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Background A goal of gender-affirming hormone therapy (GAHT) for transgender women is to use estradiol to suppress endogenous production of testosterone. However, the effects of different estradiol regimens and route of administration on testosterone suppression is unknown. This is the first open-label randomized trial comparing different GAHT regimens for optimal estradiol route and dosing. Objective To evaluate 1 month and 6 months testosterone suppression <50 ng/dL with pulsed (once- or twice-daily sublingual 17-beta estradiol) and continuous (transdermal 17-beta estradiol) GAHT. Methods This study was conducted at an outpatient adult transgender clinic. Thirty-nine transgender women undergoing initiation of GAHT were randomly assigned to receive either once-daily sublingual, twice-daily sublingual, or transdermal 17-beta estradiol. All participants received spironolactone as an antiandrogen. Doses were titrated at monthly intervals to achieve total testosterone suppression <50 ng/dL. Results Transdermal 17-beta estradiol resulted in more rapid suppression of total testosterone, lower estrone levels, with no differences in estradiol levels when compared to once-daily and twice-daily sublingual estradiol. Moreover, there was no difference in the mean estradiol dose between the once-daily and twice-daily sublingual 17-beta estradiol group. Conclusion Continuous exposure with transdermal 17-beta estradiol suppressed testosterone production more effectively and with lower overall estradiol doses relative to once or twice daily sublingual estradiol. Most transgender women achieved cisgender women testosterone levels within 2 months on 1 or 2 0.1 mg/24 hours estradiol patches. Given no difference between once- or twice-daily sublingual estradiol, pulsed 17-beta estradiol likely provides no benefit for testosterone suppression. [ABSTRACT FROM AUTHOR]

Kidney disease frequently coexists with cardiovascular (CV) diseases, and this dual presence significantly amplifies the risk of adverse clinical outcomes. Shared pathophysiological mechanisms and common CV risk factors contribute to the increased expression of mineralocorticoid receptors, which in turn can drive the progression of chronic CV–kidney disorders. The steroidal mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have demonstrated efficacy in improving patient outcomes in cases of heart failure with reduced ejection fraction or after a myocardial infarction, but have limited value in patients with chronic kidney disease. The non-steroidal MRA finerenone has now established itself as a foundational guideline-recommended therapy in patients with diabetic kidney disease. To date, these pharmacological agents have been developed in distinct patient populations. The consequences of their distinct pharmacological profiles necessitate further consideration. They have not undergone testing across the entire spectrum of cardiorenal scenarios, and the evidence base is currently being complemented with ongoing trials. In this review, we aim to synthesize the existing body of evidence and chart the future trajectory for the use of spironolactone, eplerenone and finerenone in improving clinical outcomes across the diverse spectrum of cardiorenal diseases. By consolidating the current state of knowledge, we seek to provide valuable insights for informed decision making in the management of patients with these complex and interconnected conditions. [ABSTRACT FROM AUTHOR]

Background and Aims Mineralocorticoid receptor antagonists (MRAs) improve cardiovascular outcomes in a variety of settings. This study aimed to assess whether cardioprotective effects of MRAs are modified by heart failure (HF) and atrial fibrillation (AF) status and to study their impact on AF events. Methods MEDLINE, Embase, and Cochrane Central databases were searched to 24 March 2023 for randomized controlled trials evaluating the efficacy of MRAs as compared with placebo or usual care in reducing cardiovascular outcomes and AF events in patients with or at risk for cardiovascular diseases. Random-effects models and interaction analyses were used to test for effect modification. Results Meta-analysis of seven trials (20 741 participants, mean age: 65.6 years, 32% women) showed that the efficacy of MRAs, as compared with placebo, in reducing a composite of cardiovascular death or HF hospitalization remains consistent across patients with HF [risk ratio = 0.81; 95% confidence interval (CI): 0.67–0.98] and without HF (risk ratio = 0.84; 95% CI: 0.75–0.93; interaction P =.77). Among patients with HF, MRAs reduced cardiovascular death or HF hospitalization in patients with AF (hazard ratio = 0.95; 95% CI: 0.54–1.66) to a similar extent as in those without AF (hazard ratio = 0.82; 95% CI: 0.63–1.07; interaction P =.65). Pooled data from 20 trials (21 791 participants, mean age: 65.2 years, 31.3% women) showed that MRAs reduce AF events (risk ratio = 0.76; 95% CI: 0.67–0.87) in both patients with and without prior AF. Conclusions Mineralocorticoid receptor antagonists are similarly effective in preventing cardiovascular events in patients with and without HF and most likely retain their efficacy regardless of AF status. Mineralocorticoid receptor antagonists may also be moderately effective in preventing incident or recurrent AF events. [ABSTRACT FROM AUTHOR]

Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood pressure (BP) measurement is the essential first step in the diagnosis and management of hypertension. Dietary sodium restriction is often overlooked, but can improve BP control, especially among patients treated with an agent to block the renin–angiotensin system. In the presence of very high albuminuria, international guidelines consistently and strongly recommend the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as the antihypertensive agent of first choice. Long-acting dihydropyridine calcium channel blockers and diuretics are reasonable second- and third-line therapeutic options. For patients with treatment-resistant hypertension, guidelines recommend the addition of spironolactone to the baseline antihypertensive regimen. However, the associated risk of hyperkalemia restricts the broad utilization of spironolactone in patients with moderate-to-advanced CKD. Evidence from the CLICK (Chlorthalidone in Chronic Kidney Disease) trial indicates that the thiazide-like diuretic chlorthalidone is effective and serves as an alternative therapeutic opportunity for patients with stage 4 CKD and uncontrolled hypertension, including those with treatment-resistant hypertension. Chlorthalidone can also mitigate the risk of hyperkalemia to enable the concomitant use of spironolactone, but this combination requires careful monitoring of BP and kidney function for the prevention of adverse events. Emerging agents, such as the non-steroidal mineralocorticoid receptor antagonist ocedurenone, dual endothelin receptor antagonist aprocitentan and the aldosterone synthase inhibitor baxdrostat offer novel targets and strategies to control BP better. Larger and longer term clinical trials are needed to demonstrate the safety and efficacy of these novel therapies in the future. In this article, we review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of hypertension in patients with CKD. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) in individuals with type 2 diabetes (T2D) represents a major public health issue; it develops in about 30%–40% of patients with diabetes mellitus and is the most common cause of CKD worldwide. Patients with CKD and T2D are at high risk of both developing kidney failure and of cardiovascular events. Renin–angiotensin system (RAS) blockers were considered the cornerstone of treatment of albuminuric CKD in T2D for more than 20 years. However, the residual risk of progression to more advanced CKD stages under RAS blockade remains high, while in major studies with these agents in patients with CKD and T2D no significant reductions in cardiovascular events and mortality were evident. Steroidal mineralocorticoid receptor antagonists (MRAs) are known to reduce albuminuria in individuals on RAS monotherapy, but their wide clinical use has been curtailed by the significant risk of hyperkalemia and absence of trials with hard renal outcomes. In recent years, non-steroidal MRAs have received increasing interest due to their better pharmacologic profile. Finerenone, the first compound of this class, was shown to effectively reduce the progression of kidney disease and of cardiovascular outcomes in participants with T2D in phase 3 trials. This clinical practice document prepared from a task force of the European Renal Best Practice board summarizes current knowledge on the role of MRAs in the treatment of CKD in T2D aiming to support clinicians in decision-making and everyday management of patients with this condition. [ABSTRACT FROM AUTHOR]

Background and Aims To investigate the cardiovascular effects of sodium–glucose co-transporter-2 inhibitors (SGLT2i) with concomitant mineralocorticoid receptor antagonist (MRA) use in heart failure (HF) regardless of ejection fraction (EF) and explore the risk of MRA-associated adverse events in individuals randomized to SGLT2i vs. placebo. Methods PubMed/MEDLINE, Web of Science, Embase, and clinical trial registries were searched for randomized controlled trials/ post-hoc analyses evaluating SGLT2i in HF with or without MRA use (PROSPERO: CRD42023397129). The main outcomes were composite of first hospitalization or urgent visit for HF/cardiovascular death (HHF/CVD), HHF, and CVD. Others were all-cause mortality, composite renal and safety outcomes. Hazard ratios (HR)/risk ratios were extracted. Fixed-effects meta-analyses and subgroup analyses were performed. Results Five eligible studies were included, pooling data from 21 947 people with HF (type 2 diabetes mellitus, n = 10 805). Compared to placebo, randomization to SGLT2i showed a similar reduction in HHF/CVD and HHF in people who were or were not using MRAs [HHF/CVD: hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.68–0.81 vs. HR 0.79; 95% CI 0.72–0.86; P -interaction =.43; HHF: HR 0.74; 95% CI 0.67–0.83 vs. HR 0.71; 95% CI 0.63–0.80; P -interaction =.53], with a suggestion of greater relative reduction in CVD in chronic HF people randomized to SGLT2i and using MRAs irrespective of EF (HR 0.81; 95% CI 0.72–0.91 vs. HR 0.98; 95% CI 0.86–1.13; P -interaction =.034). SGLT2i reduced all-cause mortality (P -interaction =.27) and adverse renal endpoints regardless of MRA use (P -interaction =.73) despite a higher risk of volume depletion with concomitant MRAs (P -interaction =.082). SGLT2i attenuated the risk of mild hyperkalaemia (P -interaction <.001) and severe hyperkalaemia (P -interaction =.051) associated with MRA use. Conclusions MRAs did not influence SGLT2i effects on the composite of HHF/CVD, HHF or all-cause mortality; however, findings hinted at a more pronounced relative reduction in CVD in chronic HF patients regardless of EF who were randomized to SGLT2i and receiving an MRA compared to those randomized to SGLT2i and not receiving MRAs. SGLT2i attenuated the risk of MRA-associated treatment-emergent hyperkalaemia. These findings warrant further validation in well-designed randomized controlled trials. [ABSTRACT FROM AUTHOR]

Context: Although adding spironolactone to renin-angiotensin system blockers reduces albuminuria in adults with chronic kidney disease and type 2 diabetes, it increases the risk of hyperkalemia. Objective: To assess whether a lower dose of spironolactone (12.5 mg/d) reduces the risk of hyperkalemia while maintaining its effect on reducing albuminemia. Design: Multicenter, open-label, randomized controlled trial. Setting: This study was conducted from July 2016 to November 2020 in ambulatory care at 3 diabetes medical institutions in Japan. Patients: We enrolled 130 Japanese adults with type 2 diabetes and albuminuria (≥30 mg/gCre), estimated glomerular filtration rate ≥30 mL/min/1.73 m², and serum potassium level <5.0 mEq/L. Interventions: The participants were randomly assigned to the spironolactone-administered and control groups. Main outcome measures: Changes in urine albumin-to-creatinine ratio (UACR) from baseline over the 24-week interventional period. Results: The spironolactone group showed a significant reduction in UACR from baseline (mean decrease, 103.47 ± 340.80 mg/gCre) compared with the control group, which showed an increased UACR (mean increase, 63.93 ± 310.14 mg/gCre; P = .0007, Wilcoxon rank-sum test and t test). Although the spironolactone group had a statistically significant increase in serum potassium levels, none of the participants had a potassium level ≥5.5 mEq/L at 24 weeks. Further, participants with a higher initial serum potassium level tended to have a smaller increase (estimate, -0.37, analysis of covariance). Conclusions: Low-dose spironolactone administration reduced albuminuria without causing hyperkalemia. Spironolactone administration, the oldest known and most cost-effective mineralocorticoid receptor antagonist, at lower doses should be reconsidered. [ABSTRACT FROM AUTHOR]

Dear Editor, Female-pattern hair loss (FPHL) is the most common form of alopecia affecting women. Over one-third of patients were on a concomitant medication that could cause hyperkalaemia, and patients carried an average of 3.4 comorbidities that could increase the risk of hyperkalaemia (Table 1). Nine patients (10.3%) developed hyperkalaemia, with six patients having initial serum potassium values <= 5.3 mEq L SP -1 sp (range 5.0-5.3 mEq L SP -1 sp ). [Extracted from the article]

Background Mineralocorticoid receptor antagonists (MRAs) reduce systolic blood pressure (SBP) and increase serum potassium concentration ([K+]). This indirect comparison investigated any differences in SBP-lowering and hyperkalemia risk between finerenone, a nonsteroidal MRA, and the steroidal MRA spironolactone ± a potassium binder. Methods In FIDELITY (a pooled analysis of FIDELIO-DKD and FIGARO-DKD), a subgroup of patients with treatment-resistant hypertension (TRH) and chronic kidney disease meeting eligibility criteria of the AMBER trial were identified (FIDELITY-TRH). The main outcomes were mean change in SBP, incidence of serum [K+] ≥5.5 mmol/L and hyperkalemia-associated treatment discontinuation. Results at ∼17 weeks were compared with 12 weeks from AMBER. Results In 624 FIDELITY-TRH patients and 295 AMBER patients, the least squares mean change in SBP (mmHg) from baseline was −7.1 for finerenone and −1.3 for placebo {between-group difference −5.74 [95% confidence interval (CI) −7.99 to −3.49], P  < .0001} versus −11.7 for spironolactone + patiromer and −10.8 for spironolactone + placebo [between-group difference −1.0 (95% CI −4.4–2.4), P  = .58]. The incidence of serum [K+] ≥5.5 mmol/L was 12% for finerenone and 3% for placebo versus 35% with spironolactone + patiromer and 64% with spironolactone + placebo. Treatment discontinuation due to hyperkalemia was 0.3% for finerenone and 0% for placebo versus 7% for spironolactone + patiromer and 23% for spironolactone + placebo. Conclusions In patients with TRH and chronic kidney disease compared with spironolactone with or without patiromer, finerenone was associated with a lower SBP reduction and lower risk of hyperkalemia and treatment discontinuation. Trial Registration: AMBER (NCT03071263), FIDELIO-DKD (NCT02540993), FIGARO-DKD (NCT02545049) [ABSTRACT FROM AUTHOR]

Context Current Endocrine Society guidelines recommend that transgender women taking spironolactone have their potassium levels checked every 3 months for the first year after initiating therapy and annually thereafter to monitor for hyperkalemia. Objective The goal of this study was to assess the need for such frequent potassium monitoring and to investigate whether age plays a role in potassium abnormalities in transgender, gender diverse, and nonbinary (TGDNB) individuals taking spironolactone. Methods Using EPIC-Clarity, a retrospective study of healthy, adult individuals with gender-identity disorder listed in their problem list and taking spironolactone was performed. We analyzed the incidence of hyperkalemia in this population. Data from June 2006 through November 2021 were obtained. Exclusion criteria included hypertension, renal failure, diabetes mellitus, heart failure, and medications that affect the renin–angiotensin–aldosterone system. Results 318 healthy TGDNB individuals met our inclusion criteria. We identified 8/318 (2.5%) individuals with hyperkalemia on spironolactone. There was a significant difference in incidence of hyperkalemia events in those >45 years old and those ≤45 years old (8.9% vs 1.5%, P =.016). Conclusion Our data suggest the incidence of hyperkalemia in our TGDNB population is low, particularly in those ≤45 years old; however, this risk increases with age. These findings suggest practice guidelines may need to be adjusted to minimize unnecessary testing in the population ≤45 years old who are not plagued by comorbidities that affect potassium handling. [ABSTRACT FROM AUTHOR]

Objectives: Potential interactions between feminizing hormone therapy (FHT) and pre-exposure prophylaxis (PrEP) may be a barrier to PrEP use among transgender women (TGW). We aimed to assess the impact of FHT on PrEP plasma pharmacokinetics (PK) among TGW.Methods: This was a PK substudy of the effects of FHT on tenofovir disoproxil fumarate/emtricitabine nested to a trans-specific PrEP demonstration study (NCT03220152). Participants were assigned to receive PrEP only (noFHT) or standardized FHT (sFHT; oestradiol valerate 2-6 mg plus spironolactone 100-300 mg) plus PrEP for 12 weeks, after which they could start any FHT (aFHT). Short- and long-term PK assessment occurred at Weeks 12 and 30-48, respectively (plasma samples prior and 0.5, 1, 2, 4, 6, 8 and 24 h after dose). Non-compartmental PK parameters of tenofovir and emtricitabine were compared as geometric mean ratios (GMRs) between noFHT and PrEP and FHT (sFHT at short-term PK; aFHT at long-term PK) participants.Results: No differences in tenofovir and emtricitabine plasma PK parameters were observed between the short-term PK of noFHT (n = 12) and sFHT participants (n = 18), except for emtricitabine Cmax [GMR: 1.15 (95% CI: 1.01-1.32)], or between noFHT short-term PK and aFHT long-term PK (n = 13). Most participants were on oestradiol valerate 2 mg at the short-term PK (56%) and 4 mg at the long-term PK (54%). Median (IQR) oestradiol levels were 56.8 (43.2-65.4) pg/mL at short-term PK (sFHT) and 44.8 (24.70-57.30) pg/mL at long-term PK (aFHT). No participants in this analysis seroconverted during the study.Conclusions: Our results indicate no interaction of FHT on tenofovir levels, further supporting PrEP use among TGW using FHT. [ABSTRACT FROM AUTHOR]

Context COVID-19 may cause respiratory distress syndrome and death. Treatment of COVID-19 to prevent complications remains a priority. Objective Our investigation sought to determine whether combination of spironolactone and sitagliptin could reduce mortality for inpatients with SARS-CoV-2 infection. Methods This single-blind, 4-arm, prospective randomized clinical trial was conducted at Shiraz and Bushehr University of Medical Sciences hospitals between December 2020 and April 2021. We randomized hospitalized adult patients with COVID-19 pneumonia into 4 groups: control, combination therapy, sitagliptin add-on, or spironolactone add-on. The primary outcome was the clinical improvement of the patients in the hospital as measured on an 8-point numerical scale. The secondary outcomes included intubation, ICU admission, end organ damages, CT findings, and paraclinical information. Results A total of 263 admitted patients were randomly assigned to control group (87 patients), combination group (60 patients), sitagliptin group (66 patients), and spironolactone group (50 patients). There were no significant differences in baseline characteristics, except for higher age in control group. The intervention groups, especially combination therapy, had better clinical outcomes (clinical score on fifth day of admission: 3.11 ± 2.45 for controls, 1.33 ± 0.50 for combination, 1.68 ± 1.02 for sitagliptin, and 1.64 ± 0.81 for spironolactone; P = 0.004). However, the mortality rate was lower in patients who received spironolactone (21.84% control, 13.33% combination, 13.64% sitagliptin, 10.00% spironolactone; P = 0.275). Our intervention reduced lung infiltration but not the area of involvement in lungs. Conclusion Sitagliptin and spironolactone can potentially improve clinical outcomes of hospitalized COVID-19 patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Given its widely accepted efficacy, androgen blockade therapy for hidradenitis suppurativa (HS) has become a standard of care. Although much less frequently used than spironolactone, a small number of HS studies have reported finasteride as an alternative treatment for women. In this study, we describe the response to and perception of finasteride therapy in a diverse cohort of women with HS. Aim: To describe finasteride therapy in a diverse cohort of female patients with HS. Methods: We conducted an institutional review board‐approved retrospective chart review and telephone survey of 20 female patients aged ≥ 18 years with a diagnosis of HS. Finasteride was prescribed by a single provider at a specialized HS centre. Results: The mean age of the patients was 34.3 ± 13.5 years. Finasteride was initiated predominantly because of one or more contraindications or poor responsiveness to spironolactone. Most patients interviewed (90%; n = 18) were willing to take finasteride again or continue with therapy if indicated. Of the 20 patients, 10 (50%) reported overall satisfaction with finasteride, while 7 (35%) were neutral and 3 (15%) were dissatisfied. No patient reported worsening disease activity while on finasteride and only one (5%) reported decreased quality of life. When asked about adverse effects of finasteride, 80% (n = 16) reported none, while 20% (n = 4) experienced ≥ 1 of the following: headache, nausea, menstrual irregularities, breast tenderness or reduced libido/sexual function. Conclusions: Our study suggests that androgen blockade therapy with finasteride is a safe and effective alternative for female patients with HS who have contraindication(s) or intolerance to spironolactone. [ABSTRACT FROM AUTHOR]

Purpose To provide evidence of serum potassium changes in individuals taking angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) concomitantly with spironolactone compared to ACEI/ARB therapy alone. Methods PubMed, Embase, Scopus, and Web of Science were searched for studies including exposure to both spironolactone and ACEI/ARB therapy compared to ACEI/ARB therapy alone. The primary outcome was serum potassium change over time. Main effects were calculated to estimate average treatment effect using random effects models. Heterogeneity was assessed using Cochran's Q and I 2. Risk of bias was assessed using the revised Cochrane risk of bias tool. Results From the total of 1,225 articles identified, 20 randomized controlled studies were included in the meta-analysis. The spironolactone plus ACEI/ARB group included 570 patients, while the ACEI/ARB group included 547 patients. Treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L), with intermediate heterogeneity across studies (Q statistic = 46.5, P = 0.004; I 2 = 59). Sensitivity analyses showed that the direction and magnitude of this outcome did not change with the exclusion of individual studies, indicating a high level of reliability. Reporting risk of bias was low for 16 studies (80%), unclear for 3 studies (15%) and high for 1 study (5%). Conclusion Treatment with spironolactone in combination with ACEI/ARB therapy increases the mean serum potassium concentration by less than 0.20 mEq/L compared to ACEI/ARB therapy alone. However, serum potassium and renal function must be monitored in patients starting combination therapy to avoid changes in serum potassium that could lead to hyperkalemia. [ABSTRACT FROM AUTHOR]

Mineralocorticoid receptor (MR) antagonists (MRA), also referred to as aldosterone blockers , are now well-recognized for their clinical benefit in patients who have heart failure (HF) with reduced ejection fraction (HFrEF). Recent studies have also shown MRA can improve outcomes in patients with HFpEF , where the ejection fraction is preserved but left ventricular filling is reduced. While the MR is a steroid hormone receptor best known for antinatriuretic actions on electrolyte homeostasis in the distal nephron, it is now established that the MR has many physiological and pathophysiological roles in the heart, vasculature, and other nonepithelial tissue types. It is the impact of MR activation on these tissues that underpins the use of MRA in cardiovascular disease, in particular HF. This mini-review will discuss the origins and the development of MRA and highlight how their use has evolved from the "potassium-sparing diuretics" spironolactone and canrenone over 60 years ago, to the more receptor-selective eplerenone and most recently the emergence of new nonsteroidal receptor antagonists esaxerenone and finerenone. [ABSTRACT FROM AUTHOR]

Purpose The case of a transgender female who developed gallstone pancreatitis in the context of estrogen use for gender-affirming hormone therapy is reported. Summary A 24-year-old Caucasian transgender female presented to the emergency department for abdominal pain and vomiting after referral from urgent care for suspected pancreatitis. Her home medications included estradiol, medroxyprogesterone, and spironolactone for gender-affirming hormone therapy and omeprazole for reflux. The patient reported minimal alcohol intake, presented with mildly elevated triglyceride levels, and did not have a family history of pancreatitis or gallstone disease. She underwent a laparoscopic cholecystectomy on hospital day 4 and was given a postoperative diagnosis of chronic cholecystitis, cholelithiasis, and pancreatitis. Given her history and the present illness, the use of estrogen therapy is a likely risk factor for the development of gallstone pancreatitis. Conclusion Estrogen is a cornerstone of gender-affirming hormone therapy used by transgender women; however, in addition to its role in gender identity confirmation, estrogen can result in drug-induced pancreatitis. [ABSTRACT FROM AUTHOR]

Spironolactone and cyproterone acetate are commonly used in feminizing hormone therapy to achieve the goal of female range testosterone level; however, the data on the efficacy comparing between these two anti-androgens are scarce. To compare the anti-androgenic effects between spironolactone and cyproterone acetate as the component of feminizing hormone therapy among transgender women population. The study was single-blinded randomized controlled trial involved 52 transgender women from two transgender health clinics. Each participant received oral estradiol valerate 4 mg/day combined with anti-androgen, spironolactone 100 mg/day or cyproterone acetate 25 mg/day, depending on which group they were randomized to. Clinical and biochemical variables were obtained at baseline and at 12 weeks of feminizing hormone therapy. The change of testosterone level from baseline. Other changes including free testosterone, estradiol, prolactin and lipid profile after the therapy. After a 12 weeks of feminizing hormone therapy, the change of testosterone level in the cyproterone acetate group [558.0 ng/dL (IQR 352.0 to 783.3)] was significantly higher than the spironolactone group [226.2 ng/dL (IQR,-4.3 to 480.1)](p value <0.001). Testosterone and calculated free testosterone in the cyproterone acetate group were significantly lower than the spironolactone group. Consequently, a proportion of the participants who achieved the female range testosterone (<50 ng/dL) was significantly higher in cyproterone acetate group (90%) compared to the spironolactone group (19%). Serious adverse effects observed in cyproterone acetate users were drug-induced liver injury and asymptomatic hyperprolactinemia. The data on the differences between the two anti-androgen could be benefit for the transgender health-care providers in medication selection and adverse-effects counseling. The study design was randomized controlled trial and controlled the estrogen component by prescribed the same type and dose for each participant. However, the study was suffered from the confound feminizing effects from previous hormone therapy and the high drop-out rate. For feminizing hormone therapy, cyproterone acetate had a higher testosterone suppression efficacy than spironolactone. Burinkul S, Panyakhamlerd K, Suwan A, et al. Anti-Andorgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial. J Sex Med 2021;18:1299–1307. [ABSTRACT FROM AUTHOR]

In a recent paper, Subramanian and collaborators reported a 52% increased risk of COVID-19 infection in women with polycystic ovary syndrome (PCOS) and an incidence nearly twice that of women without PCOS. The authors focused, as important factors of the increased prevalence of infection, both the inflammatory characteristic of PCOS and the increase in androgens that facilitate the entry of the virus into the cells of the target organs. We asked 200 consecutive, unvaccinated women with PCOS who had been followed with spirono lactone for more than 4 months, about COVID-19 infection and found only four patients who were infected. No ne of the infected patients were hospitalized and only one had fever and other manifestations of the syndrome, but the se symptoms resolved in a few days. The other three reported only mild or minimal symptoms. This observation needs confirmation with specific studies, considering the possibility that many other patients may have been infected by being asymptomatic and not swabbing for COVID-19. Spironolactone can increase the circulating angiotensin-converting enzyme 2 and antagonize the androgen receptor, preventing activation of transmembrane protease serine 2 in cel ls of the respiratory tract and other tissues. Drug also has potent anti-inflammatory and antithrombotic actions by antag onizing the mineralocorticoid receptor in target tissues and inflammatory cells. From Subramanian's study and rep orted observations, a proper evaluation of the use of spironolactone in COVID-19 in both PCOS and the general popu lation is urged. [ABSTRACT FROM AUTHOR]

Aims  To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure. Methods and results  Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): −0.15; 95% confidence interval (CI) −0.44 to 0.15 μg/L; P  = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: −8.1; 95% CI −11.9 to −4.3 μg/L; P  < 0.0001) and PICP/CITP ratio (mdiff: −2.9; 95% CI −4.3 to −1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: −10; 95% CI −13 to −7 mmHg; P  < 0.0001), left atrial volume (mdiff: −1; 95% CI −2 to 0 mL/m2; P  = 0.010), and NT-proBNP (mdiff: −57; 95% CI −81 to −33 ng/L; P  < 0.0001) were reduced in those assigned spironolactone. Conclusions  Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first mineralocorticoid to trials of nonsteroidal MRAs. The MR is a nuclear receptor expressed in many tissues/cell types including the kidney, heart, immune cells, and fibroblasts. The MR directly affects target gene expression—primarily fluid, electrolyte and haemodynamic homeostasis, and also, but less appreciated, tissue remodelling. Pathophysiological overactivation of the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the mechanisms of action of nonsteroidal MRAs and how they differ from steroidal MRAs. Nonsteroidal MRAs have demonstrated important differences in their distribution, binding mode to the MR and subsequent gene expression. For example, the novel nonsteroidal MRA finerenone has a balanced distribution between the heart and kidney compared with spironolactone, which is preferentially concentrated in the kidneys. Compared with eplerenone, equinatriuretic doses of finerenone show more potent anti-inflammatory and anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs appear to demonstrate a better benefit–risk ratio than steroidal MRAs, where risk is measured as the propensity for hyperkalaemia. Among patients with Type 2 diabetes, several Phase II studies of finerenone show promising results, supporting benefits on the heart and kidneys. Furthermore, finerenone significantly reduced the combined primary endpoint (chronic kidney disease progression, kidney failure, or kidney death) vs. placebo when added to the standard of care in a large Phase III trial. [ABSTRACT FROM AUTHOR]

Limited evidence on treatment options for polycystic ovarian syndrome (PCOS) has led to considerable variation in health care practices. We aimed to compare the effects of metformin and/or oral contraceptive pills (OCP) in combination with pioglitazone, spironolactone, flutamide, and lifestyle interventions among adolescents aged 11 to 19 years with PCOS. Literature searches were performed in Medline, Embase, and the Cochrane Central Register of Controlled Trials from database inception through December 2018, with no language restriction. Two reviewers screened titles and abstracts, assessed full text eligibility, and extracted information from eligible trials. Evidence was synthesized through network meta-analyses (NMA) using a Bayesian random-effects approach. We identified 37 randomized controlled trials, in which 2400 patients were randomized. NMA showed no statistically important difference among all interventions to improve menstrual regulation or body mass index. Moderate-quality evidence showed hirsutism scores were reduced by multiple interventions that included single and combination medications namely; lifestyle intervention, metformin, OCP, spironolactone, pioglitazone, metformin-OCP, metformin-spironolactone, and metformin-flutamide against placebo. Moderate-quality evidence showed OCP results in more dysglycemia compared to metformin (odds ratio, 2.98; 95% credible interval, 1.02-8.96), no intervention resulted in dysglycemia reduction. In conclusion, metformin and OCP as monotherapy or in combination with other interventions compared with placebo can reduce hirsutism scores, but none of these medications lead to effective menstrual cycle regulation or weight reduction. However, the use of OCP leads to worse cardiometabolic risk factors. Further research into new treatment options is urgently needed. PROSPERO registration number CRD42015016148. [ABSTRACT FROM AUTHOR]

Background: Transgender women and nonbinary people seeking feminizing therapy are often prescribed estrogen as a gender-affirming hormone, which will alter their reproductive hormone axis. Testosterone, estradiol, and other reproductive hormones are commonly evaluated to assess therapy, but reference intervals specific to transgender women have not been established. The objective of this study was to derive reference intervals for commonly measured analytes related to reproductive endocrinology in a cohort of healthy gender nonconforming individuals on stable feminizing hormone therapy. Methods: Healthy transgender individuals who had been prescribed estrogen (n = 93) for at least a year were recruited from internal medicine and primary care clinics that specialize in transgender medical care. Total testosterone and estradiol were measured using immunoassay and mass spectrometry; LH, FSH, sex hormone binding globulin, prolactin, progesterone, anti-mullerian hormone (AMH), and dehydroepiandrosterone sulfate (DHEAS) were measured using immunoassay; free testosterone was calculated. Reference intervals (central 95%) were calculated according to Clinical Laboratory Standards Institute guidelines. Results: The distribution of results for transgender women was different than what would be expected from cisgender men or women across all measurements. Use of spironolactone was associated with changes in the result distribution of AMH, FSH, LH, and progesterone. Compared to liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS), immunoassay was sufficient for the majority of estradiol and total testosterone measurements; free testosterone added little clinical value beyond total testosterone. Conclusion: Reference intervals specific to transgender women should be applied when evaluating reproductive endocrine analytes. Spironolactone is a significant variable for result interpretation of some tests. [ABSTRACT FROM AUTHOR]

Summary: Spironolactone is a synthetic aldosterone receptor antagonist, with a role off‐label in various dermatological conditions. Its antiandrogenic properties make it suitable for diseases in which excess androgen production results in unwanted and psychologically distressing manifestations in susceptible females. Treatment with spironolactone aims to attenuate androgen‐mediated conditions including acne, hidradenitis suppurativa, female pattern hair loss and hirsutism. We discuss the emerging utility of spironolactone in dermatology, its potential adverse effects and considerations for monitoring. Click here for the corresponding questions to this CME article. [ABSTRACT FROM AUTHOR]

The article presents case studies about female hyperandrogenism. Topics discussed include the symptoms presented by the first patient such as increased libido, facial hair growth, and acne, the cortisol, testosterone, and androstenedione levels recorded from the laboratory tests performed on the second patient, and the improvement in the mood lability of the third patient following spironolactone therapy.

Aims Improvement in left ventricular (LV) systolic reserve, including exertional increase in global longitudinal strain (GLS), may contribute to the clinical benefit from therapeutic interventions in heart failure with preserved ejection fraction (HFpEF). However, GLS is an afterload-dependent parameter, and its measurements may not adequately reflect myocardial contractility recruitment with exercise. The estimation of myocardial work (MW) allows correction of GLS for changing afterload. We sought to investigate the associations of GLS and MW parameters with the response of exercise capacity to spironolactone in HFpEF. Methods and results We analysed 114 patients (67 ± 8 years) participating in the STRUCTURE study (57 randomized to spironolactone and 57 to placebo). Resting and immediately post-exercise echocardiograms were performed at baseline and at 6-month follow-up. The following indices of MW were assessed: global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency. The amelioration of exercise intolerance at follow-up in the spironolactone group was accompanied by a significant improvement in exertional increase in GCW (P  = 0.002) but not in GLS and other MW parameters. Increase in exercise capacity at 6 months was independently correlated with change in exertional increase in GCW from baseline to follow-up (β = 0.24; P  = 0.009) but not with GLS (P  = 0.14); however, no significant interaction with the use of spironolactone on peak VO2 was found (P  = 0.97). Conclusion GCW as a measure of LV contractile response to exertion is a better determinant of exercise capacity in HFpEF than GLS. Improvement in functional capacity during follow-up is associated with improvement in exertional increment of GCW. [ABSTRACT FROM AUTHOR]

Context Current guidelines recommend close monitoring of electrolytes in transgender patients using spironolactone given the risk of hyperkalemia from mineralocorticoid antagonism. In patients taking spironolactone for other conditions, the rate of hyperkalemia is low, and the utility of frequent monitoring has been questioned. Objective We hypothesized that the rate of hyperkalemia in gender-diverse adolescents taking spironolactone is low and, when present, clinically insignificant. Design and Outcomes A retrospective chart review of adolescents seen in a specialty gender clinic at a tertiary care pediatric hospital over 10 years identified patients prescribed spironolactone for gender transition. Study outcomes were the incidence of hyperkalemia, defined as serum potassium concentration >5.0 mmol/L, and the relationship between potassium levels and spironolactone dose and duration. Results Records were reviewed for 85 subjects with a mean ± SD age of 16.6 ± 1.7 years. There were a total of 269 potassium measurements (80 prior to spironolactone initiation and 189 during spironolactone treatment). Six potassium measurements in five subjects were >5.0 mmol/L, indicating a rate of hyperkalemia of 2.2%. None of the subjects had symptoms of hyperkalemia, and all elevated measurements were normal when repeated. Only one subject discontinued spironolactone after an elevated potassium measurement. There was no relationship between hyperkalemia and spironolactone dose. Potassium measurements decreased with increasing treatment duration. Conclusions Hyperkalemia in patients taking spironolactone for gender transition is rare and when present is transient and asymptomatic. In the absence of other medical comorbidities, routine electrolyte monitoring in this population may be unnecessary. [ABSTRACT FROM AUTHOR]

An editorial is presented on the effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure. Topics include effect of spironolactone on blocking the effects of aldosterone on the renal absorption of sodium and excretion of potassium; and echocardiographic strain rate imaging and cardiac magnetic resonance imaging (MRI) measurement of urinary or serum renin/aldosterone alone.

Background Data on the true burden of hyperkalemia (HK) in patients with chronic kidney disease (CKD) in a real-world setting are scarce. Methods The incidence rate of HK [first blood test with an elevated blood potassium level level >5.0 mmol/L] in primary or hospital care was assessed in a population-based cohort of all newly diagnosed CKD patients [second estimated glomerular filtration rate (eGFR) measurement <60 mL/min/1.73 m2 or hospital diagnosis] in northern Denmark. Risk factors and clinical outcomes were compared for CKD patients with HK and matched CKD patients without HK. Results Of 157 766 patients with CKD, 28% experienced HK, for an overall HK incidence rate of 70/1000 person-years. Among patients with Stage 3A, 3B, 4 or 5 CKD, 9, 18, 31 and 42%, respectively, experienced HK within the first year. Important HK risk factors included diabetes {prevalence ratio [PR] 1.74 [95% confidence interval (CI) 1.69–1.79]}, heart failure [PR 2.31 (95% CI 2.23–2.40)] and use of angiotensin-converting enzyme inhibitors [PR 1.45 (95% CI 1.42–1.48)], potassium supplements [PR 1.59 (95% CI 1.55–1.62)] or spironolactone [PR 2.53 (95% CI 2.44–2.63)]. In CKD patients who developed HK, 34% had any acute hospitalization 6 months before the HK event, increasing to 57% 6 months after HK [before–after risk ratio 1.72 (95% CI 1.69–1.74)]. The 6-month mortality following HK was 26%, versus 6% in matched non-HK patients. Compared with non-HK patients, 6-month hazard ratios for any acute hospitalization in HK patients were 2.11-fold higher, including hazard ratios of 2.07 for cardiac diagnoses, 2.29 for ventricular arrhythmias, 3.26 for cardiac arrest, 4.77 for intensive care and 4.85 for death. Conclusions More than one in four CKD patients develops HK. Patients with severe CKD, diabetes, heart failure or use of spironolactone are at high risk. HK is associated with severe clinical outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recent evidence suggests that the mineralocorticoid receptor antagonist spironolactone should be the preferred fourth-line antihypertensive treatment in resistant hypertension (RHTN). Whether spironolactone improves blood pressure (BP) control in heart failure with preserved ejection fraction (HFpEF) and RHTN is unknown. METHODS: We identified patients with RHTN, defined as baseline systolic blood pressure (SBP) between 140 and 160 mm Hg on 3 or more medications, in the Americas cohort of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial, in which patients with HFpEF were randomized to spironolactone vs. placebo. We evaluated the effects of spironolactone vs. placebo on BP reduction in this group and related this to the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure. RESULTS: We identified 403 participants in the Americas with RHTN. Compared to people without RHTN, those with RHTN were more frequently women, non-White, diabetics, with a higher left ventricular ejection fraction and body mass index, and a lower hemoglobin concentration. In the RHTN group, spironolactone resulted in a decrease of SBP: -6.1 (-8.9, -3.3); P < 0.001 and diastolic BP: -2.9 (-4.6, -1.2); P = 0.001 mm Hg during the first 8 months. BP became controlled after 4 weeks in 63% of patients receiving spironolactone vs. 46% receiving placebo (P = 0.003), with similar responses at 8 weeks, 4 and 8 months. Patients with RHTN derived similar overall benefit from spironolactone on the primary outcomes as those without. CONCLUSIONS: In HFpEF patients with RHTN, spironolactone lowered BP substantially and was associated with similar benefit as those without RHTN. [ABSTRACT FROM AUTHOR]

Background. The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in patients with diabetes. Prior studies have shown large between-patient variability in albuminuria treatment response. We previously developed and validated a urinary proteomic classifier that predicts onset and progression of chronic kidney disease. Here, we tested whether the proteomic classifier based on 273 urinary peptides (CKD273) predicts albuminuria response to spironolactone treatment. Methods. We performed a post hoc analysis in a double-blind randomized clinical trial with allocation to either spironolactone 12.5-50mg/day (n = 57) or placebo (n = 54) for 16 weeks. Patients were diagnosed with type 2 diabetes and resistant hypertension. Treatment was an adjunct to renin-angiotensin system inhibition. Primary endpoint was the percentage change in urine albumin to creatinine ratio (UACR). Capillary electrophoresis mass spectrometry was used to quantify urinary peptides at baseline. The previously validated combination of 273 known urinary peptides was used as proteomic classifier. Results. Spironolactone reduced UACR relative to placebo by 50%, although with a large between-patient variability in UACR response (5th to 95th percentile, 7 to 312%). An interaction was detected between CKD273 and treatment assignment (β = -1.09, P = 0.026). Higher values of CKD273 at baseline were associated with a larger reduction in UACR in the spironolactone group (β = -0.70, P = 0.049), but not in the placebo group (β = 0.39, P = 0.25). Stratified in tertiles of baseline CKD273, reduction in UACR was greater in the highest tertile, 63% (95% confidence interval: 35-79%), as compared with the two other tertiles combined, 16% (-17 to 40%) (P = 0.011). Conclusions. A urinary proteomics classifier can be used to identify individuals with type 2 diabetes who are more likely to show an albuminuria-lowering response to spironolactone treatment. These results suggest that urinary proteomics may be a valuable tool to tailor therapy, but confirmation in a larger clinical trial is required. [ABSTRACT FROM AUTHOR]

Aims Spironolactone (SPL) improves endothelial dysfunction and survival in heart failure. Immune modulation, including poorly understood mineralocorticoid receptor (MR)-independent effects of SPL might contribute to these benefits and possibly be useful in other inflammatory cardiovascular diseases such as pulmonary arterial hypertension. Methods and results Using human embryonic kidney cells (HEK 293) expressing specific nuclear receptors, SPL suppressed NF-jB and AP-1 reporter activity independent of MR and other recognized nuclear receptor partners. NF-κB and AP-1 DNA binding were not affected by SPL and protein synthesis blockade did not interfere with SPL-induced suppression of inflammatory signalling. In contrast, proteasome blockade to inhibit degradation of xeroderma pigmentosum group B complementing protein (XPB), a subunit of the general transcription factor TFIIH, or XPB overexpression both prevented SPL-mediated suppression of inflammation. Similar to HEK 293 cells, a proteasome inhibitor blocked XPB loss and SPL suppression of AP-1 induced target genes in human pulmonary artery endothelial cells (PAECs). Unlike SPL, eplerenone (EPL) did not cause XPB degradation and failed to similarly suppress inflammatory signalling. SPL combined with siRNA XPB knockdown further reduced XPB protein levels and had the greatest effect on PAEC inflammatory gene transcription. Using chromatin-immunoprecipitation, PAEC target gene susceptibility to SPL was associated with low basal RNA polymerase II (RNAPII) occupancy and TNFa-induced RNAPII and XPB recruitment. XP patient-derived fibroblasts carrying an N-terminal but not C-terminal XPB mutations were insensitive to both SPL-mediated XPB degradation and TNFα-induced target gene suppression. Importantly, SPL treatment decreased whole lung XPB protein levels in a monocrotaline rat model of pulmonary hypertension and reduced inflammatory markers in an observational cohort of PAH patients. Conclusion SPL has important anti-inflammatory effects independent of aldosterone and MR, not shared with EPL. Druginduced, proteasome-dependent XPB degradation may be a useful therapeutic approach in cardiovascular diseases driven by inflammation. [ABSTRACT FROM AUTHOR]

Objective Uncontrolled rapid release of drugs can reduce their therapeutic efficacy and cause undesirable toxicity; however, controlled release from reservoir materials helps overcome this issue. The aims of this study were to determine the release profiles of ketoprofen and spironolactone from a pH-responsive self-assembling DPA- MPC- DPA triblock copolymer gel and elucidate underlying physiochemical properties. Methods Drug release profiles from DPA50- MPC250- DPA50 gel ( pH 7.5), over 32 h (37 °C), were determined using UV-Vis spectroscopy. Nanoparticle size was measured by dynamic light scattering ( DLS) and critical micelle concentration ( CMC) by pyrene fluorescence. Polymer gel viscosity was examined via rheology, nanoparticle morphology investigated using scanning transmission electron microscopy ( STEM) and the gel matrix observed using cryo-scanning electron microscopy (Cryo- SEM). Key Findings DPA50- MPC250- DPA50 copolymer (15% w/v) formed a free-standing gel ( pH 7.5) that controlled drug release relative to free drugs. The copolymer possessed a low CMC, nanoparticle size increased with copolymer concentration, and DLS data were consistent with STEM. The gel displayed thermostable viscosity at physiological temperatures, and the gel matrix was a nanostructured aggregation of smaller nanoparticles. Conclusions The DPA50- MPC250- DPA50 copolymer gel could be used as a drug delivery system to provide the controlled drug release of ketoprofen and spironolactone. [ABSTRACT FROM AUTHOR]

Objectives The study evaluated the quality of compounded sachets and hard gelatine capsules and their feasibility in paediatric drug administration. Methods Commercial tablets were compounded to sachets and capsules in hospital environment, and the uniformity of content and simulated drug dose were determined. Key findings Compounded formulations were successfully obtained for a range of drug substances; dipyridamole, spironolactone, warfarin and sotalol formulations were within acceptable limits for uniformity of content, in most cases. However, some loss of drug was seen. The type and amount of excipients were found to affect uniformity of content; good conformity of capsules was obtained using lactose monohydrate as filler, whereas microcrystalline cellulose was a better choice in sachets. In capsules, content uniformity was obtained for a range of drug doses. If the drug is aimed to be administered through a nasogastric tube, solubility of the drug and excipients should be considered, as they were found to affect the simulated drug dose in administration. Conclusions Compounded sachets and capsules fulfilled the quality requirements in most cases. In compounding, the choice of excipients should be considered as they can affect conformity of the dosage form or its usability in practice. Quality assurance of compounded formulations should be taken into consideration in hospital pharmacies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Multiple studies indicate that primary aldosteronism (PA) is common in patients with resistant hypertension, with an estimated prevalence of approximately 20%. Additional studies suggest that beyond this 20% of patients with classical PA, there is a larger proportion of patients with lesser degrees of hyperaldosteronism which contributes even more broadly to antihypertensive treatment resistance. Given these observations, it is intuitive that use of aldosterone antagonists will provide antihypertensive benefit in patients with resistant hypertension and evidence of aldosterone excess. Intriguingly, however, are clinical findings demonstrating substantive benefit of aldosterone antagonists in patients with resistant hypertension, but without demonstrative evidence of hyperaldosteronism, that is, with seemingly normal or even low aldosterone levels. CONCLUSION: Spironolactone is clearly established as the most effective fourth agent for treatment of uncontrolled resistant hypertension. Emerging observations suggest a further role of spironolactone for counteracting the effects of diet high in sodium, particularly in obese, hypertensive patients. [ABSTRACT FROM AUTHOR]

The author discusses treatment of resistant hypertension (RHTN) using spironolactone and renal denervation (RDN) and the treatments impact on blood pressure. The author mentions a study of about 24 patients with RHTN who were treated through DENervation in HyperTension (DENERHTN) trial. Result shows the effectiveness of spironolactone compared with RDN.

BACKGROUND Sympathetic renal denervation (SRD) has been proposed as a therapeutic alternative for patients with resistant hypertension not controlled on pharmacological therapy. Two studies have suggested an effect of SRD in reducing short-term blood pressure variability (BPV). However, this has not been addressed in a randomized comparative trial. We aimed to compare the effects of spironolactone and SRD on circadian BP and BPV. METHODS This is a post-hoc analysis of a randomized trial in 24 true resistant hypertensive patients (15 men, 9 women; mean age 64 years) comparing 50 mg of spironolactone (n = 13) vs. SRD (n = 11) on 24-hour BP. We report here the comparative effects on daytime (8 am-10 pm) and nighttime (0 am-6 am) BP, night-to-day ratios and BP and heart rate variabilities (SD and coefficient of variation of 24-hour, day and night, as well as weighted SD and average real variability (ARV)). RESULTS Spironolactone was more effective than SRD in reducing daytime systolic (P = 0.006), daytime diastolic (P = 0.006), and nighttime systolic (P = 0.050) BP. No differences were observed in the night-to-day ratios. In contrast, SRD-reduced diastolic BPV (24 hours, daytime, nighttime, weighted, and ARV; all P < 0.05) with respect to spironolactone, without significant differences in systolic BPV. CONCLUSION Spironolactone is more effective than SRD in reducing ambulatory BP. However, BPV is significantly more reduced with SRD. This effect could be important in terms of potential prevention beyond BP reduction and deserves further investigation. [ABSTRACT FROM AUTHOR]

Although spironolactone is an effective treatment for androgen-mediated cutaneous disorders, the potential sexual side-effects are poorly documented in current literature. The purpose of this study was to provide clinical evidence that spironolactone may be a cause of hormonally associated vestibulodynia and female sexual arousal disorder. A database search of a vulvar disorders clinic revealed 7 cases in which spironolactone may have caused or contributed to dyspareunia and decreased arousal. In all cases, the patients stopped taking spironolactone and used a compounded estradiol 0.01%/testosterone 0.1% gel to the vestibule twice daily. 2 cases are discussed to further illustrate these previously unreported side effects. Improvement in sexual function was determined after treatment. Examination of women taking spironolactone who presented with the complaints of introital dyspareunia revealed vulvar vestibular atrophy and tenderness, especially at the glandular ostia. After stopping spironolactone and applying a topical estrogen/testosterone gel to the vestibule, all women had significant improvement in their vulvar atrophy, resolution of their dyspareunia, and improved sexual arousal. Use of spironolactone may be a cause of hormonally associated vestibulodynia and female sexual arousal disorder. The influence of spironolactone on vulvar health and sexual function is poorly documented in the medical literature. The strength of this paper is that it examines the potential deleterious side effects of this medication on female sexual function. However, the most significant limitation of this case series is that it was not a prospective, controlled study. Although treatment of androgen-mediated cutaneous disorders is warranted, medical providers should be aware of the potential sexual side effects of this anti-androgenic medication. Mitchell L, Govind V, Barela K, et al. Spironolactone May be a Cause of Hormonally Associated Vestibulodynia and Female Sexual Arousal Disorder. J Sex Med 2019;16:1481–1483. [ABSTRACT FROM AUTHOR]

An editorial is presented on the Emperor-Preserved trial at the 2021 European Society of Cardiology (ESC) Congress and its subsequent publication,1 the cardiology world. It expresses the view that spironolactone and sacubitril– valsartan reported modest non-significant effects on outcomes in patients with HFpEF. An overview of the dearth of awareness, difficulty in diagnosis, heterogeneity in patients, lack of specific treatment is presented.

Introduction Spironolactone and cyproterone acetate (CPA) are the two main antiandrogen medications used in feminizing hormone therapy in transgender women. Previous studies have suggested that these two agents might have opposite effects on high-density lipoprotein (HDL) level when used in this context, and limited data have suggested CPA increases prolactin more than spironolactone. Aim To compare the effects of spironolactone and CPA on HDL and prolactin serum concentrations in transgender women. Methods A retrospective chart review was conducted at three clinical sites in Toronto, Ontario, Canada. Patients were selected if they (i) identified as a transgender woman, (ii) had newly started spironolactone or CPA with estrogen or restarted spironolactone or CPA after a washout period of at least 6 months, and (iii) had not used other antiandrogens within the previous 6 months. Main Outcome Measures HDL and prolactin concentrations between the two treatment groups at baseline and at 12 months. Results Eighty-two patients were included in the spironolactone group and 31 patients were included in the CPA group. Baseline HDL and prolactin levels were not significantly different between the two groups. At 12 months, HDL increased by 0.10 mmol/L (SD = 0.24) in the spironolactone group but decreased by 0.07 mmol/L (SD = 0.21) in the CPA group ( P = .002). The difference remained significant after adjusting for baseline HDL, use of lipid-lowering drugs, and age. The change in prolactin was +3.10 μg/L (SD = 5.70) in the spironolactone group and +11.8 μg/L (SD = 8.63) in the CPA group ( P < 0.001). This difference also remained significant after adjusting for baseline prolactin level. Conclusion These data suggest that spironolactone use in transgender women increases HDL levels and that CPA has the opposite effect. CPA also is associated with a larger increase in prolactin. These factors should be considered when choosing between these two antiandrogen agents. [ABSTRACT FROM AUTHOR]

Although patients with heart failure and preserved ejection fraction (HF-PEF) represent nearly half of the population with chronic heart failure, few evidence-based medical therapies are available. The neutral overall results of the TOPCAT trial of spironolactone in HF-PEF leave clinicians who treat heart failure with an ongoing clinical dilemma. In this review, we outline an approach to the clinical management of the patient with HF-PEF synthesizing data from available clinical trials and expert consensus. [ABSTRACT FROM AUTHOR]

This review and update focuses on the clinical features of hydrochlorothiazide (HCTZ), the thiazide-like agents chlorthalidone (CTDN) and indapamide (INDAP), potassium-sparing ENaC inhibitors and aldosterone receptor antagonists, and loop diuretics. Diuretics are the second most commonly prescribed class of antihypertensive medication, and thiazide-related diuretics have increased at a rate greater than that of antihypertensive medications as a whole. The latest hypertension guidelines have underscored the importance of diuretics for all patients, but particularly for those with salt-sensitive and resistant hypertension. HCTZ is 4.2-6.2 systolic mm Hg less potent than CTDN, angiotensin-converting enzyme inhibitors, beta blockers, and calcium channel blockers by 24-hour measurements and 5.1 mm Hg systolic less potent than INDAP by office measurements. For reducing cardiovascular events (CVEs), HCTZ is less effective than enalapril and amlodipine in randomized trials, and, in network analysis of trials, it is less effective than CTDN and HCTZ-amiloride. Combined with thiazide- type diuretics, potassium-sparing agents decrease ventricular ectopy and reduce the risk for sudden cardiac death relative to thiazide- type diuretics used alone. A recent synthesis of 44 trials has shown that the relative potencies in milligrams among spironolactone (SPIR), amiloride, and eplerenone (EPLER) are approximately from 25 to 10 to 100, respectively, which may be important when SPIR is poorly tolerated. SPIR reduces proteinuria beyond that provided by other renin angiotensin aldosterone inhibitors. EPLER also reduces proteinuria and has beneficial effects on endothelial function. While guidelines often do not differentiate among specific diuretics, this review demonstrates that these distinctions are important for managing hypertension. [ABSTRACT FROM AUTHOR]

Context: Primary aldosteronism (PA) is the most common cause of endocrine hypertension that is diagnosed following a two-step process: an initial screening test, based on the serum aldosterone-to-renin ratio (ARR), followed by a relatively laborious and time-consuming confirmatory test to document autonomous aldosterone (ALD) secretion. Objective: The aim of this study is to develop a simple overnight test for the early and definite diagnosis of PA. Patients and methods: Totally, 148 hypertensive patients underwent a fludrocortisone-dexamethasone suppression test (FDST) and the new overnight diagnostic test (DCVT) using pharmaceutical RAAS (renin-angiotensin-aldosterone system) blockade with dexamethasone, captopril and valsartan. Results: Of the 148 patients, 45 were diagnosed as having PA and they all normalized their elevated blood pressure (BP) after administration of spironolactone or eplerenone. The remaining 103 patients were considered as having essential hypertension and served as controls. Using ROC analysis, the estimated sensitivity and specificity were 91 and 100%, respectively, for the post-FDST ARR, whereas 98% and 89% and 100% and 82% for the post-DCVT ARR and post-DCVT ALD, respectively, with selected cutoffs of 0.32 ng/dL/µU/mL and 3 ng/dL respectively. However, considering these cutoffs simultaneously, the estimated sensitivity and specificity were 98 and 100% respectively. Applying these cutoffs, the diagnosis of PA was confirmed in 44 (98%) of the 45 patients who were considered to have the disease. Conclusions: In this study, a highly sensitive and specific, low-cost, rapid, safe, and easy-to-perform diagnostic test (DCVT) for PA is described, which could be utilized on an outpatient basis potentially substituting conventional laborious testing. [ABSTRACT FROM AUTHOR]

Aims While mineralocorticoid receptor antagonists (MRAs) have been shown to benefit patients with reduced left ventricular ejection fraction (LVEF), spironolactone did not reduce the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT trial, which enrolled patients with LVEF of 45% or greater. We utilized data from TOPCAT to assess the relationship between LVEF as well as outcomes and efficacy of spironolactone. Methods and results We assessed differences in baseline characteristics and outcomes across LVEF categories in 3444 patients with HFpEF, and determined whether LVEF modified the treatment effect of spironolactone. Ejection fraction ranged from 44 to 85%. Patients with higher ejection fraction were older, more likely to be female, less likely to have a history of myocardial infarction, and more likely to have a history of hypertension and diabetes. The incidence of the primary endpoint and cardiovascular death was highest in patients at the lower end of the ejection fraction spectrum. Ejection fraction modified the spironolactone treatment effect, particularly in the patients enrolled in the Americas, for the primary outcome (P = 0.046) and for heart failure hospitalization (P = 0.039), with stronger estimated benefits of spironolactone at the lower end of the ejection fraction spectrum with respect to the primary endpoint (LVEF <50%: HR 0.72, 95% CI 0.50, 1.05; LVEF ≥60%: HR 0.97, 95% CI 0.76, 1.23) and heart failure hospitalization (LVEF,50%: HR 0.76, 95% CI 0.46, 1.27; LVEF ≥60%: HR 0.98, 95% CI 0.74, 1.30). Conclusion In patients with HFpEF enrolled in TOPCAT, patient characteristics and outcomes varied substantially by LVEF. The potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum. [ABSTRACT FROM AUTHOR]

Aims: Aldosterone has been implicated in atrial remodelling representing a potential target for upstream therapies. Accumulating evidence suggests that mineralocorticoid receptor blockade may have favourable effects on atrial fibrillation (AF) development, although some controversial results have been published. We, therefore, conducted a meta-analysis of randomized clinical trials (RCTs) and observational studies in order to examine the protective role of mineralocorticoid receptor antagonists (MRAs) on AF.Methods and Results: Of the 1337 initially identified records, 3 RCTs and 2 observational studies with 3640 patients were finally analysed. The pooled analysis of the included studies demonstrated that patients treated with MRAs have 31% lower risk of AF compared with controls [relative ratio (RR): 0.69; 95% confidence interval (CI): 0.58-0.83] without any heterogeneity across the studies (I(2) = 0%). This effect was consistent across RCTs (RR: 0.72; 95% CI: 0.55-0.94) and observational studies (RR: 0.67; 95% CI: 0.53-0.84) without heterogeneity. Also, MRAs reduce the risk of AF in both heart failure (HF) (RR: 0.63; 95% CI: 0.50-0.80) and after cardiac surgery (RR: 0.77; 95% CI: 0.61-0.98). Analysing the relative impact of eplerenone and spironolactone, we showed that only eplerenone significantly reduces AF burden (RR: 0.64; 95% CI: 0.44-0.90).Conclusion: Our meta-analysis suggests that MRAs may be effective in AF prevention especially in the HF setting. However, there are insufficient data for the widespread use of aldosterone antagonists solely for AF prevention. Larger RCTs with long-term follow-up in different clinical settings are needed to clarify the impact of MRAs on AF. [ABSTRACT FROM AUTHOR]

BACKGROUND A few studies have shown aldosterone antagonists (AA) to be effective therapy in patients with resistant hypertension (RH). We performed a meta-analysis of randomized and nonrandomized studies of AA in patients with RH. METHODS We searched PUBMED, EMBASE, and CENTRAL for studies on the use of AA in patients with RH. Meta-analysis was performed using random-effects model. The change in office and ambulatory blood pressures (BP), effects on biochemical profile, change in the number of antihypertensive agents, and adverse events were main outcomes. RESULTS We included 15 studies (3 randomized controlled trials, 1 nonrandomized comparative study, and 11 single-arm studies) with 1,204 total patients in the meta-analysis. In comparative studies, AA reduced systolic BP (SBP) by 24.26 mm Hg (95% CI: 8.65–39.87, P = 0.002) and diastolic BP (DBP) by 7.79 mm Hg (3.79–11.79, P = 0.0001). Similarly, AA reduced SBP by 22.74 mm Hg (18.21–27.27, P < 0.00001) and DBP by 10.49 mm Hg (8.85–12.13, P < 0.00001) in single-arm studies. AA resulted in significant change in serum electrolytes in single-arm studies but not in comparative studies. Significantly more adverse events were noted in single-arm studies but not in comparative studies. CONCLUSIONS On the basis of the current meta-analysis, we conclude that AA is safe and effective therapy in patients with RH. [ABSTRACT FROM AUTHOR]

The article reports on a 2015 study on the possible role of mitral leaflet remodelling in the pathophysiology of functional mitral regurgitation (FMR). Patients with FMR were studied for their three-dimensional transesophageal echocardiographic data of the mitral valve (MV). Results show that MV leaflet remodelling in FMR is common and is linked to globe left ventricular function and sphericity, MV tenting volume, and annulus dilatation.