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Short term effects of spironolactone on blood lipid profile: A 3-month study on a cohort of young women with hirsutism
British Journal of Clinical Pharmacology
Abstract
To investigate the effects of spironolactone on serum lipids in women with hirsutism over a 3-month period.
In a prospective setting, 27 hirsute women (20 with polycystic ovary syndrome and seven with idiopathic hirsutism) with a mean age of 23.0 +/- 5.1 years were studied at baseline and 3 months after receiving a daily dose of 100 mg of spironolactone. Patients did not receive any other medications and did not go through a specific diet during the study. Lipid profile, fasting blood glucose, testosterone, dehydroepiandrosterone sulphate (DHEAS) and prolactin (PRL) were measured at baseline and 3 months after therapy.
Mean body mass index of patients was 26.1 +/- 5.1 kg m(-2) before treatment and 25.9 +/- 5.7 kg m(-2) after treatment (NS). The therapy was associated with a significant decline of mean high-density lipoprotein (HDL), 39.5 mg dl(-1)[95% confidence interval (CI) 35.6, 43.4]vs. 32.2 mg dl(-1) (95% CI 29.2, 35.2), and a significant increase in mean low-density lipoprotein (LDL), 133.1 mg dl(-1) (95% CI 120.2, 146) vs. 150.8 mg dl(-1) (95% CI 139.1, 162.5), and cholesterol/HDL ratio, 5 (95% CI 4.4, 5.6) vs. 6.4 (95% CI 5.7, 7.1) (P < 0.05). No significant change was noted in total cholesterol, triglyceride or fasting blood glucose levels. Serum values of testosterone, DHEAS and PRL decreased significantly after 3 months of therapy (P < 0.05).
Spironolactone might have adverse effects on serum lipoprotein levels by increasing LDL and decreasing HDL over a short course of treatment. While treating hirsutism with spironolactone, special care should be given to women with metabolic disorders such as dyslipidaemia.
... In the study by Long et al, significant weight loss and a significant decrease in HOMA-IR were observed in PCOS patients, both in the group receiving spironolactone alone and in the group receiving metformin [22]. However no change in weight was observed in the study by Nakhjavani et al [23]. In our study, the group of patients taking 100 mg spironolactone, there was also a significant decrease in BMI and HOMAIR scores after treatment compared to baseline. ...
... These results suggest that spironolactone may have effects on weight and insulin resistance in PCOS in addition to its antiandrogenic effects. In studies on the effect of spironolactone on lipids different results have been obtained [23,27,28]. Gökmen et al [28] and Nakhjavani et al [23] found a decrease in HDL levels when spironolactone was used in patients with hirsutism, similar to our study. ...
... In studies on the effect of spironolactone on lipids different results have been obtained [23,27,28]. Gökmen et al [28] and Nakhjavani et al [23] found a decrease in HDL levels when spironolactone was used in patients with hirsutism, similar to our study. ...
Aim: To investigate the effects of short-term oral intake of spironolactone on parathyroid hormone (PTH) and calcium levels, as well as other biochemical and clinical parameters in normotensive female patients with polycystic ovary syndrome (PCOS). Method: 32 PCOS patients were studied at baseline and three months after regular intake of a daily dose of 50 mg or 100 mg spironolactone. PTH, calcium and other biochemical tests as well as clinical parameters were evaluated at baseline and after three months. Results: Body mass index and serum PTH levels decreased significantly after treatment (p: 0.021 and p: 0.043, respectively). Mean high-density lipoprotein was significantly decreased after treatment (p: 0.011). No significant change was observed in calcium, phosphorus, total cholesterol, triglycerides, and fasting blood glucose levels. Serum testosterone and dehydroepiandrosterone sulphate decreased significantly after 3 months of therapy (p: 0.000 and p: 0.006; respectively). Conclusions: In our study, taking spironolactone at a dose of 100 mg/day lowered PTH levels and had a positive effect on weight loss and insulin resistance. New studies are needed to investigate the effects of treatment with spironolactone on bone and metabolism. It is recommended to monitor dyslipidemia while taking the drug.
... Fourteen studies evaluated the effect of SPIRO on patients with disorders related to hyperandrogenism (polycystic ovary syndrome [PCOS] or idiopathic hirsutism) ( Table 6). [65][66][67][68][69][70][71][72][73][74][75][76][77][78] Among this large number of studies, 7 were RCTs, [65][66][67][68][69][70][71] 4 studies were prospective but without controls, [72][73][74][75] 2 studies were prospective with medication assigned based on each patient's needs, [76,77] and one study was of observational design. [78] Sample sizes and duration of follow-up were somewhat limited. ...
... Fourteen studies evaluated the effect of SPIRO on patients with disorders related to hyperandrogenism (polycystic ovary syndrome [PCOS] or idiopathic hirsutism) ( Table 6). [65][66][67][68][69][70][71][72][73][74][75][76][77][78] Among this large number of studies, 7 were RCTs, [65][66][67][68][69][70][71] 4 studies were prospective but without controls, [72][73][74][75] 2 studies were prospective with medication assigned based on each patient's needs, [76,77] and one study was of observational design. [78] Sample sizes and duration of follow-up were somewhat limited. ...
Background
Spironolactone, a nonselective mineralocorticoid receptor antagonist (MRA), may have a deleterious effect on glycemia. The objective of this review was to assess current knowledge on MRAs’ influence (spironolactone, eplerenone, and canrenone) on glucose homeostasis and the risk of diabetes.
Method
A systematic review was conducted using the Medline database on articles published from 1946 to January 2017 that studied the effects of MRAs on any glucose-related endpoints, without any restrictions regarding the participants’ characteristics.
Study design, patient population, dose and duration of intervention, and the quantitative results on glycemic markers were extracted, interpreted for result synthesis, and evaluated for sources of bias. From the articles included in the qualitative analysis, a select number were used in a meta-analysis on studies having measured glycated hemoglobin (HbA1c) or risk of diabetes.
Results
Seventy-two articles were selected from the Medline database and references of articles. Results on spironolactone were heterogeneous, but seemed to be disease-specific. A potential negative effect on glucose regulation was mainly observed in heart failure and diabetes trials, while a neutral or positive effect was detected in diseases characterized by hyperandrogenism, and inconclusive for hypertension. Interpretation of data from heart failure trials was limited by the small number of studies. From a meta-analysis of 12 randomized controlled studies evaluating spironolactone's impact on HbA1c in diabetic patients, spironolactone had a nonsignificant effect in parallel-group studies (mean difference 0.03 [−0.20;0.26]), but significantly increased HbA1c in crossover studies (mean difference 0.24 [0.18;0.31]). Finally, eplerenone did not seem to influence glycemia, while limited data indicated that canrenone may exert a neutral or beneficial effect.
The studies had important limitations regarding study design, sample size, duration of follow-up, and choice of glycemic markers.
Conclusion
Spironolactone may induce disease-specific and modest alterations on glycemia. It is uncertain whether these effects are transient or not. Data from the most extensively studied population, individuals with diabetes, do not support a long-term glycemic impact in these patients. Further prospective studies are necessary to establish spironolactone's true biological effects and their clinical implications.
... In the group taking spironolactone in association with lifestyle dietary modification, both overweight and lean women demonstrated a reduction of IR and TG, and an elevation of HDL-C levels [60]. However, in another study where PCOS women with hirsutism and slight baseline dyslipidemia were given spironolactone (100 mg) for three months [61], there was elevation of LDL-C and a reduction of HDL-C, suggesting that this drug may deteriorate the lipid profile over short term and should not be administered to dyslipidemic women [61]. A six-month long, open label, randomized clinical trial compared the efficacy of a combination therapy of spironolactone (50 mg) and metformin (1000 mg) in PCOS women with that of single therapies with each of the drugs. ...
... In the group taking spironolactone in association with lifestyle dietary modification, both overweight and lean women demonstrated a reduction of IR and TG, and an elevation of HDL-C levels [60]. However, in another study where PCOS women with hirsutism and slight baseline dyslipidemia were given spironolactone (100 mg) for three months [61], there was elevation of LDL-C and a reduction of HDL-C, suggesting that this drug may deteriorate the lipid profile over short term and should not be administered to dyslipidemic women [61]. A six-month long, open label, randomized clinical trial compared the efficacy of a combination therapy of spironolactone (50 mg) and metformin (1000 mg) in PCOS women with that of single therapies with each of the drugs. ...
Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder amongst women of reproductive age, which is characterized by reproductive and cardiometabolic disturbances with long-term health repercussions. Insulin resistance (IR), impaired glucose tolerance, type 2 diabetes mellitus (DM2), obesity and dyslipidemia occur more in women with PCOS than in age-comparable women without PCOS. Long term data regarding risks or benefits of medical intervention for metabolic dysfunction of PCOS are lacking. Therapies, such as oral contraceptives (OCPs) and anti-androgenic medications used to manage the reproductive manifestations of PCOS, may themselves be the cause of cardiometabolic perturbations. Hence, strategies regarding the management of reproductive issues in PCOS encompass a patient-specific tailored approach. Factors that influence the cardiometabolic side effects arising during treatment of the reproductive manifestations of PCOS (hirsutism/anovulation) are also discussed in this paper in order to build future strategies to minimize the overall cardiometabolic risk.
... In the medical literature, there is little evidence of unfavorable effects of spironolactone on the lipid profile. Nakhjavani et al. (2009) [38] noted a significant decline of high-density lipoprotein (HDL) and an increase in low-density lipoprotein (LDL) levels in women with hirsutism after a 3month treatment with spironolactone. These authors suggested that agonist activity of spironolactone at progesterone receptors may cause progestin-like effects on blood lipids, which can adversely affect the lipid profile. ...
... In the medical literature, there is little evidence of unfavorable effects of spironolactone on the lipid profile. Nakhjavani et al. (2009) [38] noted a significant decline of high-density lipoprotein (HDL) and an increase in low-density lipoprotein (LDL) levels in women with hirsutism after a 3month treatment with spironolactone. These authors suggested that agonist activity of spironolactone at progesterone receptors may cause progestin-like effects on blood lipids, which can adversely affect the lipid profile. ...
Mineralocorticoid receptors (MRs), which are activated by mineralocorticoids and glucocorticoids, actively participate in mechanisms that affect the structure and function of blood vessels. Although experimental and clinical evidence shows that vascular damage in diabetes is associated with structural alterations in large and small arteries, the role of MR in this process needs further studies. Thus, we tested the hypothesis that MR, through redox-sensitive mechanisms, plays a role in diabetes-associated vascular remodelling. Male, 12-14-weeks-old db/db mice, a model of type 2 diabetes and their non-diabetic counterpart controls (db/+) were treated with spironolactone (MR antagonist, 50 mg/kg/day) or vehicle for 6 weeks. Spironolactone treatment did not affect blood pressure, fasting glucose levels or weight gain, but increased serum potassium and total cholesterol in both, diabetic and control mice. In addition, spironolactone significantly reduced serum insulin levels, but not aldosterone levels in diabetic mice. Insulin sensitivity, evaluated by the HOMA (homoeostatic model assessment)-index, was improved in spironolactone-treated diabetic mice. Mesenteric resistance arteries from vehicle-treated db/db mice exhibited inward hypertrophic remodelling, increased number of smooth muscle cells and increased vascular stiffness. These structural changes, determined by morphometric analysis and with a myography for pressurized arteries, were prevented by spironolactone treatment. Arteries from vehicle-treated db/db mice also exhibited augmented collagen content, determined by Picrosirius Red staining and Western blotting, increased reactive oxygen species (ROS) generation, determined by dihydroethidium (DHE) fluorescence, as well as increased expression of NAD(P)H oxidases 1 and 4 and increased activity of mitogen-activated protein kinases (MAPKs). Spironolactone treatment prevented all these changes, indicating that MR importantly contributes to diabetes-associated vascular dysfunction by inducing oxidative stress and by increasing the activity of redox-sensitive proteins.
© 2015 Authors; published by Portland Press Limited.
... 4 In humans, serum glucose remained unaffected in most studies with patients with hypertension, 5-7 type 2 diabetes mellitus (T2DM) complicated with diabetic nephropathy 8 or polycystic ovary syndrome (PCOS). [9][10][11] The effect of spironolactone on IR has been mainly investigated in women with PCOS, considered to be the ovarian component of MetS, because of its antiandrogenic action. Spironolactone (100 mg ⁄ d) either alone (12 months) 9 or in combination with ethinyl estradiol ⁄ cyproterone acetate (3 months) 10 decreased both insulin and HOMA-IR. ...
... With respect to serum lipid levels, spironolactone administration decreased serum total cholesterol and LDL-C in two studies of women with PCOS. 10,12 Nevertheless, spironolactone had no effect on serum lipids in other studies that recruited patients with hypertension, [5][6][7]13 T2DM complicated with nephropathy, 8 or PCOS, 9,11 apart from a decrease in triglycerides in one of them. 9 Differences in population, duration and ⁄ or drug coadministration (ie, estrogens, progestins, diuretics, angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers) might have accounted for these controversial results. ...
... These approaches use the information on both protein and drug molecules and combine their spaces for accurate predictions 25 . They can be further classified into 2 types: feature-based and similarity-based [44][45][46][47][48] . ...
The dawn of computational models in healthcare has revolutionised the drug development industry. The wet lab experiments entail enormously expensive and laborious procedures. As a result, the applications of computational designs have been a better replacement for manual experimentations. Identifying drug-target interaction (DTI) is a vital drug design process. In this review, we have explored the various computational methodologies actively used in the field of DTI prediction. We have hierarchically categorised the models into three broad domains: ligand-based, structure-based and chemogenic. We have further classified the domains into their subcategories. The functioning and latest developments achieved in each subcategory are further analysed in depth. This review offers a comprehensive overview of the tools and methodologies of each model. We have also compared the advantages and limitations of each model in every category. Finally, we look into the future scope of the machine learning models by addressing the possible difficulties faced in DTI. This article serves as an insight into the various models used in DTI prediction.
... Furthermore, spironolactone therapy in women with PCOS has been associated with a significant improvement in metabolic phenotype (Zulian et al. 2005). However this is not the case in all studies, with either no effect observed (Diri et al. 2016) or an adverse effect reported on serum lipoprotein levels (Nakhjavani et al. 2009). ...
In the last decade it has been revealed that androgens play a direct and important role in regulating female reproductive function. Androgens mediate their actions via the androgen receptor (AR), and global and cell-specific Ar knockout mouse models have confirmed that AR-mediated androgen actions play a role in regulating female fertility and follicle health, development and ovulation. This knowledge, along with the clinical data reporting a beneficial effect of androgens or androgen-modulating agents in augmenting in vitro fertilization (IVF) stimulation in women termed poor responders, has supported the adoption of this concept in many IVF clinics worldwide. On the other hand, substantial evidence from human and animal studies now supports the hypothesis that androgens in excess, acting via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). The identification of the target sites of these AR actions and the molecular mechanisms involved in underpinning the development of PCOS, is essential to provide the knowledge required for the future development of novel, mechanism-based therapies for the treatment of PCOS. This review will summarize the basic scientific discoveries that have enhanced our knowledge of the roles of androgens in female reproductive function, discuss the impact these findings have had in the clinic, and how a greater understanding of the role androgens play in female physiology may shape the future development of effective strategies to improve IVF outcomes in poor responders and the amelioration of symptoms in patients with PCOS.
... Spironolactone inhibits microsomal cholesterol 7a-hy- droxylase activity and increases bile salt-independent bile flow (choleresis) in the liver, resulting in increased cholesterol excretion into the bile [42]. However, subse- quent clinical studies revealed controversial findings, indi- cating that spironolactone may or may not affect total cholesterol level in human subjects [9,17,39,48]. Elevated levels of plasma cholesterol are strongly associated with atherosclerosis development [4]. Therefore, we investigated spironolactone's effect on total plasma cholesterol level in the Ossabaw pig model. ...
Coronary transient receptor potential canonical (TRPC) channel expression is elevated in metabolic syndrome (MetS). However, differential contribution of TRPCs to coronary pathology in MetS is not fully elucidated.
We investigated the roles of TRPC1 and TRPC6 isoforms in coronary arteries of MetS pigs and determined
whether long-term treatment with a mineralocorticoid receptor inhibitor, spironolactone, attenuates coronary
TRPC expression and associated dysfunctions. MetS coronary arteries exhibited significant atherosclerosis,
endothelial dysfunction, and increased histamine-induced contractions. Immunohistochemical studies revealed that TRPC6 immunostaining was significantly greater in the medial layer of MetS pig coronary arteries compared to that in Lean pigs, whereas little TRPC6 immunostaining was found in atheromas. Conversely, TRPC1 immunostaining was weak in the medial layer but strong in MetS atheromas, where it was predominantly localized to macrophages. Spironolactone treatment significantly decreased coronary TRPC expression and dysfunctions in MetS pigs. In vivo targeted delivery of the dominant-negative (DN)-TRPC6 cDNA to the coronary wall reduced histamine-induced calcium transients in the MetS coronary artery medial layer, implying a role for TRPC6 in mediating calcium influx in MetS coronary smooth muscles. Monocyte adhesion was increased in Lean pig coronary arteries cultured in the presence of aldosterone; and spironolactone
antagonized this effect, suggesting that coronary mineralocorticoid receptor activation may regulate macrophage infiltration. TRPC1 expression in atheroma macrophages was associated with advanced atherosclerosis, whereas medial TRPC6 upregulation correlated with increased histamine-induced calcium transients and coronary contractility. We propose that long-term spironolactone treatment may be a therapeutic strategy to decrease TRPC expression and coronary pathology associated with MetS.
... Spironolactone inhibits microsomal cholesterol 7a-hydroxylase activity and increases bile salt-independent bile flow (choleresis) in the liver, resulting in increased cholesterol excretion into the bile [42]. However, subsequent clinical studies revealed controversial findings, indicating that spironolactone may or may not affect total cholesterol level in human subjects [9,17,39,48]. Elevated levels of plasma cholesterol are strongly associated with atherosclerosis development [4]. Therefore, we investigated spironolactone's effect on total plasma cholesterol level in the Ossabaw pig model. ...
Coronary transient receptor potential canonical (TRPC) channel expression is elevated in metabolic syndrome (MetS). However, differential contribution of TRPCs to coronary pathology in MetS is not fully elucidated. We investigated the roles of TRPC1 and TRPC6 isoforms in coronary arteries of MetS pigs and determined whether long-term treatment with a mineralocorticoid receptor inhibitor, spironolactone, attenuates coronary TRPC expression and associated dysfunctions. MetS coronary arteries exhibited significant atherosclerosis, endothelial dysfunction, and increased histamine-induced contractions. Immunohistochemical studies revealed that TRPC6 immunostaining was significantly greater in the medial layer of MetS pig coronary arteries compared to that in Lean pigs, whereas little TRPC6 immunostaining was found in atheromas. Conversely, TRPC1 immunostaining was weak in the medial layer but strong in MetS atheromas, where it was predominantly localized to macrophages. Spironolactone treatment significantly decreased coronary TRPC expression and dysfunctions in MetS pigs. In vivo targeted delivery of the dominant-negative (DN)-TRPC6 cDNA to the coronary wall reduced histamine-induced calcium transients in the MetS coronary artery medial layer, implying a role for TRPC6 in mediating calcium influx in MetS coronary smooth muscles. Monocyte adhesion was increased in Lean pig coronary arteries cultured in the presence of aldosterone; and spironolactone antagonized this effect, suggesting that coronary mineralocorticoid receptor activation may regulate macrophage infiltration. TRPC1 expression in atheroma macrophages was associated with advanced atherosclerosis, whereas medial TRPC6 upregulation correlated with increased histamine-induced calcium transients and coronary contractility. We propose that long-term spironolactone treatment may be a therapeutic strategy to decrease TRPC expression and coronary pathology associated with MetS.
... In our paper, we focus on the application of link prediction to DTIs -an emerging approach starting to gain more attention in the past decade [4][5][6][7]. Just one recent example is the work of [4] that uncovered the potential interaction between spironolactone and membrane progestin receptor gamma protein, and that has been confirmed in recent clinical studies [8]. ...
Background In silico drug-target interaction (DTI) prediction plays an integral role in drug repositioning: the discovery of new uses for existing drugs. One popular method of drug repositioning is network-based DTI prediction, which uses complex network theory to predict DTIs from a drug-target network. Currently, most network-based DTI prediction is based on machine learning – methods such as Restricted Boltzmann Machines (RBM) or Support Vector Machines (SVM). These methods require additional information about the characteristics of drugs, targets and DTIs, such as chemical structure, genome sequence, binding types, causes of interactions, etc., and do not perform satisfactorily when such information is unavailable. We propose a new, alternative method for DTI prediction that makes use of only network topology information attempting to solve this problem. Results We compare our method for DTI prediction against the well-known RBM approach. We show that when applied to the MATADOR database, our approach based on node neighborhoods yield higher precision for high-ranking predictions than RBM when no information regarding DTI types is available. Conclusion This demonstrates that approaches purely based on network topology provide a more suitable approach to DTI prediction in the many real-life situations where little or no prior knowledge is available about the characteristics of drugs, targets, or their interactions.
... In our paper, we focus on the application of link prediction to DTIs -an emerging approach starting to gain more attention in the past decade [4][5][6][7]. Just one recent example is the work of [4] that uncovered the potential interaction between spironolactone and membrane progestin receptor gamma protein, and that has been confirmed in recent clinical studies [8]. ...
Background
In silico drug-target interaction (DTI) prediction plays an integral role in drug repositioning: the discovery of new uses for existing drugs. One popular method of drug repositioning is network-based DTI prediction, which uses complex network theory to predict DTIs from a drug-target network. Currently, most network-based DTI prediction is based on machine learning – methods such as Restricted Boltzmann Machines (RBM) or Support Vector Machines (SVM). These methods require additional information about the characteristics of drugs, targets and DTIs, such as chemical structure, genome sequence, binding types, causes of interactions, etc., and do not perform satisfactorily when such information is unavailable. We propose a new, alternative method for DTI prediction that makes use of only network topology information attempting to solve this problem. ResultsWe compare our method for DTI prediction against the well-known RBM approach. We show that when applied to the MATADOR database, our approach based on node neighborhoods yield higher precision for high-ranking predictions than RBM when no information regarding DTI types is available. Conclusion
This demonstrates that approaches purely based on network topology provide a more suitable approach to DTI prediction in the many real-life situations where little or no prior knowledge is available about the characteristics of drugs, targets, or their interactions.
... In the medical literature, there is little evidence of unfavourable effects of spironolactone on the lipid profile. Nakhjavani et al. [38] noted a significant decline of high-density lipoprotein (HDL) and an increase in low-density lipoprotein (LDL) levels in women with hirsutism after a 3-month treatment with spironolactone. These authors suggested that agonist activity of spironolactone at progesterone receptors may cause progestin-like effects on blood lipids, which can adversely affect the lipid profile. ...
... While the lipid parameters were increased (TC, LDL, TG, HDL), no changes were observed in insulin resistance and glucose metabolism. Nakhjavani et al. (50) gave 100 mg spironolactone to 27 patients (20 PCOS + 7 idiopathic hirsutism) for 3 months and evaluated the lipid profile. Testosterone, dehydroepiandrosterone sulfate and prolactin levels decreased. ...
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. It is characterized by menstrual disorders, hyperandrogenism (clinical and/or biochemical) and ultrasonographic features. It is well known that PCOS has unfavourable effects on carbohydrate metabolism, the parameters of cardiovascular disease and lipid profile. Mode of treatment is mainly guided by the main complaint of the patient. A lot of medicines have been used for many years to treat these women. For that reason the recognition the effects of these drugs on the metabolic risk profile is important. The aim of this review was to evaluate the effects of these drugs on metabolic parameters in women with PCOS.
... Our predicted interaction between spironolactone and membrane progestin receptor gamma protein indicates that spironolactone may have some progestogenic function. Interestingly, this hypothesis can be confirmed from the clinical studies performed in (Nakhjavani et al., 2009). In addition, mesalazine is an anti-inflammatory drug that is primarily used to treat inflammatory bowel disease (Sandborn et al., 2007). ...
Motivation:
In silico prediction of drug-target interactions plays an important role toward identifying and developing new uses of existing or abandoned drugs. Network-based approaches have recently become a popular tool for discovering new drug-target interactions (DTIs). Unfortunately, most of these network-based approaches can only predict binary interactions between drugs and targets, and information about different types of interactions has not been well exploited for DTI prediction in previous studies. On the other hand, incorporating additional information about drug-target relationships or drug modes of action can improve prediction of DTIs. Furthermore, the predicted types of DTIs can broaden our understanding about the molecular basis of drug action.
Results:
We propose a first machine learning approach to integrate multiple types of DTIs and predict unknown drug-target relationships or drug modes of action. We cast the new DTI prediction problem into a two-layer graphical model, called restricted Boltzmann machine, and apply a practical learning algorithm to train our model and make predictions. Tests on two public databases show that our restricted Boltzmann machine model can effectively capture the latent features of a DTI network and achieve excellent performance on predicting different types of DTIs, with the area under precision-recall curve up to 89.6. In addition, we demonstrate that integrating multiple types of DTIs can significantly outperform other predictions either by simply mixing multiple types of interactions without distinction or using only a single interaction type. Further tests show that our approach can infer a high fraction of novel DTIs that has been validated by known experiments in the literature or other databases. These results indicate that our approach can have highly practical relevance to DTI prediction and drug repositioning, and hence advance the drug discovery process.
Availability:
Software and datasets are available on request.
Supplementary information:
Supplementary data are available at Bioinformatics online.
... 25,26 Spironolactone does not have an influence on body weight in PCOS. 26 However, no change 27 or improvement in insulin sensitivity, 26 and no change, 27 deterioration (increase in LDL and decrease in HDL) 28 or improvement (decrease in total and LDL) 15 of lipid profile have all been reported with spironolactone monotherapy in PCOS. ...
Oral contraceptives alone or in combination with antiandrogens are commonly used in the treatment for polycystic ovary syndrome (PCOS). We aimed to determine the effects of ethinyl estradiol/drospirenone (EE-DRSP) plus spironolactone therapy on inflammation and cardiometabolic risk in PCOS.
Prospective cohort study.
Twenty-three lean, normal glucose-tolerant patients with PCOS and 23 age- and body mass index (BMI)-matched healthy control women.
Androgens, high-sensitivity C-reactive protein (hsCRP), homocysteine, lipids, fasting insulin, and glucose levels during a standard 75-g, 2-h oral glucose tolerance test were measured. Patients with PCOS were evaluated before and after receiving EE-DRSP (3 mg/30 μg) plus spironolactone (100 mg/day) for 6 months. Healthy controls were evaluated at baseline only.
hsCRP, homocysteine, lipids, insulin and glucose levels were similar between patient and control groups at baseline. EE-DRSP plus spironolactone increased hsCRP and homocysteine levels in patients with PCOS (0·50 ± 0·28 vs 1·5 ± 1·3 mg/l, P < 0·05 and 13·1 ± 5·2 vs 17·6 ± 5·3 μm, P < 0·05, respectively). BMI, waist-to-hip ratio, LDL, HDL cholesterol and triglycerides, and glucose tolerance did not change. Modified Ferriman–Gallwey hirsutism scores, testosterone levels and free androgen index improved (9·1 ± 4·2 vs 6·2 ± 3·4, P = 0·001; 80·6 ± 31·1 47·8 ± 20·3 ng/dl, P < 0·05; and 10·5 ± 7·4 vs 1·1 ± 0·8, P < 0·001, respectively).
EE-DRSP plus spironolactone therapy in 6 months improves androgen excess in lean PCOS women without any adverse effects on adiposity, glucose tolerance status or lipid profile. However, this combination increases hsCRP and homocysteine levels.
Whilst topical steroids represent one of the most frequently administered treatments for skin and hair diseases, predominantly based on their glucocorticoid receptor-mediated anti-inflammatory effects, the mineralocorticoid effects of topical steroids have received surprisingly little attention. However, the role of mineralocorticoid receptor (MR) signaling is now known to extend beyond the kidney, with human skin, including the hair follicle (HF), expressing the MR. Using microdissected female HFs treated ex vivo with MR agonists and antagonists, we sought to determine the effects of MR-mediated signaling in the cutaneous context. Indeed, not only did the skin and HF epithelium express the MR at both the gene and protein level, but its expression was hair cycle dependent. Moreover, the selective MR antagonist eplerenone promoted hair shaft elongation and hair matrix keratinocyte proliferation whilst delaying catagen (HF regression). These novel observations suggest that the female human HF is sensitive to the inhibition of MR signaling and provide the first evidence that sustained MR signaling may even be required to maintain the growth phase (anagen) of human scalp HFs. Indeed, these data encourage the systematic evaluation of MR agonists and antagonists in human hair growth control so as to identify much-needed, novel anti-hirsutism and/or hair growth-promoting agents, respectively.
Purpose
Some evidence suggests that spironolactone may have a deleterious effect on glucose homeostasis. The objective of this study was to assess whether spironolactone use is associated with a higher risk of developing diabetes in a large cohort of patients with heart failure (HF).
Methods
Two Quebec government administrative databases were used to identify a cohort of hospitalized patients discharged between January 1995 and December 2009 with a primary discharge diagnosis of HF and without secondary discharge diagnosis of diabetes. Patients were categorized as new users of spironolactone and non-users. The primary outcome was defined as new-onset diabetes (NOD) during 5 years of follow-up and was ascertained using ICD codes for diabetes or use of hypoglycemic agents.
Results
Among the 2974 patients that were included in the cohort analysis, 769 were given a new prescription of spironolactone. The incidence rate of NOD was similar among spironolactone users (5.0 per 100 person-years) and non-users (4.9 per 100 person-years). There was no significant association between the use of spironolactone and NOD in the crude, unadjusted model (hazard ratio (HR) 1.01; 95% confidence interval (CI) 0.80–1.28; p = 0.9217), and it remained unchanged in the adjusted Cox proportional hazard model (HR = 0.92; 95% CI = 0.72–1.18; p = 0.5227). The results were consistent with those observed in sensitivity analyses of a 1:3 propensity score-matched cohort (HR = 0.97; CI = 0.76–1.25; p = 0.8169).
Conclusion
We found no evidence supporting the claim that use of spironolactone is associated with a higher risk of diabetes among patients hospitalized for HF.
This chapter discusses the effects of diuretics, such as carbonic anhydrase inhibitors, thiazide and thiazide, loop diuretics, and aldosterone-receptor antagonists. The hypothesis that acetazolamide, by dilating cerebral arterioles but not arteries and reducing pulsatile stretching of the wall of the large arteries and their perivascular sensory nerves, would reduce or prevent headache because of glyceryl trinitrate was tested in 14 healthy volunteers in a randomized, double-blind, cross-over study. Acetazolamide combined with glyceryl trinitrate caused a more delayed headache than glyceryl trinitrate alone. It is suggested that cases of hyponatremia and hypokalemia continue to be reported in patients taking thiazide and thiazide-like diuretics. In a prospective study in 27 hirsute women, mean age 23 years, spironolactone 100 mg/day for three months was associated with a small but significant fall in mean high density lipoprotein cholesterol by 0.19 mmol/L and a significant rise in mean low density lipoprotein cholesterol by 0.72 mmol/L. There were no significant changes in total cholesterol, triglycerides, or fasting blood glucose. Serum concentrations of testosterone, dehydroepiandrosterone, and prolactin fell significantly.
Objective:
To compare the combination spironolactone-norgestimate-ethinyl estradiol in hirsutism with other protocols including the same dose of estrogen.
Study design:
In this open prospective study, 167 women with hirsutism due to polycystic ovary syndrome (PCOS) were randomly assigned to the following treatment protocols: Group A (n = 72): spironolactone 100 mg-norgestimate 250 mcg-ethinyl estradiol 35 microg; Group B (n = 70): cyproterone acetate 12 mg-ethinyl estradiol 35 microg; Group C (n = 25): norgestimate 250 microg-ethinyl estradiol 35 microg.
Results:
The decrease in the hirsutism score was higher in group A than in the other groups (p < 0.001) and comparable in groups B and C. The decrease in acne score, androgen and estradiol levels, and ovary volume was similar in groups A and B. C-reactive protein increase was similar in all groups, but the augmentation of fibrinogen (p = 0.04), triglycerides (p < 0.01), monocyte count (p = 0.04), platelet number (p < 0.001) and mean volume (p = 0.01) was more pronounced in group B than in group A. Low-density lipoprotein/high-density lipoprotein cholesterol ratio decreased in groups A and C.
Conclusion:
Spironolactone-norgestimate-ethinyl estradiol is an effective and well-tolerated combination for the treatment of hirsutism in PCOS, with a favorable influence on lipids and indices of low-grade inflammation.
The renin-angiotensin-aldosterone system has been implicated in the pathogenesis of insulin resistance and nonalcoholic fatty liver disease (NAFLD). The beneficial effect of spironolactone in a mouse model with diabetes and NAFLD has recently been reported. The main aim was assessment of the effect of spironolactone on serum metabolic parameters and insulin resistance in patients with NAFLD.
This study includes preliminary results of a single-centre randomised controlled trial of treatment with vitamin E (group 1, 10 patients) versus spironolactone plus vitamin E (group 2, 10 patients) in biopsy-proven NAFLD. Serum transaminases, lipids, potassium, sodium, glucose and insulin were measured, and homeostatic model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were calculated before and 8( )weeks after baseline assessment.
Insulin was decreased within group 2 (15.3 ± 2.7 at baseline vs. 10.3 ± 5.0 at week 8, p = 0.013). Although no difference in glucose was observed, HOMA-IR significantly decreased (4.4 ± 0.9 vs. 2.8 ± 0.5, respectively, p = 0.047). QUICKI was increased, but not statistically significantly.
Spironolactone and vitamin E combined therapy seems to exhibit a favourable effect on serum insulin and HOMA-IR in patients with NAFLD. If validated in a large-scale clinical trial, it may prove an inexpensive therapeutic approach for the management of NAFLD patients.
Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes.
The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients.
Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.
BACKGROUND: TO determine the frequency and the type of adrenal steroidogenic abnormalities in hirsute women. SUBJECTS AND METHODS: ACTH test was performed during follicular phase in 127 hirsute and 40 normal (control) women. Before ACTH injection we measured in serum by RIA: 170H-pregnenolone (170HP5), 170H-progesterone (170HP4), androstendione (AN), cortisol (CT), 11-deoxycortisol (DCT), dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), total (TT) and free (FT) testosterone, oestradiol (E-2), progesterone (PR), androstendiol glucuronide (AG), LH, FSH and prolactin. After 60 min of ACTH injection 170HP5, 170HP4, AN, DHEA, CT and DCT were measured. Net increment of stimulated steroids and the ratios 170HP5/170HP4, DHEA/AN, 170HP4/CT, 170HP5/CT and DCT/CT were calculated. Pelvic ultrasonographic exploration was done when irregular menses were reported. RESULTS: UP to 31% of the patients presented enzymatic defects in adrenal steroidogenesis. Diagnostic criteria for enzyme defects were established. Late-onset 21-hydroxylase deficiency was diagnosed in 6 (4.5%) patients, HLA typing of these patients demonstrated that 4 out of 6 had B14-DR1. Sixteen women (12.6%) displayed a 170HP4 response and the net increment 2 SD above the normal mean concentration, which are diagnostic criteria for late-onset 21-hydroxylase deficiency carriers. We diagnosed a 3 beta-hydroxysteroid dehydrogenase defect when 170HP5 and DHEA responses, their net increment and the 170HP5/170HP4 and 170HP5/CT ratios were 2 SD above the normal mean after ACTH: 14 women were diagnosed. 11 beta-hydroxylase deficiency diagnosis was made when DCT response, its net increment and the DCT/CT ratio after ACTH were 2 SD above the normal mean: 7 women were detected. Associated biosynthetic defects were described. CONCLUSIONS: One third of our patients with hirsutism presented anomalous response to ACTH, consistent with enzymatic abnormalities in adrenal steroidogenesis.
• Twenty-three men had an increase in serum levels of total cholesterol and triglycerides after starting a diet to lower their serum cholesterol. They had simultaneously started therapy with, or increased the dosage of, chlorthalidone or hydrochlorothiazide for the treatment of hypertension. To evaluate a possible role of the diuretics in the increase in serum lipid concentrations, 11 of the men were randomly allocated to spironolactone therapy for two to four months. After receiving spironolactone, cholesterol levels decreased by 24 mg/dL, whereas cholesterol levels decreased by only 3 mg/dL in the 12 men still receiving chlorthalidone (P<.05). The triglyceride level decreased by 58 mg/dL after the change to spironolactone therapy, whereas it decreased by 10 mg/dL during continued chlorthalidone treatment (P<.05). When the 11 men again received chlorthalidone, their cholesterol levels increased 16 mg/dL, whereas cholesterol levels decreased by 11 mg/dL in men receiving uninterrupted chlorthalidone treatment (P<.01). These observations suggest that spironolactone may be a preferable alternative to thiazide-type agents as first-line therapy for hypertension because of the more favorable influence on serum lipid concentrations.(Arch Intern Med 1984;144:710-714)
BACKGROUND AND METHODS: Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. RESULTS: The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from p
LR: 20071115; JID: 0255562; 0 (Aldosterone Antagonists); 0 (Angiotensin-Converting Enzyme Inhibitors); 0 (Diuretics); 52-01-7 (Spironolactone); CIN: ACP J Club. 2000 Jan-Feb;132(1):2; CIN: N Engl J Med. 1999 Sep 2;341(10):753-5. PMID: 10471464; CIN: N Engl J Med. 2000 Jan 13;342(2):132-3; author reply 133-4. PMID: 10636751; CIN: N Engl J Med. 2000 Jan 13;342(2):132; author reply 133-4. PMID: 10636750; CIN: N Engl J Med. 2000 Jan 13;342(2):133; author reply 133-4. PMID: 10636753; CIN: N Engl J Med. 2000 Jan 13;342(2):133; author reply 133-4. PMID: 10636752; CIN: N Engl J Med. 2001 Sep 20;345(12):925-6. PMID: 11565535; CIN: N Engl J Med. 2001 Sep 27;345(13):998; author reply 998-9. PMID: 11575300; CIN: N Engl J Med. 2003 Jul 3;349(1):88-9; author reply 88-9. PMID: 12840098; CIN: N Engl J Med. 2003 Jul 3;349(1):88-9; author reply 88-9. PMID: 12846223; CIN: N Engl J Med. 2003 Jul 3;349(1):88-9; author reply 88-9.. PMID: 12846224; CIN: N Engl J Med. 2004 Aug 5;351(6):526-8. PMID: 15295043; CIN: Nephrol Dial
Fifty-one hirsute women were randomly treated for nine months with ethinyl estradiol 35 ug plus norethindrone 0.4 mg or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate if they needed contraception or spironolactone 200 mg daily if they did not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the two oral contraceptives but not with spironolactone. While systolic blood pressure was lower with spironolactone, fasting insulin levels were higher as opposed to either low-dose oral contraceptive preparation. Ethinyl estradiol 30 ug plus 1.5 mg norethindrone acetate lowered 3-alpha-diol glucuronide levels, yet ethinyl estradiol 35 ug plus norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey Scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.
PIP
51 hirsute women were randomly treated for 9 months with ethinyl estradiol (EE) 35 mcg + norethindrone 0.4 mg or 30 mcg EE + 1.5 mg norethindrone acetate if contraception was necessary or spironolactone 200 mg daily if it was not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the 2 oral contraceptives (OCs) but not with spironolactone. While systolic blood pressure was lower with it, fasting insulin levels were higher as opposed to either low-dose OC preparation. EE 30 mcg + 1.5 mg norethindrone acetate lowered 3-alpha-diol-glucuronide levels; however, E 35 mcg + norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.
The metabolic side effects of thiazide diuretics are believed to be responsible for the failure of thiazide diuretics to reduce cardiovascular morbidity in patients with hypertension. However, the decrease in the incidence of osteoporotic fractures that are associated with thiazide administration may be relevant in elderly patients with arterial hypertension. Spironolactone (SP) appears not to influence the metabolic risk profile of the patient with hypertension, and no studies have examined its effect on calcium metabolism. Therefore, in 22 patients with mild to moderate essential hypertension, the authors performed a parallel, randomized, double-blind, placebo-controlled study that compared the effects on serum urate and lipid, potassium, magnesium, and calcium metabolism of hydrochlorothiazide (HC) (mean [+/- SD] dose, 72 +/- 26 mg/d) and SP (144 +/- 53 mg/d) during a 52-week period. As compared with placebo, HC significantly increased serum urate and total cholesterol concentrations, and decreased serum potassium levels. SP did not affect serum urate or cholesterol levels but increased serum potassium concentrations. Neither diuretic significantly modified magnesium metabolism. Little changes were seen in serum calcium levels during HC or SP treatment, whereas urinary calcium excretion was significantly decreased by HC (mean decrease, 45%; P less than .01) or SP (40%; P less than .01). The authors conclude that SP, in addition to its potassium-sparing properties, has a calcium-sparing effect that may be beneficial for patients in whom reduction of urinary calcium excretion has a therapeutic value.
The effect of spironolactone on adrenal androgen and cortisol production was studied in six hirsute women. Hirsute women were evaluated before and 1 month after receiving 200 mg of spironolactone daily. Basal levels of serum androgens, 17-hydroxyprogesterone (17-OHP), cortisol (F), corticosteroid-binding globulin, and plasma adrenocorticotropic hormone (ACTH) were normal and did not change with therapy. The delta maximum (delta max) responses after dexamethasone suppression and ACTH administration of dehydroepiandrosterone (DHEA), androstenedione (delta 4A), 17-hydroxypregnenolone, and 17-OHP were similar in hirsute women and ovulatory control subjects. After spironolactone administration, the delta max DHEA response was unchanged, whereas the delta max delta 4A response was decreased (P less than 0.05). The delta max ratios of DHEA/delta 4A and 17-OHP/delta 4A were significantly increased after spironolactone in hirsute women, which suggested inhibitions of 3 beta-ol-dehydrogenase-isomerase and delta 4 17,20 desmolase activities. A significant reduction in delta max F occurred after spironolactone administration (P less than 0.05). Although baseline 11-desoxycortisol (S) and the plasma S/ACTH ratio were unaltered, the delta max S/F ratio increased after treatment (P less than 0.01), suggesting an inhibition of 11 beta-hydroxylase activity. Inhibition of adrenal androgen production occurs with spironolactone, but only serum levels of delta 4A are decreased, whereas DHEA and its sulfate (DHEA-S) levels remain unchanged.
The long-term efficacy and tolerance of spironolactone in essential hypertension was evaluated among 20,812 patients referred to the Broussais and St. Joseph systemic hypertension clinics between 1976 and 1985 by using information prospectively collected in the computerized ARTEMIS data bank. In 182 patients (51 men, 131 women) treated with spironolactone alone during a mean follow-up period of 23 months, a mean dose of 96.5 mg decreased systolic and diastolic blood pressure (BP) by 18 and 10 mm Hg, respectively, below pretherapeutic levels. The BP decrease was greater with doses of 75 to 100 mg (12.4% and 12.2%) than with doses of 25 to 50 mg (5.3 and 6.5%, p less than 0.001), but no additional decrease was found with doses above 150 mg. Plasma creatinine level increased modestly (8.3 mumol/liters), as did plasma potassium level (0.6 mmol/liters) (both p less than 0.001); uric acid level increased, but not significantly (10.5 mumol/liter). Fasting blood glucose and total cholesterol levels did not change, triglyceride levels increased slightly (0.1 mmol/liter, p less than 0.05). These changes were similar in both sexes and were not influenced by length of follow-up. Among the 699 men prescribed spironolactone alone or in association with another antihypertensive treatment, 91 cases of gynecomastia developed (13%). Gynecomastia was reversible and dose-related; at doses of 50 mg or less the incidence was 6.9%, but 52.2% for doses of 150 mg or higher. Despite limitations inherent in the interpretation of data banks, it is concluded that spironolactone administered in daily practice reduced BP without inducing adverse metabolic adverse effects and that in patients with essential hypertension, doses should be kept below 100 mg.
Spironolactone, an aldosterone antagonist, was given in a daily dose of 100 mg to 15 patients with primary hypertension for one year. Fasting levels of lipids, uric acid, glucose, insulin, potassium and growth hormone were measured before and after 6 and 12 months of treatment. Total cholesterol, LDL cholesterol, glucose, potassium and growth hormone were unchanged, HDL cholesterol fell from (mean +/- SD) 1.5 +/- 0.6 to 1.1 +/- 0.3 mmol/l (p less than 0.05) after 6 months of treatment and remained lowered (1.0 +/- 0.3 mmol/l) (p less than 0.01) after 12 months of treatment. There was a transient fall after 6 months of treatment in triglycerides from 2.4 +/- 1.5 to 2.0 +/- 1.1 mmol/l (p less than 0.05), uric acid from 380 +/- 73 to 342 +/- 58 mumol/l (p less than 0.05) and an increase in insulin from 16 +/- 9.5 to 28.6 +/- 26.8 mU/l (p less than 0.05). The blood glucose curves above fasting levels after glucose loading were unchanged during spironolactone treatment, whereas the area under the net insulin curve was higher after 6 months of treatment (163 +/- 103 mU X h/l) than before treatment (105 +/- 71 mU X h/l), indicating a small and transient insulin resistance. Thus, spironolactone impaired the glucose tolerance transiently and gave small and almost transient changes in fasting serum lipid and uric acid levels.
Twenty-three men had an increase in serum levels of total cholesterol and triglycerides after starting a diet to lower their serum cholesterol. They had simultaneously started therapy with, or increased the dosage of, chlorthalidone or hydrochlorothiazide for the treatment of hypertension. To evaluate a possible role of the diuretics in the increase in serum lipid concentrations, 11 of the men were randomly allocated to spironolactone therapy for two to four months. After receiving spironolactone, cholesterol levels decreased by 24 mg/dL, whereas cholesterol levels decreased by only 3 mg/dL in the 12 men still receiving chlorthalidone (P less than .05). The triglyceride level decreased by 58 mg/dL after the change to spironolactone therapy, whereas it decreased by 10 mg/dL during continued chlorthalidone treatment (P less than .05). When the 11 men again received chlorthalidone, their cholesterol levels increased 16 mg/dL, whereas cholesterol levels decreased by 11 mg/dL in men receiving uninterrupted chlorthalidone treatment (P less than .01). These observations suggest that spironolactone may be a preferable alternative to thiazide-type agents as first-line therapy for hypertension because of the more favorable influence on serum lipid concentrations.
The authors examined the effect of three months' treatment with spironolactone in 34 women with polycystic ovary syndrome. In all patients a significant decrease in hirsutism was noted as well as restoration of a regular although anovulatory menstrual pattern. Plasma luteinizing hormone and follicle-stimulating hormone levels remained unchanged after spironolactone treatment; however, prolactin levels were lowered in both women with normal and those with elevated basal levels. Plasma testosterone, androstenedione, and dehydroepiandrosterone sulfate levels were decreased after three months of therapy. No side effects were observed. Plasma electrolytes and liver function tests were normal during the entire time of treatment. This therapy is recommended as initial nontoxic but effective treatment for women with polycystic ovary syndrome who are hirsute and have menstrual disturbances.
In a prospective, double-blind, intraindividual, cross-over, placebo-controlled multicenter study, clinical and biochemical effects of once daily postprandial dose regimens of 50, 100, and 200 mg spironolactone were investigated in 45 outpatients with primary hypertension, WHO (World Health Organization) Stage I-II. Each of the three active therapy periods, which were randomly allocated to patients, were of 2 months' duration, with intervening placebo periods, Clinical and biochemical parameters, including furosemide-stimulated plasma renin activity (PRA), were recorded at regular intervals. All three spironolactone doses resulted in statistically significant blood pressure (BP) reductions independent of initial pretreatment levels and yielded satisfactory BP control in more than half of the patients. The 200 mg daily dose of spironolactone was found to be more effective than 50 but not 100 mg. When, correlating blood pressure response (delta MAP) to PRA, the profiling for positive spironolactone responders was characterized by high age and low PRA, irrespective of sex. Spironolactone therapy resulted in decreased serum sodium and magnesium values; potassium, creatinine, urate, and triglyceride levels were increased. However, all treatment values were within normal ranges. Side effects were infrequent and mainly of endocrine nature.
Polycystic ovary syndrome is the most common endocrinological problem associated with hirsutism. The objective of this study was to compare four different treatment modalities for hirsutism related to this syndrome. Pelvic ultrasonography was performed on all patients who were referred to our Reproductive Endocrinology Outpatient Clinic because of complaints of hirsutism. After exclusion of hyperandrogenism caused by endocrine abnormalities other than polycystic ovary syndrome, 141 patients were included in the study. Patients were divided into four groups in regard to the drug chosen for treatment. Group 1 (n = 48) received low-dose combined oral contraceptive. Group 2 (n = 65) was treated with cyproterone acetate 100 mg daily for the first 10 days of a 21-day cycle with an oral contraceptive containing 2 mg cyproterone acetate, Group 3 (n = 12) with spironolactone (100-200 mg daily) and Group 4 (n = 16) with ketoconazole (400 mg daily). All patients were followed frequently with respect to side-effects, hirsutism scoring, and lipid and hormonal levels. All four drug regimens were effective in the treatment of hirsutism related to polycystic ovary syndrome, but the most effective seemed to be ketoconazole. The decrement level in hirsutism scoring was the largest in the ketoconazole group, followed by the cyproterone, oral contraceptive and spironolactone groups (34.6 +/- 2.2%, 20.1 +/- 2.7%, 18.1 +/- 2.7% and 12.8 +/- 3.7%, respectively, p < 0.05). Although high-density lipoprotein-cholesterol levels increased in all groups, this increment was smaller in Group 4 than in Groups 1 and 2 (5.1 +/- 2.8%, 34.1 +/- 5.5% and 29.1 +/- 4.9%, respectively, p < 0.05), but not statistically different from that in Group 3 (22.3 +/- 5.9%). The free testosterone levels decreased after treatment in all groups, but the decrement ratios did not differ significantly among groups, although the decrease in free testosterone levels with treatment seemed to be higher in the ketoconazole group than in Groups 1, 2 and 3 (57.0 +/- 2.5%, 22.7 +/- 10.2%, 26.7 +/- 6.5% and 9.5 +/- 19.9%, respectively). In conclusion, ketoconazole seems to be an excellent alternative to more-recognized therapies, but its effect on lipoprotein profile requires further study, because the hyperandrogenism, and the other problems related to hyperandrogenism besides hirsutism, should also be treated.
To examine the influence on aromatase and sulfatase pathways in estrogen pool by drugs reported to cause gynecomastia as the side effect, 29 ethical drugs were incubated with human placental microsomes as an enzyme source. The percent inhibition of drugs on aromatase pathway was obtained by sum of the velocity constants of two products, estrone (E1) and estradiol (E2) from testosterone (T) as the substrate, and that on sulfatase pathway was obtained as the velocity constant of production of E1 from estrone sulfate (E1S). Although several drugs including ketoconazole showed a significant inhibition effect on aromatase pathway at their non-clinical over-dose concentration (100 microM), no influence on the inhibition was observed in any drugs at their approximately therapeutic concentration (1 microM). However, several drugs including spironolactone gave the product ratio (E2/E1) having higher value than that of the control, the result means spironolactone inhibits the conversion of E2 to E1. No inhibitory effect of the drugs tested on estrogen production from E1S (sulfatase pathway) was confirmed. The results suggest the possibility that the tested drugs known to cause gynecomastia have no inhibitory effect essentially on aromatase and sulfatase pathways.
Since the isolation and purification of aldosterone from adrenal extracts 50 years ago (Experientia 9 (1953) 33), scientists have learned a great deal about how and where aldosterone acts, the factors that control its release, what is its role in the pathophysiology of cardiovascular disease, how to make and study aldosterone antagonists, and for what medical purposes these agents are useful. In this paper, we will discuss the evolution of aldosterone antagonists from the relatively nonselective spironolactone (Aldactone), to the highly selective eplerenone (Inspra). Eplerenone represents a molecule with improved steroid receptor selectivity and pharmacokinetic properties in man compared to spironolactone. Recent clinical results have demonstrated that these improvements translate into tolerability and efficacy in patients with cardiovascular disease.
This prospective clinical trial was designed to assess the effects of a long-term therapy with spironolactone, with and without dietary-induced weight-loss, on clinical features, lipid profile and insulin levels in women with polycystic ovary syndrome (PCOS). Twenty-five patients (range of age 16-32 yr; 13 lean and 12 overweight) fulfilling formal diagnostic criteria for PCOS (oligomenorrhea and/or amenorrhea, biochemical and/or clinical evidence of hyperadrogenism) were studied at baseline and then received oral spironolactone (100 mg/die) for 12 months; association with lifestyle modifications was recommended to all over-weight patients. Clinical, endocrine and metabolic parameters [oral glucose tolerance test (OGTT), lipid profile] were measured at baseline and at the end of the antiandrogen treatment. The therapy was associated with a significant average decline of triglycerides in overweight subjects and with increased HDL-cholesterol levels in lean patients. The insulin levels at 60 min during OGTT, homeostasis model assessment-insulin resistance and area under curve of insulin were significantly lowered in overweight women after 12 months of spironolactone and weight loss and no negative changes in insulin secretion and sensitivity were observed in PCOS women after pharmacological treatment alone. The efficacy of spironolactone on the androgenic clinical aspects of PCOS has been confirmed in this study. Furthermore, our data show that long-term treatment with spironolactone exerts no negative effects on lipoprotein profile and glucose metabolism; more relevant beneficial effects on glucose and lipid metabolism were observed when the antiandrogen was associated with weight loss in overweight PCOS women.
To evaluate the lipid profile, insulin resistance and vasomotricity, and the interaction between these factors, in postmenopausal women receiving hormone therapy.
A prospective, randomized, double-blind study was carried out in which 77 postmenopausal women received one of the three treatment regimens: (A) 2mg oral micronized estradiol (E2) (n=25); (B) 2mg oral E2+1mg oral norethisterone acetate (NETA) (n=28); or C) placebo (n=24), daily for 6 months. Evaluations were carried out at baseline and at the end of treatment on lipid and lipoprotein profiles, homeostasis model assessment of insulin resistance (HOMA-IR) and pulsatility index (PI) of the internal carotid artery by Doppler ultrasonography.
Mean increases of 15.6% and 2.4% and a reduction of 6.4% in high-density lipoprotein (HDL) levels were found for the E2, E2+NETA and placebo groups, respectively. Reductions of 9.5% and 3.7% and an increase of 12.1% in low-density lipoprotein (LDL), and reductions of 20.0% and 3.8% and an increase of 28.8% in the LDL:HDL ratio were found for the E2, E2+NETA and placebo groups, respectively (p<0.001 in all cases). Insulin levels and HOMA-IR decreased 12.8% and 12.3% in the E2 group and increased 12.9% and 16.0% in the E2+NETA group (p<0.05), respectively. Carotid PI following treatment was 1.18+/-0.23, 1.38+/-0.20 and 1.41+/-0.21 for the E2, E2+NETA and placebo groups, respectively (p=0.0006).
Oral estrogen therapy led to an improvement in lipid profile, insulin resistance and carotid blood flow, which was cancelled when NETA was associated.
Diagnostic criteria for polycystic ovary syndrome: towards a rational approach
- Jk Zawadski
- A Dunaif
The effects of spironolactone on adrenal steroidogenesis in hirsute women
- Searafini P