Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by androgen excess and ovarian dysfunction and presents with increased cardiometabolic risk factors such as obesity, insulin resistance, and elevated blood pressure (BP). We previously reported that administration of dihydrotestosterone (DHT) to female rats elicits cardiometabolic derangements similar to those found in women with PCOS. In this study, we tested the hypothesis that the DHT-mediated cardiometabolic derangements observed in PCOS are long lasting despite DHT withdrawal. Four-week-old female Sprague Dawley rats were treated with DHT (7.5 mg/90 days) or placebo for 6 months. DHT was discontinued (ex-DHT), and rats were followed for 6 additional months. After 6 months of DHT withdrawal, food intake, body weight, fat and lean mass, fasting plasma insulin, leptin, and adiponectin were elevated in ex-DHT rats. BP remained significantly elevated, and enalapril, an angiotensin-converting enzyme (ACE) inhibitor, normalized BP in ex-DHT rats. Expression of components of the intrarenal renin-angiotensin system was increased in ex-DHT rats. The cardiometabolic features found in ex-DHT rats were associated with lower plasma androgen levels but increased expression of renal and adipose tissue androgen receptors. In summary, androgen-induced cardiometabolic effects persisted after DHT withdrawal in a PCOS experimental model. Activation of intrarenal renin-angiotensin system plays a major role in the androgen-mediated increase in BP in ex-DHT. Upregulation of the renal and adipose tissue androgen receptor may explain the long-lasting effects of androgens. In clinical scenarios characterized by hyperandrogenemia in women, prompt normalization of androgen levels may be necessary to prevent their long-lasting cardiometabolic effects.

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Introduction: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. PCOS is characterized by androgen excess and ovulatory dysfunction high prevalence of cardiovascular risk factors such as increased blood pressure (BP), insulin resistance (IR), and obesity. We have demonstrated previously that exposing prepubertal female rats to dihydrotestosterone (DHT) leads to increase in food intake (FI), body weight (BW), BP, and IR. We tested the hypothesis that administration of the AR blocker bicalutamide (BICA) would decrease BP, IR, and obesity in PCOS model. As there are previous reports of severe hepatotoxicity with the AR blocker flutamide, we also examined BICA effects in the liver. Methods: Four-week old female Sprague Dawley rats implanted with DHT pellets (7.5mg/90 days) or placebo (PBO) were randomized to standard chow diet with or without the AR blocker bicalutamide (BICA) at a dose of 250 mg/kg/day throughout the study (n=10/group). BW and FI were measured weekly. BP and heart rate (HR) were measured by radiotelemetry. Fasting plasma was collected for IR (Homeostatic model assessment for IR, HOMA-IR). At euthanasia, the liver was collected, as well as plasma for gamma glutamyl transferase (GGT), alanine transaminase (ALT), and aspartate transaminase (AST) quantification. Results: PCOS rats had increased BW, FI, IR, and BP compared to PBO. BICA treatment had no impact on BW (285.3 ± 7.0 vs 270 ± 8.2 g, P=0.2) as well as FI and HR in PCOS. However, in PCOS, BICA decreased HOMA-IR (5.10 ± 0.40 vs 3.33 ± 0.31, P<0.05) and BP (115.4 ± 0.7 vs 105.3 ± 0.2 mmHg, P<0.01). Compared to PBO, PCOS+BICA rats had similar IR (3.83 ± 0.28 vs 3.33 ± 0.31, P=0.7) and BP (107.4 ± 0.8 vs 105.3 ± 0.2 mmHg, P=0.9). In addition, the liver weight to tibia length ratio was drastically increased by BICA in PCOS (222.9 ± 9.5 vs 360.4 ± 16.9 mg/mm, P<0.0001) as well as GGT (0.88 ± 0.88 vs 11.67 ± 0.58 U/L, P<0.0001), though it decreased AST (60.2 ± 6.9 vs 42.4 ± 1.9 U/L, P<0.05) and had no impact on ALT. Conclusion: In summary, in a model of PCOS, BICA treatment abolished IR and BP, independent of FI, BW and HR. Prompt treatment with an AR blocker can normalize increased IR and BP triggered by androgen excess in females. Further studies need to be done to fully understand the effect of BICA in the liver in PCOS. The beneficial effect of AR blockers as a therapeutic option to improve the cardiometabolic profile in PCOS may be hampered by its liver toxicity.

Background Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in women, is characterized by androgen‐excess and ovarian dysfunction. PCOS is associated with obesity, insulin resistance (IR) and increased blood pressure (BP). Currently therapeutic options to treat PCOS‐associated cardiovascular risk factors are limited. We have previously characterized a rat model of PCOS in which chronic androgen‐excess causes increased body weight (BW), fat mass (FM), IR, BP, and activation of some intrarenal Renin Angiotensin System (RAS) components. Still, the mechanisms responsible for increased BP in women with PCOS remain unclear. In the present study, we tested how chronic androgen‐excess changes the renal mRNA expression profile of the androgen receptor (AR) and RAS components in a model of PCOS. Methods Four‐week old female SD rats were randomized to subcutaneously receive dihydrotestosterone (DHT, 7.5 mg/90 days) pellets (DHT) or sham surgeries (control) for 90 days (n= 6–10/grp). At the end of the experimental period, food intake (FI), BW, FM measured by Echo‐MRI, and BP using radiotelemetry were assessed in conscious, freely moving animals. Renal mRNA expression was assessed in cortical and medullary tissues separately by RT‐qPCR. Results At the end of the experimental period, DHT rats exhibited higher FI, BW, FM and BP compared to control. In DHT rats, renal cortical mRNA expression of AR, angiotensinogen, AT1R, renin receptor, cathepsin A, aminoendopeptidase A, dipeptidyl peptidase 3, neprilysin, neurolysin, prolylendopeptidase, insulin‐like growth factor 2 receptor were significantly increased. In addition, renal medullary mRNA expression of angiotensin converting enzyme (ACE), angiotensin converting enzyme type 2 (ACE2), angiotensinogen, angiotensin 2 receptor type 1 (AT1R), membrane alanyl aminopeptidase, dipeptidyl peptidase 3, aminopeptidase A, kallikrein 1, neprilysin, neurolysin, prolylendopeptidase, and thimet oligopeptidase were significantly increased. Renal medullary mRNA expression of renin and aminopeptidase B were significantly decreased in DHT rats. Summary and Conclusions In summary, hyperandrogenemia leads to upregulation of AR in renal cortex and medulla. The mRNA expression of renal cortical and medullar ACE/AT1R axis components was upregulated in DHT rats. Additionally, mRNA expression of the ACE2 was upregulated mainly in the kidney medulla of DHT rats which could be a compensatory mechanism. This study highlights the effect of androgen‐excess modulating the intrarenal RAS and AR. Treatments focused on targeting RAS system components could be promising therapeutic tools to ameliorate the cardiovascular and renal abnormalities observes in women with PCOS. Support or Funding Information AHA 0830239N (L.L.Y.C.) and 12SDG8980032 (D.G.R.), EFFERG (L.L.Y.C.), and NIH R21 DK‐113500 (D.G.R.) and P20 GM‐121334 (L.L.Y.C.)

IntroductionPolycystic Ovary Syndrome (PCOS), the most common endocrine disorder in women, is characterized by androgen excess and ovarian dysfunction. PCOS is often associated with components of metabolic syndrome (MS) such as visceral obesity, dyslipidemia, insulin resistance (IR) and increased blood pressure (BP). Liraglutide, a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), has been found to cause weight loss in several small clinical trials on young women with PCOS. Moreover, it has been reported that Liraglutide decreases IR and BP in reproductive age‐PCOS rats. Postmenopausal women who have had PCOS and chronic androgen excess may be at a greater risk for MS and cardiovascular disease than normo‐androgenemic postmenopausal women. We have previously characterized a rat model of chronic androgen excess that resembles many components of MS in postmenopausal PCOS women: increased body weight, fat mass, dyslipidemia, IR and BP. In the present study, we tested the hypothesis that Liraglutide administration improves the MS found in the rat model of postmenopausal PCOS.MethodsFemale Sprague Dawley rats, 4 week‐old, were randomized to chronically receive DHT (dihydrotestosterone, 7.5 mg/90 days) or placebo (n=18/group). At 17 months of age, postmenopausal PCOS and aged‐matched placebo rats were randomized to receive liraglutide (0.3 mg/kg/day) or vehicle subcutaneously for 3 weeks. During liraglutide treatment, food intake, body weight and mean arterial blood pressure (MAP), measured by radiotelemetry, were recorded. Before and after liraglutide treatment body composition (by Echo‐MRI) and insulin resistance (using HOMA‐IR index) were measured. At the end of the study, circulating insulin, leptin, cholesterol and triglycerides levels were quantified.ResultsPostmenopausal PCOS rats exhibit significantly higher food intake, body weight, fat mass, total cholesterol, triglycerides, leptin and MAP compared to aged‐matched placebo. After 3 weeks of treatment, liraglutide caused significant greater reduction in cumulative food intake (−65.7 ± 9.6 vs −46 ± 10 g, p<0.01), body weight (−38.4 ± 4.7 vs −28.8 ± 2.4 g, p<0.05), fat mass/body weight (−7.7 ± 0.6 vs −4.8 ± 0.7, p<0.01), HOMA‐IR index (−4.5 ± 0.6 vs −1.4 ± 1.1, p<0.05), leptin, cholesterol, and triglycerides levels in postmenopausal PCOS compared to aged‐matched placebo. In contrast, liraglutide decreased MAP in aged‐matched placebo (108 ± 1 vs 101 ± 1 mmHg, p<0.0001), however, did not lowered MAP in postmenopausal PCOS (123 ± 2 vs 126 ± 3 mmHg, p=0.56). In summary, the GLP‐1 receptor agonist liraglutide exhibit beneficial effects in several components of the MS: body weight, cumulative food intake, fat mass/body weight, HOMA‐IR index, leptin, cholesterol and triglycerides levels found in the rat model postmenopausal PCOS. In contrast, liraglutide treatment failed to lower MAP in postmenopausal PCOS. Liraglutide treatment is a promising therapeutic agent to treat obesity and dyslipidemia in postmenopausal PCOS; however, these women will need additional treatments to maintain their MAP under control.Support or Funding InformationAmerican Heart Association Grants 0830239N (L.L.Y.C.) and 12SDG8980032 (D.G.R.), Endocrine Fellows Foundation Endocrine Research Grant (L.L.Y.C.), and National Institutes of Health grants R21 DK‐113500 (D.G.R.), and P20 GM‐121334 (L.L.Y.C.)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.