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Metabolic impact of current therapeutic strategies in Polycystic Ovary Syndrome: a preliminary study.
De Diego, MV, Gómez-Pardo, O, Groar, JK, López-Escobar, A, Martín-Estal, I, Castilla-Cortázar, I, Rodríguez-Zambrano, MÁ
Archives of gynecology and obstetrics. 2020;(5):1169-1179
Abstract
PURPOSE To investigate the metabolic impact of currently used therapies in polycystic ovary syndrome (PCOS). METHODS This is an observational, retrospective and transversal protocol. A small cohort of 133 patients, aged 14-48 years, diagnosed with PCOS was divided into four experimental groups: 1) untreated PCOS patients (n = 51); 2) PCOS patients treated with one of the following therapies (n = 82): a) combined oral contraceptives (COC, n = 35); b) metformin (n = 11); and c) inositols (n = 36). RESULTS Although only < 10% of patients included in this cohort can be strictly encompassed in the development of metabolic syndrome, approximately 20% had insulin resistance. In PCOS patients, COC treatment modified the hormonal profile and worsened lipid parameters (increasing cholesterol and triglyceride levels) and insulin resistance, whereas inositol therapies improved significantly insulin resistance and glycosylated hemoglobin, reducing cholesterol and triglyceride levels. In these women, obesity was associated with greater alterations in lipid and glycemic metabolism and with higher blood pressure levels. PCOS patients with phenotype A presented vaster alterations in lipid metabolism and higher values of glycosylated hemoglobin as well as blood pressure compared to other PCOS phenotypes. CONCLUSIONS Results in this paper suggest that inositol therapies (alone or combined with COC) are the most useful therapies with the best benefits against PCOS symptoms. Thus, integrative treatment may become a more efficient long-term choice to control PCOS symptoms. Furthermore, obesity can be considered as an adverse symptom and calorie restriction a key element of combined treatment in PCOS, not only for fertility management but also in long-term metabolic sequelae.
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Reduced circulating levels of chemokine CXCL14 in adolescent girls with polycystic ovary syndrome: normalization after insulin sensitization.
García-Beltran, C, Cereijo, R, Quesada-López, T, Malpique, R, López-Bermejo, A, de Zegher, F, Ibáñez, L, Villarroya, F
BMJ open diabetes research & care. 2020;(1)
Abstract
OBJECTIVE CXCL14 (C-X-C motif chemokine ligand-14) is a chemokine released by active brown fat, showing protective effects against insulin resistance in experimental models. Polycystic ovary syndrome (PCOS) in adolescent girls is usually related to hepato-visceral fat excess and insulin resistance, and associates with comorbidities such as type 2 diabetes. Treatment with a low-dose combination of one antiandrogen and antimineralocorticoid drug (spironolactone) and two insulin sensitizers (pioglitazone/metformin) (SPIOMET) is particularly effective in improving these metabolic derangements. Adipose tissue may be involved in the metabolic alterations of PCOS, and it is a likely target of therapeutic action. We investigated the alterations in CXCL14 levels and the effects of drugs composing SPIOMET treatment on CXCL14 in human adipocytes. RESEARCH DESIGN AND METHODS We studied 51 adolescent patients with PCOS and 21 age-matched healthy controls. Thirty-one adolescent patients with PCOS under SPIOMET or oral contraception-based treatment were also studied. For studies in vitro, Simpson Golabi Behmel Syndrome (SGBS) adipose cells were used. Gene expression for CXCL14 and other genes was quantified using quantitative real-time PCR. The levels of CXCL14 and adipokines in serum and cell culture media were determined by ELISA. RESULTS Serum CXCL14 levels are reduced in patients with PCOS. One-year SPIOMET treatment normalized CXCL14 concentrations and improved the metabolic status of patients with PCOS. Pioglitazone induced CXCL14 expression in differentiating human SGBS adipocytes, in parallel with the induction of marker genes of brown adipogenesis. Spironolactone induced CXCL14 expression and release in differentiated human adipocytes. CONCLUSION Insulin sensitization with SPIOMET normalizes the abnormally low levels of CXCL14 in girls with PCOS. This is consistent with the effects of pioglitazone and spironolactone inducing CXCL14 expression and promoting a brown-like phenotype in adipocytes. CXCL14 may be a novel biomarker for PCOS as well as a potential mediator of the beneficial effects of the SPIOMET combination and may hold promise as a therapeutic modulator of the disorder. TRIAL REGISTRATION NUMBERS ISRCTN29234515 and ISCRCTN11062950.
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Comparing the individual effects of metformin and rosiglitazone and their combination in obese women with polycystic ovary syndrome: a randomized controlled trial.
Li, Y, Tan, J, Wang, Q, Duan, C, Hu, Y, Huang, W
Fertility and sterility. 2020;(1):197-204
Abstract
OBJECTIVE To compare the effects of metformin, rosiglitazone, and their combination in obese polycystic ovary syndrome (PCOS) patients with insulin resistance. DESIGN Prospective randomized controlled trail. SETTING Tertiary teaching hospital. PATIENT(S): Obese Chinese women (body mass index [BMI] ≥25 kg/m2) with insulin resistance who fulfilled the Rotterdam criteria of PCOS. INTERVENTION(S): In group 1, 68 patients administered metformin (1,500 mg/day); in group 2, 67 patients administered rosiglitazone (4 mg/day); in group 3, 69 patients administered metformin (1,000 mg/day) and rosiglitazone (4 mg/day) for 6 months, all with the same diet and regular exercise lifestyle recommendation. MAIN OUTCOME MEASURE(S): Average menstrual interval, anthropometric measurements, androgen-related parameters, and metabolic features of insulin, carbohydrates, and lipids, with intention-to-treat analysis. RESULT(S): The baseline parameters showed no statistically significant differences. After the 6-month treatment, most participants showed an improved menstrual pattern. There were statistically significant decreases in acne scores, weight, BMI, waist circumference, waist-to-hip ratio, and serum testosterone. The metabolic indexes of insulin, carbohydrates, and lipids were improved obviously compared with the baseline in each group. Among the three groups, the patients administered 1,500 mg/day metformin experienced greater reductions in weight. However, the rosiglitazone users (alone or combined with metformin) showed a more notable decline in total cholesterol and triglyceride levels. CONCLUSION(S): Considering the benefits of metformin on weight loss, high-dose metformin (1,500 mg/day) along with lifestyle modification should be recommended for obese, insulin-resistant women with PCOS. Rosiglitazone alone or combined with low-dosage metformin plus lifestyle modification should be considered for the women with abnormal lipid profiles. CLINICAL TRIAL REGISTRATION NUMBER ChiCTR-TRC-13003642 (Chinese Clinical Trial Registry).
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Effect of clomiphene citrate treatment on the Sertoli cells of dysmetabolic obese men with low testosterone levels.
Pelusi, C, Fanelli, F, Baccini, M, Triggiani, V, Bartolomeo, N, Carbone, MD, De Pergola, G, Di Dalmazi, G, Pagotto, U, Pasquali, R, et al
Clinical endocrinology. 2020;(1):38-45
Abstract
BACKGROUND Clomiphene citrate (CC) has been shown to restore the hypothalamic-pituitary-gonadal (HPG) axis by increasing testosterone (T) levels to physiological levels in patients with dysmetabolic conditions such as obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). However, the data are unclear regarding the effects on Sertoli cell (SC) function. AIM: To study SC function by assessing Inhibin B (IB) and anti-Mullerian hormone (AMH) levels at baseline and after 3 months of CC treatment. MATERIALS AND METHODS This is an ancillary study of a cross-over, randomised, double-blind, placebo-controlled trial performed to evaluate androgen response to CC treatment in dysmetabolic obese subjects with low T levels treated with metformin. We evaluated SC function by assessing IB and AMH levels at baseline and after 3 months of each treatment in ten dysmetabolic obese subjects with low T levels. In all subjects, the influence of the clinical characteristics, metabolic and hormonal baseline parameters on SC and Leydig (LC) function, evaluated respectively with AMH, IB, follicle-stimulating hormone (FSH) and T levels, was tested. RESULTS No significant changes were observed for IB and AMH concentrations after each treatment period. Whereas T and oestradiol (E2) levels were shown to be significantly higher in the CC plus metformin phase (CC/Met) only. No clinical, metabolic or hormonal parameters showed significant effects on serum AMH at baseline or after treatments. However, baseline T, dihydrotestosterone (DHT) and E2 positively affected IB levels during CC/Met therapy (P = .003, P = .038 and P = .049, respectively). Baseline leptin and FSH had a negative (P = 031) and positive (P = .048) respectively role on T levels during CC/Met, as they were statistically significant compared to the placebo period (Plac/Met). CONCLUSION Unlike the LC activity, CC was unable to influence SC function, as shown by the lack of IB and AMH serum modifications, thus suggesting an intrinsic nonreversible defect of SC cells in patients with dysmetabolic conditions.
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The effectiveness of metformin, oral contraceptives, and lifestyle modification in improving the metabolism of overweight women with polycystic ovary syndrome: a network meta-analysis.
Wang, A, Mo, T, Li, Q, Shen, C, Liu, M
Endocrine. 2019;(2):220-232
Abstract
PURPOSE We designed a network meta-analysis that investigated relatively different interventions that included the effects of metformin, oral contraceptives, and lifestyle modification on the metabolic parameters of patients with polycystic ovary syndrome. In addition, we searched for eligible interventions that improved the metabolism of glucose and lipids. METHODS We searched the PubMed, EMBASE, and Cochrane Central databases from inception to May 2018. Publication types that were categorized as randomized controlled trials met our inclusion criteria. The main outcome included the homeostasis model assessment of insulin resistance, total cholesterol, low-density lipoprotein cholesterol, and total triglycerides. We performed both a pairwise meta-analysis and a network meta-analysis to evaluate the mean difference value and 95% credibility intervals, and we calculated the surface cumulative rank curve. RESULTS There were a total of 12 kinds of interventions: metformin, 2 mg cyproterone acetate plus 0.05 mg ethinylestradiol (EE/CA), 0.15 mg desogestrel plus 0.03 mg ethinylestradiol (EE/DSG), and 3 mg drospirenone plus 0.03 mg ethinylestradiol (EE/DRSP), lifestyle, exercise, diet, metformin + lifestyle, metformin + diet, EE/CA + lifestyle, metformin + EE/CA, and EE/DRSP + lifestyle from the 20 eligible RCTs that were included in this study. Our meta-analysis results showed that metformin + lifestyle (MD = -2.04, 95% CrI = -3.64 to -0.41), EE/CA + lifestyle (MD = -2.23, 95% CrI = -4.11 to -0.35), and EE/DRSP + lifestyle (MD = -2.59, 95% CrI = -4.66 to -0.50) resulted in lower in the levels of total cholesterol. Women treated with metformin + lifestyle (MD = -1.82, 95% CrI = -2.88 to -0.79), EE/CA + lifestyle (MD = -2.25, 95% CrI = -3.58 to -1.08), or EE/DRSP + lifestyle (MD = -2.29, 95% CrI = -3.69 to -1.07) exhibited significantly lower low-density lipoprotein cholesterol when compared with the placebo group. There was no significant difference between any of the interventions compared with a placebo in the levels of homeostasis model assessment of insulin resistance and total triglycerides. The surface cumulative rank curve revealed that metformin + lifestyle might be the best intervention with respect to the improvement of the homeostasis model of assessment insulin resistance and EE/DRSP + lifestyle appeared to be the best intervention for the reduction of total cholesterol and low-density lipoprotein cholesterol. Moreover, the metformin + diet intervention was more effective in reducing the level of total triglycerides. CONCLUSIONS For overweight polycystic ovary syndrome patients, our evidence revealed that EE/CA and EE/SRSP combined with metformin or lifestyle changes can reduce the adverse effects on glucose and lipid metabolism of the use of oral contraceptive agents alone. Conventional PCOS treatments, such as metformin, EE/CA, and EE/DRSP, combined with lifestyle control can be particularly effective in improving the homeostasis model assessment of insulin resistance and lipid metabolism.
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Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials.
Facchinetti, F, Orrù, B, Grandi, G, Unfer, V
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2019;(3):198-206
Abstract
Metformin (MET), the most commonly used insulin sensitizer, is the reference off-label drug for the treatment of polycystic ovary syndrome (PCOS), worldwide. However, its use may be limited mainly by gastrointestinal adverse effects. Myo-inositol (MI), a well-recognized food supplement, also represents an evidence-based treatment for PCOS women, popular in many countries. Our aim is to provide a systematic review of the literature and a meta-analysis which compares these two treatments, for their short-term efficacy and safety in PCOS patients. Systematic review and meta-analysis of randomized clinical trials (RCTs). RCTs were identified from 1994 through 2017 using MEDLINE, Cochrane Library, PubMed, and ResearchGate. Included studies were limited to those one directly comparing MET to MI on several hormones changes. Standardized mean difference (SMD) or risk ratios (RRs) with 95% CIs were calculated. Changes in fasting insulin was the main outcome of measure. Six trials with a total of 355 patients were included. At the end of treatment, no difference between MET and MI was found on fasting insulin (SMD=0.08 µU/ml, 95% CI: -0.31-0.46, p=.697), HOMA index (SMD =0.17, 95% CI: -0.53-0.88, p=.635), testosterone (SMD= -0.01, 95% CI: -0.24-0.21, p=.922), SHBG levels (SMD= -0.50 nmol/l, 95% CI: -1.39-0.38, p=.263) and body mass index (BMI) (SMD= -0.22, 95% CI: -0.60-0.16, p=.265). There was strong evidence of an increased risk of adverse events among women receiving MET compared to those receiving MI (RR =5.17, 95% CI: 2.91-9.17, p<.001). No differences were found in the effect of MET and MI on short-term hormone changes. The better tolerability of MI makes it more acceptable for the recovery of androgenic and metabolic profile in PCOS women.
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Effect of Metformin on Microvascular Endothelial Function in Polycystic Ovary Syndrome.
Heidari, B, Lerman, A, Lalia, AZ, Lerman, LO, Chang, AY
Mayo Clinic proceedings. 2019;(12):2455-2466
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Abstract
OBJECTIVE To investigate the factors that are associated with the effect of metformin on endothelial dysfunction in polycystic ovary syndrome (PCOS). PATIENTS AND METHODS From March 24, 2014, to November 18, 2016, 48 women with PCOS were randomly assigned to 1500 mg/d of metformin (N=29) or no treatment (N=13) for 3 months; 42 patients (29 in the initial treatment group and 13 in the no treatment group) completed the study. Study variables were measured at baseline and after 3 months. Participants who did not receive metformin initially were then treated with metformin for another 3 months, and study variables were measured again. Endothelial function was measured as reactive hyperemia-peripheral arterial tonometry (RH-PAT) from the index finger. RESULTS The age and baseline endothelial function (mean ± SD) of the participants were 32.7±6.9 years and 1.8±0.5, respectively. No notable change was observed in endothelial function after 3 months with metformin compared with no treatment. However, after stratifying participants who received metformin based on baseline endothelial function, there was a significant improvement following metformin treatment in participants with abnormal baseline endothelial function (1.3±0.3 vs 1.7±0.3; P<.001) but not in those with normal baseline endothelial function (2.1±0.4 vs 2.0±0.5; P=.11). CONCLUSION Metformin improves endothelial function in women with PCOS and endothelial dysfunction independent of changes in glucose metabolism, dyslipidemia, or presence of prediabetes. Metformin has a direct effect on endothelial function in PCOS, and measurement of endothelial function can stratify and follow response to metformin treatment in PCOS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02086526.
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Circulating zinc-α2-glycoprotein is reduced in women with polycystic ovary syndrome, but can be increased by exenatide or metformin treatment.
Zheng, S, Liu, E, Zhang, Y, Long, T, Liu, X, Gong, Y, Mai, T, Shen, H, Chen, H, Lin, R, et al
Endocrine journal. 2019;(6):555-562
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Abstract
The study was to investigate circulating zinc-α2-glycoprotein (ZAG) concentrations in women with PCOS, and changes in ZAG levels after exenatide or metformin treatment. One hundred eighty-two women with polycystic ovary syndrome (PCOS) who met the 2003 Rotterdam diagnostic criteria and 150 controls without PCOS were recruited. We partitioned women with PCOS into groups according to body mass index or blood glucose concentrations, determined serum ZAG, anthropometric parameters, metabolic and endocrine indicators, and inflammatory markers, and statistically analyzed the results. Eighty-two overweight/obese subjects of the recruited women with PCOS were then randomly assigned to groups administered either 12 weeks of exenatide injection (10 μg b.i.d.) or oral metformin (1,000 mg b.i.d.). Circulating ZAG levels were determined after 12 weeks of treatment. The results showed that circulating ZAG was significantly lower in PCOS women than in healthy women (p < 0.01). Overweight/obese women and those with higher blood glucose levels had lower circulating ZAG. After 12 weeks of exenatide or metformin treatment, there were significant increases (p < 0.01) in circulating ZAG in both treatment groups (the exenatide baseline level was 46.54 ± 2.38 ng/mL vs. 56.41 ± 2.02 ng/mL after treatment, p < 0.01; metformin baseline was 47.81 ± 2.14 ng/mL vs. 55.67 ± 2.01 ng/mL after treatment, p < 0.01), however there was no statistical difference between the 2 treatments (p > 0.05). Circulating ZAG is closely related to PCOS and could be an important adipokine involved in the occurrence and development of PCOS. ZAG might possibly be applicable as a new observational indicator in the treatment of PCOS.
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Should metformin still be the first-line of treatment in type 2 diabetes mellitus? A comprehensive review and suggested algorithm.
Bin Hussain, AK, Abdelgadir, E, Rashid, F, Al Haj, A, Thadani, P, Bashier, AMK
Diabetes & metabolic syndrome. 2019;(3):1935-1942
Abstract
For more than a century, the high occurrences of coronary and peripheral artery diseases in diabetes mellitus patients has been well recognised; despite that, the ability to improve CV event rates by optimizing glycaemic control has remained elusive. Nevertheless, the last decade has seen several cardiovascular outcome clinical trials (CVOTs) of many antihyperglycemic agents that reported promising results for cardiovascular and renal outcomes. This leads to a hot debate on the ideal drug choice for first-line treatment in T2DM. The purpose of this paper is to review the evidence supporting the use of metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors and incretin-based therapies for the management of individuals with T2DM and, discuss the rationale for selection.
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A randomized controlled trial of Mediterranean diet and metformin to prevent age-related diseases in people with metabolic syndrome.
Pasanisi, P, Gargano, G, Gaetana Di Mauro, M, Cortellini, M, Casagrande, A, Villarini, A, Bruno, E, Roveda, E, Saibene, G, Venturelli, E, et al
Tumori. 2018;(2):137-142
Abstract
PURPOSE Age-related non-communicable chronic diseases (ArCDs) are the leading cause of mortality. The major metabolic risk factor for their development is the metabolic syndrome (MetS), defined as a clustering of risk factors of metabolic origin such as abdominal obesity, high blood pressure, dyslipidemia and high fasting glycemia. There is increasing observational and experimental evidence that improving diet and the use of metformin (a calorie-restriction mimetic drug) may modify the risk of developing MetS and ArCD. We designed a phase III randomized controlled trial (the Me.Me.Me trial) to evaluate the effect of a comprehensive lifestyle intervention (including moderate physical activity and a Mediterranean-macrobiotic diet) and the effect of treatment with metformin in the prevention of ArCDs in healthy people with MetS. This report describes the scientific protocol of this trial. METHODS The design of the study is 2 × 2 factorial with 2,000 volunteers to be randomized into 4 equal groups of 500 each, which are allocated to the following treatments: metformin (1,700 mg/day) + active lifestyle intervention, placebo + active lifestyle intervention, metformin (1,700 mg/day) alone, and placebo alone. The metformin/placebo component of the study is double blind. The study is planned for a term of 5 years. RESULTS The Me.Me.Me. trial is ongoing and recruitment of participants is underway. No patient has completed the 5 years of follow-up. CONCLUSIONS We believe that the results of the trial will clarify the importance of lifestyle for primary prevention and the role of metformin as a potential chemopreventive agent. The trial is registred on ClinicalTrials.gov with the identification NCT02960711.