Spironolactone Treatment Research Articles

Cost-effectiveness of Spironolactone for Adult Female Acne (SAFA): economic evaluation alongside a randomised controlled trial

ObjectiveThis study aims to estimate the cost-effectiveness of oral spironolactone plus routine topical treatment compared with routine topical treatment alone for persistent acne in adult women from a British NHS...

Metabolic Outcomes of Primary Aldosteronism Patients Receiving Adrenalectomy or Spironolactone Treatments

To investigate the metabolic outcomes of primary aldosteronism (PA) patients receiving adrenalectomy (ADX) or spironolactone treatment and the contributing factors to the metabolic outcomes. The clinical data of 70 patients with aldosterone-producing adenoma (APA) and 86 patients with idiopathic hyperaldosteronism (IHA) were retrospectively analyzed. All subjects received confirmatory diagnosis of APA or IHA at the Department of Endocrinology and Metabolism, West China Hospital between March 2018 and October 2020. APA patients underwent ADX, while IHA patients were given spironolactone, a mineralocorticoid receptor antagonist (MRA). After ADX or spironolactone treatment, the outcomes of the metabolic indicators and the inter-group differences between the APA patients and IHA patients were studied. There was no significant difference between the baseline data of the APA group and those of the IHA group in terms of age, sex, duration of hypertension, maximum systolic blood pressure (SBP-max), maximum diastolic blood pressure (DBP-max), body mass index (BMI), fasting blood glucose (FBG), lipid parameters, and renal function. IHA patients had higher waist circumference, serum potassium, and plasma renin activity (PRA) than those of the APA patients (all P<0.05). All patients showed significant improvement in blood pressure, blood potassium, and plasma aldosterone at follow-up. However, they also showed increased triglycerides (TG) accompanied by deterioration in renal function (P≤0.001). Multiple regression showed that TG levels were associated with spironolactone treatment for IHA patients and post-treatment BMI and creatinine levels. Furthermore, APA patients showed improvement in their FBG after ADX (P=0.041), while IHA patients showed elevated levels of FBG after spironolactone treatment (P=0.037). After treatment, PA patients still may experience abnormal lipid metabolism and deteriorating renal function. Spironolactone therapy may give rise to worse glucolipid metabolism than ADX therapy does.

Small extracellular vesicles from failing heart accelerate tumour growth

Abstract Background Heart failure (HF) is associated with an increased incidence of cancer independently of shared risk factors. The mechanism behind this link is not entirely clear. Purpose We aimed to test the hypothesis that cardiac extracellular vesicles (cEVs) contribute to the link between HF and cancer. In addition, we aimed to determine if heart failure (HF) therapy will reduce the tumour-promoting effects of HF. Methods We used a mouse model of heterotopic lung cancer tumours and post-myocardial infarction (MI) HF. To determine the role of cEVs in tumour growth, we focused on cardiac mesenchymal stromal cells (cMSCs). First, we isolated cMSCs from mice hearts 10d after MI or sham MI and purified cMSC-EVs from the conditioned medium using size exclusion chromatography. Then, we analyzed cMSC-EV characteristics, cargo, and neoplastic effects on lung cancer cells. We also used cMSC-EV transfer to assess EV biodistribution and its effect on tumour growth. Next, we tested the effects of EV depletion on tumour growth. Finally, we used spironolactone to determine if HF therapy would attenuate the harmful interaction between HF and cancer. Results Mice with HF developed larger lung tumours than sham-MI mice during 28 days of follow-up. Failing hearts, particularly cMSCs, produced twice more EVs with neoplastic properties than non-failing hearts (Fig-A). Proteomics analysis revealed unique protein profiles of cMSC-EVs from failing hearts (Fig-B). cMSC-EVs from the failing hearts harbored higher quantities of tumour-promoting cytokines such as periostin, osteopontin, vascular endothelial growth factor, interleukin-6 and tumour necrosis factor-alpha; and tumorigenic microRNAs (miR) such as miR-221 and mir-21. Transfer of labeled cMSC-EVs from the failing heart into the systemic circulation of tumour-bearing mice targeted tumour cells and accelerated tumour growth (Fig-C). Moreover, EV depletion reduced the tumour-promoting effects of HF, and adoptive transfer of cMSC-EVs from failing hearts accelerated tumour growth in mice during systemic EV depletion (Fig-D). Finally, we used spironolactone to determine if HF therapy would inhibit the tumour trophic effects of HF. Spironolactone attenuated LV dilatation and improved global longitudinal strain following MI. Subsequently, spironolactone treatment reduced the number of EVs secreted by cMSCs from failing hearts by 26% and reduced the accelerated tumour growth after MI and HF (Fig E). Notably, spironolactone treatment did not reduce the volume of the tumours in sham-MI mice, indicating that the anti-tumour effects of spironolactone were related to its effects on the faling heart. Conclusions Our results provide new insight into the link between heart failure and cancer. We show, for the first time, that cardiac extracellular vesicles promote tumour growth independently of other secreted factors. Moreover, heart failure therapy reduces the tumour-promoting effects of heart failure.

Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction.

Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by LMNA mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient's neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies.

Abstract 17781: Spironolactone Improves Left Atrial Function and Atrioventricular Coupling in Resistant Hypertension

Purpose: To determine the blood pressure independent effects of spironolactone on left atrial (LA) size and function in patients with resistant hypertension (RHTN). Methods: Patients with RHTN (N=36, 55±7 years) were prospectively recruited. Spironolactone was initiated at 25 mg/day and increased to 50 mg/day after four weeks. Other antihypertensives were withdrawn to maintain constant blood pressure. Cardiac magnetic resonance imaging was performed at baseline and after six months of spironolactone treatment and changes in LA functional metrics were assessed (Figure 1). The statistical analysis was conducted using two-sided tests of significance. Results: LA size and function parameters improved from baseline to month-six: LA volumes indexed to body surface area (LAVI) were reduced (LAVI max 41.4±12 vs 33.2±9.7 ml/m 2 ; LAVI pre-A 32.6±9.8 vs 25.6±8.1 ml/m 2 ; LAVI min 18.5 [13.9 - 24.8] vs 14.1 [10.9 - 19.2] ml/m 2 ; all p &lt; 0.05); left atrioventricular coupling index was reduced (28.2±11.5 vs 22.7±9.2 %, p &lt; 0.05); LA emptying fractions (LAEF) were increased (total LAEF 52.4 [48.7 - 60.3] vs 55.9 [50.3 - 61.1] %; active LAEF 40.2±8.6 vs 43.1±7.8 %, both p &lt; 0.05). There was a substantial increase in reservoir strain (29.1 ± 8.5 % vs 30.9 ± 5.5 %, p = 0.068) whereas active strain was significantly increased from baseline (16.3 ± 4.1 % vs 17.8 ± 4.2 %, p &lt; 0.05). Changes in passive strain and strain rates were not statistically significant (p &gt; 0.1). The effect of spironolactone was similar in patients with high (N = 18) and normal (N = 18) aldosterone status (defined by plasma renin activity and 24-hour urine aldosterone). Conclusion: Treatment of RHTN with spironolactone is associated with improvements in LA size and function regardless of whether aldosterone levels were normal or high. This study suggests the need for larger prospective studies examining effects of mineralocorticoid receptor antagonists on atrial function and atrioventricular coupling.

SAT376 Luteinizing Hormone Secretion in Hyperandrogenic Girls Taking Spironolactone or Metformin

Abstract Disclosure: C.M. Burt Solorzano: None. M. Gilrain: None. S.H. Kim: None. C.R. McCartney: None. Peri-pubertal hyperandrogenism (HA) typically relates to excess adrenal and/or ovarian androgen production in response to adrenocorticotropin (ACTH) and/or luteinizing hormone (LH), respectively. Spironolactone and metformin are commonly used medications to treat adolescent androgen excess. We examined how end-organ responsiveness and LH pulse patterns are affected by these medications in adolescents with HA. We studied free testosterone (T) levels (including baseline and peaks after ACTH and recombinant human chorionic gonadotropin [r-hCG] stimulation), oral glucose tolerance testing (OGTT), and 12-hr overnight LH secretion (sampled q 10 min) in post-menarcheal girls with HA before and after 3-months of either spironolactone (100 mg BID) or metformin (500 mg BID). Free T was calculated using total T (LC-MS/MS) and sex hormone binding globulin (SHBG).To date, 3 girls (aged 12-18) have been studied using spironolactone and 4 girls (aged 14-17) using metformin. (1 girl was studied twice, once with each medication.) After spironolactone treatment, free T changed by -19% (-58 to +37) (median [range]) unstimulated, by -53% (-62 to -15) after ACTH, and by -54% (-66 to +12) after r-hCG. Peak insulin level during OGTT changed by +28% (+16 to +98). Overnight LH pulse frequency changed by -64% (-89 to -10) and LH mean by -74% (-89 to -17). Two subjects in the spironolactone group demonstrated luteal LH patterns despite serum progesterone concentrations &amp;lt; 0.7 ng/mL. In the metformin group, free T changed by +35% (-32 to +125) unstimulated, by 36% (-54 to +66) after ACTH, and by 21% (-41 to +105) after r-hCG. Peak insulin level during OGTT changed by -47% (-74 to +102). LH pulse frequency changed by +10% (-29 to +22) and LH mean by +1% (-2 to +74). To summarize findings to date, mean LH and LH pulse frequency decreased in all three subjects taking spironolactone, including marked reductions in two subjects who demonstrated luteal LH patterns. While free T levels decreased in some of these girls, this seems unlikely to account for such marked changes in LH secretion. And despite similar decreases in T and also decreases in peak insulin in some girls taking metformin, LH pulse frequency did not change markedly. LH pulse patterns in two girls taking spironolactone suggest a progesterone-like effect on LH pulsatility. Spironolactone can cause irregular uterine bleeding, and canrenone (the major metabolite of spironolactone) binds to uterine progesterone receptors competitively (Fernandez MD, Br J Clin Pharm 1983). However, to our knowledge, this is the first report of LH pulse changes in HA girls using spironolactone. Further studies are needed to confirm this finding. Presentation Date: Saturday, June 17, 2023

Treatment response to spironolactone in patients with heart failure with preserved ejection fraction: a machine learning-based analysis of two randomized controlled trials

Whether there is a subset of patients with heart failure with preserved ejection fraction (HFpEF) that benefit from spironolactone therapy is unclear. We applied a machine learning approach to identify responders and non-responders to spironolactone among patients with HFpEF in two large randomized clinical trials. Using a reiterative cluster allocating permutation approach, patients from the derivation cohort (Aldo-DHF) were identified according to their treatment response to spironolactone with respect to improvement in E/e'. Heterogenous features of response ('responders' and 'non-responders') were characterized by an extreme gradient boosting (XGBoost) algorithm. XGBoost was used to predict treatment response in the validation cohort (TOPCAT). The primary endpoint of the validation cohort was a combined endpoint of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization. Patients with missing variables for the XGboost model were excluded from the validation analysis. Out of 422 patients from the derivation cohort, reiterative cluster allocating permutation identified 159 patients (38%) as spironolactone responders, in whom E/e' significantly improved (p=0.005). Within the validation cohort (n=525) spironolactone treatment significantly reduced the occurrence of the primary outcome among responders (n=185, p log rank=0.008), but not among patients in the non-responder group (n=340, p log rank=0.52). Machine learning approaches might aid in identifying HFpEF patients who are likely to show a favorable therapeutic response to spironolactone. See Acknowledgements section at the end of the manuscript.

Basigin is released in extracellular vesicles derived from the renal tubular epithelium in response to albuminuria.

Irrespective of the cause, albumin/proteinuria induces tubulointerstitial damage and accelerates the progression of kidney diseases. Our series of studies demonstrated that proteinuria, an independent prognostic factor for chronic kidney disease (CKD), is correlated with urinary basigin/CD147 (Bsg) levels. We examined the morphology and origin of Bsg in the tubular lumen through the effects of filtered glucose and protein solutes on the tubules. Diabetic kidney disease (DKD) patients (N = 50) were treated with spironolactone 25 mg for 4 weeks or by conservative treatment. The associations between urinary Bsg values and clinical indicators were examined. Primary-cultured proximal tubular epithelial cells (PTECs) from human adult kidneys were exposed to high glucose or bovine serum albumin (BSA). In patients with early phase DKD, urinary Bsg levels were closely correlated with proteinuria but not HbA1c. Full-length Bsg on extracellular vesicles (EVs) was investigated primarily in urine collected from DKD patients. EVs obtained from the urine of DKD patients included Bsg and SGLT2 proteins. Notably, spironolactone treatment concomitantly suppressed the release of Bsg-bearing EVs in correlation with decreased albuminuria. Exposure of PTECs to BSA (but not high glucose) enhanced the storage of supernatant Bsg in EVs despite the absence of exposure-specific changes in Bsg transcription. Proteinuria induces the release of Bsg-bearing EVs derived from PTECs into the tubular lumen.

Decaying kidney function during cirrhosis correlates with remodeling of distal colon aldosterone target gene expression.

Liver cirrhosis is associated to circulatory abnormalities leading to hypovolemia and stimulation of the renin-angiotensin-aldosterone system (RAAS). Advanced stages of the disease cause renal failure, impairing K+ and Na+ homeostasis. It has been proposed that the distal colon undergoes functional remodeling during renal failure, in particular by aldosterone-driven increased K+ excretion. In this study, we compared the transcriptional response of aldosterone target genes in the rat distal colon under two models of increased circulating aldosterone (one with concomitant RAAS activation) and in a model of secondary hyperaldosteronism induced by cirrhosis. The expression of a subset of these genes was also tested in distal colon biopsies from control subjects or patients with cirrhosis with varying levels of disease progression and treated or not with mineralocorticoid receptor inhibitor spironolactone. We examined known aldosterone-regulated transcripts involved in corticosteroid signaling and transepithelial ion transport. In addition, we included aldosterone-regulated genes related to cell proliferation. Our comparison revealed multiple aldosterone target genes upregulated in the rat distal colon during decompensated cirrhosis. Epithelial Na+ channel β and γ subunit expression correlated positively with plasma aldosterone concentration and negatively with glomerular filtration rate. Patients with cirrhosis showed increased expression of 11-β-hydroxysteroid-dehydrogenase 2 (11βHSD2), which was reverted by spironolactone treatment, suggesting a sensitization of the distal colon to aldosterone action. In summary, our data show that decaying kidney function during cirrhosis progression toward a decompensated state with hypovolemia correlates with remodeling of distal colon ion transporter expression, supporting a role for aldosterone in the process.NEW & NOTEWORTHY Liver cirrhosis progression significantly alters ion transporter subunit expression in the rat distal colon, a change that correlated well with declining kidney function and the severity of the disease. Our data suggest that the steroid hormone aldosterone participates in this homeostatic response to maintain electrolyte balance.

#5482 CIRCULATING BIOMARKERS OF COLLAGEN REMODELING AS MARKERS FOR DEVELOPMENT OF MICROALBUMINURIA IN TYPE 2 DIABETES: THE PRIORITY TRIAL

Abstract Background and Aims Kidney disease progression is characterized by extensive deposition of extracellular matrix components such as collagen. Therefore, we assessed the effect of spironolactone on collagen remodeling biomarkers and investigated the association between the markers and development of microalbuminuria in serum of persons with type 2 diabetes and normoalbuminuria. Method We measured collagen type III (PRO-C3), VI (PRO-C6; endotrophin), VII (PRO-C7), and XXVIII (PRO-C28) formation, and a fragment of degraded crosslinked collagen type III (CTX-III) in serum of persons with high-risk (stratified by a urinary proteomics classifier, CKD273) for development of microalbuminuria, randomized to either spironolactone 25 mg or placebo. Crude and adjusted Cox models were applied to investigate the association between baseline biomarker levels and development of the primary outcome, persistent microalbuminuria, and development of microalbuminuria in at least one morning void sample, used as a secondary outcome. Results In the PRIORITY trial, spironolactone treatment did not prevent progression to microalbuminuria compared to placebo. All biomarkers were measured in 154 participants at baseline and 117 at end-of-study (week 208). Treatment with spironolactone did not affect serum levels of any of the investigated collagen remodeling biomarkers compared to placebo, and there were no differences in delta-biomarker levels between baseline and end-of-study (p ranging 0.277-0.875). In crude analyses, serum endotrophin was associated with both the primary (n = 44) and secondary outcome (n = 74) (HR per two-fold higher level: 1.58, 95% CI: 1.03-2.44, p = 0.037 and 1.62, 1.12-2.35, p = 0.010), whereas serum PRO-C3 was only associated with the secondary outcome (1.89, 1.19-2.99, p = 0.007). After adjustment for sex, baseline age, systolic blood pressure, estimated glomerular filtration rate, urinary albumin-creatinine ratio, and HbA1c, serum endotrophin and PRO-C3 remained significantly associated with the secondary outcome (1.52, 1.03-2.24, p = 0.036 and 1.73, 1.08-2.78, p = 0.022). Levels of PRO-C7, PRO-C28, and CTX-III were not associated with the specified outcomes. Neither baseline levels of serum endotrophin nor PRO-C3 correlated with baseline CKD273 levels (R: 0.00-0.06, p&amp;gt;0.47). Conclusion Treatment with spironolactone did not change serum levels of collagen remodeling biomarkers. Serum endotrophin, reflecting collagen type VI formation and the pro-fibrotic molecule endotrophin, and PRO-C3, a marker of collagen type III formation, were associated with development of microalbuminuria in at least one urine sample, suggesting that these biomarkers are relevant risk markers for kidney disease development in type 2 diabetes.

(106) Hormonally-Mediated Vestibulodynia: A Chart Review

Abstract Introduction The borders of the vestibule are Hart’s line laterally, hymen medially, frenulum of the clitoris anteriorly, and fourchette posteriorly. Provoked vestibulodynia (PVD) is characterized by severe burning pain in response to pressure localized to the vestibule. Numerous factors may negatively affect the vestibule causing PVD such as hormonal changes, infections, trauma, exaggerated immunologic or inflammatory responses, dermatologic conditions, high-tone pelvic floor dysfunction, pudendal neuropathy, and sacral radiculopathy. PVD specifically associated with hormonal changes in pre-menopausal women has been termed hormonally mediated vestibulodynia (HMV). Dense labeling of androgen receptors has been noted in the germinal layer of the vestibular epithelium and mucinous minor vestibular glands, implying a critical role of testosterone in vestibular health. Low calculated free testosterone caused by elevated sex hormone binding globulin (SHBG) in pre-menopausal women using combined hormonal contraception may thus be harmful to the vestibular epithelium and minor vestibular glands, resulting in HMV. In HMV, vulvoscopy shows diffuse vestibular tenderness of the entire vestibule, the ostia of the minor vestibular glands are frequently erythematous (Fig 1) and blood testing is consistent with a low calculated free testosterone. Objective We describe the variation in etiologies for HMV and emphasize the importance of measuring total testosterone and SHBG to monitor calculated free testosterone levels in patients with HMV. Methods This is a retrospective chart review of premenopausal patients presenting to a clinic with entrance dyspareunia who were diagnosed with HMV, and whose symptoms were alleviated by treatment. Inclusion criteria were as follows: premenopausal females with initial testosterone and SHBG blood values below the reference range, initial vulvoscopy findings significant for vestibulodynia, follow-up testosterone and SHBG approaching the reference range, and follow-up vulvoscopies demonstrating a relief from symptoms. Results A total of 9 patients met the inclusion criteria. The mean age was 32 years old, with a range of 22 years old to 39 years old. Presenting complaints in addition to dyspareunia (n=9) included recurrent irritative bladder voiding symptoms without positive urine culture (n=3) and pelvic pain (n=4). Vulvoscopic examination including cotton-tipped swab testing of the vestibule revealed signs of vestibular hypersensitivity with pain ranging from 1 to 9 in all 7 regions of the vestibule tested. Patients had histories of having taken combined hormonal contraceptives (n=6), isotretinoin (n=1), spironolactone (n=1) and/or hormonal treatment for breast cancer (n=1), all of which can decrease calculated free testosterone. All patients were treated with systemic testosterone and compounded estradiol/testosterone cream to be applied daily to the vestibule. On follow-up blood testing, all patients had calculated free testosterone values approaching 0.6-0.8 ng/dl, established by Guay et al. as the optimum range. All patients reported significantly decreased dyspareunia and significant relief of other bothersome symptoms, especially bladder symptoms. Conclusions This chart review illustrates a variety of etiologies associated with low calculated free testosterone and the diagnosis of HMV. This data emphasizes the importance of calculating free testosterone and performing vulvoscopy to establish a diagnosis in pre-menopausal patients with entrance dyspareunia. Additionally, this chart review demonstrates the efficacy of systemic testosterone and local vestibular androgen/estradiol therapies in ameliorating vestibular pain and associated symptoms in patients with HMV. Disclosure No

Studying the effect of spironolactone treatment on right ventricular function in patients with pulmonary hypertension group 1

Studying the effect of spironolactone treatment on right ventricular function in patients with pulmonary hypertension group 1

The Efficacy and Safety of Oral and Topical Spironolactone in Androgenetic Alopecia Treatment: A Systematic Review.

Androgenetic alopecia (AGA) has negative impacts on both men and women in terms of appearance and mental stress. Spironolactone is a synthetic aldosterone receptor antagonist known to stimulate hair growth and has been widely used by dermatologists to treat AGA. To conduct a systematic review evaluating the efficacy and safety of topical and oral spironolactone in AGA treatment. We searched PubMed, Embase, the Cochrane Library, and the Web of Science until October 23rd, 2022, for human studies evaluating the efficacy of spironolactone for the treatment of AGA, regardless of doses and routes. We retrieved 784 papers and ultimately 7 articles matched our inclusion criteria and comprised 618 AGA patients (65 men, 553 women), 414 of them received spironolactone treatment. Oral spironolactone doses ranged from 25mg to 200mg daily, with the vast majority between 80mg and 110 mg. Dosage forms for topical spironolactone use include gels of 1% and solutions of 5% twice daily. Both oral and topical spironolactone have been shown efficacy for alopecia recovery, but topical use has significantly fewer side effects and is suitable for any gender. It showed better efficacy in combination with other therapies such as oral or topical minoxidil compared with monotherapy. Spironolactone is an effective and safe treatment of androgenic alopecia which can enhance the efficacy when combined with other conventional treatments such as minoxidil. Topical spironolactone is safer than oral administration and is suitable for both male and female patients, and is expected to become a common drug for those who do not have a good response to minoxidil. Furthermore, more high-quality clinical randomized controlled studies should be performed.

Effects of Spironolactone on Arrhythmias in Hemodialysis Patients: Secondary Results of the SPin-D Randomized Controlled Trial.

Background Patients receiving maintenance hemodialysis (HD) have a high incidence of cardiovascular events, including arrhythmia and sudden death. Spironolactone reduces the risk of cardiovascular events and sudden death in patients with heart failure, but the effects of spironolactone on arrhythmic events in patients treated with maintenance HD are unclear. Methods The Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent ESRD (SPin-D) trial, was a 36-week randomized, placebo-controlled, double-blind trial comparing 3 different doses of spironolactone with placebo in maintenance HD patients. We performed a post-hoc analysis in a subset (n=57) who underwent extended electrocardiographic monitoring using a wearable device at baseline and follow-up. Generalized estimating equations models were fit to determine the associations of spironolactone (individual doses and combined) versus placebo on the incidence rate of predefined categories of arrhythmic events. Results The average age of participants was 55 ±12 years; 61% were male; and 77% were Black. The overall proportion of patients with at least one arrhythmia event was 43% (15/35) at baseline and 81% (43/53) at the end of follow-up. At the end of follow-up, the rate of bradycardic events or conduction blocks was higher in the combined spironolactone group, compared with placebo, (82.4 versus 38.7 events/100 patient days; P<0.001). Similar findings were noted in adjusted models, but did not meet statistical significance (adjusted rate ratio of 2.04; 95%CI 0.83 - 5.05). Conclusions In a 36-week trial of patients receiving maintenance hemodialysis, a higher frequency of bradycardia and conduction blocks was observed among those treated with spironolactone treatment compared with placebo. Larger studies are required to investigate the longer-term effects of spironolactone on cardiac conduction in patients receiving hemodialysis.

Long-Lasting Effects of Spironolactone after its Withdrawal in Patients with Hyperandrogenic Skin Disorders.

Hyperandrogenic skin disorders, such as hirsutism, acne and alopecia, affect approximately 10-20% of women of reproductive age, reducing quality of life and causing psychological impairment. Spironolactone is a commonly used antiandrogen, especially in women who are not sexually active or have contraindications to hormonal contraceptives. The aim of this study was to evaluate the effects of spironolactone, especially after its withdrawal, in patients with hyperandrogenic skin disorders. Retrospective analysis of 63 women with hyperandrogenic skin symptoms due to polycystic ovary syndrome (PCOS), treated with spironolactone for at least 6 months as first-line treatment. After a mean time of treatment of 25.7 months, all patients reported a significant improvement in hyperandrogenic skin disorders; only 5 patients were dissatisfied and required the addition of an oral contraceptive. The therapy was well tolerated and the most frequent side-effect was intermestrual bleeding in 68.2% of cases, affecting mainly classic PCOS phenotype. Thirthyeight patients showed prolonged effects 33.7 months after spironolactone withdrawal, whereas 20 relapsed 17.5 months after discontinuation. No significant difference in clinical and biochemical parameters was observed between these two groups both at baseline and after spironolactone treatment. Ovulatory PCOS patients were treated for a shorter time and reported earlier relapse than classic PCOS patients. Spironolactone is an effective and safe treatment for hyperandrogenic skin disorders, showing long-lasting effects even several months after its discontinuation.

Pharmacologic inhibition by spironolactone attenuates experimental abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAA) are characterized by vascular inflammation and remodeling that can lead to aortic rupture resulting in significant mortality. Pannexin-1 channels on endothelial cells (ECs) can modulate ATP secretion to regulate the pathogenesis of AAA formation. Our hypothesis focused on potential of spironolactone to inhibit EC-mediated ATP release for the mitigation of AAA formation. A topical elastase AAA model was used initially in C57BL/6 (wild-type; WT) male mice. Mice were administered either a vehicle control (saline) or spironolactone and analyzed on day 14. In a second chronic AAA model, mice were subjected to elastase and β-aminopropionitrile (BAPN) treatment with/without administration of spironolactone to pre-formed aneurysms starting on day 14 and analyzed on day 28. Aortic diameter was evaluated by video micrometry and aortic tissue was analyzed for cytokine expression and histology. ATP measurement and matrix metalloproteinase (MMP2) activity was evaluated in aortic tissue on days 14 or -28. In vitro studies were performed to evaluate the crosstalk between aortic ECs with macrophages or smooth muscle cells. In the elastase AAA model, spironolactone treatment displayed a significant decrease in aortic diameter compared to elastase-treated controls on day 14. A significant increase in smooth muscle α-actin expression as well as decrease in elastic fiber disruption and immune cell (macrophages and neutrophils) infiltration was observed in mice treated with spironolactone compared to saline-treated controls. Spironolactone treatment also significantly mitigated pro-inflammatory cytokine expression, MMP2 activity and ATP content in aortic tissue compared to controls. Moreover, in the chronic AAA model, spironolactone treatment of pre-formed aneurysms significantly attenuated vascular inflammation and remodeling to attenuate the progression of AAAs compared to controls. Mechanistically, in vitro data demonstrated that spironolactone treatment attenuates extracellular ATP release from endothelial cells to mitigate macrophage activation (IL-1β and HMGB1 expression) and smooth muscle cell-dependent vascular remodeling (MMP2 activity). These results demonstrate that spironolactone can mitigate aortic inflammation and remodeling to attenuate AAA formation as well as decrease growth of pre-formed aneurysms via inhibition of EC-dependent ATP release. Therefore, this study implicates a therapeutic application of spironolactone in the treatment of AAAs.

ODP425 Potassium Level Trends in Trans Females Using Spironolactone: A Retrospective Chart Review

Abstract Introduction Endocrine Society guidelines for the treatment of gender dysphoric individuals recommend close monitoring of serum electrolytes, particularly potassium in trans females using spironolactone every 3 months (first year) and annually afterwards (1) due to risk of hyperkalemia from mineralocorticoid antagonism (2). Unless patients have kidney disease, the risk of hyperkalemia with spironolactone use is low and therefore monitoring of potassium levels has been questioned. A study conducted in trans youth on spironolactone treatment showed asymptomatic hyperkalemia in 2.2% of study subjects but no clinically significant hyperkalemia (3). Objectives We hypothesized that the incidence of hyperkalemia in trans females using spironolactone is low and therefore when present is clinically insignificant. Methods This was a retrospective chart review of trans females who received gender-affirming hormone therapy that included spironolactone from the endocrinology clinic between January 1, 2000 and September 6, 2018. Out of a cohort of 244 trans subjects, 77 trans females had serum potassium levels documented. 6 trans women only on estrogen and 21 trans women with only one potassium measurement were excluded. The remaining 50 subjects that had an initial and at least 1 follow-up potassium were included and analyzed. ​ Study outcomes included incidence of hyperkalemia (serum potassium &amp;gt;5.5 mmol/L), the relationship between duration and degree of hyperkalemia and difference between potassium levels at the beginning of spironolactone treatment vs last potassium level as of September 2018. Results The mean age of the subjects was 42.8 years (SD 14.39 years). The cohort was predominantly of Caucasian race (62.8%). All subjects had spironolactone doses in the range of 100- 400 mg/ day. No potassium level was above 5.5 mmol/ L and all subjects had creatinine &amp;lt; 2 mg/dL. The average duration of treatment was 25 months (range 2- 142 months) and total 140 post-spironolactone potassium levels were available. The mean pre-spironolactone potassium level (3.88 mmol/L) was lower than mean post spironolactone potassium level (3.98 mmol/L) but the difference was statistically and clinically insignificant (p=0.106, paired t-test). The mean of cumulative post spironolactone potassium levels (4.03mmol/L) was higher than the mean of baseline potassium levels (p=0.012, unpaired t-test) but clinically insignificant. Conclusion No subjects had laboratory evidence of hyperkalemia in our cohort of patients. This implies that frequent measurement of potassium levels might be unnecessary in trans women taking spironolactone, in patients with no history of chronic kidney disease. References 1 Hembree, W.C., et al., Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2017 2 Epstein, M. and D.A. Calhoun, Aldosterone blockers (mineralocorticoid receptor antagonism) and potassium-sparing diuretics. J Clin Hypertens (Greenwich), 2011 3 Millington, K., E. Liu, and Y.M. Chan, The Utility of Potassium Monitoring in Gender-Diverse Adolescents Taking Spironolactone. J Endocr Soc, 2019 Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Targeting efficacy of spironolactone in patients with heart failure with preserved ejection fraction: the TOPCAT study.

We aimed to explore the heterogeneous treatment effects (HTEs) for spironolactone treatment in patients with Heart failure with preserved ejection fraction (HFpEF) and examine the efficacy and safety of spironolactone medication, ensuring a better individualized therapy. We used the causal forest algorithm to discover the heterogeneous treatment effects (HTEs) from patients in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Cox regressions were performed to assess the hazard ratios (HRs) of spironolactone medication for cardiovascular death and drug discontinuation in each group. The causal forest model revealed three representative covariates and participants were partitioned into four subgroups which were Group 1 (baseline BMI≤31.71kg/m2 and baseline ALP≤80U/L, n=759); Group 2 (BMI≤31.71kg/m2 and ALP>80U/L, n=1088); Group 3 (BMI>31.71kg/m2 , and WBC≤6.6 cells/μL, n=633); Group 4 (BMI>31.71kg/m2 and WBC>6.6 cells/μL, n=832), respectively. In the four subgroups, spironolactone therapy reduced the risk of cardiovascular death in high-risk group (Group 4) with both high BMI and WBC count (HR: 0.76; 95% CI 0.58 to 0.99; P=0.045) but increased the risk in low-risk group (Group 1) with both low BMI and ALP (HR: 1.45; 95% CI 1.02 to 2.07; P=0.041; P for interaction=0.020) but showed similar risk of drug discontinuation (P for interaction=0.498). Our study manifested the HTEs of spironolactone in patients with HFpEF. Spironolactone treatment in HFpEF patients is feasible and effective in patients with high BMI and WBC while harmful in patients with low BMI and ALP. Machine learning model could be meaningful for improved categorization of patients with HFpEF, ensuring a better individualized therapy in the clinical setting.

Combined antagonist treatment of glucocorticoid and mineralocorticoid receptor does not affect weight loss of fasting rainbow trout but inhibits a fasting-induced elevation of cortisol secretion

The gastrointestinal system of fish reacts rapidly to food deprivation. The relative masses of digestive organs and activities of digestive enzymes decrease within days of fasting. This is believed to be an energy-conserving strategy as the metabolic cost of maintaining digestive capacity is high. Cortisol is known for its role in energy mobilization following stress exposure, and prolonged elevated cortisol levels have been shown to reduce growth rates in fish. Fish experiencing chronic cortisol elevations show structural changes to their digestive tissues and overall reductions in relative digestive tissue masses. In fish fasting for prolonged periods, circulating cortisol levels have been reported to be downregulated, upregulated, or unchanged compared to feeding fish. This study aimed to investigate if RU486 and spironolactone, antagonists of the glucocorticoid receptor (GR), and mineralocorticoid receptor (MR), respectively, alone or in combination affect circulating cortisol levels during prolonged starvation. In addition, we tested the effects of blocking GR and MR, on the down-regulation of relative digestive tissue mass during starvation, and its effects on weight loss. Three treatment groups of rainbow trout were intraperitoneally implanted with either GR, MR, or GR and MR blockers. A fourth group was implanted with cortisol, while a fifth group served as a control. All treatment groups were sampled over a course of four weeks of food deprivation and compared against each other and fed control fish at day 0 of the trial. Starvation for 2 weeks and longer significantly increased circulating cortisol levels in all groups except for the group implanted with GR and MR antagonists. Loss of body mass occurred most rapidly during the first week of starvation. Spironolactone treatment resulted in significantly reduced loss of mass during the first week, however, over the following weeks, no differences in mass loss were observed in the groups implanted with blockers, while cortisol-treated fish showed the highest decrease in body mass over time. Relative digestive tissue mass decreased in all groups but apparently, the fasting-induced elevation in plasma cortisol levels did not affect the relative weight loss of digestive tissues as no differences were observed between control fish and GR + MR antagonist treated fish. Very high cortisol levels caused by cortisol treatment however caused a faster decrease in the relative mass of some digestive organs, particularly the stomach.

Characteristics, prognosis, and treatment response in HFpEF patients with high vs. normal ejection fraction.

BackgroundHeart failure with preserved ejection fraction (HFpEF) patients varied by left ventricular ejection fraction (LVEF) have different clinical characteristics, prognosis, and treatment response. With data from our prospective HFpEF cohort, we assessed the possible relationship between clinical characteristics, outcome as well as treatment response and LVEF.MethodsWe compared differences in baseline characteristics and clinical outcomes across LVEF categories (50%≤LVEF <60% vs. LVEF≥60%) in 1,502 HFpEF patients, and determined whether LVEF modified the treatment response. During 5-year follow-up, all-cause mortality was used as the primary endpoints, and composite endpoints (all-cause mortality or HF hospitalization) were set as the secondary endpoint.ResultsPatients with higher LVEF were statistically older, more likely to be women and have a history of atrial fibrillation. Patients with lower LVEF category were more likely to have a history of coronary artery disease. The incidences of all-cause mortality and composite endpoints were higher in patients with higher LVEF. Also, LVEF modified the spironolactone treatment effect for the primary outcome and secondary endpoint with stronger estimated benefits at the lower LVEF category with respect to all-cause mortality (HR 0.734, 95% CI 0.541–0.997, P = 0.048) and all-cause mortality or HF hospitalization (HR 0.767, 95% CI 0.604–0.972, P = 0.029).ConclusionThe characteristics and outcomes of HFpEF patients varied substantially by LVEF. Patients with higher LVEF encountered more adverse events than those with lower LVEF. The potential efficacy of spironolactone was greatest at the lower category of LVEF spectrum in HFpEF.