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.
Coronavirus disease 2019 (COVID-19) has reached pandemic proportions affecting millions of people worldwide. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the COVID-19. Epidemiological reports showed that the severity of SARS-CoV-2 infection is associated with preexisting comorbidities such as hypertension, diabetes mellitus, cardiovascular diseases and chronic kidney diseases; all of which are also risk factors for acute kidney injury (AKI). The kidney has emerged as a key organ affected by the SARS-CoV-2. AKI is associated with an increased morbidity and mortality in COVID-19 patients. Male sex is an independent predictor for AKI and increased death rate has been reported in male patients with COVID-19 worldwide. The mechanism(s) that mediate the sex discrepancy in mortality due to COVID-19 remain unknown. ACE2 is the receptor for SARS-CoV-2. Alteration in the ACE/ACE2 ratio had been implicated in renal diseases. The aim of this perspective is to discuss data that suggest that androgens, via alterations in the intra-renal renin angiotensin system, impair renal hemodynamic predisposing patients to AKI during COVID-19 infection, which could explain the higher mortality observed in men with COVID-19. Clinicians should ensure early and effective cardiometabolic control for all patients to ameliorate the compensatory elevation of ACE2 and alterations in the ACE/ACE2 ratio. A better understanding of the role of androgens in SARS-CoV-2 associated AKI and mortality is imperative. The kidney could constitute a key organ that may explain the sex disparities of the higher mortality and worst outcomes associated with COVID-19 in men.
Background Polycystic ovary syndrome (PCOS), characterized by androgen excess and ovulatory dysfunction, is associated with a high prevalence of obesity and insulin resistance (IR) in women. We demonstrated that sodium–glucose cotransporter-2 inhibitor (SGLT2i) administration decreases fat mass without affecting IR in the PCOS model. In male models of IR, administration of SGLT2i decreases oxidative stress and improves mitochondrial function in white adipose tissue (WAT). Therefore, we hypothesized that SGLT2i reduces adiposity via improvement in mitochondrial function and oxidative stress in WAT in PCOS model. Methods Four-week-old female rats were treated with dihydrotestosterone for 90 days (PCOS model), and SGLT2i (empagliflozin) was co-administered during the last 3 weeks. Body composition was measured before and after SGLT2i treatment by EchoMRI. Subcutaneous (SAT) and visceral (VAT) WAT were collected for histological and molecular studies at the end of the study. Results PCOS model had an increase in food intake, body weight, body mass index, and fat mass/lean mass ratio compared to the control group. SGLT2i lowered fat mass/lean ratio in PCOS. Glucosuria was observed in both groups, but had a larger magnitude in controls. The net glucose balance was similar in both SGLT2i-treated groups. The PCOS SAT had a higher frequency of small adipocytes and a lower frequency of large adipocytes. In SAT of controls, SGLT2i increased frequencies of small and medium adipocytes while decreasing the frequency of large adipocytes, and this effect was blunted in PCOS. In VAT, PCOS had a lower frequency of small adipocytes while SGLT2i increased the frequency of small adipocytes in PCOS. PCOS model had decreased mitochondrial content in SAT and VAT without impacting oxidative stress in WAT or the circulation. SGLT2i did not modify mitochondrial function or oxidative stress in WAT in both treated groups. Conclusions Hyperandrogenemia in PCOS causes expansion of WAT, which is associated with decreases in mitochondrial content and function in SAT and VAT. SGLT2i increases the frequency of small adipocytes in VAT only without affecting mitochondrial dysfunction, oxidative stress, or IR in the PCOS model. SGLT2i decreases adiposity independently of adipose mitochondrial and oxidative stress mechanisms in the PCOS model.
Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by androgen excess, oligo/anovulation, and polycystic appearance of the ovaries. Women with PCOS have an increased prevalence of multiple cardiovascular risk factors such as insulin resistance, hypertension, renal injury, and obesity. Unfortunately, there is a lack of effective, evidence-based pharmacotherapeutics to target these cardiometabolic complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors provide cardiovascular protection in patients with and without type 2 diabetes mellitus. Although the exact mechanisms of how SGLT2 inhibitors confer cardiovascular protection remains unclear, numerous mechanistic hypotheses for this protection include modulation of the renin-angiotensin system and/or the sympathetic nervous system and improvement in mitochondrial function. Data from recent clinical trials and basic research show a potential role for SGLT2 inhibitors in treating obesity-associated cardiometabolic complications in PCOS. This narrative review discusses the mechanisms of the beneficial effect of SGLT2 inhibitors in cardiometabolic diseases in PCOS.
Introduction In addition to their antihyperglycemic action, sodium-glucose cotransporter-2 (SGLT2) inhibitors are used in patients with Type 2 Diabetes due to their cardioprotective effects. Meta-analyses of large clinical trials have reported mixed results when examining sex differences in their cardioprotective effects. For example, some studies reported that, compared to women, men had a greater reduction in cardiovascular risk with SGLT2 inhibition. Taking advantage of several recently-completed large-scale randomized controlled clinical trials, we tested the hypothesis that women have an attenuated response in primary cardiorenal outcomes to SGLT2 inhibition compared to men. Methods We performed a systematic search using PubMed and the Cochrane Library to find completed large-scale, prospective, randomized-controlled Phase III clinical trials with primary outcomes testing cardiovascular or renal benefit. Studies had to include at least 1,000 participants and report data about sex differences in their primary cardiovascular or renal outcomes. Results The present meta-analysis confirmed that SGLT2 inhibition decreased adverse cardiorenal outcomes in a pooled sex analysis using 13 large-scale clinical trials. SGLT2 inhibition exhibited similar reduction in hazard ratios for both men (0.79, 95% confidence interval 0.73-0.85) and women (0.78, 95% confidence interval 0.72-0.84) for adverse cardiorenal outcomes. Conclusion In contrast to previous findings, our updated meta-analysis suggests that women and men experience similar cardiorenal benefit in response to SGLT2 inhibition. These findings strongly suggest that SGLT2 inhibition therapy should be considered in patients with high risk for cardiovascular disease irrespective of the patient sex.
Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. PCOS is diagnosed by the combination of hyperandrogenemia, oligo/anovulation, and polycystic ovaries. PCOS is also associated with cardiometabolic abnormalities such as: obesity, insulin resistance, dyslipidemia, increased blood pressure (BP), and renal injury. In PCOS, obesity worsens the metabolic outcomes and evidence suggests that the sympathetic nervous system activation increases BP. However, the mechanisms responsible for elevated BP in women with PCOS are still unclear. We tested the hypothesis that obesity, by activating the sympathetic nervous system, mediates the androgen‐induced cardiometabolic abnormalities in PCOS. Four‐week old female SD rats were randomized to subcutaneously receive dihydrotestosterone (DHT, 7.5 mg/ 90 days) pellets (DHT) or sham surgeries (control). Then, DHT animals were assigned to have access to food either ad libitum or on a daily pair‐feeding schedule based on control food intake (PF‐DHT). Body composition (by EchoMRI) and proteinuria were determined every 4 weeks. At the end of the experiment, α1,β1,2‐adrenergic receptor antagonism response was assessed measuring BP by radiotelemetry in conscious, freely moving animals using propranolol (10mg/kg/d) and terazosin (10mg/kg/d) subcutaneously for 14 days. DHT rats had increased daily food intake (18.7 ± 0.1 vs 15.2 ± 0.1 g, p<0.0001) compared to control. During pair‐feeding, food intake in PF‐DHT was decreased to the same level as control. DHT rats had higher BW, fat, and lean mass compared to control. Pair‐feeding abolished the increase in fat mass (12.5 ± 1.7 vs 22 ± 2.5 g, p<0.001) and attenuated the increase in BW (269 ± 6 vs 308 ± 7 g, p<0.001) and lean mass induced by androgens in PCOS. DHT rats had higher BP and proteinuria compared to control. In PCOS, pair‐feeding normalized BP (103.8 ± 0.6 vs 109.6 ± 0.7 mmHg, p<0.0001) and ameliorated the androgen‐induced increase in proteinuria (11.8 ± 1 vs 31.3 ± 2 mg/24h, p<0.0001). Acute adrenergic antagonism caused a bigger BP decrease in control than in DHT (88.1 ± 0.7 vs 93 ± 0.8 mmHg, p<0.05) or in PF‐DHT (88.1 ± 0.7 vs 93 ± 0.5 mmHg, p<0.05). Chronic adrenergic antagonism, however, normalized BP in PF‐DHT (95.5 ± 0.2 vs 97.3 ± 0.3 mmHg, p<0.05), but it did not in DHT (95.5 ± 0.2 vs 100.1 ± 0.3 mmHg, p<0.05). DHT rats showed increased food intake, fat mass, BP, and proteinuria compared to control rats. PF‐DHT rats had decreased fat mass, BP, and proteinuria compared to ad libitum‐fed DHT. In PCOS, the BP lowering effect of acute adrenergic antagonism is blunted by androgen‐excess independently of obesity. Chronic adrenergic antagonism, however, normalizes BP in PCOS in absence of obesity. In summary, obesity plays a key role mediating the negative cardiometabolic consequences of hyperandrogenemia in women with PCOS. Chronic adrenergic antagonism in addition to weight loss may be a promising therapeutic approach for androgen‐induced hypertension in PCOS. Support or Funding Info...
Purpose: Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in reproductive-age women, is characterized by androgen excess and ovarian dysfunction. PCOS women have an increased prevalence of metabolic syndrome components, such as an increased blood pressure (BP), insulin resistance (IR), and obesity. Metformin is the most frequently prescribed insulin sensitizer in women with PCOS. Recent evidence suggests that Black Women (BW) with PCOS have an increased incidence of cardiometabolic (CM) risk factors compared to their White Women (WW) counterparts. It is unclear if metformin has a different effect in BW versus WW with PCOS. Thus, the aim of the current study is to elucidate whether the effect of metformin on CM risk factors is different between BW with PCOS and WW with PCOS at the University of Mississippi Medical Center (UMMC). Hypothesis: CM risk factors will be more pronounced in BW with PCOS compared to WW with PCOS. There will be no difference in the impact of metformin on CM risk factors when comparing BW with PCOS to WW with PCOS. Methods Used: UMMC de-identified patient data from 2013-2022 were obtained from electronic medical records (EMR) using UMMC's Research Data Warehouse. The ICD-10 code of PCOS, E28.2, and code for Type 2 Diabetes Mellitus (T2DM), E11.9, were used to filter patients and encounters. Metformin users were then identified. CM risk factors were analyzed and compared between BW and WW with PCOS. Data are expressed as averages and statistical analysis was performed using SPSS, with p <0.05 considered significant. Summary of Results: From 2013 to 2022, EMRs of 3,260 PCOS patients were analyzed. Of these, 322 patients were co-diagnosed with T2DM. A total of 169 patients were identified as metformin users. BW with PCOS were younger than WW with PCOS (27 yo versus 34 yo). Compared to WW with PCOS, BW women with PCOS have significantly higher body mass index (45.5 vs. 41.16, p<0.001). There was no difference in BP between groups. The rate of current or former smoking doubled in WW with PCOS compared to BW with PCOS. BW with PCOS presented with an HbA1c of 7.5% whereas WW with PCOS presented with an HbA1c of 7.1%. Conclusions: BW with PCOS on metformin have a significantly higher body mass index than WW with PCOS. In contrast, former and current smoking status was more prevalent in WW with PCOS. Race/ethnicity plays a significant role in the CM risk factors in women with PCOS. Implementing strategies to ameliorate cardiovascular diseases in women with PCOS should consider the impact of race in clinical manifestations. No external funding sources This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Background: Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in reproductive-age women, is characterized by androgen excess, polycystic appearance of the ovaries, and ovulatory dysfunction. PCOS women have an increased prevalence of cardiovascular risk factors, such as increased blood pressure, insulin resistance (IR), and obesity. We have previously demonstrated that glucagon-like peptide-1 receptor agonists (GLP1RA) improve IR and obesity in a rat model of PCOS. Recent evidence suggests that Black Women (BW) with PCOS have an increased incidence of cardiometabolic risk factors compared to their White Women (WW) counterparts. We tested the hypothesis that GLP1RA has a differential effect on cardiometabolic risk factors in BW with PCOS versus WW with PCOS. Methods: The University of Mississippi Medical Center de-identified patient data from January 2013 – September 2022 were obtained from electronic medical records (EMR) using UMMC's Research Data Warehouse. Patients with 1) PCOS, 2) type 2 diabetes mellitus (T2DM), 3) documented hemoglobin A1c (HbA1c), and 4) GLP1RA prescription were identified. Cardiometabolic risk factors such as HbA1c, body mass index (BMI), and systolic and diastolic blood pressure (SBP and DBP respectively) were analyzed and compared between BW and WW with PCOS/T2DM. ICD-10 code of PCOS and T2DM: E28.2 and E11.9 respectively. Data are presented as mean ± standard deviation. Results: EMRs of 3756 PCOS patients were obtained. 13.8% of PCOS patients also had a diagnosis of T2DM with documented HbA1c, and 10.4% of them (54 patients) were on a GLP1RA. Of the 54 patients, 35 were BW. In our cohort, BW with PCOS/T2DM had a similar age (38 ± 12 vs 34 ± 11 years of age, p=NS), perimenopausal status, and smoking status as WW with PCOS/T2DM. Compared to WW with PCOS/T2DM on GLP1RA, BW women with PCOS/T2DM had significantly higher HbA1c (8.0 ± 1.0 vs 7.0 ± 0.7 %, p<0.05). There was no difference in BMI, SBP, or DBP between groups. Furthermore, on GLP1RA, there was no difference in the magnitude of change of HbA1c, BMI, SBP, or DBP in BW compared in WW on GLP1RA. Conclusions: BW with PCOS/T2DM had higher HbA1c on GLP1RA compared to WW counterparts. However, there was similar BMI, SBP, and DBP between the two groups. Furthermore, there was no difference in the magnitude of change in cardiometabolic parameters on GLP1RA between the two groups. Race/ethnicity may significantly effect HbA1c, but it does not appear to affect the efficaciousness of GLP1RA on the cardiometabolic profile in women with PCOS. NIGMS P20GM121334 and P20GM104357, NIDDK R21DK11350 and F30DK127527, NHLBI P01HL51971 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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