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 characterized by androgen excess, oligo/anovulation, and polycystic ovaries. Obesity, insulin resistance (IR) and increased blood pressure (BP) are associated with PCOS. Therapeutic options for PCOS are limited and the mechanisms responsible for the cardiometabolic complications seen in PCOS are uncertain. It is unclear if androgen‐mediated increases in BP contribute to obesity and/or IR in PCOS. The renin angiotensin system (RAS), a regulator of BP, is affected by androgens and is associated with increased BP in PCOS. To investigate the role of androgens and the contribution of the RAS in PCOS, RAS inhibition via an angiotensin‐converting enzyme inhibitor (ACEi) was performed in a PCOS‐like rat model. We hypothesized that ACEi would attenuate obesity and IR in PCOS. Female SD rats (4 week old) received dihydrotestosterone (DHT, 7.5 mg/ 90 days) pellets (HAF) subcutaneously or sham surgeries (CON). The rats were then assigned tap water or tap water with the ACEi, enalapril (ENA) (250mg/L) for n=10/group. At the end of the study (16 week old) body weight (BW), body composition by EchoMRI, and IR by HOMA‐IR were assessed. Renal RAS gene expression was assessed by qPCR. BP was measured by radiotelemetry and plasma and renal ACE and ACE2 activities were assessed. HAF had increased BW, fat mass and IR vs CON. ENA reduced BW in only HAF. Overall, ENA decreased fat mass, and the decrease in HAF neared significance. ENA did not attenuate IR in HAF. In HAF, angiotensinogen (Agt) mRNA was increased in the renal cortex and medulla, while ACE and angiotensin II receptor type 1a (Atr1a) mRNA was increased in the medulla vs CON. In HAF, ENA had no impact on renal Agt, ACE or Atr1a mRNA. ACE2 mRNA was increased in the medulla of HAF vs CON, and ENA increased medulla ACE2 mRNA in both HAF and CON. HAF had increased BP, and ENA decreased BP in both HAF and CON by a similar degree. Overall, ENA decreased plasma ACE activity but only increased plasma ACE2 activity in HAF. ENA increased cortical ACE2 activity in both HAF and CON. In summary, ACEi therapy in a PCOS model reduced BW, BP and adiposity but had no impact on IR. Renal classic RAS gene expression is upregulated in the HAF but unchanged by ENA. Furthermore, only ACE2 mRNA expression was altered in the HAF with ENA. In addition, the expression of other RAS component genes that were unchanged by ACEi in HAF were significantly impacted by ACEi in CON. This reveals a complex interaction between androgen exposure and renal RAS component gene expression. Increased BP in the HAF did not correlate with plasma or renal ACE or ACE2 activities. Chronic RAS inhibition may be a promising therapeutic approach for androgen‐mediated increases in BP and obesity in AE‐PCOS, though additional therapy would be needed for IR.

Introduction : Polycystic Ovary Syndrome (PCOS) is characterized by androgen excess, oligo/anovulation, and polycystic ovaries. PCOS is co‐prevalent with insulin resistance (IR), increased blood pressure (BP), and a dysfunctional renin‐angiotensin system (RAS). The RAS has both a vasoconstrictive arm with angiotensin‐converting enzyme (ACE) and a vasodilatory arm with ACE2. While PCOS patients require multiple medications to control their comorbidities, it is unknown how these medications interact with each other. ACE inhibitors (ACEi) and sodium‐glucose cotransporter 2 inhibitors (SGLT2i) seem to influence each other in male rodents. However, how androgens influence these interactions in females is unknown. We have a well‐established rat model that mimics PCOS, including IR, increased BP, and overactive RAS. Using this model, we tested the hypothesis that SGLT2i would attenuate the RAS and that ACEi would decrease renal SGLT2 expression in a rat model of PCOS. Methods : In Experiment 1, four‐week old female Sprague Dawley (SD) rats implanted with DHT pellets (7.5mg/90 days) or control were randomized to drinking water with and without the SGLT2i empagliflozin at a dose of 10 mg/kg/day during the last 3 weeks of the study (n=10/group). At 3 months of DHT, fasting plasma was collected for the homeostatic model assessment of IR (HOMA‐IR). BP was measured by radiotelemetry. Renal cortex and medulla were collected for quantitative real‐time polymerase chain reaction (qRT‐PCR) and western blot for ACE and ACE2. In Experiment 2, four‐week old female SD rats implanted with DHT pellets (7.5mg/90 days) or control were randomized to drinking water with and without the ACEi enalapril at a dose of 250 mg/mL throughout the study (n=10/group). At 3 months of DHT, kidneys were collected for qRT‐PCR for SGLT2. Results : PCOS rats had increased IR, BP, and renal expression of ACE and ACE2 compared to controls. SGLT2i had no impact on IR while causing a small reduction in BP in both groups. SGLT2i decreased cortical ACE mRNA and protein (1.03 ± 0.08 vs 1.37 ± 0.04, P<0.05) in PCOS, and had no impact in controls. SGLT2i also decreased cortical ACE2 protein (1.02 ± 0.05 vs 1.18 ± 0.03, P<0.05) in PCOS, but not in controls. SGLT2i decreased mRNA and protein of medullar ACE and ACE2 in both groups. In Experiment 2, cortical SGLT2 mRNA was increased in PCOS compared to controls. ACEi increased SGLT2 mRNA in controls (30.32 ± 8.03 vs 1.00 ± 0.32, P<0.01) with no effect in PCOS. Conclusions In summary, PCOS rats had increased IR, BP, and intrarenal ACE. Without impacting IR, SGLT2i attenuated both intrarenal ACE and ACE2 expression in PCOS. This suggests ACEi could work synergistically with SGLT2i to reduce BP. PCOS rats have increased SGLT2 mRNA, suggesting a differential response to SGLT2i between PCOS rats and controls, such as shown with cortical ACE. ACEi also increased cortical SGLT2 mRNA in controls, but androgen excess appeared to blunt this effect. Overall, this suggests that there could be a differential response in hyperandrog...

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...