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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 1000 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% CI, 0.73-0.85) and women (0.78, 95% CI, 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.

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 COVID-19. Epidemiological reports have shown 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 SARS-CoV-2. AKI is associated with increased morbidity and mortality in patients with COVID-19. Male sex is an independent predictor for AKI, and an 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(s) unknown. Angiotensin-converting enzyme (ACE)2 is the receptor for SARS-CoV-2. Alterations in the ACE-to-ACE2 ratio have been implicated in renal diseases. This perspective aims to discuss data that suggest that androgens, via alterations in the intrarenal renin-angiotensin system, impair renal hemodynamics, 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-to-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.

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. Clinical or biochemical signs of androgen excess is a cardinal feature of the syndrome and are present in approximately 80% of women with PCOS. Increased blood pressure and insulin resistance, two major cardiovascular risk factors, are frequently present in women with PCOS. This chapter aims to highlight the fundamental role of androgens in mediating the increased blood pressure and insulin resistance in women with PCOS. This chapter is also a call for action to develop new pharmacological therapies that target the androgen synthesis and androgen receptor activation dysregulation present in women with PCOS. These novel therapies will allow to prevent or mitigate the excess androgen-mediated cardiovascular risk factors that affect women with PCOS.

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.

Numerous epidemiological studies have shown explicit sex and gender differences in the respiratory system under both physiological and pathological conditions. Here, we review the impact of sex steroids, with emphasis on androgens, upon the respiratory system in two endocrine hyperandrogenemic clinical scenarios: polycystic ovary syndrome and postmenopausal women. The primary sex hormones are testosterone in men and estrogens in women. Interestingly, in women, the plasma concentration of testosterone is much higher than estradiol; however, whether and how the excess of androgens may affect the respiratory system in women remain unclear. Hence, here we review some of the evidence that highlights the crucial role of androgens modulating respiratory physiology in these hyperandrogenemic endocrine conditions.

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