The foremost target of the current work was to formulate and optimize a novel bergamot essential oil (BEO) loaded nano-phytosomes (NPs) and then combine it with spironolactone (SP) in order to clinically compare the efficiency of both formulations against acne vulgaris. The BEO-loaded NPs formulations were fabricated by the thin-film hydration and optimized by 32 factorial design. NPs' assessments were conducted by measuring entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). In addition, the selected BEO-NPs formulation was further combined with SP and then examined for morphology employing transmission electron microscopy and three months storage stability. Both BEO-loaded NPs selected formula and its combination with SP (BEO-NPs-SP) were investigated clinically for their effect against acne vulgaris after an appropriate in silico study. The optimum BEO-NPs-SP showed PS of 300.40 ± 22.56 nm, PDI of 0.571 ± 0.16, EE% of 87.89 ± 4.14%, and an acceptable ZP value of -29.7 ± 1.54 mV. Molecular modeling simulations showed the beneficial role of BEO constituents as supportive/connecting platforms for favored anchoring of SP on the Phosphatidylcholine (PC) interface. Clinical studies revealed significant improvement in the therapeutic response of BEO-loaded NPs that were combined with SP over BEO-NPs alone. In conclusion, the results proved the ability to utilize NPs as a successful nanovesicle for topical BEO delivery as well as the superior synergistic effect when combined with SP in combating acne vulgaris.

Introduction Polycystic ovary syndrome (PCOS) in women associates with raised levels of circulating thyroid stimulating hormone (TSH) and with high rates of gestational complications. A low range of preconception TSH is followed by low rates of gestational complications. It is unknown whether TSH levels are elevated in adolescents with PCOS and, if so, whether traditional or exploratory treatments can lower them into safe preconception range. We investigated TSH in non-obese adolescents with PCOS, including the effects of randomized interventions. Methods Morning TSH was a safety marker in randomized pilot studies comparing the effects of an oral contraceptive (OC) versus those of a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET) in non-obese adolescents with PCOS. A post-hoc analysis compared: TSH levels in PCOS (N= 62) vs controls; TSH changes on treatment (for 1 year); TSH levels post treatment (for 1 year). Results Mean TSH levels were higher in PCOS patients than in control girls (P<0.01). On-treatment TSH levels diverged (P<0.001), remaining elevated on OC, and descending swiftly on SPIOMET, well into safe preconception range. Post-treatment TSH levels were stable in both subgroups. On-treatment changes of circulating TSH associated to those of liver fat (R= 0.307, P= 0.017). Conclusion The endocrine signature of early PCOS is herewith extended to include modestly raised levels of circulating TSH; the normalizing effects of SPIOMET intervention in non-obese adolescents with PCOS are herewith extended to include on- and post-treatment TSH.

Recently, gender-affirming hormone therapy for gender incongruence has become an issue in various countries and organizations with various guidelines. In South Korea, several clinical treatments are also used with many possible options. These treatments include masculinizing (female-to-male [FTM]) or feminizing (male-to-female [MTF]) hormone therapies, with regimens usually driven by standards of hormonal replacement therapy for hypogonadism (i.e., hypogonadal natal men and postmenopausal women). This cross-sex hormone therapy can change patients' physical appearance to better match their gender identity and expression. Regarding masculinizing therapy, injection and transdermal gel types of testosterone are used according to international guidelines. Progesterone is utilized in the form of oral pills, injections, or intrauterine devices to suppress menstruation and avoid pregnancy. Essentially, feminizing therapy uses androgen blockers along with estrogen. This is because estrogen alone cannot exert sufficient androgen-suppressing effects. In South Korea, the most commonly used androgen blockers are spironolactone and cyproterone acetate. Gonadotropin-releasing hormone (GnRH) agonist is also available. Regarding estrogen, oral pills, injections, and transdermal gels are utilized. This review introduces these gender-affirming hormone therapies in South Korea and discusses the side effects of each regimen.

The QRS duration can be easily obtained from a 12-lead electrocardiogram. Increased QRS duration reflects greater ventricular activation times and often ventricular dyssynchrony. Dyssynchrony causes an impairment of the global cardiac function and adversely affects the prognosis of patients with heart failure (HF). Little is known about the impact of pharmacologic therapies on the QRS duration, particularly for patients with presymptomatic HF with a preserved left ventricular (LV) ejection fraction (i.e., stage B HF with preserved ejection fraction [HFpEF]). The HOMAGE (Heart OMics in AGEing) trial enrolled patients at risk factors for developing HF and assigned them to receive either spironolactone or the usual care for approximately 9 months in a randomized manner. This analysis reports the effect of spironolactone on the QRS duration. A total of 525 patients was included in the analysis. The median (percentile25-75) QRS duration at baseline was 92 (84 to 106) ms. Spironolactone reduced the QRS duration at month 9 by -2.8, 95% confidence interval -4.6 to -1.0 ms, p = 0.003. No significant associations were found between month 9 changes in the QRS duration and corresponding changes in the LV ejection fraction, LV mass, LV end-diastolic volume, blood pressure, N-terminal pro-brain natriuretic peptide, and procollagen type I carboxy-terminal propeptide (all p >0.05). This analysis shows that for patients with stage B HFpEF, therapy with spironolactone for 9 months shortened the QRS duration, an effect that was not associated with reductions in LV mass or volume, supporting the hypothesis that spironolactone has direct beneficial effects to improve myocardial electrical activation in patients with stage B HFpEF.

A 76-year-old man was evaluated in our emergency department (ED) for right toe swelling and pain. His initial ED workup revealed volume overload, uncontrolled hypertension, slow atrial fibrillation, refractory hypokalemia, mixed metabolic alkalosis and respiratory acidosis, with a normal plasma pH, and hypernatremia. His medical chart revealed long standing hyperkalemia and metabolic acidosis, related to his diabetic kidney disease. We hypothesized that a short course of daily SPS ingestion (Sodium Polystyrene Sulfonate, "Kayexalate") was the sole etiology for the compound electrolyte abnormalities and the electrolyte "flip flop". SPS ingestion can cause hypokalemia by excessive potassium binding in the gut. SPS exchanging potassium for sodium caused excessive sodium retention leading to hypernatremia, hypertension and volume overload. Volume overload worsened his chronic obstructive sleep apnea and yielded respiratory acidosis. Finally hypokalemia by itself was the main trigger for generation and maintenance of metabolic alkalosis. Urinary electrolytes, and renin and aldosterone levels taken at the ED ruled out primary aldosteronism and renal potassium and hydrogen loss. The patient's potassium was replenished by both PO and IV routes. He was treated for his volume overload and hypertension with furosemide. Spironolactone and amiloride, potassium sparing diuretics, were cautiously given only during his hypokalemic phase. His plasma sodium and potassium levels, blood pressure and volume status gradually improved. "Kayexalate" effect should be suspected in a patient presenting with unexplained hypokalemia and alkalosis, accompanied by volume overload rather than volume depletion, developing shortly after SPS ingestion. ED doctors should specifically ask CKD or ESRD patients on SPS, as it otherwise can skip the medication reconciliation process.

Menstrual irregularities are one of the main clinical symptoms caused by polycystic ovary syndrome (PCOS). Pharmacological treatment options for non-fertility indications to restore menstrual frequency play an important role in the management of PCOS. Oral contraceptive pills are commonly prescribed for adolescents with menstrual irregularities, however, when contraindicated or poorly tolerated, further pharmacological therapy is required. This systematic literature research aims to provide an overview concerning the effects of non-hormonal pharmacological treatment options on menstrual irregularities in adolescents suffering from PCOS. A systematic literature search in PubMed, Cochrane, Embase, Bio-SISS and Web of Science was performed, including literature from January 1998 to September 2022, using specific keywords in order to find related studies. n = 265 studies were identified of which n = 164 were eligible for further evaluation. Only four placebo-controlled studies were identified, with diverging inclusion and exclusion criteria. Available data on specific non-hormonal off-label use medication primarily consisted of metformin, Glucagon-like peptide 1 receptor agonists, thiazolidinediones, anti-androgen agents (spironolactone, finasteride, flutamide) and supplements (chromium picolinate, myo-inositol). However, only a few have partly pointed out beneficial effects on improving menstrual frequency in patients diagnosed with PCOS. In summary, metformin in dosages of 1500-2550 g/day, GLP-1-analogues and supplements were effective in regulation of menstrual cycles in adolescents diagnosed with PCOS. Menstrual frequency in adolescents with PCOS is essential to prevent hypoestrogenism with long-term consequences. In this context, MET is the most effective and cost- efficient in overweight adolescent girls, also showing beneficial effects in the regulation of insulin sensitivity, especially if COCs are contraindicated or not well-tolerated. Further studies are needed to evaluate therapies in lean and normal-weight girls with PCOS.

Endometriosis is a chronic inflammatory disease associated with pelvic pain, infertility, and increased cardiovascular risk. Recent studies suggest a possible role of aldosterone as a pro-inflammatory hormone in the pathogenesis of the disease. Cortisol is also an important mediator of stress reaction, but its role is controversial in endometriosis. The aim of this study was to evaluate aldosterone and cortisol levels and blood pressure values in women with endometriosis. We measured blood pressure, plasma aldosterone, renin, cortisol, and dehydroepiandrosterone sulfate (DHEAS) in 20 women with untreated minimal or mild pelvic endometriosis compared with 20 healthy controls matched for age and body mass index. Aldosterone values were similar in the two groups, while renin was significantly lower and the aldosterone to renin ratio was significantly higher in patients with endometriosis than in controls. Systolic blood pressure was in the normal range, but significantly higher in patients with endometriosis. Morning plasma cortisol was normal, but significantly lower in patients with endometriosis compared with controls, while DHEAS to cortisol ratio was similar in the two groups. These preliminary results are evidence of increased biological aldosterone activity and dysregulation of the hypothalamic-pituitary-adrenal axis in early stages of endometriosis. These alterations could play a role in disease development, suggesting new therapeutic targets for aldosterone receptor blockers.

Colonic pseudo-obstruction is an acute non-obstructive colonic dilation associated with constipation or secretory diarrhea. The secretory diarrhea phenotype is associated with refractory hypokalemia that may require different interventions to treat. We present a case of a 51-year-old male who was admitted with a hemorrhagic stroke whose hospital course was complicated by severe abdominal distension, diarrhea, and hypokalemia. Initial investigations excluded infectious causes. Imaging confirmed colonic pseudo-obstruction. The hypokalemia was severe and refractory, requiring daily potassium replacement along with rectal tube decompression and spironolactone. Despite these interventions, the hypokalemia persists and requires nearly 100 days to resolve completely.

Mineralocorticoid receptor antagonists not only are used as a diuretics to treat essential hypertension, but also protect the heart and kidney by inhibiting inflammation and fibrosis. Since the discovery of spironolactone, the first generation of mineralocorticoid receptor antagonist, two types of non-steroid mineralocorticoid receptor antagonists (finerenone and esaxerenone) approved for clinical use have been developed, which have the advantages of high affinity, high selectivity and balanced distribution in heart and kidney, and can be used in clinic as a cardiorenal protective drug. In this paper, the development history of mineralocorticoid receptor antagonists was reviewed, and the pathophysiological mechanism of inflammation and fibrosis caused by mineralocorticoid receptors and the similarities and differences of different generations of mineralocorticoid receptor antagonists were analyzed. In particular, the phase III clinical research evidence of finerenone and esaxerenone was discussed. This paper also reviews the research progress of cardiorenal protection of non-steroid mineralocorticoid receptor antagonists in patients with chronic kidney disease.

The study's objective was to ascertain the results of sub-chronic therapy of various diuretics on the ischemia/reperfusion dysfunction of the heart in hypertensive rats by a global ischemia in an isolated rat heart model. The research included 40 spontaneously hypertensive male rats (Wistar Kyoto strain, body mass 250 ± 30 g, 8 weeks old) grouped into four groups. The animals were treated for 4 weeks with 10 mg/kg of hydrochlorothiazide, indapamide, or spironolactone per os. After a period of sub-chronic treatment, we analyzed hemodynamic measurements, echocardiography, and myocardial function according to the Langendorff retrograde perfusion method. The hearts were subjected to 20 min of global ischemia and then reperfused for 30 min (I20:R30). Cardiovascular parameters that depict the left ventricle functions were continuously monitored, while flowmetry was used to determine coronary flow values. Markers of oxidative stress were estimated from coronary venous effluent using spectrophotometry. All three examined diuretics (hydrochlorothiazide, spironolactone, indapamide) lowered the production of the majority of the detected prooxidants, reducing myocardial oxidative damage. The cardiological examination of heart function in vivo demonstrated that treatment with indapamide and spironolactone mitigates left ventricular hypertrophy but without significant lowering of blood pressure or increment in ejection fraction. Additionally, monitoring of cardiac function ex vivo indicated the cardiodepressant effect of spironolactone in spontaneously hypertensive rats.

An extremely dystrophic, premature female infant, born at 25 3/7 weeks of gestational age (birth weight: 430 g) with severe pulmonary hypertension (PH), was admitted to our neonatal intensive care unit (ICU) requiring cardiorespiratory support, including mechanical ventilation and pulmonary vasodilators such as inhaled nitric oxide (iNO) and continuous intravenous sildenafil infusions. The diagnosis of bronchopulmonary dysplasia (BPD) was made. A hemodynamically relevant, persistent ductus arteriosus (PDA) was surgically ligated after failed pharmacologic PDA closure using indomethacin and ibuprofen. The patient was discharged with an estimated 2/3 systemic pulmonary artery pressure. One month after hospital discharge, on low-flow oxygen supplementation (0.5 L/min FiO2 100%), at the corrected age of 16 weeks, she was readmitted to our emergency department with signs of respiratory distress and circulatory decompensation. Echocardiography demonstrated suprasystemic PH. Severe PH persisted despite initiated invasive mechanical ventilation, triple vasodilating therapy [iNO, macitentan, and continuous intravenous (IV) sildenafil], as well as levosimendan, milrinone, and norepinephrine for recompensation from cardiac shock. Thus, we started off-label oral selexipag therapy (oral IP receptor agonist) in the smallest patient reported so far (4 kg body weight). Subsequently, RV systolic pressure decreased to half-systemic, allowing successful weaning of iNO, norepinephrine, and milrinone, and extubation of the patient over 4 days. The infant was discharged 4 weeks after pediatric intensive care unit (PICU) admission in stable cardiorespiratory condition, with an oral, specific, triple antihypertensive PAH-targeted therapy using selexipag, macitentan, and sildenafil as well as oxygen therapy at low-flow (0.5 l/min) and spironolactone. The first cardiac catheterization at the age of 9 months under aforementioned triple PAH-targeted therapy revealed mild PH with 35% systemic PA pressure (mPAP/mSAP = 0.35) and isolated pulmonary vein stenosis. A transthoracic biopsy at the age of 12 months confirmed the diagnosis of BPD and further showed pulmonary interstitial glycogenosis and severe pulmonary capillary hemangiomatosis, without involvement of the pulmonary venules (chILD A2, A3, and B4 according to the Deutsch-Classification). The patient is currently in stable cardiorespiratory condition undergoing triple PH-targeted therapy including selexipag. This report highlights the potential benefits of the oral prostacyclin mimetic selexipag as an early add-on PH-targeted drug in chronic PH of infancy (cPHi).

Microbiota has a crucial role in the host blood pressure (BP) regulation. The present study analyzes whether the mineralocorticoid receptor antagonist spironolactone ameliorates the dysbiosic state in a genetic model of neurogenic hypertension. Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were randomly allocated into three groups: untreated WKY, untreated SHR, and SHR treated with spironolactone for 5 weeks. Spironolactone restored the Firmicutes/Bacteroidetes proportion, and acetate-producing bacteria populations to WKY levels. Spironolactone reduced the percentage of intestinal aerobic bacteria. The amelioration of gut dysbiosis was linked to a reduction in the gut pathology, an enhanced colonic integrity, a reduced gut permeability and an attenuated sympathetic drive in the gut. Spironolactone was unable to reduce neuroinflammation and oxidative stress in the paraventricular nuclei in the hypothalamus. Spironolactone reduced the higher Th17 cells proportion in mesenteric lymph nodes and Th17 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that spironolactone reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity and pathology due to reduced sympathetic drive in the gut.

Metabolic effects of physical activity may be reno-protective in the context of hypertension, although exercise stresses kidneys. Aldosterone participates in renal disease in hypertension, but exercise affects the plasma concentration of aldosterone. This study was designed to evaluate whether physical activity and pharmacological treatment by aldosterone have additive effects on renal protection in hypertensive rats. Female spontaneously hypertensive rats (SHR) or normotensive Wistar rats performed voluntary running wheel activity alone or in combination with aldosterone blockade (spironolactone). The following groups were studied: young and pre-hypertensive SHR (n = 5 sedentary; n = 10 running wheels, mean body weight 129 g), 10-month-old Wistar rats (n = 6 sedentary; n = 6 running wheels, mean body weight 263 g), 10-month-old SHRs (n = 18 sedentary, mean body weight 224 g; n = 6 running wheels, mean body weight 272 g; n = 6 aldosterone, mean body weight 219 g; n = 6 aldosterone and running wheels, mean body weight 265 g). Another group of SHRs had free access to running wheels for 6 months and kept sedentary for the last 3 months (n = 6, mean body weight 240 g). Aldosterone was given for the last 4 months. SHRs from the running groups had free access to running wheels beginning at the age of 6 weeks. Renal function was analyzed by microalbuminuria (Alb/Cre), urinary secretion of kidney injury molecule-1 (uKim-1), and plasma blood urea nitrogen (BUN) concentration. Molecular adaptation of the kidney to hypertension and its modification by spironolactone and/or exercise were analyzed by real-time PCR, immunoblots, and histology. After six months of hypertension, rats had increased Alb/Cre and BUN but normal uKim-1. Voluntary free running activity normalized BUN but not Alb/Cre, whereas spironolactone reduced Alb/Cre but not BUN. Exercise constitutively increased renal expression of proprotein convertase subtilisin/kexin type 9 (PCSK9; mRNA and protein) and arginase-2 (mRNA). Spironolactone reduced these effects. uKim-1 increased in rats performing voluntary running wheel activity exercise irrespectively of blood pressure and aldosterone blockade. We observed independent but no additive effects of aldosterone blockade and physical activity on renal function and on molecules potentially affecting renal lipid metabolism.

The renal kallikrein-kinin system (RKKS) has been related to blood pressure control and sodium and water balance. We have previously shown that female spontaneously hypertensive rats (SHR) have high urinary kallikrein activity (UKa) and lower blood pressure (BP) than males whereas ovariectomy stimulates UKa and diminishes BP. We also showed that high K+ intake and prepuberal gonadectomy (Gx) diminish BP with a concomitant increase in UKa and plasma aldosterone levels. Since kallikrein co-localize in the same distal nephron segments of aldosterone effectors, we explored the effect of pharmacological blockage of aldosterone receptor, epithelial Na+ (ENaC) and the rectifying outer medulla K+ (ROMK) channels in different gonad contexts on the gene expression, renal tissue content and urine release of kallikrein. Klk1 gene expression was determined by real-time PCR and enzymatic activity of kallikrein by the amidolytic method. We found that the inhibition of the aldosterone receptor by spironolactone increases kallikrein renal tissue storage and decreases its urinary activity, especially in Gx rats. Moreover, ENaC blockade by benzamil increases the renal content of kallikrein without affecting synthesis or excretion, especially in females and Gx animals, while the inhibition of ROMK by glibenclamide increases the synthesis and renal content of kallikrein only in intact male animals. We concluded that RKKS regulation showed sexual dimorphism and seemed to be modulated by sex hormones throughout a process involving aldosterone and the aldosterone-sensitive ion channels..