We reviewed the literature regarding the effects of lifestyle changes and anti-obesity agents on the metabolic and endocrine abnormalities of PCOS. Lifestyle changes, including diet, exercise, and behavioral modification, appear to improve the metabolic and reproductive abnormalities of overweight and obese patients with PCOS. Therefore, lifestyle changes appear to represent the first-line management for all overweight and obese patients with PCOS. However, the optimal composition of diet and the optimal type of exercise in these patients are unknown. Anti-obesity agents that have been studied in PCOS include orlistat, sibutramine, and rimonabant. However, the latter two agents have been withdrawn from the market because of side effects. Long-term studies with orlistat in overweight and obese diabetic patients showed greater weight loss and metabolic and cardiovascular benefits than those achieved with lifestyle changes alone. However, there are limited data on the efficacy of orlistat in women with PCOS. In conclusion, lifestyle changes (diet, exercise and behavioral modification), particularly when combined with anti-obesity agents, exert beneficial effects on the endocrine abnormalities of obese patients with PCOS and improve metabolic parameters. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is frequently characterized by abdominal obesity and insulin resistance, which also represent the hallmarks of the metabolic syndrome (MetS). It is well established that MetS is associated with increased risk for both Type 2 diabetes mellitus and cardiovascular disease (CVD) and accumulating data suggest that PCOS is also a risk factor for Type 2 diabetes mellitus and CVD. Accordingly, the association of PCOS with MetS has major health care implications given also the high prevalence of both disorders. We aimed to critically analyze the major studies that compared the prevalence of MetS between women with PCOS and controls, to discuss the anthropometric, endocrine and metabolic characteristics of PCOS, which are implicated in the pathogenesis of Mets in women with PCOS and to comment on the implications and management of MetS in this population. We thus summarize the evidence regarding the prevalence of MetS in PCOS and discuss the primary determinants driving this association. Current evidence shows that MetS is frequently observed in women with PCOS, but this appears to be mainly due to the more pronounced abdominal obesity in these women and not due to PCOS per se. Lifestyle changes are the treatment of choice for MetS in women with PCOS, whereas pharmacotherapy should be individualized. [ABSTRACT FROM AUTHOR]

Aim: To compare the prevalence of metabolic syndrome (MetS) between women with polycystic ovary syndrome (PCOS) and controls across different age (≤20, 21-30 and 31-39 years old) and body mass index (BMI) (normal weight, overweight and obese) groups. Methods: We studied 1223 women with PCOS and 277 BMI-matched controls. The prevalence of MetS in women with PCOS and controls was estimated according to four different MetS definitions. Results: In subjects ≤20 and 21-30 years old, the prevalence of MetS did not differ between women with PCOS and controls regardless of the MetS definition, even though women with PCOS were more obese than controls in the ≤20 years old group. In subjects 31-39 years old, the prevalence of MetS was higher in women with PCOS than in controls but the former were more obese than controls. The prevalence of MetS did not differ significantly between women with PCOS and controls in any of the BMI groups (normal weight, overweight or obese) regardless of the MetS definition. Conclusion: The prevalence of Mets appears to be primarily determined by obesity and age whereas PCOS per se appears to be a less important contributing factor. [ABSTRACT FROM AUTHOR]

Objective: Hirsutism is frequently present in patients with polycystic ovary syndrome (PCOS) and is a major sign of hyperandrogenism. However, other disorders frequently present in PCOS, particularly abdominal obesity and insulin resistance (IR), have also been implicated in the development of hirsutism in this population but relevant data are limited. We aimed to define the determinants of the presence of hirsutism in PCOS. Design: Observational study. Methods: We studied 1297 patients with PCOS (age 24.3 ± 5.8 years, BMI 26.8 ± 6.9 kg/m²). Hirsutism was defined as a modified Ferriman-Gallwey score ≥8. Results: Women with hirsutism were younger, had greater BMI, and had higher levels of circulating androgens than women without hirsutism; markers of IR did not differ between the two groups after adjustment for age and BMI. The prevalence of hirsutism progressively declined with age, was lower in normal-weight women than in overweight and obese women, and was comparably prevalent in the hyperandrogenemic phenotypes of PCOS. In binary logistic regression analysis, independent predictors of the presence of hirsutism were younger age, larger waist circumference (W), and higher serum testosterone levels. In stepwise linear regression analysis, the Ferriman-Gallwey score independently correlated with age, W, free androgen index, and serum Δ4-androstenedione and DHEAS levels. Conclusions: Besides hyperandrogenemia, abdominal obesity, and young age are independently associated with the presence of hirsutism. In contrast, the relationship between IR and hirsutism appears to be mediated by the more severe obesity of insulin-resistant patients with PCOS. [ABSTRACT FROM AUTHOR]

Objective The polycystic ovary syndrome ( PCOS) and the metabolic syndrome ( Met S) are common disorders that share many characteristics, particularly abdominal obesity and insulin resistance. Our objective was to compare the prevalence of Met S between a large cohort of patients with PCOS and body mass index -matched controls. Design Cross-sectional study. Patients We studied 1223 patients with PCOS and 277 healthy women. Diagnosis of PCOS was based on the revised Rotterdam criteria. Women with PCOS were divided into those who fulfilled both the Rotterdam criteria and the diagnostic criteria of the 1990 National Institutes of Health definition of PCOS (group 1, n = 905) and into those with the additional phenotypes introduced by the Rotterdam criteria (group 2, n = 318). Diagnosis of Met S was based on four different definitions. Measurements Anthropometric, metabolic, hormonal and ultrasonographic features of PCOS. Results The prevalence of metabolic syndrome ( Met S) was higher in women with PCOS than in controls when the National Cholesterol Education Program Adult Treatment Panel III definition of Met S was applied (15·8% and 10·1%, respectively; P = 0·021) but not with the three more recent Met S definitions. The prevalence of Met S was higher in group 1 than in controls regardless of the applied Met S definition. In contrast, the prevalence of Met S was similar in group 2 and in controls regardless of the applied Met S definition. In logistic regression analysis, PCOS did not predict the presence of Met S. Conclusions Polycystic ovary syndrome per se does not appear to increase the risk of Met S independent of abdominal obesity. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do women with the polycystic ovary syndrome (PCOS) differ from those with the metabolic syndrome (MetS) in markers of insulin resistance (IR) and circulating androgens? SUMMARY ANSWER Women with MetS have more pronounced IR than those with PCOS whereas only the latter have elevated circulating androgens. WHAT IS KNOWN ALREADY PCOS and MetS share many similarities, including abdominal obesity and IR, and PCOS is regarded as the ovarian manifestation of MetS. However, there are limited data on the differences between markers of IR and circulating androgens between women with these two syndromes. STUDY DESIGN, SIZE, DURATION A prospective study in 1223 Caucasian women with PCOS and 277 women without PCOS, matched for BMI, was performed between May 2004 and December 2011. The presence/absence of MetS in PCOS+ and PCOS− women was recorded and comparisons among the resulting four groups were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS This study was performed in a university department of obstetrics and gynecology. The following markers of IR were determined: serum glucose and insulin levels, glucose/insulin ratio, area under the oral glucose tolerance test, homeostasis model assessment of IR index and quantitative insulin sensitivity check index. MAIN RESULTS AND THE ROLE OF CHANCE PCOS+MetS+ women (n = 361) were more insulin-resistant than PCOS+MetS− women (n = 862) (P < 0.001 for the comparisons in all markers of IR). Similarly, PCOS−MetS+ women (n = 66) were more insulin-resistant than PCOS−MetS− women (n = 211) (P < 0.001 for the comparisons in all markers of IR). In contrast, PCOS+MetS+ showed only borderline significant differences in some markers of IR compared with PCOS−MetS+ women (P < 0.05). Similarly, PCOS+MetS− women showed only borderline significant differences in some markers of IR compared with PCOS−MetS− women (P = 0.037). Moreover, PCOS−MetS+ women were more insulin-resistant than PCOS + MetS− women (P < 0.001 for the comparisons in all markers of IR). Regarding circulating androgens, PCOS+MetS+ women had higher levels of circulating androgens than PCOS−MetS+ women (P < 0.001 for the comparisons in all circulating androgens). Similarly, PCOS+MetS− women had higher levels of circulating androgens than PCOS−MetS− women (P < 0.001 for the comparisons in all circulating androgens). In contrast, circulating androgens did not differ between PCOS+MetS+ women and PCOS+MetS− women. Similarly, circulating androgens did not differ between PCOS−MetS+ women and PCOS−MetS− women. LIMITATIONS, REASONS FOR CAUTION Only Caucasian women were included in the study. IR was not assessed with the euglycemic hyperinsulinemic clamp. WIDER IMPLICATIONS OF THE FINDINGS Even though MetS and PCOS have many similarities, they are distinct disorders. PCOS does not appear to simply represent the ovarian manifestation of MetS. Further studies are required to assess the contribution of hyperandrogenism to the pathogenesis of IR in PCOS. STUDY FUNDING/COMPETING INTEREST(S) No external funding was either sought or obtained for this study. [ABSTRACT FROM AUTHOR]

The present study investigates the combined effect of diet, physical exercise and Orlistat for 24 weeks, on serum Anti-Müllerian Hormone (AMH) levels in overweight and obese women with polycystic ovary syndrome (PCOS) and in overweight and obese controls. Sixty-one (61) selected women with PCOS and 20 overweight and obese controls followed an energy-restricted diet, physical exercise plus Orlistat administration (120 mg, 3 times per day) for 24 weeks. At baseline, week 12 and week 24, serum levels of AMH, FSH, LH, PRL, androgens, sex hormone-binding globulin (SHBG), glucose, and insulin were measured and Free Androgen Index (FAI) and Insulin Resistance (IR) indices were calculated. In PCOS women, serum AMH levels increased after 12 and 24 weeks of treatment. After 12 weeks LH and SHBG were increased, while Testosterone decreased. After 12 and 24 weeks, FAI was decreased and all indices of IR were significantly improved. We concluded that in overweight and obese women with PCOS Orlistat administration, combined with diet and physical exercise, for 24 weeks, resulted in significant weight loss, improvement of hyperandrogenism and insulin sensitivity, and increased serum AMH levels. [ABSTRACT FROM AUTHOR]

A substantial proportion of women with the polycystic ovary syndrome (PCOS) are obese and obesity is considered as a prothrombotic state. Platelet-derived microparticles (PMPs) might be implicated in the activation of the coagulation cascade. We aimed to assess plasma PMPs in overweight/obese women with PCOS. We measured plasma PMPs and determined anthropometric, metabolic, hormonal and ultrasonographic features of PCOS in 67 overweight/obese women with PCOS (with body mass index [BMI] >25.0 kg/m2) and in 21 BMI-matched healthy women. Circulating androgens and markers of insulin resistance (IR) were higher in women with PCOS than in controls. Plasma PMPs were also higher in women with PCOS than in controls ( p = 0.046). In women with PCOS, plasma PMPs correlated with the mean number of follicles in the ovaries ( r = 0.343; p = 0.006). In controls, plasma PMPs did not correlate with any of the studied parameters. In conclusion, plasma PMPs are elevated in overweight/obese women with PCOS compared with BMI-matched controls. The cause of this increase is unclear but both IR and hyperandrogenemia might be implicated. More studies are required to elucidate the pathogenesis of the elevation of PMPs in PCOS and to assess its implications on the cardiovascular risk of these patients. [ABSTRACT FROM AUTHOR]

Objective: Insulin resistance (IR) is frequent in polycystic ovary syndrome (PCOS) and contributes to the increased risk for type 2 diabetes mellitus and cardiovascular disease of this population. Several markers of IR are used but most are expensive or have limited sensitivity and specificity. Preliminary data suggest that the menstrual cycle pattern correlates with IR in PCOS but existing studies are small. We aimed to assess the relationship between the type of menstrual cycle irregularities and IR in PCOS. Design: Prospective study. Methods: We studied 1285 women with PCOS, divided according to the menstrual cycle pattern. Results: Patients with isolated secondary amenorrhea and those with secondary amenorrhea alternating with regular menstrual cycles were more insulin resistant than patients with regular cycles (Group D). Patients with isolated oligomenorrhea were also more insulin resistant than Group D. However, patients with oligomenorrhea alternating with regular cycles, secondary amenorrhea, or polymenorrhea had comparable levels of markers of IR with Group D. Moreover, patients with oligomenorrhea alternating with regular cycles were less insulin resistant than patients with secondary amenorrhea alternating with regular cycles. Finally, patients with isolated polymenorrhea and those with polymenorrhea alternating with regular cycles had comparable levels of markers of IR with Group D. Conclusions: Amenorrhea is associated with more pronounced IR in PCOS, and oligomenorrhea portends a less excessive risk for IR than amenorrhea whereas polymenorrhea appears to be even more benign metabolically. Therefore, the type of menstrual cycle abnormality appears to represent a useful tool for identifying a more adverse metabolic profile in PCOS. [ABSTRACT FROM AUTHOR]

Objective: The polycystic ovary syndrome (PCOS) is a common and complex disease with unclear pattern of inheritance, characterized by an androgen excess, while hyperinsulinemia and insulin resistance (IR) are common features of the syndrome. The angiotensin I converting enzyme (ACE) insertion (I)/deletion (D) gene polymorphism was proved to be involved in many pathophysiological conditions, including hypertension and IR. Design: The purpose of this study was to evaluate the involvement of the ACE gene polymorphism in the pathogenesis of PCOS. Methods: In a case-control association study involving 801 PCOS women and 266 healthy controls, hormonal determinations and ACE polymorphism genotyping were performed. The PCOS women were classified into three groups: Group A presented biochemical hyperandrogenism, combined with anovulation and polycystic ovarian morphology; Group B, clinical hyperandrogenism combined with anovulation and polycystic ovarian morphology; and Group C, chronic anovulation and polycystic ovarian morphology. Results: A significant increase in the frequency of the DI genotype of the ACE polymorphism was detected in PCOS women as a whole (P=0.035), in PCOS Group A (P=0.039) and Group B (P=0.010), while there was no difference in Group C (P=0.939). Significant difference was also observed in hyperandrogenic PCOS women as a whole (Group ACB) (P=0.017). The II genotype was positively correlated with HOMA-IR and QUICKI and with fasting insulin and glucose/insulin ratio in these groups. Conclusions: The association study of the ACE I/D polymorphism in PCOS women demonstrates an increase in the DI genotype incidence and an association of the II genotype with IR. [ABSTRACT FROM AUTHOR]

BACKGROUND Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by oligo- or anovulation (ANOV), biochemical or clinical manifestations of hyperandrogenemia (HA) and PCOs. Four phenotypes of PCOS exist [phenotype 1 (ANOV + HA + PCO), phenotype 2 (ANOV + HA), phenotype 3 (HA + PCO) and phenotype 4 (ANOV + PCO)] but the differences between them are not well studied. We compared markers of insulin resistance (IR) and endocrine characteristics between the different PCOS phenotypes. METHODS We prospectively studied 1212 consecutive women with PCOS and 254 BMI-matched healthy women. RESULTS Phenotypes 1–4 were present in 48.2, 30.7, 9.7 and 11.4% of patients, respectively. BMI did not differ between the four phenotypes and controls. Both normal weight and overweight/obese women with phenotypes 1 and 2 were more insulin resistant than controls. Overweight/obese, but not normal weight, women with phenotype 4 were more insulin resistant than controls, while IR in women with phenotype 3 did not differ from controls regardless of obesity. In normal weight subjects, women with phenotypes 1 and 2 were more insulin resistant than women with phenotype 4. In overweight/obese subjects, women with phenotype 1 were more insulin resistant than women with phenotypes 2 and 3 and women with phenotype 4 were more insulin resistant than those with phenotype 3. Circulating androgens were higher in normal weight and overweight/obese PCOS patients with phenotypes 1–3 compared with those with phenotype 4, and higher in normal weight PCOS patients with phenotype 1 than in those with phenotype 2. CONCLUSIONS Phenotype 1 is associated with more IR and more pronounced HA than phenotype 2. Phenotypes 2 and 4 with obesity, are also characterized by IR. In contrast, phenotype 3 is not associated with IR. [ABSTRACT FROM PUBLISHER]

Serum lipocalin-2 levels are elevated in obese patients. We assessed serum lipocalin-2 levels in polycystic ovary syndrome (PCOS) and the effects of weight loss or metformin on these levels. Forty-seven overweight/obese patients with PCOS [body mass index (BMI) >27 kg/m2] were instructed to follow a low-calorie diet, to exercise and were given orlistat or sibutramine for 6 months. Twenty-five normal weight patients with PCOS (BMI <25 kg/m2) were treated with metformin for 6 months. Twenty-five normal weight and 25 overweight/obese healthy female volunteers comprised the control groups. Serum lipocalin-2 levels did not differ between overweight/obese patients with PCOS and overweight/obese controls ( p == 0.258), or between normal weight patients with PCOS and normal weight controls ( p == 0.878). Lipocalin-2 levels were higher in overweight/obese patients with PCOS than in normal weight patients with PCOS ( p < 0.001). In overweight/obese patients with PCOS, weight loss resulted in a fall in lipocalin-2 levels ( p < 0.001). In normal weight patients with PCOS, treatment with metformin did not affect lipocalin-2 levels ( p == 0.484). In conclusion, PCOS per se is not associated with elevated lipocalin-2 levels. Weight loss induces a significant reduction in lipocalin-2 levels in overweight/obese patients with PCOS. [ABSTRACT FROM AUTHOR]

Objective. To assess the impact of metformin and of two different oral contraceptives (OCs) containing cyproterone acetate and drospirenone, on serum anti-Müllerian hormone (AMH) levels, in a cohort of women with polycystic ovary syndrome (PCOS) with hyperandrogenism. Design. Prospective randomised study. Setting. Division of Endocrinology and Human Reproduction, Aristotle University of Thessaloniki. Patients. Forty-five (45) women with PCOS diagnosed according to the criteria proposed in 1990 by the NIH. Interventions. Women with PCOS were randomised into three groups, all treated for 6 months: Group A received an OC containing 35 μg ethinylestradiol plus 2 mg cyproterone acetate, Group B received an OC containing 30 μg ethinylestradiol plus 3 mg drospirenone and Group C received metformin 850 mg × 2. Main outcome measure(s). Anti-Müllerian hormone levels were measured by a specific ELISA. Results. AMH was significantly decreased under treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate (p=0.002 at 3 months and p<0.001 at 6 months). Treatment with 30 μg ethinylestradiol plus 3 mg drospirenone, and treatment with metformin 850 mg × 2 did not significantly affect serum AMH levels. AMH was significantly decreased under OCs treatment compared to metformin 850 mg × 2 (p=0.005). Conclusion(s). AMH serum levels were significantly decreased under treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate, due to decrease in androgens and suppression of gonadotropins. [ABSTRACT FROM AUTHOR]

Intriguing studies suggest that osteocalcin (OC) and its carboxylated (Gla)/uncarboxylated form are involved in the regulation of insulin secretion and action. Additionally, advanced glycated end products (AGEs) directly regulate the secretion of these osteoblast-derived molecules. In polycystic ovarian syndrome (PCOS), among the pathophysiological aberrations, deregulation of insulin secretion and action as well as elevated AGEs levels have been demonstrated. In this study, we evaluated the serum levels of osteocalcin and Gla osteocalcin and their possible associations with metabolic, hormonal, and ultrasonographic components of PSOS: 97 women were studied, 50 PCOS patients and 47 controls, matched for age and body mass index (BMI). In each subject, the levels of bone metabolism markers have been evaluated, and metabolic and hormonal profiles as well as ovarian ultrasound were carried out. Osteocalcin (4.30 ± 1.74 vs. 6.20 ± 1.78 ng/ml, P < 0.0005) values were significantly lower, whereas Gla osteocalcin (37.93 ± 6.87 vs. 9.64 ± 8.21 ng/ml, P < 0.0005) and receptor activator for nuclear factor-κB ligand (0.54 ± 0.26 vs. 0.16 ± 0.15 pmol/l, P < 0.0005) values were significantly higher in PCOS subjects compared to the control group, independently of obesity. A significant association was disclosed between osteocalcin and Gla osteocalcin with androgens, insulin resistance, AGEs, and ovarian morphology. Receiver operating curve analysis revealed that Gla osteocalcin [AUC, 0.975 (95% CI, 0.93-1.00)] as well as AGEs are significant prognostic factors of PCOS [AUC, 0.986 (95% CI, 0.97-1.00)]. Lower osteocalcin and elevated serum levels of its carboxylated form are displayed in PCOS subjects and are associated with several PCOS components. These findings suggest a potential interaction between bone-derived markers and the metabolic/hormonal abnormalities observed in PCOS. However, the pathophysiological mechanisms and moreover the possible clinical implications require further investigation. [ABSTRACT FROM AUTHOR]

Objective. Insulin receptor substrate (IRS) proteins are critical to signal transduction in insulin target tissues. The present study was undertaken to determine whether IRS-1 Gly972Arg and IRS-2 Gly1057Asp influence hormonal and metabolic characteristics in Greek patients with polycystic ovary syndrome (PCOS) and controls. Material and methods. One hundred and eighty-three women with PCOS and 88 healthy volunteers were enrolled. Venous blood samples were obtained for genetic study and hormonal profile, glucose, and insulin assays, on days 3 to 7 from cycling patients. DNA was extracted by whole blood samples for genotyping and detection of IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms. Results. Fifty-six women with PCOS (30.60%), whereas 12 women in the control group (13.64%) carried the IRS-1 polymorphism ( p = 0.0026). No statistically significant differences in genotypes or allele frequencies for IRS-2 polymorphism were observed between controls and PCOS women. No significant differences in any clinical or hormonal measures between subjects on the basis of genotype were observed, except the increased levels of fasting glucose that exhibit the carriers of the Asp allele of the IRS-2 polymorphism. Conclusions. Only the IRS-1 polymorphism is associated with increased susceptibility to PCOS in a Greek population. These loci should not be considered as major contributors to the hormonal and metabolic phenotype of PCOS. [ABSTRACT FROM AUTHOR]

The study evaluated the effect of 5 hormonal regimes on serum levels of high-sensitivity C-reactive protein (hsCRP) and homo- cysteine (Hcy) in women with polycystic ovary syndrome (PCOS). Women with PCOS received (1) conjugated estrogens and cyproterone acetate (n = 22), (2) 17β-estradiol and cyproterone acetate (n = 17), (3) ethinyl-estradiol and cyproterone acetate (high dose; n = 20), (4) ethinyl-estradiol plus cyproterone acetate (low dose; n = 12), or (5) ethinyl-estradiol plus desogetrel (n = 12). Both hsCRP and Hcy levels were measured at baseline and after 4, 7, and 12 months. The 17β-estradiol/cyproterone acetate regime resulted in significant reduction of both hsCRP and Hcy levels (P < .001). The other 4 regimes only resulted in a reduction of Hcy levels (P < .001). In conclusion, the 17β-estradiol/cyproterone acetate regime had the most favorable effects in women with PCOS regarding serum levels of hsCRP and Hcy. [ABSTRACT FROM AUTHOR]

Background: Lipocalin-2 is a novel adipokine that appears to play a role in the development of insulin resistance. Serum lipocalin-2 levels are elevated in obese patients. Obesity and insulin resistance are cardinal characteristics of the polycystic ovary syndrome (PCOS). However, there are limited data on serum lipocalin-2 levels in patients with PCOS. The aim of the present study was to assess serum lipocalin-2 levels in PCOS. Methods: We studied 200 patients with PCOS and 50 healthy female volunteers. Results: Serum lipocalin-2 levels were slightly higher in women with PCOS compared with controls (65.4 +/- 34.3 vs. 60.3 +/- 26.0 ng/ml, respectively) but this difference did not reach statistical significance. In contrast, lipocalin-2 levels were higher in overweight/obese women with PCOS than in normal weight women with the syndrome (76.2 +/- 37.3 vs. 54.5 +/- 27.2 ng/ml, respectively; p < 0.001). Serum lipocalin-2 levels were also higher in overweight/obese controls compared with normal weight controls (70.1 +/- 24.9 vs. 50.5 +/- 23.7 ng/ml, respectively; p = 0.004). In the total study population (patients with PCOS and controls), lipocalin-2 levels were independently correlated with the body mass index (p < 0.001). In women with PCOS, lipocalin-2 levels were independently correlated with the waist (p < 0.001). Conclusions: Obesity is associated with elevated serum lipocalin-2 levels. In contrast, PCOS does not appear to affect lipocalin-2 levels. [ABSTRACT FROM AUTHOR]

Piouka A, Fannakiotis D, Katsikis I, Macut D, Gerou S, Panidis D. Anti-Müllerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels. Am J Physiol Endocrinol Metab 296: E238 -E243, 2009. First published October 28, 2008; doi:10.1152/ajpendo.90684.2008.— The objective of the study was the comparison of anti-Müllerian hormone (AMH) levels among obese or overweight and normal- weight women with the four different polycystic ovary syndrome (PCOS) phenotypes and healthy control subjects. AMH levels were evaluated in four age- and body mass index (BMI)-matched groups of 25 normal-weight and 25 obese or overweight women each, belonging to the four main subsets of the syndrome resulting from combinations of the three diagnostic criteria [group 1: oligo- and/or anovulation (ANOV), hyperandrogenemia (HA), and polycystic ovaries (PCO) on ultrasonographic evaluation; group 2: ANOV and HA; group 3: HA and PCO, group 4: ANOV and PCO], and in 50 (25 obese or overweight and 25 normal weight) age- and BMI-matched healthy control subjects. Age, BMI, waist circumference, FSH, LH, prolactin, testosterone, Δ4-androstenedione, dehydroepiandrosterone-sulfate, 17α-OH-progesterone, fasting insulin, glucose, AMH, free andro- gen index, and homeostasis model assessment for insulin resis- tance index were analyzed. AMH levels were significantly higher in PCOS groups 1 and 2 compared with groups 3 and 4 and the control group and higher in PCOS groups 3 and 4 compared with the control group. AMH levels were significantly increased in normal-weight compared with obese and overweight women. AMH concentrations were independently predicted, in order of significance, by LH and testosterone levels, BMI (negatively), and the total number of follicles 2-9 mm in diameter. The differences in circulating AMH levels between the main phenotypic groups of PCOS women appear to reflect the severity of the syndrome, but are negatively affected by obesity. Increased LH levels might be the most significant independent link between PCOS-associated disorders of ovulation and the observed increase in circulating AMH concentration. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is characterized by chronic anovulation, hyperandrogenemia and insulin resistance. Hyperreninemia is observed in insulin resistance and hyperandrogenemic states. Aims: To investigate the levels of total plasma renin and their possible relationship with insulin resistance and hyperandrogenemia and to explore the effect of metformin on these parameters in PCOS women. Methods: 48 PCOS women who were age- and body mass index (BMI)-matched with 21 healthy women were studied. Total renin, aldosterone levels, glucose and insulin levels were measured at basal state and during an oral glucose tolerance test in all subjects. A subgroup of women with PCOS was evaluated 6 months after metformin administration. Results: Total renin levels were significantly higher in PCOS women compared to controls. PCOS women compared to controls displayed higher areas under the curve for glucose, insulin and total renin (AUCREN). Mean AUCREN was correlated significantly with insulin resistance indices and positively with free testosterone levels. Total renin, aldosterone, androgen levels and insulin sensitivity indices were significantly improved after 6 months on metformin treatment. Conclusions: PCOS women demonstrated an insulin resistance and hyperandogenemia-related increase in serum total renin levels. Metformin treatment was shown to significantly reduce total renin levels. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background Nonenzymatic advanced glycation and oxidation end-products, advanced glycation end-products (AGEs), impart a potent impact on vessels and other tissues in diabetic state and in euglycaemic conditions with increased oxidative stress. Insulin resistant (IR) polycystic ovary syndrome (PCOS) women, have elevated serum AGEs, increased receptor (RAGE) expression, and increased deposition with differential localization in the polycystic ovarian tissue (theca and granulosa) compared to normal. Objective To determine whether the raised AGE levels in noninsulin resistant women with PCOS is a distinct finding compared with those presenting the isolated components of the syndrome and among PCOS subphenotypes. Noninsulin resistant women were selected in order to show that serum AGEs are elevated in PCOS independently of the presence of IR. Design Clinical trial. Patients One hundred and ninety-three age- and BMI-matched young lean noninsulin resistant women were studied. Among them, 100 women were diagnosed with PCOS according to Rotterdam criteria, and divided to subphenotypes (hyperandrogenaemia with or without PCO morphology and with or without anovulation). Sixty-eight women with the isolated components of the PCOS phenotype were also studied along with 25 healthy women. Measurements Serum AGE levels, metabolic, hormonal profiles and intravaginal ultrasound were determined in all subjects. Results The studied population did not differ in BMI, fasting insulin concentration, waist : hip and glucose : insulin ratios. PCOS women exhibited statistically higher AGEs levels (7·96 ± 1·87 U/ml, P < 0·001) compared with those with isolated hyperandrogenaemia (5·61 ± 0·61 U/ml), anovulation (5·53 ± 1·06 U/ml), US-PCO morphology (5·26 ± 0·25 U/ml) and controls (5·86 ± 0·89 U/ml). Conclusions In PCOS, serum AGEs are distinctly elevated compared with women having the isolated characteristics of the syndrome. No difference was observed between PCOS subphenotypes. As chronic inflammation and increased oxidant stress have been incriminated in the pathophysiology of PCOS, the role of AGEs as inflammatory and oxidant mediators, may be linked with the metabolic and reproductive abnormalities of the syndrome. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS), the most common reproductive endocrine disorder of premenopausal women, is strongly associated with hyperinsulinemia and type 2 diabetes mellitus (T2DM). Given the phenotypic overlap between PCOS and T2DM, our objective was to investigate whether the TCF7L2 rs7903146(C/T) and the KCNJ11 E23K variants are involved in susceptibility to PCOS and related traits in a Greek population. A total of 183 PCOS patients and 148 healthy controls participated. All participants were Greeks. Blood was taken before hormonal therapy. PCOS patients and healthy controls were genotyped for the TCF7L2 and KCNJ11 variants. The T allele of the TCF7L2 rs7903146 variant was found to be marginally over-represented in Greek patients with PCOS. There was no association between KCNJ11 E23K polymorphism and PCOS in the present study. In addition, there were no associations observed between hormone levels and insulin resistance in PCOS carriers of TCF7L2 rs7903146 and KCNJ11 E23K variants. These data provide evidence that the rs7903146 variant of the TCF7L2 gene might influence PCOS predisposition, while no association is observed between the E23K variant of KCNJ11 and susceptibility to PCOS and related traits. [ABSTRACT FROM AUTHOR]

Aims. To investigate the existence of ghrelin in seminal plasma and the levels of serum ghrelin in men with normospermia and dyspermia. Subjects and methods. Ninety-eight men were classified into three groups: Group 1, men with normospermia and proven fertility (n = 26); Group 2, men with idiopathic oligo-astheno-teratozoospermia (n = 62); and Group 3, men with idiopathic azoospermia (n = 10). Spermiograms and determination of ghrelin in serum and seminal plasma were performed in all men. Results. Ghrelin was present in the seminal plasma of men from all groups at a concentration of 27%, 18% and 30% of the corresponding serum levels (mean ± standard error: Group 1, 127.7 ± 14.7 vs. 468.3 ± 35.5 pmol/l, p = 0.003; Group 2, 117.0 ± 10.1 vs. 637.0 ± 29.3 pmol/l, p < 0.001; Group 3, 166.2 ± 32.5 vs. 557.7 ± 25.4 pmol/l, p = 0.068). When Group 1 men were compared with men from Groups 2 and 3 combined, there were no significant differences in serum (mean ± standard error: 468.3 ± 35.5 vs. 628.0 ± 26.4 pmol/l, p = not significant) or seminal plasma ghrelin (mean ± standard error: 127.7 ± 14.7 vs. 123.9 ± 9.9 pmol/l, p = not significant). In the total group of studied men (Groups 1 to 3), serum ghrelin was positively correlated with semen volume (r = 0.309, p = 0.037), whereas seminal plasma ghrelin was negatively correlated with age (r = -0.268, p = 0.008) and semen volume (r = -0.385, p < 0.000). Conclusions. Ghrelin is present in human seminal plasma at lower levels than in serum. There is no difference in seminal plasma ghrelin levels between men with normospermia and dyspermia. [ABSTRACT FROM AUTHOR]

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Background The phenotypic spectrum of PCOS has been broadened but the prevalence and clinical significance of PCOS phenotypes continue to challenge the scientific community. Objective Analysis of the phenotypic spectrum of PCOS and determination of the association between metabolic, hormonal and new ultrasonographic criteria. Design Clinical prospective study. Patients Six hundred and thirty-four women with PCOS (18–35 years) and comparable body mass index (BMI), diagnosed by ESHRE/ASRM criteria, were categorized into two major groups of phenotypes: classic (NIH) and nonclassic (ESHRE/ASRM), and then subdivided into phenotypes with all possible combinations of diagnostic characteristics. One hundred and eight healthy women of reproductive age, matched for BMI, were recruited as the control group. Measurements Ultrasonographic (ovarian follicle number and volume), hormonal and metabolic parameters. Results Classic PCOS phenotype was more frequent (85·96%) than the nonclassic phenotype (14·04%). The patients were also classified according to the presence of biochemical (80·60%) or clinical hyperandrogenaemia (12·62%), and, in the newly introduced group, to absence of evidence of hyperandrogenaemia (6·78%). Subjects with classic PCOS with biochemical hyperandrogenaemia (74·76%) were more insulin resistant than controls. In women with PCOS, follicle number was positively related to both insulin resistance and biochemical hyperandrogenaemia. Additionally, women with PCOS had a 6·58-fold increased relative risk (RR) of > 12 follicles on intravaginal ultrasound and a 2·94-fold increased RR of ovarian volume > 10 cm3 compared to controls. Conclusion The most frequent PCOS phenotype is the subgroup with biochemical hyperandrogenaemia only within the classic phenotype, which is more insulin resistant than the control group. The follicle number, a newly introduced ultrasonographic marker, is related to both metabolic and hormonal features of PCOS. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the localization/immunohistochemical distribution of AGEs and RAGE, as well as their putative signalling mediator NF-κB in ovaries of women with polycystic ovary syndrome (PCOS) compared to normal. Archival ovarian-tissue samples from biopsies of six women with PCOS and from six healthy of similar age women, were examined immunohistochemically with monoclonal anti-AGEs, anti-RAGE and anti-NF-κB(p50/p65) specific antibodies. In healthy women, AGE immunoreactivity was observed in follicular cell layers (granulosa and theca) and luteinized cells, but not in endothelial cells. PCOS specimens displayed AGE immunoexpression in theca interna and granulosa cells as well as in endothelial cells, but staining of granulosa cells was stronger than in that of normal ovaries. RAGE was highly expressed in normal and PCOS tissues. Normal tissue exhibited no staining differences between granulosa cell layer and theca interna. However, in PCOS ovaries, granulosa cells displayed stronger RAGE expression compared to theca interna cells in comparison to controls. NF-κB(p50/p65) was expressed in the cytoplasm of theca interna and granulosa cells of both normal and PCOS ovaries; whereas the NF-κB p65 subunit was only observed in granulosa cells nuclei in PCOS tissue. In conclusion, these findings demonstrate for the first time that RAGE and AGE-modified proteins with activated NF-κB are expressed in human ovarian tissue. Furthermore, a differential qualitative distribution of AGE, RAGE and NF-κB p65 subunit was observed in women with PCOS compared to healthy controls, where a stronger localization of both AGE and RAGE was observed in the granulosa cell layer of PCOS ovaries. [ABSTRACT FROM AUTHOR]

Background Women with polycystic ovary syndrome (PCOS) exhibit elevated serum advanced glycation end-products (AGE) compared with healthy subjects. Short-term administration of orlistat has been shown to reduce the postmeal increase in serum AGE levels in women with PCOS and in controls. Objective To evaluate the long-term effect of orlistat and a low-calorie diet on serum AGE levels, and on the hormonal and metabolic profile of obese PCOS and normal women. Design A clinical trial of 6 months of orlistat administration with an energy-restricted diet [basic metabolic rate (BMR) 600 kcal/day] in all subjects. Subjects Twenty-nine women with PCOS [aged 27·52 ± 5·77 years; body mass index (BMI) 35·43 ± 5·31 kg/m2] and 18 controls (aged 32·06 ± 5·64 years; BMI 36·39 ± 6·47 kg/m2). Measurements Serum AGE levels (U/ml), hormonal and metabolic profile. Results PCOS and controls did not differ in BMI ( P = 0·58), waist-to-hip ratio (WHR) ( P = 0·44), fasting insulin concentration ( P = 0·45) and glucose-to-insulin ratio (GIR) ( P = 0·34). PCOS women exhibited statistically higher AGE ( P < 0·001) and testosterone levels ( P < 0·001) compared with controls. After 6 months of orlistat treatment, AGE levels showed a statistically significant decrease in both groups (PCOS: baseline 9·08 ± 1·84, post-orlistat 8·56 ± 1·95, P = 0·001; controls: baseline 5·02 ± 0·62, post-orlistat 4·91 ± 0·69, P = 0·03), independently of the BMI reduction in the PCOS group. A significant reduction was observed in BMI (PCOS: P < 0·001; controls: P < 0·001), WHR (PCOS: P = 0·002; controls: P = 0·04), fasting insulin (PCOS: P < 0·001; controls: P = 0·008), and testosterone concentrations in PCOS ( P < 0·001). SHBG concentration (PCOS: P = 0·004; controls: P = 0·008) and GIR (PCOS: P < 0·001; controls: P = 0·03) were significantly increased. A significant improvement was also observed in insulin resistance indices post-treatment in both groups. Conclusions Our data suggest that orlistat has a beneficial effect in reducing elevated AGE levels and improving the hormonal and metabolic profile in women with PCOS after 6 months of treatment, independently of BMI changes. [ABSTRACT FROM AUTHOR]

Combined pituitary hormone deficiency (CPHD) is a rare disorder resulting from an impaired pituitary function due to different causes, characterized by impaired secretion of growth hormone (GH) and one or more of the other anterior pituitary hormones. To date, 16 distinct human Prophet of Pit-1 (Prop1) gene mutations have been identified in patients with CPHD, inducing a phenotype involving GH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin and thyroid-stimulating hormone (TSH), and rarely adrenocorticotropic hormone, deficiency. Herein we present two siblings of different sexes from a family with parental consanguinity presenting the 301–302delAG mutation in the Prop1 gene. The female presented failure of growth from the age of 6 years and was treated for 10 years with GH, ending in a final height (standard deviation score) of -0.28. TSH deficiency was manifested after the initiation of GH and was treated with thyroxine while puberty was initiated with conjugated estrogens. The male presented TSH deficiency since childhood, treated with thyroxine, and growth failure at the age of 14 years, treated for a period of 2 years with GH. Puberty was initiated with increasing doses of testosterone, while human chorionic gonadotropin was added in order to achieve increased testicular volume. In conclusion, these two siblings of different sexes with CPHD carrying the 301–302delAG mutation in the Prop1 gene presented a variable phenotype characterized by GH, TSH, LH and FSH deficiency. [ABSTRACT FROM AUTHOR]