Endocrine DOI 10.1007/s12020-014-0275-1

REVIEW

Gastrointestinal hormones and polycystic ovary syndrome Jing Ma • Tzu Chun Lin • Wei Liu

Received: 19 February 2014 / Accepted: 16 April 2014 Ó Springer Science+Business Media New York 2014

Abstract Polycystic ovary syndrome (PCOS) is an endocrine disease of women in reproductive age. It is characterized by anovulation and hyperandrogenism. Most often patients with PCOS have metabolic abnormalities such as dyslipidemia, insulin resistance, and glucose intolerance. It is not surprising that obesity is high prevalent in PCOS. Over 60 % of PCOS women are obese or overweight. Modulation of appetite and energy intake is essential to maintain energy balance and body weight. The gastrointestinal tract, where nutrients are digested and absorbed, plays a central role in energy homeostasis. The signals from the gastrointestinal tract arise from the stomach (ghrelin release), proximal small intestine (CCK release), and distal small intestine (GLP-1 and PYY) in response to food. These hormones are recognized as ‘‘appetite regulatory hormones.’’ Weight loss is the key in the treatments of obese/overweight patients with PCOS. However, current non-pharmacologic management of body weight is hard to achieve. This review highlighted the gastrointestinal hormones, and discussed the potential strategies aimed at modifying hormones for treatment in PCOS. Keywords

Gastrointestinal hormones  Obesity  PCOS

reproductive age according to the National Institutes of Health (NIH) criteria [1, 2] or 15–18 % according to the criteria of the European Society of Human Reproductive and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) [3]. The etiology of PCOS remains unclear. Recent study reported that adiponectin gene polymorphisms are related to the development of PCOS [4]. The clinical features of PCOS include hyperandrogenism and ovarian dysfunction. Women with PCOS have increased chance of metabolism dysfunctions [5], such as hyperinsulinaemia and dyslipidemia, eventually develop into obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases (CVD) [3]. Chronic low-grade inflammation is likely the important factor of insulin resistance in PCOS [6]. High prevalence of obesity exacerbates insulin resistance, the abdominal fat deposition, and androgen secretion in women with PCOS [7] (Fig. 1). Animal models of PCOS exposure to chronic hyperandrogenism present increased food intake [8]. It suggests that impaired appetite regulation might contribute to the pathophysiology of PCOS [9]. Therefore, dietary, exercise, medication and surgery are always major therapies of weight loss in patients with PCOS [10, 11]. The paper focused on the body weight management related to gastrointestinal hormones modification in PCOS.

Introduction

Energy intake and gastrointestinal hormones in PCOS

Polycystic ovary syndrome (PCOS) is a common reason for female infertility, affecting up to 4–7 % of women at

Modulation of appetite and energy intake is essential to maintain energy balance and body weight. Short-term appetite and food intake can be regulated by the hypothalamus, which constitutes a central control mechanism, and by a peripheral mechanism, constituted by signals arising from the gastrointestinal tract [12]. The crucial roles of gastric emptying/distention and the release of peptide hormones such as cholecystokinin (CCK), glucagon-like peptide

J. Ma  T. C. Lin  W. Liu (&) Division of Endocrinology and Metabolism, Department of Internal Medicine, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China e-mail: [email protected]

123

Endocrine

(GLP-1), and peptide tyrosine–tyrosine (PYY) in response to nutrient intake are increasingly being recognized as important physiological regulators of appetite (Fig. 2). A better understanding of the appetite regulation in PCOS is required to enable the development of effective therapies [13, 14]. Ghrelin Ghrelin, a 28-amino acid peptide, is an orexigenic hormone, which is secreted mostly from the gastric mucosa; small quantities can be found in the duodenum and hypothalamus [15]. Plasma ghrelin concentrations are high in the fasting state and decrease with nutrient ingestion [16]. Ghrelin declines equally after gastric, intraduodenal, and intrajejunal nutrient infusions in rodents and humans, suggesting that gastric distension does not regulate its suppression [17, 18]. Rather, exposure of the small intestine to nutrients is required to suppress ghrelin [18]. Fasting and postprandial fluctuations of ghrelin are also related to insulin concentrations and sensitivity [19]. For example, obese individuals with insulin resistance have a blunted suppression of ghrelin in response to nutrients [20]. In both rodents [15] and humans [21], exogenous ghrelin administration increases energy intake, while patients with Prader-Willi syndrome, characterized by excessive feeding

behavior, have high levels of circulating ghrelin [22]. Proximal Roux-en-Y gastric bypass decreases ghrelin secretion, which may contribute to weight loss after this procedure [23]. Ghrelin modulates appetite via the arcuate nucleus (ARC) of the hypothalamus [24]; it enhances neuropeptide Y (NPY) and agouti-related peptide (AgRY) gene expression and release in the lateral hypothalamic nucleus (LHA), and inhibits the anorexigenic proopiomelanocortin (POMC) neurons in the ARC [25]. In contrast to ghrelin, leptin, an anorexigenic hormone, inhibits orexigenic neurons containing NPY and AgRY, while stimulating POMC neurons in the ARC [26]. Leptin attenuates the activity of ghrelin in the ARC and suppresses food intake. Thus, ghrelin and leptin interact with each other in the appetite center, in the so-called ‘‘ghrelin-leptin tango’’ [27]. Ghrelin receptor antagonist, JMV 2959, which is under research, might have the benefit in the treatment of obesity [28]. Ghrelin levels in PCOS patients are reported to be decreased [29] or not different [30] compared to control subjects. Postprandial fluctuations of ghrelin are related to insulin concentrations and insulin sensitivity [31]. Ghrelin levels are lower in obese women suffering from PCOS than lean women with PCOS and health controls [32]. The impaired postprandial ghrelin levels may be involved in the development of obesity in PCOS [32]. Some studies suggested that low ghrelin levels in PCOS might be a consequence of the high androgen levels [33]. Moreover, luteinizing hormone/follicle-stimulating hormone ratio is also related to ghrelin levels [34]. GLP-1

Fig. 1 The reproductive and metabolic disorder of PCOS and the relationship with obesity

Fig. 2 Schematic representation of gastrointestinal regulation of appetite

123

GLP-1 is released from L-cells, most densely located in the ileum and colon, although they have also been found more proximally in the duodenum and jejunum [35]. Fasting plasma concentrations of total and intact GLP-1 are low

Endocrine

(5–10 pmol/L); in response to a meal rich in fat or carbohydrate, circulating levels of GLP-1 increase up to five fold within minutes [36]. The half-life of GLP-1 is short (*2 min), due largely to rapid degradation by the enzyme, dipeptidyl peptidase-IV (DPP-IV) [37]. DPP-IV, also known as CD26, cleaves dipeptides from the N-terminal to inactivate GLP-1 [38]. A large proportion of GLP-1 is degraded before entering the systemic circulation, by DPP IV expressed on blood vessels draining the intestinal mucosa [39]. GLP-1 is one of two known incretin hormones, together with glucose-dependent insulinotropic polypeptide (GIP). The insulinotropic effect of GLP-1 is glucose-dependent, via interaction with a specific receptor expressed on the cell membrane of b-cells [40]. GLP-1 receptors are found on b- and D-cells of the pancreas, parietal cells of the stomach, pylorus, adipose tissue, lungs, and the brain. It has been shown that GLP-1 stimulates b-cell proliferation and induces islet neogenesis, inhibits apoptosis, and enhances the differentiation of new b-cells from progenitors in the pancreatic duct epithelium [41]. In healthy subjects, endogenous GLP-1 reduces glucagon release from the a-cells of the pancreas [42], and intravenous administration of GLP-1 lowers glucagon secretion in patients with T2DM [43]. Among the multiple physiological effects of GLP-1, its effect on gastric emptying may outweigh its insulinotropic effect in the regulation of postprandial glycaemia [44]. The mechanism underlying the action of GLP-1 on motility is complex and not well understood. Intracerebroventricular injection of GLP-1 inhibits feeding in rats [45], as does peripheral infusion of GLP-1 and its agonist, exendin-4 [46]. Peripheral administration of GLP-1 is associated with enhanced satiety and reduction of food intake in healthy humans [47], the obese [48], and patients with T2DM [49]. GLP-1 analogs, such as exenatide and liraglutide, and DPPIV inhibitors, such as sitagliptin are used for the management of glycaemia control in type 2 diabetic patients. The incretin effect is reported to be substantially attenuated, which potentially leads to insufficient insulin secretion and potentiates postprandial hyperglycaemia in type 2 patients [50]. A direct comparison of the incretin response to intraduodenal glucose deliver between type 2 patients and healthy subjects has been undertaken [51]. It has shown there were no differences in overall GLP-1 responses to each glucose load between type 2 patients and healthy subjects. However, an early, albeit transient, peak in GLP-1 secretion, in response to glucose in healthy volunteers is missing in patients with T2DM. Some studies reported that the incretin effect is impaired in obesity with normal glucose tolerance compared to the lean subjects. It seems that plasma GLP-1 level is inversely related to BMI. In response to glucose, obese subjects have

lower plasma GLP-1 concentrations [52]. The decreased levels of incretin hormones may explain the impaired incretin effect in obese subjects [53]. Although some other studies reported that there were no differences in plasma GLP-1 between obese and lean people [54, 55], restored postprandial GLP-1 secretion following weight loss suggests that GLP-1 plays a role in regulation of satiation [56]. The mechanism is likely to be related to exposure of more distal small intestinal regions (with a larger density of L-cells) to ingested nutrients. There is evidence of interaction between GLP-1 and leptin at peripheral and central level. Study showed that leptin stimulated GLP-1 secretion in human L-cells in vitro and in obese mouse [57]. This interaction is important for understanding the potential to achieve and maintain weight loss in obesity [58]. Studies on the levels of GLP-1 in PCOS patients have not been consistent. It has been reported that there was no difference in incretin hormones between lean patients with PCOS and controls [59, 60]. It seems that GIP and GLP-1 secretions are not related to hyperinsulinaemia in PCOS. However, in some larger studies, during OGTT, it exhibited a lower level of GIP [60] or GLP-1 [61] in obese women with PCOS compared with lean healthy volunteers. The enteroinsular axis might be impaired in women with PCOS. It still needs more research studies about the GLP-1 secretion in PCOS. CCK CCK is secreted from the I-cells in the duodenum and upper jejunum, and is also found in the brain. There are a number of bioactive forms, such as CCK-8, CCK-22, CCK33, and CCK-58, of which CCK-33 is the major form in human plasma and intestine [62]. The half-life of CCK is *1-2 min. In healthy volunteers, the fasting CCK concentration of 1 pmol/L increases to 5–10 pmol/L in response to a mixed meal [63], peaks at about 30 min, and returns to the fasting value after *3–5 h [64]. Protein, and particularly fat, are strong stimuli for CCK secretion, whereas carbohydrate results in much less stimulation [65]. Small intestinal fat exerts a potent action on slowing gastric emptying which, in humans, is regulated predominantly by CCK, via CCK-1 receptors, and abolished by the CCK-1 antagonist, loxiglumide [66, 67]. CCK slows gastric emptying by relaxing the proximal stomach, increasing basal and phasic pyloric pressures and suppressing antral motility [67, 68], mediated by a vago-vagal reflex pathway [69]. In contrast to its actions on the stomach, exogenous CCK increases small intestinal motor activity and shortens the intestinal transit time [70]. CCK was the first gastrointestinal hormone found to be related to appetite [71]. CCK exerts its effects via two receptors, CCK-1 and CCK-2. The suppressive effect of

123

Endocrine

CCK on energy intake in rats and humans is predominantly mediated by CCK-1 receptors [72]. CCK-1 receptor antagonists increase meal size, while CCK-1 receptor deficient rats develop hyperphagia and obesity [73]. In rats, it has been demonstrated that chronic administration of a CCK antagonist results in weight gain out of proportion to increased feeding [74], but this probably reflects a synergistic effect between CCK and leptin on energy intake and long-term balance of body weight [75]. In humans, exogenous CCK dose-dependently reduces energy intake at a buffet style meal [76] and the CCK-1 antagonist, loxiglumide, increases energy intake modestly in healthy adults [77]. Just as GLP-1, potential medications based on CCK to treat obesity were unsuccessful due to the rapid enzymatic degradation within minutes [78]. Following studies develop CCK-1 receptors agonist, (pGlu-Gln)-CCK-8, which is modified N-terminally. (pGlu-Gln)-CCK-8 is enzymatically stable with improved therapeutic action profile. In animals studies, (pGlu-Gln)-CCK-8 markedly reduces energy intake and body weight [79]. Meantime, (pGlu-Gln)-CCK-8 injection is associated with modulation of blood glucose and IR [80]. Further development of (pGlu-Gln)-CCK-8 is hindered by renal filtration [81]. Recently, potential therapy of (pGlu-Gln)-CCK-8 is the PEGylated form of (pGlu-Gln)-CCK-8. (pGlu-Gln)-CCK8[mPEG] provides antiobesity and antidiabetes effects with prolonged half-life of CCK-8 [82]. Further studies of (pGlu-Gln)-CCK-8[mPEG] in human are needed for the future treatment for obesity and diabetes. CCK levels are lower in women with PCOS [9, 83]. Obese PCOS patients with hyperandrogenism had lower levels of CCK compared to obese PCOS women without hyperandrogenism [83]. It suggests the postprandial CCK is negatively correlated with the levels of free testosterone [9]. So far, there are just a few studies about CCK levels in PCOS. It needs further studies to clarify the mechanism under the correlation between hyperandrogenism and plasma CCK in PCOS patients. PYY PYY is co-located with GLP-1 in the L-cells of the distal gut and is involved in the so-called ‘‘ileal brake’’ [84]. Plasma concentrations of PYY are low in the fasting state, and increase about 30 min after exposure of the small intestine to nutrients [85]. PYY is secreted in a loaddependent fashion, with fat being the most potent stimulus, followed by carbohydrate and then protein [86, 87]. The secretion of PYY in response to small intestinal fat is mediated partly by CCK [88]. Because of its capacity to slow gastric emptying, PYY is also likely to improve postprandial glycaemia, although there is no evidence for an insulinotropic effect.

123

PYY circulates as two main forms, PYY3-36 and PYY1-36, with the former being active in suppressing appetite [89]. In addition to delaying gastric and gallbladder emptying, inhibiting gastric and pancreatic secretion, and slowing colonic transit [90], peripheral administration of PYY3-36 reduces food intake in rats, monkeys, and humans [91–93]. In humans, both pharmacological and ‘‘physiological’’ intravenous PYY3-36 infusions elicit fullness and suppression of food intake, the latter lasting over 12 h, despite the plasma PYY concentration falling to baseline [94]. In addition, there is a synergistic effect of exogenous PYY3-36 with GLP-17-36 on reduction of energy intake [93], whereas exogenous PYY reduces circulating ghrelin concentrations [95]. It remains contentious whether the suppressive effect of PYY3-36 on energy intake in humans represents an aversive effect; there are no specific antagonists of PYY which are available for use in humans. Injection of PYY3-36 into the ARC in rats decreases NPY expression while stimulating expression of POMC, which would account for reduced food intake [94]. The putative pre-synaptic NPY Y2 receptor (Y2R) in the ARC of the hypothalamus appears to mediate these effects [96]. Like GLP-1, plasma concentrations of PYY are slightly lower in the fasting and postprandial states and hunger is greater, in obese compared to lean individuals [97]. Low PYY levels predict a trend to overweight, but in obese children, PYY is normalized following weight loss [98]. However, the obese are as sensitive as lean subjects to suppression of food intake by exogenous PYY3-36 [95]. Again, like GLP-1, obese patients have elevated PYY levels after jejunoileal bypass surgery, which may contribute to loss of appetite [99]. Thus, the analogs and degradation inhibitor of PYY3–36 have the potential for the treatment of obesity [100, 101]. There is no difference in fasting PYY between lean patients with PCOS and controls [102]. However, fasting and postprandial PYY levels are lower in obese patients with PCOS [103]. It has been observed that there is an inverse correlation between fasting levels of PYY and HOMA-IR in women with PCOS. The impaired postprandial PYY levels may contribute to insulin resistance [103]. Metformin treatment in PCOS increased PYY levels which are parallel with improvement of insulin sensitivity [102]. Weight management in the treatment of PCOS Weight loss is primary therapy for overweight or obese patients with PCOS. Even slight weight loss as 5 % reduction significantly improves IR and ovulation resumption [104]. Body weight loss increases the efficiency of several infertility treatments in PCOS. Current

Endocrine

therapies for weight loss are all related to changes of gut hormones. Diet Lifestyle adjustment (diet, exercise, and behavioral modification) is always the first-line treatment for overweight/ obese females with PCOS [105]. Both Low Glucose Index (GI) diet and hypocarloric diet interventions have beneficial effects for obese PCOS patients [106]. Low GI diet improves irregular menstrual patterns compared with conventional diet [107]. The effect of a hypocaloric diet on insulin resistance was even better than metformin [108]. Compared to glucose ingestion, protein causes less glucose/insulin fluctuation [109]. Whey protein supplement profoundly slows gastric emptying of the carbohydrate and stimulates the release of GLP-1 [110]. Fat restriction is equally effective in weight loss and menstrual cycle improvement as low carbohydrate diet. Fatty acids also play a role in the treatment of metabolic disorder in PCOS. It has been reported that diet supplied with LC n - 3 PUFA suppressed plasma bioavailable testosterone concentrations [111]. However, the dietary strategies alone normally are not sufficient. Acupuncture Acupuncture is an important part of the traditional Chinese treatment. Manual and electrical acupuncture activates the afferent nerve fibers [112] to reduce abdominal visceral adipose tissue and BMI in patients with PCOS [113]. After a few weeks of treatment of acupuncture, the reduction of body weight is related to decreased serum insulin and leptin levels, and increased plasma PYY and CCK levels in obese women [114, 115]. When the acupuncture is combined with low-calorie diet, lipid profile is improved [116]. Acupuncture is an effective treatment for obesity with less adverse effect [117]. Metformin Metformin is widely used in treatment of T2DM, in particular, in overweight or obesity. The primary effect of metformin is believed to suppress hepatic gluconeogenesis, reduce glucose absorption, improve insulin sensitivity, and increase peripheral glucose uptake. Since hyperinsulinaemia plays an important role in the pathogenesis of PCOS, metformin intervention is used to restore endocrine function in PCOS. It has been observed that combination of metformin and lifestyle modification resulted in a significantly weight loss compared to lifestyle modification alone [118]. Clinical trials confirmed that metformin is effective in the improvement of ovarian function and menstrual

cycle, and reduction of serum androgen levels in obese patients with PCOS [119]. The weight reduction is related to the increase in plasma PYY, ghrelin, and GLP-1 levels [102, 120, 121]. Unfortunately, many of the above-discussed effects of metformin were not observed consistently. Berberine Berberine (BBR), a type of isoquinoline derivative alkaloid, is extracted from Chinese medical herbs. Normally, it is used as an oral drug for the treatment of gastrointestinal infections. Recent studies showed that 3 months of treatment of BBR decreased WC, waist-hip ratio, TC, TG, and LDL-C, increased HDL-C and SHBG, and improved insulin resistance in women with PCOS [122]. Compared to metformin, BBR brings more potential benefits to patients with PCOS both in metabolic and endocrine parameters [123]. The possible mechanisms of BBR include upregulating hepatic low-density lipoprotein receptor mRNA expression, activating AMP-activated protein kinase in both adipose and muscle tissues, stimulating glycolysis in peripheral tissue cells, promoting secretion of insulin, inhibiting liver gluconeogenesis, and promoting secretion of intestinal GLP-1 [124]. The effect of BBR on antimicrobial activity may be involved in the development of anti-obesity treatment [125]. The major side effects of BBR include diarrhea, constipation, flatulence, and abdominal pain. GLP-1 agonists GLP-1receptor agonists were used as a medication in the treatment of diabetes. Recent studies provided data about the safety and efficacy of GLP-1 receptor agonist on weight loss in overweight and obese adults and adolescents [126– 128]. Peripheral GLP-1 administration is associated with enhanced postmeal satiety and reduced food intake at the subsequent meal [129]. A meta-analysis showed that energy intake was reduced by 174 kcal or 11.7 % in ad libitum following intravenous GLP-1 infusion [130]. Exenatide treatment for 3 months reduced BMI and improved insulin resistance of adolescents with severe obesity [131]. During the treatment, subjects experienced more gastrointestinal adverse events such as nausea, vomiting, and diarrhea after exenatide compared with placebo. However, the symptoms decreased over time. It appeared that gastrointestinal symptoms were not correlated with weight loss reduction [132]. The overall patient satisfaction with GLP-1R agonist treatment is fairly high [133]. A further reduction in BMI was observed in longerterm use of exenatide [134]. In patients with PCOS, exenatide was more effective than metformin in promoting

123

Endocrine

weight loss [135]. The combination of exenatide/liraglutide and metformin was superior to exenatide/liraglutide or metformin monotherapy in improving menstrual cyclicity, ovulation rate, free androgen index, and insulin sensitivity [135, 136].

Acknowledgments This work was supported by grant from the Shanghai Jiaotong University, School of Medicine, Science and Technology Fund (Grant No. 12XJ10015). Disclosure

There are no conflicts of interest to disclose.

References Surgical therapy Patients with PCOS require a combination therapy of life modification and drug treatment. However, weight loss with these approaches is often difficult to achieve for patients. Bariatric surgery could be an alternative treatment in metabolic dysfunction restoration and pregnancy outcomes improvement [137]. For example, the mean weight loss in 12 women with PCOS was 41 kg after bariatric surgery (either biliopancreatic diversion or Laparoscopic adjustable gastric banding) [138]. Following the weight loss, various clinical problems such as dyslipidemia, fertility, and/or hirsutism related to PCOS were significantly improved [139]. The mechanism of weight loss induced by bariatric surgery is not certain. One possible mechanism is that the gastric volume is reduced [140, 141]. The other mechanism is the changes of gastrointestinal hormones [140]. In postoperative state, a quick delivery of nutrients to the small intestine leads to an overstimulation or proliferation of the endocrine cells, or reduced degradation of the secreted hormones [142]. Therefore, the increased postprandial PYY and GLP-1 response [141, 143, 144] were observed. Plasma PYY and GLP-1 start increasing as early as 2 days after surgery and before important weight loss [144]. Recent study reported that weight loss after Roux-en-Y gastric bypass (RYGB) surgery is also related to reductions of brain activation in response to high caloric foods [145].

Conclusion PCOS is one of most common endocrine diseases in women of reproductive age with clinical feature of polycystic ovaries, hyperandrogen, and insulin resistance. Woman with PCOS has a high prevalence of T2DM and CVD. Most patients are overweight or obese. Therefore, weight loss is important in the treatment of PCOS. Current therapy for weight loss is less than ideal, and bariatric surgery is invasive. Gastrointestinal hormones are crucial in regulation of food intake and body weight. Dietary or pharmacological strategies based on regulation of gastrointestinal hormones are likely to be of fundamental importance in the management of obesity. Therapy aimed at the gastrointestinal hormones will be the new direction of treatment for PCOS.

123

1. E.S. Knochenhauer, T.J. Key, M. Kahsar-Miller, W. Waggoner, L.R. Boots, R. Azziz, Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J. Clin. Endocrinol. Metab. 83, 3078–3082 (1998) 2. E. Diamanti-Kandarakis, C.R. Kouli, A.T. Bergiele, F.A. Filandra, T.C. Tsianateli, G.G. Spina, E.D. Zapanti, M.I. Bartzis, A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J. Clin. Endocrinol. Metab. 84, 4006–4011 (1999) 3. W.A. March, V.M. Moore, K.J. Willson, D.I. Phillips, R.J. Norman, M.J. Davies, The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum. Reprod. 25, 544–551 (2010) 4. H. Jia, L. Yu, X. Guo, W. Gao, Z. Jiang, Associations of adiponectin gene polymorphisms with polycystic ovary syndrome: a meta-analysis. Endocrine 42, 299–306 (2012) 5. M. Brower, K. Brennan, M. Pall, R. Azziz, The severity of menstrual dysfunction as a predictor of insulin resistance in PCOS. J. Clin. Endocrinol. Metab. 98, E1967–E1971 (2013) 6. S.F. Witchel, S.E. Recabarren, F. Gonzalez, E. DiamantiKandarakis, K.I. Cheang, A.J. Duleba, R.S. Legro, R. Homburg, R. Pasquali, R.A. Lobo, C.C. Zouboulis, F. Kelestimur, F. Fruzzetti, W. Futterweit, R.J. Norman, D.H. Abbott, Emerging concepts about prenatal genesis, aberrant metabolism and treatment paradigms in polycystic ovary syndrome. Endocrine 42, 526–534 (2012) 7. S.S. Lim, R.J. Norman, M.J. Davies, L.J. Moran, The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obes. Rev. 14, 95–109 (2013) 8. N. Kanaya, S. Vonderfecht, S. Chen, Androgen (dihydrotestosterone)-mediated regulation of food intake and obesity in female mice. J.Steroid Biochem. Mol. Biol. 138, 100–106 (2013) 9. A.L. Hirschberg, S. Naessen, M. Stridsberg, B. Bystrom, J. Holtet, Impaired cholecystokinin secretion and disturbed appetite regulation in women with polycystic ovary syndrome. Gynecol. Endocrinol. 19, 79–87 (2004) 10. D. Mahoney, Lifestyle modification intervention among infertile overweight and obese women with polycystic ovary syndrome. J. Am. Assoc. Nurse Pract. (2013). doi:10.1002/2327-6924. 12073 11. B.A. Gower, P.C. Chandler-Laney, F. Ovalle, L.L. Goree, R. Azziz, R.A. Desmond, W.M. Granger, A.M. Goss, G.W. Bates, Favourable metabolic effects of a eucaloric lower-carbohydrate diet in women with PCOS. Clin. Endocrinol. 79, 550–557 (2013) 12. P.J. Havel, Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp. Biol. Med. (Maywood) 226, 963–977 (2001) 13. R. Deniz, B. Gurates, S. Aydin, H. Celik, I. Sahin, Y. Baykus, Z. Catak, A. Aksoy, C. Citil, S. Gungor, Nesfatin-1 and other hormone alterations in polycystic ovary syndrome. Endocrine 42, 694–699 (2012) 14. S. Aydin, Multi-functional peptide hormone NUCB2/nesfatin-1. Endocrine 44, 312–325 (2013)

Endocrine 15. M. Tschop, D.L. Smiley, M.L. Heiman, Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000) 16. G. Gomez, E.W. Englander, G.H. Greeley Jr, Nutrient inhibition of ghrelin secretion in the fasted rat. Regul. Pept. 117, 33–36 (2004) 17. J. Overduin, R.S. Frayo, H.J. Grill, J.M. Kaplan, D.E. Cummings, Role of the duodenum and macronutrient type in ghrelin regulation. Endocrinology 146, 845–850 (2005) 18. B.A. Parker, S. Doran, J. Wishart, M. Horowitz, I.M. Chapman, Effects of small intestinal and gastric glucose administration on the suppression of plasma ghrelin concentrations in healthy older men and women. Clin. Endocrinol. 62, 539–546 (2005) 19. W.A. Blom, A. Stafleu, C. de Graaf, F.J. Kok, G. Schaafsma, H.F. Hendriks, Ghrelin response to carbohydrate-enriched breakfast is related to insulin. Am. J. Clin. Nutr. 81, 367–375 (2005) 20. Y. Greenman, N. Golani, S. Gilad, M. Yaron, R. Limor, N. Stern, Ghrelin secretion is modulated in a nutrient- and genderspecific manner. Clin. Endocrinol. 60, 382–388 (2004) 21. A.M. Wren, L.J. Seal, M.A. Cohen, A.E. Brynes, G.S. Frost, K.G. Murphy, W.S. Dhillo, M.A. Ghatei, S.R. Bloom, Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86, 5992 (2001) 22. D.E. Cummings, K. Clement, J.Q. Purnell, C. Vaisse, K.E. Foster, R.S. Frayo, M.W. Schwartz, A. Basdevant, D.S. Weigle, Elevated plasma ghrelin levels in Prader Willi syndrome. Nat. Med. 8, 643–644 (2002) 23. D.E. Cummings, D.S. Weigle, R.S. Frayo, P.A. Breen, M.K. Ma, E.P. Dellinger, J.Q. Purnell, Plasma ghrelin levels after dietinduced weight loss or gastric bypass surgery. N. Engl. J. Med. 346, 1623–1630 (2002) 24. P.J. Currie, A. Mirza, R. Fuld, D. Park, J.R. Vasselli, Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R353–R358 (2005) 25. M. Nakazato, N. Murakami, Y. Date, M. Kojima, H. Matsuo, K. Kangawa, S. Matsukura, A role for ghrelin in the central regulation of feeding. Nature 409, 194–198 (2001) 26. M.A. Cowley, J.L. Smart, M. Rubinstein, M.G. Cerdan, S. Diano, T.L. Horvath, R.D. Cone, M.J. Low, Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001) 27. D.E. Cummings, K.E. Foster, Ghrelin-leptin tango in bodyweight regulation. Gastroenterology 124, 1532–1535 (2003) 28. A. Moulin, L. Brunel, D. Boeglin, L. Demange, J. Ryan, C. M’Kadmi, S. Denoyelle, J. Martinez, J.A. Fehrentz, The 1,2,4triazole as a scaffold for the design of ghrelin receptor ligands: development of JMV 2959, a potent antagonist. Amino Acids 44, 301–314 (2013) 29. G. Arusoglu, G. Koksal, N. Cinar, S. Tapan, D.Y. Aksoy, B.O. Yildiz, Basal and meal-stimulated ghrelin, PYY, CCK levels and satiety in lean women with polycystic ovary syndrome: effect of low-dose oral contraceptive. J. Clin. Endocrinol. Metab. 98, 4475–4482 (2013) 30. Japur, CC, Diez-Garcia, RW, de Oliveira Penaforte, FR, de Sa, MF, Imbalance between postprandial ghrelin and insulin responses to an ad libitum meal in obese women with polycystic ovary syndrome. Reprod. Sci. (2014) [Epub ahead of print] 31. I.T. Ozgen, M. Aydin, A. Guven, Y. Aliyazicioglu, Characteristics of polycystic ovarian syndrome and relationship with ghrelin in adolescents. J. Pediatr. Adolesc. Gynecol. 23, 285–289 (2010) 32. T.M. Barber, F.F. Casanueva, F. Karpe, M. Lage, S. Franks, M.I. McCarthy, J.A. Wass, Ghrelin levels are suppressed and show a blunted response to oral glucose in women with polycystic ovary syndrome. Eur. J. Endocrinol 158, 511–516 (2008)

33. M. Mitkov, B. Pehlivanov, Orbetzova, M:Serum ghrelin level in women with polycystic ovary syndrome and its relationship with endocrine and metabolic parameters. Gynecol. Endocrinol. 24, 625–630 (2008) 34. A. Bideci, M.O. Camurdan, E. Yesilkaya, F. Demirel, P. Cinaz, Serum ghrelin, leptin and resistin levels in adolescent girls with polycystic ovary syndrome. J. Obstet. Gynaecol. Res. 34, 578–584 (2008) 35. M.J. Theodorakis, O. Carlson, S. Michopoulos, M.E. Doyle, M. Juhaszova, K. Petraki, J.M. Egan, Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am. J. Physiol. Endocrinol. Metab. 290, E550–E559 (2006) 36. C.F. Deacon, What do we know about the secretion and degradation of incretin hormones? Regul. Pept. 128, 117–124 (2005) 37. R. Mentlein, B. Gallwitz, W.E. Schmidt, Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 214, 829–835 (1993) 38. R. Mentlein, Dipeptidyl-peptidase IV (CD26)–role in the inactivation of regulatory peptides. Regul. Pept. 85, 9–24 (1999) 39. L. Hansen, C.F. Deacon, C. Orskov, J.J. Holst, Glucagon-like peptide-1-(7–36)amide is transformed to glucagon-like peptide1-(9–36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140, 5356–5363 (1999) 40. L.A. Scrocchi, T.J. Brown, N. MaClusky, P.L. Brubaker, A.B. Auerbach, A.L. Joyner, D.J. Drucker, Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat. Med. 2, 1254–1258 (1996) 41. R. Perfetti, J. Zhou, M.E. Doyle, J.M. Egan, Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology 141, 4600–4605 (2000) 42. J. Schirra, M. Nicolaus, R. Roggel, M. Katschinski, M. Storr, H.J. Woerle, B. Goke, Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut 55, 243–251 (2006) 43. J.J. Meier, B. Gallwitz, S. Salmen, O. Goetze, J.J. Holst, W.E. Schmidt, M.A. Nauck, Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 88, 2719–2725 (2003) 44. M.A. Nauck, U. Niedereichholz, R. Ettler, J.J. Holst, C. Orskov, R. Ritzel, W.H. Schmiegel, Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am. J. Physiol. 273, E981–E988 (1997) 45. J.J. Hwa, L. Ghibaudi, P. Williams, M.B. Witten, R. Tedesco, C.D. Strader, Differential effects of intracerebroventricular glucagon-like peptide-1 on feeding and energy expenditure regulation. Peptides 19, 869–875 (1998) 46. F. Rodriquez de Fonseca, M. Navarro, E. Alvarez, I. Roncero, J.A. Chowen, O. Maestre, R. Gomez, R.M. Munoz, J. Eng, E. Blazquez, Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats. Metabolism 49, 709–717 (2000) 47. J.J. Meier, M.A. Nauck, Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab. Res. Rev. 21, 91–117 (2005) 48. E. Naslund, M. Gutniak, S. Skogar, S. Rossner, P.M. Hellstrom, Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am. J. Clin. Nutr. 68, 525–530 (1998) 49. M.A. Nauck, J.J. Meier, Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regul. Pept. 128, 135–148 (2005)

123

Endocrine 50. M. Nauck, F. Stockmann, R. Ebert, W. Creutzfeldt, Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29, 46–52 (1986) 51. J. Ma, A.N. Pilichiewicz, C. Feinle-Bisset, J.M. Wishart, K.L. Jones, M. Horowitz, C.K. Rayner, Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes. Diabet. Med. 29, 604–608 (2012) 52. L.R. Ranganath, J.M. Beety, L.M. Morgan, J.W. Wright, R. Howland, V. Marks, Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 38, 916–919 (1996) 53. S. Madsbad, The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabet. Obes. Metab. 16, 9–21 (2014) 54. F.K. Knop, K. Aaboe, T. Vilsboll, A. Volund, J.J. Holst, T. Krarup, S. Madsbad, Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabet. Obes. Metab. 14, 500–510 (2012) 55. T. Vilsboll, T. Krarup, J. Sonne, S. Madsbad, A. Volund, A.G. Juul, J.J. Holst, Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 88, 2706–2713 (2003) 56. C. Verdich, S. Toubro, B. Buemann, L. Madsen, J. Juul, J. Holst, A. Astrup, The role of postprandial releases of insulin and incretin hormones in meal-induced satiety–effect of obesity and weight reduction. Int. J. Obes. Relat. Metab. Disord. 25, 1206–1214 (2001) 57. Y. Anini, P.L. Brubaker, Role of leptin in the regulation of glucagon-like peptide-1 secretion. Diabetes 52, 252–259 (2003) 58. J.G. Barrera, D.A. Sandoval, D.A. D’Alessio, R.J. Seeley, GLP1 and energy balance: an integrated model of short-term and long-term control. Nat. Rev. Endocrinol. 7, 507–516 (2011) 59. R. Gama, F. Norris, J. Wright, L. Morgan, S. Hampton, S. Watkins, V. Marks, The entero-insular axis in polycystic ovarian syndrome. Ann. Clin. Biochem. 33(Pt 3), 190–195 (1996) 60. C. Pontikis, M.P. Yavropoulou, K.A. Toulis, K. Kotsa, K. Kazakos, A. Papazisi, A. Gotzamani-Psarakou, J.G. Yovos, The incretin effect and secretion in obese and lean women with polycystic ovary syndrome: a pilot study. J. Women’s Health 20, 971–976 (2011) 61. J. Vrbikova, M. Hill, B. Bendlova, T. Grimmichova, K. Dvorakova, K. Vondra, G. Pacini, Incretin levels in polycystic ovary syndrome. Eur. J. Endocrinol. 159, 121–127 (2008) 62. J.F. Rehfeld, G. Sun, T. Christensen, J.G. Hillingso, The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33. J. Clin. Endocrinol. Metab. 86, 251–258 (2001) 63. R.A. Liddle, I.D. Goldfine, M.S. Rosen, R.A. Taplitz, J.A. Williams, Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. J. Clin. Invest. 75, 1144–1152 (1985) 64. T.H. Moran, K.P. Kinzig, Gastrointestinal satiety signals II. Cholecystokinin. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G183–G188 (2004) 65. R.A. Liddle, Regulation of cholecystokinin secretion in humans. J. Gastroenterol. 35, 181–187 (2000) 66. C. Feinle, M. D’Amato, N.W. Read, Cholecystokinin-A receptors modulate gastric sensory and motor responses to gastric distension and duodenal lipid. Gastroenterology 110, 1379–1385 (1996) 67. W. Schwizer, J. Borovicka, P. Kunz, R. Fraser, C. Kreiss, M. D’Amato, G. Crelier, P. Boesiger, M. Fried, Role of cholecystokinin in the regulation of liquid gastric emptying and gastric motility in humans: studies with the CCK antagonist loxiglumide. Gut 41, 500–504 (1997)

123

68. C.K. Rayner, H.S. Park, S.M. Doran, I.M. Chapman, M. Horowitz, Effects of cholecystokinin on appetite and pyloric motility during physiological hyperglycemia. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G98–G104 (2000) 69. J. Glatzle, Y. Wang, D.W. Adelson, T.J. Kalogeris, T.T. Zittel, P. Tso, J.Y. Wei, H.E. Raybould, Chylomicron components activate duodenal vagal afferents via a cholecystokinin A receptor-mediated pathway to inhibit gastric motor function in the rat. J. Physiol. 550, 657–664 (2003) 70. J.G. Gutierrez, W.Y. Chey, V.P. Dinoso, Actions of cholecystokinin and secretin on the motor activity of the small intestine in man. Gastroenterology 67, 35–41 (1974) 71. J. Gibbs, R.C. Young, G.P. Smith, Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245, 323–325 (1973) 72. T.H. Moran, P.J. Ameglio, G.J. Schwartz, P.R. McHugh, Blockade of type A, not type B, CCK receptors attenuates satiety actions of exogenous and endogenous CCK. Am. J. Physiol. 262, R46–R50 (1992) 73. T.H. Moran, S. Bi, Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors. Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1211–1218 (2006) 74. K. Meereis-Schwanke, H. Klonowski-Stumpe, L. Herberg, C. Niederau, Long-term effects of CCK-agonist and -antagonist on food intake and body weight in Zucker lean and obese rats. Peptides 19, 291–299 (1998) 75. L. Wang, M.D. Barachina, V. Martinez, J.Y. Wei, Y. Tache, Synergistic interaction between CCK and leptin to regulate food intake. Regul. Pept. 92, 79–85 (2000) 76. I.M. Brennan, T.J. Little, K.L. Feltrin, A.J. Smout, J.M. Wishart, M. Horowitz, C. Feinle-Bisset, Dose-dependent effects of cholecystokinin-8 on antropyloroduodenal motility, gastrointestinal hormones, appetite, and energy intake in healthy men. Am. J. Physiol. Endocrinol. Metab. 295, E1487–E1494 (2008) 77. C. Beglinger, L. Degen, D. Matzinger, M. D’Amato, J. Drewe, Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R1149–R1154 (2001) 78. F.P. O’Harte, M.H. Mooney, C.M. Kelly, P.R. Flatt, Glycated cholecystokinin-8 has an enhanced satiating activity and is protected against enzymatic degradation. Diabetes 47, 1619–1624 (1998) 79. I.A. Montgomery, N. Irwin, P.R. Flatt, Beneficial effects of (pGlu-Gln)-CCK-8 on energy intake and metabolism in high fat fed mice are associated with alterations of hypothalamic gene expression. Hormon. Metab. Res. 45(6), 471–473 (2013) 80. N. Irwin, I.A. Montgomery, R.C. Moffett, P.R. Flatt, Chemical cholecystokinin receptor activation protects against obesitydiabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice. Biochem. Pharmacol. 85, 81–91 (2013) 81. N. Irwin, P.R. Flatt, Enteroendocrine hormone mimetics for the treatment of obesity and diabetes. Curr. Opin. Pharmacol. 13, 989–995 (2013) 82. N. Irwin, P. Frizelle, F.P. O’Harte, P.R. Flatt, (pGlu-Gln)-CCK8[mPEG]: a novel, long-acting, mini-PEGylated cholecystokinin (CCK) agonist that improves metabolic status in dietary-induced diabetes. Biochim. et Biophys. Acta 1830, 4009–4016 (2013) 83. B. Bidzinska-Speichert, A. Lenarcik, U. Tworowska-Bardzinska, R. Slezak, G. Bednarek-Tupikowska, A. Milewicz, Pro12Ala PPAR gamma2 gene polymorphism in PCOS women: the role of compounds regulating satiety. Gynecol. Endocrinol. 28, 195–198 (2012) 84. J. Wen, S.F. Phillips, M.G. Sarr, L.J. Kost, Holst, JJ:PYY and GLP-1 contribute to feedback inhibition from the canine ileum and colon. Am. J. Physiol. 269, G945–G952 (1995)

Endocrine 85. R.P. Vincent, C.W. le Roux, The satiety hormone peptide YY as a regulator of appetite. J. Clin. Pathol. 61, 548–552 (2008) 86. M.S. Huda, J.P. Wilding, J.H. Pinkney, Gut peptides and the regulation of appetite. Obes. Rev. 7, 163–182 (2006) 87. L. Degen, S. Oesch, M. Casanova, S. Graf, S. Ketterer, J. Drewe, C. Beglinger, Effect of peptide YY3-36 on food intake in humans. Gastroenterology 129, 1430–1436 (2005) 88. H.C. Lin, W.Y. Chey, X. Zhao, Release of distal gut peptide YY (PYY) by fat in proximal gut depends on CCK. Peptides 21, 1561–1563 (2000) 89. G.A. Eberlein, V.E. Eysselein, M. Schaeffer, P. Layer, D. Grandt, H. Goebell, W. Niebel, M. Davis, T.D. Lee, J.E. Shively et al., A new molecular form of PYY: structural characterization of human PYY(3–36) and PYY(1–36). Peptides 10, 797–803 (1989) 90. R.L. Conter, J.J. Roslyn, I.L. Taylor, Effects of peptide YY on gallbladder motility. Am. J. Physiol. 252, G736–G741 (1987) 91. N. Vrang, A.N. Madsen, M. Tang-Christensen, G. Hansen, P.J. Larsen, PYY(3–36) reduces food intake and body weight and improves insulin sensitivity in rodent models of diet-induced obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R367–R375 (2006) 92. T.H. Moran, U. Smedh, K.P. Kinzig, K.A. Scott, S. Knipp, E.E. Ladenheim, Peptide YY(3–36) inhibits gastric emptying and produces acute reductions in food intake in rhesus monkeys. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R384–R388 (2005) 93. N.M. Neary, C.J. Small, M.R. Druce, A.J. Park, S.M. Ellis, N.M. Semjonous, C.L. Dakin, K. Filipsson, F. Wang, A.S. Kent, G.S. Frost, M.A. Ghatei, S.R. Bloom, Peptide YY3-36 and glucagonlike peptide-17–36 inhibit food intake additively. Endocrinology 146, 5120–5127 (2005) 94. R.L. Batterham, M.A. Cowley, C.J. Small, H. Herzog, M.A. Cohen, C.L. Dakin, A.M. Wren, A.E. Brynes, M.J. Low, M.A. Ghatei, R.D. Cone, S.R. Bloom, Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 418, 650–654 (2002) 95. R.L. Batterham, M.A. Cohen, S.M. Ellis, C.W. Le Roux, D.J. Withers, G.S. Frost, M.A. Ghatei, S.R. Bloom, Inhibition of food intake in obese subjects by peptide YY3-36. N. Engl. J. Med. 349, 941–948 (2003) 96. C.R. Abbott, C.J. Small, A.R. Kennedy, N.M. Neary, A. Sajedi, M.A. Ghatei, S.R. Bloom, Blockade of the neuropeptide Y Y2 receptor with the specific antagonist BIIE0246 attenuates the effect of endogenous and exogenous peptide YY(3–36) on food intake. Brain Res. 1043, 139–144 (2005) 97. C.W. le Roux, R.L. Batterham, S.J. Aylwin, M. Patterson, C.M. Borg, K.J. Wynne, A. Kent, R.P. Vincent, J. Gardiner, M.A. Ghatei, S.R. Bloom, Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology 147, 3–8 (2006) 98. C.L. Roth, P.J. Enriori, K. Harz, J. Woelfle, M.A. Cowley, T. Reinehr, Peptide YY is a regulator of energy homeostasis in obese children before and after weight loss. J. Clin. Endocrinol. Metab. 90, 6386–6391 (2005) 99. E. Naslund, P. Gryback, P.M. Hellstrom, H. Jacobsson, J.J. Holst, E. Theodorsson, L. Backman, Gastrointestinal hormones and gastric emptying 20 years after jejunoileal bypass for massive obesity. Int. J. Obes. Relat. Metab. Disord. 21, 387–392 (1997) 100. S.L. Pedersen, P.G. Sasikumar, S. Chelur, B. Holst, A. Artmann, K.J. Jensen, N. Vrang, Peptide hormone isoforms: N-terminally branched PYY3–36 isoforms give improved lipid and fat-cell metabolism in diet-induced obese mice. J. Pept. Sci. 16, 664–673 (2010)

101. M.L. Addison, J.S. Minnion, J.C. Shillito, K. Suzuki, T.M. Tan, B.C. Field, N. Germain-Zito, C. Becker-Pauly, M.A. Ghatei, S.R. Bloom, K.G. Murphy, A role for metalloendopeptidases in the breakdown of the gut hormone, PYY 3–36. Endocrinology 152, 4630–4640 (2011) 102. T. Tsilchorozidou, R.L. Batterham, G.S. Conway, Metformin increases fasting plasma peptide tyrosine tyrosine (PYY) in women with polycystic ovarian syndrome (PCOS). Clin. Endocrinol. 69, 936–942 (2008) 103. K. Zwirska-Korczala, K. Sodowski, S.J. Konturek, D. Kuka, M. Kukla, T. Brzozowski, W. Cnota, E. Wozniak-Grygiel, J. Jaworek, R. Buldak, B. Rybus-Kalinowska, M. Fryczowski, Postprandial response of ghrelin and PYY and indices of lowgrade chronic inflammation in lean young women with polycystic ovary syndrome. J. Physiol. Pharmacol. 59(Suppl 2), 161–178 (2008) 104. H. Lee, J.Y. Oh, Y.A. Sung, H. Chung, Is insulin resistance an intrinsic defect in asian polycystic ovary syndrome? Yonsei Med. J. 54, 609–614 (2013) 105. D. Panidis, K. Tziomalos, E. Papadakis, C. Vosnakis, P. Chatzis, I. Katsikis, Lifestyle intervention and anti-obesity therapies in the polycystic ovary syndrome: impact on metabolism and fertility. Endocrine 44, 583–590 (2013) 106. R.L. Thomson, J.D. Buckley, M. Noakes, P.M. Clifton, R.J. Norman, G.D. Brinkworth, The effect of a hypocaloric diet with and without exercise training on body composition, cardiometabolic risk profile, and reproductive function in overweight and obese women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 3373–3380 (2008) 107. K.A. Marsh, K.S. Steinbeck, F.S. Atkinson, P. Petocz, J.C. Brand-Miller, Effect of a low glycemic index compared with a conventional healthy diet on polycystic ovary syndrome. Am. Erican J. Clin. Nutr. 92, 83–92 (2010) 108. F. Esfahanian, M.M. Zamani, R. Heshmat, F. Moini nia, Effect of metformin compared with hypocaloric diet on serum C-reactive protein level and insulin resistance in obese and overweight women with polycystic ovary syndrome. J. Obstet. Gynaecol. Res. 39, 806–813 (2013) 109. S.E. Kasim-Karakas, W.M. Cunningham, A. Tsodikov, Relation of nutrients and hormones in polycystic ovary syndrome. Am. J. Clin. Nutr. 85, 688–694 (2007) 110. A. Karamanlis, R. Chaikomin, S. Doran, M. Bellon, F.D. Bartholomeusz, J.M. Wishart, K.L. Jones, M. Horowitz, C.K. Rayner, Effects of protein on glycemic and incretin responses and gastric emptying after oral glucose in healthy subjects. Am. J. Clin. Nutr. 86, 1364–1368 (2007) 111. N. Phelan, A. O’Connor, T. Kyaw Tun, N. Correia, G. Boran, H.M. Roche, J. Gibney, Hormonal and metabolic effects of polyunsaturated fatty acids in young women with polycystic ovary syndrome: results from a cross-sectional analysis and a randomized, placebo-controlled, crossover trial. Am. J. Clin. Nutr. 93, 652–662 (2011) 112. Y.H. Zheng, X.H. Wang, M.H. Lai, H. Yao, H. Liu, H.X. Ma, Effectiveness of abdominal acupuncture for patients with obesity-type polycystic ovary syndrome: a randomized controlled trial. J. Altern. Complement. Med. 19, 740–745 (2013) 113. H. Zhang, Y. Peng, Z. Liu, S. Li, Z. Lv, L. Tian, J. Zhu, X. Zhao, M. Chen, Effects of acupuncture therapy on abdominal fat and hepatic fat content in obese children: a magnetic resonance imaging and proton magnetic resonance spectroscopy study. J. Altern. Complement. Med. 17, 413–420 (2011) 114. B. Xu, J.H. Yuan, Z.C. Liu, M. Chen, X.J. Wang, Effect of acupuncture on plasma peptide YY in the patient of simple obesity. Zhongguo zhen jiu (Chin. Acupunct. Moxib.) 25, 837–840 (2005)

123

Endocrine 115. F. Gucel, B. Bahar, C. Demirtas, S. Mit, C. Cevik, Influence of acupuncture on leptin, ghrelin, insulin and cholecystokinin in obese women: a randomised, sham-controlled preliminary trial. Acupunct. Med. 30, 203–207 (2012) 116. H. Abdi, B. Zhao, M. Darbandi, M. Ghayour-Mobarhan, S. Tavallaie, A.A. Rahsepar, S.M. Parizadeh, M. Safariyan, M. Nemati, M. Mohammadi, P. Abbasi-Parizad, S. Darbandi, S. Akhlaghi, G.A. Ferns, The effects of body acupuncture on obesity: anthropometric parameters, lipid profile, and inflammatory and immunologic markers. Sci.World. J. 2012, 603539 (2012) 117. S.H. Cho, J.S. Lee, L. Thabane, J. Lee, Acupuncture for obesity: a systematic review and meta-analysis. Int. J. Obes. 33, 183–196 (2009) 118. K.M. Hoeger, L. Kochman, N. Wixom, K. Craig, R.K. Miller, D.S. Guzick, A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil. Steril. 82, 421–429 (2004) 119. J. Xiao, S. Chen, C. Zhang, S. Chang, The effectiveness of metformin ovulation induction treatment in patients with PCOS: a systematic review and meta-analysis. Gynecol. Endocrinol. 28, 956–960 (2012) 120. M. Shaker, Z.I. Mashhadani, A.A. Mehdi, Effect of Treatment with Metformin on Omentin-1, Ghrelin and other Biochemical, Clinical Features in PCOS Patients. Oman Med. J. 25, 289–293 (2010) 121. P.F. Svendsen, L. Nilas, S. Madsbad, J.J. Holst, Incretin hormone secretion in women with polycystic ovary syndrome: roles of obesity, insulin sensitivity, and treatment with metformin. Metabolism 58, 586–593 (2009) 122. W. Wei, H. Zhao, A. Wang, M. Sui, K. Liang, H. Deng, Y. Ma, Y. Zhang, H. Zhang, Y. Guan, A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur. J. Endocrinol. 166, 99–105 (2012) 123. Y. An, Z. Sun, Y. Zhang, B. Liu, Y. Guan, M. Lu, The use of berberine for women with polycystic ovary syndrome undergoing IVF treatment. Clin. Endocrinol. 80, 425–431 (2014) 124. X. Zhang, Y. Zhao, M. Zhang, X. Pang, J. Xu, C. Kang, M. Li, C. Zhang, Z. Zhang, Y. Zhang, X. Li, G. Ning, L. Zhao, Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PloS One 7, e42529 (2012) 125. W. Xie, D. Gu, J. Li, K. Cui, Y. Zhang, Effects and action mechanisms of berberine and Rhizoma coptidis on gut microbes and obesity in high-fat diet-fed C57BL/6 J mice. PloS One 6, e24520 (2011) 126. T. Vilsboll, M. Christensen, A.E. Junker, F.K. Knop, L.L. Gluud, Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. Br. Med. J. 344, d7771 (2012) 127. M. Monami, I. Dicembrini, N. Marchionni, C.M. Rotella, E. Mannucci, Effects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis. Exp. Diabetes Res. 2012, 672658 (2012) 128. A.S. Kelly, K.D. Rudser, B.M. Nathan, C.K. Fox, A.M. Metzig, B.J. Coombes, A.K. Fitch, E.M. Bomberg, M.J. Abuzzahab, The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity: a randomized, placebo-controlled, clinical trial. J. Am. Med. Assoc. Pediatr. 167, 355–360 (2013) 129. Gallwitz, B, Extra-pancreatic effects of incretin-based therapies. Endocrine. (2014) [Epub ahead of print] 130. C. Verdich, A. Flint, J.P. Gutzwiller, E. Naslund, C. Beglinger, P.M. Hellstrom, S.J. Long, L.M. Morgan, J.J. Holst, A. Astrup,

123

131.

132.

133.

134.

135.

136.

137. 138.

139.

140.

141.

142.

143.

144.

A meta-analysis of the effect of glucagon-like peptide-1 (7–36) amide on ad libitum energy intake in humans. J. Clin. Endocrinol. Metab. 86, 4382–4389 (2001) A.S. Kelly, A.M. Metzig, K.D. Rudser, A.K. Fitch, C.K. Fox, B.M. Nathan, M.M. Deering, B.L. Schwartz, M.J. Abuzzahab, L.M. Gandrud, A. Moran, C.J. Billington, Schwarzenberg, SJ:Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study. Obesity 20, 364–370 (2012) R.A. DeFronzo, R.E. Ratner, J. Han, D.D. Kim, M.S. Fineman, A.D. Baron, Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28, 1092–1100 (2005) M. Davies, R. Pratley, M. Hammer, A.B. Thomsen, R. Cuddihy, Liraglutide improves treatment satisfaction in people with Type 2 diabetes compared with sitagliptin, each as an add on to metformin. Diabet. Med. 28, 333–337 (2011) J. Rosenstock, L.J. Klaff, S. Schwartz, J. Northrup, J.H. Holcombe, K. Wilhelm, M. Trautmann, Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes. Diabetes Care 33, 1173–1175 (2010) K. Elkind-Hirsch, O. Marrioneaux, M. Bhushan, D. Vernor, R. Bhushan, Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 2670–2678 (2008) S.M. Jensterle, T. Kocjan, M. Pfeifer, N.A. Kravos, A. Janez, Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin. Eur. J. Endocrinol. 170, 451–459 (2014) H.F. Escobar-Morreale, Surgical management of metabolic dysfunction in PCOS. Steroids 77, 312–316 (2012) H.F. Escobar-Morreale, J.I. Botella-Carretero, F. Alvarez-Blasco, J. Sancho, J.L. San Millan, The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab. 90, 6364–6369 (2005) G.M. Eid, D.R. Cottam, L.M. Velcu, S.G. Mattar, M.T. Korytkowski, G. Gosman, P. Hindi, P.R. Schauer, Effective treatment of polycystic ovarian syndrome with Roux-en-Y gastric bypass. Surg. Obes. Relat. Dis. 1, 77–80 (2005) R. Morinigo, V. Moize, M. Musri, A.M. Lacy, S. Navarro, J.L. Marin, S. Delgado, R. Casamitjana, J. Vidal, Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J. Clin. Endocrinol. Metab. 91, 1735–1740 (2006) S. Evans, Z. Pamuklar, J. Rosko, P. Mahaney, N. Jiang, C. Park, A. Torquati, Gastric bypass surgery restores meal stimulation of the anorexigenic gut hormones glucagon-like peptide-1 and peptide YY independently of caloric restriction. Surg. Endosc. 26, 1086–1094 (2012) M.B. Mumphrey, L.M. Patterson, H. Zheng, H.R. Berthoud, Roux-en-Y gastric bypass surgery increases number but not density of CCK-, GLP-1-, 5-HT-, and neurotensin-expressing enteroendocrine cells in rats. Neurogastroenterol. Motil. 25, e70–e79 (2013) J. Korner, M. Bessler, L.J. Cirilo, I.M. Conwell, A. Daud, N.L. Restuccia, S.L. Wardlaw, Effects of Roux-en-Y gastric bypass surgery on fasting and postprandial concentrations of plasma ghrelin, peptide YY, and insulin. J. Clin. Endocrinol. Metab. 90, 359–365 (2005) C.W. le Roux, R. Welbourn, M. Werling, A. Osborne, A. Kokkinos, A. Laurenius, H. Lonroth, L. Fandriks, M.A. Ghatei, S.R. Bloom, T. Olbers, Gut hormones as mediators of appetite

Endocrine and weight loss after Roux-en-Y gastric bypass. Ann. Surg. 246, 780–785 (2007) 145. C.N. Ochner, E. Stice, E. Hutchins, L. Afifi, A. Geliebter, J. Hirsch, J. Teixeira, Relation between changes in neural

responsivity and reductions in desire to eat high-calorie foods following gastric bypass surgery. Neuroscience 209, 128–135 (2012)

123

Gastrointestinal hormones and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine disease of women in reproductive age. It is characterized by anovulation and hyperandrogenism. Most o...
585KB Sizes 0 Downloads 5 Views