scholarly journals A Dietary Medium-Chain Fatty Acid, Decanoic Acid, Inhibits Recruitment of Nur77 to the HSD3B2 Promoter In Vitro and Reverses Endocrine and Metabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 382-394 ◽  
Author(s):  
Bao Hui Lee ◽  
Inthrani Raja Indran ◽  
Huey Min Tan ◽  
Yu Li ◽  
Zhiwei Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Polycystic Ovary Syndrome ◽  
Rat Model ◽  
Polycystic Ovary ◽  
Decanoic Acid ◽  
Chain Fatty Acid ◽  
Metabolic Abnormalities ◽  
Ovary Syndrome

Abstract Hyperandrogenism is the central feature of polycystic ovary syndrome (PCOS). Due to the intricate relationship between hyperandrogenism and insulin resistance in PCOS, 50%–70% of these patients also present with hyperinsulinemia. Metformin, an insulin sensitizer, has been used to reduce insulin resistance and improve fertility in women with PCOS. In previous work, we have noted that a dietary medium-chain fatty acid, decanoic acid (DA), improves glucose tolerance and lipid profile in a mouse model of diabetes. Here, we report for the first time that DA, like metformin, inhibits androgen biosynthesis in NCI-H295R steroidogenic cells by regulating the enzyme 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase type 2 (HSD3B2). The inhibitory effect on HSD3B2 and androgen production required cAMP stimulation, suggesting a mechanistic action via the cAMP-stimulated pathway. Specifically, both DA and metformin reduced cAMP-enhanced recruitment of the orphan nuclear receptor Nur77 to the HSD3B2 promoter, coupled with decreased transcription and protein expression of HSD3B2. In a letrozole-induced PCOS rat model, treatment with DA or metformin reduced serum-free testosterone, lowered fasting insulin, and restored estrous cyclicity. In addition, DA treatment lowered serum total testosterone and decreased HSD3B2 protein expression in the adrenals and ovaries. We conclude that DA inhibits androgen biosynthesis via mechanisms resulting in the suppression of HSD3B2 expression, an effect consistently observed both in vitro and in vivo. The efficacy of DA in reversing the endocrine and metabolic abnormalities of the letrozole-induced PCOS rat model are promising, raising the possibility that diets including DA could be beneficial for the management of both hyperandrogenism and insulin resistance in PCOS.

scholarly journals Effects of Sleeve Gastrectomy on Fecal Gut Microbiota and Short-Chain Fatty Acid Content in a Rat Model of Polycystic Ovary Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Lin ◽  
Lingying Wen ◽  
Junping Wen ◽  
Guangda Xiang
Keyword(s):  
Sleeve Gastrectomy ◽  
Fatty Acid ◽  
Polycystic Ovary Syndrome ◽  
Gut Microbiota ◽  
Rat Model ◽  
Short Chain Fatty Acid ◽  
Polycystic Ovary ◽  
Chain Fatty Acid ◽  
Short Chain ◽  
Ovary Syndrome

PurposeSleeve gastrectomy (SG) is a surgical intervention for polycystic ovary syndrome (PCOS), especially for patients with obesity. Here, we explored the effects of SG on the gut microbiota of rats with PCOS and investigated the association between the intestinal flora and efficacy of SG in PCOS.MethodsDehydroepiandrosterone (DHEA) injection was administered alone and in combination with a high-fat diet to induce PCOS in rats. SG was performed in rats with PCOS, and the effects of SG on the fecal and gut microbiota and the short-chain fatty acid (SCFA) content were observed. Furthermore, the association among gut microbiota, SCFA content and hyperandrogenism or other hallmarks of PCOS was evaluated.ResultsThe abundance of Firmicutes reduced and that of Bacteroidetes increased in response to SG in the DHEA-induced PCOS rat model. At the genus level, the abundances of Bacteroides and Blautia increased and those of Ruminococcus, Clostridium, and Alistipes reduced distinctly in the PCOS-SG groups. Moreover, the levels of fecal SCFAs, especially butyric acid, reduced after SG. SG significantly ameliorated PCOS-related symptoms such as hyperandrogenism, disrupted ovary function, and impaired glucose tolerance. Bacteroides and Blautia exhibited a negative correlation and Ruminococcus, Clostridium, and Alistipes exhibited a positive correlation with the levels of fecal SCFAs, luteinizing hormone, testosterone, and inflammatory factors.ConclusionsThe amelioration of PCOS-related reproductive and metabolic disorders following SG was associated with the regulation of microbial taxa and SCFA content. Our findings provide a novel perspective on the microbial mechanisms in PCOS after SG.

scholarly journals Hyperandrogenism and Insulin Resistance, Not Changes in Body Weight, Mediate the Development of Endothelial Dysfunction in a Female Rat Model of Polycystic Ovary Syndrome (PCOS)

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4071-4080 ◽  
Author(s):  
Amanda Hurliman ◽  
Jennifer Keller Brown ◽  
Nicole Maille ◽  
Maurizio Mandala ◽  
Peter Casson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Endothelial Dysfunction ◽  
Polycystic Ovary Syndrome ◽  
Rat Model ◽  
Polycystic Ovary ◽  
Phase 1 ◽  
Ovary Syndrome

This study was designed to differentiate the contributions of hyperandrogenism, insulin resistance (IR), and body weight to the development of endothelial dysfunction in polycystic ovary syndrome and determine the effectiveness of insulin sensitization and antiandrogenic therapy after the establishment of vascular and metabolic dysfunction using a rat model of polycystic ovary syndrome. We hypothesized that the observed endothelial dysfunction was a direct steroidal effect, as opposed to changes in insulin sensitivity or body weight. Prepubertal female rats were randomized to the implantation of a pellet containing DHT or sham procedure. In phase 1, DHT-exposed animals were randomized to pair feeding to prevent weight gain or metformin, an insulin-sensitizing agent, from 5 to 14 weeks. In phase 2, DHT-exposed animals were randomized to treatment with metformin or flutamide, a nonsteroidal androgen receptor blocker from 12 to 16 weeks. Endothelial function was assessed by the vasodilatory response of preconstricted arteries to acetylcholine. Serum steroid levels were analyzed in phase 1 animals. Fasting blood glucose and plasma insulin were analyzed and homeostasis model assessment index calculated in all animals. Our data confirm the presence of endothelial dysfunction as well as increased body weight, hypertension, hyperinsulinemia, and greater IR among DHT-treated animals. Even when normal weight was maintained through pair feeding, endothelial dysfunction, hyperinsulinemia, and IR still developed. Furthermore, despite weight gain, treatment with metformin and flutamide improved insulin sensitivity and blood pressure and restored normal endothelial function. Therefore, the observed endothelial dysfunction is most likely a direct result of hyperandrogenism-induced reductions in insulin sensitivity, as opposed to weight gain.

scholarly journals Serum Testosterone to Androstenedione Ratio Predicts Metabolic Health in Normal-Weight Polycystic Ovary Syndrome Women

2021 ◽  
Author(s):  
Daniel A Dumesic ◽  
Ayli Tulberg ◽  
Megan McNamara ◽  
Tristan R Grogan ◽  
David H Abbott ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Elevated Serum ◽  
Normal Weight ◽  
Model Assessment ◽  
Metabolic Function ◽  
Ovary Syndrome ◽  
Intravenous Glucose

Abstract Context Increased aldo-keto reductase 1C3 (AKR1C3)-mediated conversion of androstenedione (A4) to testosterone (T) promotes lipid storage in subcutaneous (SC) abdominal adipose in overweight/obese polycystic ovary syndrome (PCOS) women. Objective To examine whether an elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts metabolic function in normal-weight PCOS women. Design Prospective cohort study. Setting Academic center. Patients Nineteen normal-weight PCOS women; 21 age- and body mass index-matched controls. Intervention(s) Circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total body dual-energy x-ray absorptiometry, SC abdominal fat biopsy. Main Outcome Measure(s) Serum T/A4 ratios, hormone/metabolic measures and AKR1C3 expression of adipocytes matured in vitro were compared between female types; serum T/A4 ratios were correlated with serum lipids, adipose insulin resistance (adipose-IR), homeostatic model assessment of insulin resistance (HOMA-IR) and insulin sensitivity (Si). Results Increased serum T/A4 ratios (P=0.040) and log adipose-IR values (P=0.002) in PCOS women versus controls were accompanied by AKR1C3 mRNA overexpression of PCOS adipocytes matured in vitro (P=0.016). Serum T/A4 ratios in PCOS women, but not controls, negatively correlated with log triglycerides (TG: R=-0.65, P=0.002) and the TG index (R=-0.57, P=0.011). Adjusting for serum free T, serum T/A4 ratios in PCOS women remained negatively correlated with log TG (R=-0.57, P=0.013) and TG index (R=-0.50, P=0.036), respectively, without significant relationships with other metabolic measures. Conclusion An elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts healthy metabolic function in normal-weight PCOS women.

Obesity, hormonal and metabolic abnormalities in adolescent girls with polycystic ovary syndrome

2013 ◽  
Vol 154 (31) ◽  
pp. 1226-1234
Author(s):  
László Ságodi ◽  
Béla Lombay ◽  
Ildikó Vámosi ◽  
László Barkai
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Body Mass Index ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Polycystic Ovary Syndrome ◽  
Adolescent Girls ◽  
Polycystic Ovary ◽  
Metabolic Abnormalities ◽  
Ovary Syndrome

Introduction: Polycystic ovary syndrome is associated with metabolic abnormalities, such as dyslipidemia, obesity, glucose intolerance, which are also components of the metabolic syndrome. Central obesity and insulin resistance appear to play an important role in the pathogenesis of polycystic ovary syndrome, perhaps via subsequent steroidogenic dysregulation. Aim: The aim of the authors was to assess metabolic and hormonal abnormalities in adolescent girls with polycystic ovary syndrome. Method: The study included 52 adolescents diagnosed with polycystic ovary syndrome based on the Rotterdam criteria. Anthropometric, hormonal and metabolic parameters were evaluated among all subjects. 20 healthy, age-matched, non-obese, regularly menstruating girls were used as controls. Of the 52 patients, 15 patients were born with low-birth-weight and 37 patients were born with normal birth weight. Oral glucose tolerance test was performed in all patients and controls. The age of patients was 16.8±3.1 years, and the age of controls was 16.95±2.1 years. Results: Among patients with polycystic ovary syndrome the prevalence of overweight and obesity was 35% (n = 18), while impaired fasting glucose occurred in one patient, impaired glucose tolerance in 8 patients, insulin resistance in 25 patients and metabolic syndrome in 12 patients. Serum triglyceride levels in patients and controls were 1.4±0.8 and 0.9±0.3 mmol/l, respectively (p<0.05), while fasting blood glucose, total cholesterol, HDL and LDL cholesterol were not different in the two groups. Metabolic abnormalities and obesity were more severe and more frequent in patients with low-birth-weight compared to those born with normal weight. There was a negative correlation between birth weight and body mass index SDS values and a positive correlation between fasting insulin levels and body mass index SDS (r = 0.37) in patients born with low-birth-weight. Conclusions: Abnormal glucose metabolism is frequently present in adolescents with polycystic ovary syndrome. It is possible that early diagnosis of polycystic ovary syndrome in adolescences may prevent some of the long-term complications associated with this syndrome. Orv. Hetil., 2013, 154, 1226–1234.

scholarly journals Role of Lipotoxicity and Contribution of the Renin-Angiotensin System in the Development of Polycystic Ovary Syndrome

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Alexandre Connolly ◽  
Samuel Leblanc ◽  
Jean-Patrice Baillargeon
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Rat Model ◽  
Polycystic Ovary ◽  
Renin Angiotensin System ◽  
Ovary Syndrome ◽  
Nonesterified Fatty Acids ◽  
Insulin Resistant ◽  
Cellular Dysfunction

Polycystic ovary syndrome (PCOS) is a common and significant condition associated with hyperandrogenism, infertility, low quality of life, and metabolic comorbidities. One possible explanation of PCOS development is cellular dysfunction induced by nonesterified fatty acids (NEFAs), that is, lipotoxicity, which could explain both the hyperandrogenemia and insulin resistance that characterize women with PCOS. The literature suggests that androgen biosynthesis may be induced by overexposure of androgen-secreting tissues to NEFA and/or defective NEFA metabolism, leading to lipotoxic effects. Indeed, lipotoxicity could trigger androgenic hyperresponsiveness to insulin, LH, and ACTH. In most PCOS women, lipotoxicity also causes insulin resistance, inducing compensatory hyperinsulinemia, and may thus further increase hyperandrogenemia. Many approaches aimed at insulin sensitization also reduce lipotoxicity and have been shown to treat PCOS hyperandrogenemia. Furthermore, our group and others found that angiotensin II type 2 receptor (AT2R) activation is able to improve lipotoxicity. We provided evidence, using C21/M24, that AT2R activation improves adipocytes’ size and insulin sensitivity in an insulin-resistant rat model, as well as androgen levels in a PCOS obese rat model. Taken together, these findings point toward the important role of lipotoxicity in PCOS development and of the RAS system as a new target for the treatment of PCOS.

scholarly journals Contemporary approaches to the management of polycystic ovary syndrome

2018 ◽  
Vol 9 (4) ◽  
pp. 123-134 ◽  
Author(s):  
Renato Pasquali
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Review Article ◽  
Metabolic Abnormalities ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Ovulatory Dysfunction ◽  
Ovarian Morphology

Polycystic ovary syndrome (PCOS) is a common disorder in women in their reproductive years and is characterized by androgen excess, ovulatory dysfunction, and polycystic ovarian morphology. It is also associated with several metabolic abnormalities, particularly insulin resistance and obesity, which play an important role in the pathophysiology of PCOS and, in particular, negatively influence ovarian function and fertility. This review article summarizes the available treatment for women with PCOS. Specifically, current and potentially new therapies are discussed.

scholarly journals Anti-Müllerian Hormone Accelerates Pathological Process of Insulin Resistance in Polycystic Ovary Syndrome Patients

2021 ◽  
Vol 53 (08) ◽  
pp. 504-511
Author(s):  
Xiang-Juan Li ◽  
Hui Wang ◽  
Dan-Yang Lu ◽  
Tian-Tian Yu ◽  
Kamran Ullah ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Fasting Blood Glucose ◽  
Density Lipoprotein ◽  
Pathological Process ◽  
Model Assessment ◽  
High Concentration ◽  
Ovary Syndrome

AbstractInsulin resistance (IR) is one of the most common features of polycystic ovary syndrome (PCOS), which is related to obesity. Whether increased anti-Müllerian hormone (AMH) levels in PCOS are involved in the pathogenesis of insulin resistance remains unclear. We investigated serum levels of leptin and AMH along with basic clinical and metabolic parameters in 114 PCOS patients and 181 non-PCOS women. PCOS patients presented higher fasting blood glucose, insulin concentrations and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in addition to body mass index (BMI), lipids profiles and hormone levels. HOMA-IR showed a positive correlation with BMI, AMH, leptin, and low-density lipoprotein-cholesterol (LDL-c) levels. Interestingly, AMH is strongly positively correlated with HOMA-IR and insulin concentrations for 1st and 2nd hours of glucose treatment after fasting. Among PCOS women with BMI≥25 kg/m2, high AMH level group showed an increased HOMA-IR when compared to normal AMH level. However, among PCOS women with normal BMI, women with high AMH presented an elevated fasting insulin levels but not HOMA-IR when compared to normal AMH group. In vitro treatment of isolated islet cells with high concentration of leptin (200 ng/ml) or high leptin plus high concentration of AMH (1 ng/ml) significantly enhanced insulin secretion. Importantly, co-treatment of AMH plus leptin upregulates the expression of pro-apoptotic proteins, such as Bax, caspase-3, and caspase-8 after incubating with a high level of glucose. These results suggest that AMH may involve in the pathological process of pancreatic β-cells in obese PCOS women.

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