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The impact of metformin with or without lifestyle modification versus placebo on polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials.
Melin, J, Forslund, M, Alesi, S, Piltonen, T, Romualdi, D, Spritzer, PM, Tay, CT, Pena, A, Witchel, SF, Mousa, A, et al
European journal of endocrinology. 2023;(2):S37-S63
Abstract
OBJECTIVE Available evidence has shown that metformin improves insulin sensitivity and weight management in polycystic ovary syndrome (PCOS). Nevertheless, key knowledge gaps remain regarding its efficacy and the specific outcomes in this population. This review evaluates the effectiveness of metformin and lifestyle modification compared with placebo in the management of PCOS and will inform the forthcoming, 2023 evidence-based PCOS guidelines. DESIGN Systematic review and meta-analysis of the literature. METHODS A search was performed in MEDLINE, EMBASE, PsycINFO, All EBM, and CINAHL. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and included randomized controlled trials published in English through July 2022. RESULTS Moderate certainty of evidence showed a larger reduction of body mass index (BMI) (mean difference [MD] -0.53, 95% confidence interval [CI] -0.95 to -0.12 kg/m2), homeostatic model assessment for insulin resistance (MD -0.50, 95% CI -0.91 to -0.09) (critical outcomes), and fasting glucose (MD -0.13, 95% CI -0.19 to -0.07 mmol/L) with metformin compared to placebo with increased mild gastrointestinal adverse effects (odds ratio [OR] 7.67, 95% CI 2.74-21.46). Low certainty of evidence showed a larger reduction of waist-hip ratio (MD -0.02, 95% CI -0.03 to -0.00), total cholesterol (MD -0.24, 95% CI -0.43 to -0.05 mmol/L), low-density lipoprotein (MD -0.16, 95% CI -0.30 to -0.01 mmol/L), and triglycerides (MD -0.11, 95% CI -0.20 to -0.02 mmol/L) with metformin than placebo. CONCLUSIONS Metformin should be considered an efficacious adjunct to lifestyle interventions in adults with PCOS, especially for those with a higher BMI, to improve weight loss, insulin resistance, and lipids.
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Body composition in patients with hepatic glycogen storage diseases.
Dos Santos, BB, Colonetti, K, Nalin, T, de Oliveira, BM, de Souza, CFM, Spritzer, PM, Schwartz, IVD
Nutrition (Burbank, Los Angeles County, Calif.). 2022;:111763
Abstract
OBJECTIVES The present study aimed to evaluate the body composition of hepatic glycogen storage disorders (GSDs) through dual energy x-ray absorptiometry. METHODS This was an exploratory, observational, cross-sectional study. Twenty-four patients with GSD (type Ia: n = 13, Ib: n = 5, III: n = 2, and IX-α/β/γ: n = 4; female sex: n = 13; age <8 y: n = 3, 8-19 y: n = 14, and >19 y: n = 7) were included. Three-day dietary records were collected in the week preceding dual energy x-ray absorptiometry. Body composition findings were correlated with clinical parameters, uncooked cornstarch (UCCS) regimen, dietary intake, and markers of treatment adherence. RESULTS An elevated fat mass (FM) index was found in 16 of 21 patients (age 8-19 y: n = 10 and >19 y: n = 6; GSD type Ia: n = 12, Ib: n = 2, III: n = 1, and IX-γ: n = 1). A lean mass (LM) index evaluation showed no LM deficits in relation to corresponding reference populations. Relative skeletal muscle index values were decreased in 2 of 7 adult patients (type Ib: n = 1 and IX-α: n = 1). UCCS (g/d) correlated positively with the FM index (rs = 0.7; P ≤ 0.01). In contrast, relative UCCS intake (g/kg body weight) was negatively associated with LM/kg (rs = -0.8; P ≤ 0.01). CONCLUSIONS These findings suggest a high frequency of elevated FM in patients with hepatic GSDs. We also suggest that treatment with UCCS is associated with excess weight in these patients. Additionally, the treatment strategy can impair protein intake, and lead to a decrease in LM.
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Nutrition in Menopausal Women: A Narrative Review.
Silva, TR, Oppermann, K, Reis, FM, Spritzer, PM
Nutrients. 2021;13(7)
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Menopause is the permanent cessation of menstrual cycles following the loss of ovarian follicular activity. It is associated with increased prevalence of obesity, metabolic syndrome, cardiovascular disease, and osteoporosis. The aim of this narrative review was to discuss the current evidence on the association between dietary patterns and clinical endpoints in postmenopausal women (body composition, bone mass, and risk markers for cardiovascular disease), and thereby providing novel insight into the establishment of optimal dietary guidelines for healthy postmenopausal period. Research shows that: - the changes in weight and fat distribution in women are associated with aging and mainly with the decrease in oestradiol levels during peri- and post-menopause. - calcium, vitamin D, vitamin K, selenium, magnesium, and beta-carotene adequate intake could be linked with better BMD in postmenopausal women. - diet is a major modifiable risk factor for cardiovascular disease and could be a powerful intervention to reduce cardiovascular risks in postmenopausal women. - the Mediterranean diet is composed of healthy foods that have anti-inflammatory and antioxidant properties. Authors indicate that future studies evaluating the effects of low-fat, plant-based diets on fat mass in post-menopausal women are needed.
Abstract
Among the various aspects of health promotion and lifestyle adaptation to the postmenopausal period, nutritional habits are essential because they concern all women, can be modified, and impact both longevity and quality of life. In this narrative review, we discuss the current evidence on the association between dietary patterns and clinical endpoints in postmenopausal women, such as body composition, bone mass, and risk markers for cardiovascular disease. Current evidence suggests that low-fat, plant-based diets are associated with beneficial effects on body composition, but further studies are needed to confirm these results in postmenopausal women. The Mediterranean diet pattern along with other healthy habits may help the primary prevention of bone, metabolic, and cardiovascular diseases in the postmenopausal period. It consists on the use of healthy foods that have anti-inflammatory and antioxidant properties, and is associated with a small but significant decrease in blood pressure, reduction of fat mass, and improvement in cholesterol levels. These effects remain to be evaluated over a longer period of time, with the assessment of hard outcomes such as bone fractures, diabetes, and coronary ischemia.
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Effects of high protein, low-glycemic index diet on lean body mass, strength, and physical performance in late postmenopausal women: a randomized controlled trial.
Silva, TR, Lago, SC, Yavorivski, A, Ferreira, LL, Fighera, TM, Spritzer, PM
Menopause (New York, N.Y.). 2020;(3):307-317
Abstract
OBJECTIVE To investigate whether increasing protein consumption to twice the recommended daily allowance (RDA) by The Institute of Medicine affects lean body mass (LBM), muscle strength, and physical performance in late postmenopausal women. METHODS Parallel-group randomized trial with 26 apparently healthy women aged ≥ 65 years. Participants were randomly assigned to low-glycemic index diets with protein consumption at current RDA (0.8 g/kg body weight) or twice the RDA (2RDA, 1.6 g/kg body weight). Protein intake was assessed by 24-hours urinary nitrogen excretion. Change in LBM was measured by dual-energy X-ray absorptiometry at 3 and 6 months. Secondary outcomes were appendicular lean mass, handgrip strength by dynamometry, and physical performance by gait speed. RESULTS Mean age was 70.8 ± 3.6 years, and mean BMI was 26.1 ± 3.5 kg/m2 in the overall sample. The RDA and 2RDA groups did not differ regarding baseline dietary intake. Changes from baseline in LBM (0.07 kg; 95% CI, -0.39; 0.52 kg; P = 0.100) and appendicular lean mass (0.07 kg; 95% CI, -0.34; 0.47 kg; P = 0.100) did not differ between the groups. Total body fat (-1.41 kg; 95% CI, -2.62; 0.20 kg; P = 0.019) and trunk fat mass (-0.90 kg; 95% CI, -1.55; -0.24 kg; P = 0.005) decreased similarly in both groups at the end of intervention. Adjusting for baseline BMI did not alter these findings. Handgrip strength and 4-m gait speed increased after the intervention, with no significant difference between the groups. CONCLUSIONS Protein intake exceeding the RDA did not increase LBM, strength, and physical performance in a sample of late postmenopausal woman consuming a low-glycemic index diet for 6 months.
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Impact of vitamin D receptor and binding protein gene polymorphisms in clinical and laboratory data of HCV patients: Cross sectional study.
Scalioni, LP, Santos, BRD, Spritzer, PM, Villela-Nogueira, CA, Laura Lewis-Ximenez, L, Pollo-Flores, P, Bordalo Cathalá Esberard, E, Brandão-Mello, CE, Lampe, E, Villar, LM
Medicine. 2018;(8):e9881
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Abstract
Potential relationship of vitamin D, vitamin D receptor (VDR), and vitamin D binding protein (DBP) have been suggested in the pathophysiology of hepatitis C virus (HCV) infection. The aim of this observational study is to determine vitamin D levels, and VDR and DBP genetic polymorphism according demographic and laboratory data in chronic HCV patients (CHC).A total of 148 CHC patients gave serum samples for testing 25-hydroxyvitamin D (25 (OH)D) level by immunochemiluminometric assay (<20 ng/mL defined as deficient) and donated blood samples to allelic discrimination analysis using TaqMan assays. Analyzed single nucleotide polymorphisms (SNPs) were: VDR-rs7975232 (ApaI) C>A, rs731236 A>G (TaqI), rs1544410 C>T (BsmI), rs10735810 T>C (FokI) and carrier globulin/binding protein (GC)-rs4588 and rs7041 and the haplotype bAt [CCA]. Hepatic fibrosis was assessed using Fib-4 and Forns index.Eighty-two (54.40%) patients demonstrated deficiency of vitamin D and this was associated to AST (P = .019 [CI: 1.003-1.034]), total cholesterol (P = .038 [CI: 1.004-1.164]), fibrosis grade (P < .001 [CI: 0.000-0.844]), and FokI (P = .028) allele T presence. Association was found between VDR polymorphism and fibrosis (BsmI andTaqI), triglycerides (TaqI), and HDL (FokI). DBP polymorphism was associated to HCV genotype (GC rs7041), previous HCV treatment, and GGT (GC rs4588).In conclusion, low frequency of vitamin D deficiency was found, but VDR polymorphisms were frequently associated to fibrosis grade suggesting that they could be used as disease evaluation markers to understand the mechanisms underlying the virus-host interaction.
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Bioavailable and free 25-hydroxyvitamin D and vitamin D binding protein in polycystic ovary syndrome: Relationships with obesity and insulin resistance.
Naderpoor, N, Shorakae, S, Abell, SK, Mousa, A, Joham, AE, Moran, LJ, Stepto, NK, Spritzer, PM, Teede, HJ, de Courten, B
The Journal of steroid biochemistry and molecular biology. 2018;:209-215
Abstract
Polycystic ovary syndrome (PCOS) is a common condition characterised by both reproductive and metabolic features (obesity, insulin resistance, diabetes risk). Some evidence suggests that women with PCOS have lower vitamin D levels compared to healthy controls. Vitamin D binding protein (DBP) is the main carrier of vitamin D in circulation and plays an important role in regulating vitamin D concentration and bioavailability for target tissues. To our knowledge, no previous studies have examined DBP, bioavailable and free 25-hydroxyvitamin D (25(OH)D) in women with PCOS. The primary aim of this study was to compare DBP, bioavailable and free 25(OH)D concentrations in women with PCOS and controls. The secondary aim was to investigate relationships between DBP, bioavailable and free 25(OH)D and metabolic features (anthropometric measures, insulin resistance, and lipid profile). In a cross sectional study using bio-banked samples, we measured 25(OH)D, DBP and albumin. Bioavailable and free 25(OH)D were calculated using previously validated formula. BMI, body composition (dual X-ray absorptiometry, DXA), insulin resistance (homeostatic model assessment of insulin resistance (HOMA-IR)) and glucose infusion rate (GIR) from hyperinsulinaemic euglycaemic clamp and serum lipids (ELISA) were also measured in a physically and biochemically well-characterised cohort of women with and without PCOS. We studied 90 women with PCOS and 59 controls aged 18-48 years. DBP concentrations were lower in PCOS compared to controls (median [IQR]: 443.40 [314.4] vs 482.4 [156.8] μg/ml, p=0.02). No significant differences were found in bioavailable or free 25(OH)D concentrations between groups. DBP was not associated with BMI, percent body fat or markers of insulin resistance (all p>0.2). High-density lipoprotein (HDL) was the main determinant of DBP in the overall cohort (β=-0.12, p=0.02), after adjusting for covariates including PCOS/control status, age, BMI, total 25(OH)D and HOMA-IR. In PCOS, total and free 25(OH)D were related to markers of insulin resistance and lipids. Only the associations between free 25(OH)D and triglycerides (p=0.02), and HDL (p=0.03) remained significant after adjusting for age and BMI. In conclusion, women with PCOS had lower DBP, but similar bioavailable or free 25(OH)D concentrations compared to controls, independent of BMI and age. DBP was not associated with insulin resistance or BMI in PCOS. Further studies are needed to investigate the pathophysiology and clinical implications of reduced DBP in PCOS.
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Blood Trace Element Concentrations in Polycystic Ovary Syndrome: Systematic Review and Meta-analysis.
Spritzer, PM, Lecke, SB, Fabris, VC, Ziegelmann, PK, Amaral, L
Biological trace element research. 2017;(2):254-262
Abstract
Polycystic ovary syndrome (PCOS) is a prevalent condition in women of reproductive age. PCOS is characterized by androgen excess and chronic anovulation and associated with low-grade inflammation and metabolic comorbidities. Some trace elements have been linked to pathophysiological mechanisms of oxidative stress and inflammation in different disorders. Therefore, we conducted a systematic review and meta-analysis of the available evidence regarding trace element concentrations in PCOS. We reviewed MEDLINE and EMBASE in search of case-control, cross-sectional, and cohort studies published until September 2015. Of 183 studies identified, six were selected for systematic review. All used the Rotterdam criteria for the diagnosis of PCOS. Two studies evaluating chromium and one assessing cobalt levels did not observe differences between PCOS and controls. Another study recorded similar nickel and vanadium levels between the groups, but lower selenium concentrations in women with PCOS compared to controls. Four studies were included in the random effects model meta-analysis, for a total of 264 PCOS and 151 control women. Copper levels were found to be higher in women with PCOS than in controls [mean difference 0.12 ppm (95 % CI 0.07; 0.17 ppm); I 2 = 0 %]. Manganese [mean difference 0.04 ppm (95 % CI -0.05; 0.13 ppm); I 2 = 94.4 %] and zinc concentrations [mean difference 0.02 ppm (95 % CI -0.12; 0.16 ppm); I 2 = 92.4 %] were similar between the groups. The present results suggest a relationship between increased copper concentration and PCOS. This systematic review and meta-analysis is registered in PROSPERO under number CRD42016034036.
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Effects of testosterone therapy on BMI, blood pressure, and laboratory profile of transgender men: a systematic review.
Velho, I, Fighera, TM, Ziegelmann, PK, Spritzer, PM
Andrology. 2017;(5):881-888
Abstract
Testosterone is the main hormonal agent used for cross-sex hormone therapy in female-to-male transgender persons. Our aim was to systematically review the literature concerning the effects of testosterone on body mass index (BMI), blood pressure, hematocrit, hemoglobin, lipid profile, and liver enzymes in transgender men. PUBMED and EMBASE were searched for studies published until March 2017. Studies were included if they reported interventions with any dose of testosterone and comparison of variables before and during treatment. Of 455 potentially eligible articles, 13 were reviewed. Study duration ranged from 6 to 60 months, sample size ranged from 12 to 97 patients, and the most common treatment was parenteral testosterone undecanoate 1000 mg/12 weeks. Slight but significant increases in BMI were reported (from 1.3 to 11.4%). Three out of seven studies assessing the impact of different testosterone formulations on blood pressure detected modest increases or clinically irrelevant changes in this variable. In another study, however, two patients developed hypertension, which was resolved after cessation of testosterone therapy. Decreases in HDL-cholesterol and increases in LDL-cholesterol were consistently observed. Eight studies observed a relationship between testosterone and increased hemoglobin (range: 4.9-12.5%) and hematocrit (range: 4.4-17.6%), but discontinuation of androgen therapy was not necessary. In one study, two patients developed erythrocytosis (hematocrit >52%) after 9 and 12 months of treatment. One study analyzing testosterone formulations observed smaller increases in hemoglobin and hematocrit with testosterone gel. Six studies assessing liver function showed slight or no changes. Overall, the quality of evidence was low, given the lack of randomized clinical/controlled trials and the small sample sizes. In conclusion, exogenous testosterone administration to transgender men was associated with modest increases in BMI, hemoglobin/hematocrit, and LDL-cholesterol, and with decreases in HDL-cholesterol. Long-term studies are needed to assess the long-term risks of testosterone therapy, particularly as they relate to cardiometabolic risks such as diabetes, dyslipidemia and the metabolic syndrome.
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Novel strategies in the management of polycystic ovary syndrome.
Spritzer, PM, Motta, AB, Sir-Petermann, T, Diamanti-Kandarakis, E
Minerva endocrinologica. 2015;(3):195-212
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting reproductive-aged women. PCOS has been recognized as a syndrome combining reproductive and metabolic abnormalities with lifelong health implications. Cardiometabolic alterations require regular screening and effective and targeted lifestyle advice to lose weight as well as to prevent weight gain. Pharmacological therapy includes insulin-sensitizer drugs and agents that act directly on metabolic comorbidities, such as statins and antiobesity drugs. Bariatric surgery may be an option for severely obese women with PCOS Regarding reproductive aspects, ovulation induction with antiestrogens such as clomiphene citrate or letrozole is the first-line medical treatment. Exogenous gonadotropins and in vitro fertilization (IVF) are recommended as second-line treatment for anovulatory infertility. Laparoscopic ovarian diathermy may be used in special cases and metformin is no longer recommended for ovulation induction. Combined oral contraceptives (OCs) are the first-line treatment for the management of menstrual irregularities in women not seeking pregnancy, also providing endometrial protection and contraception. Progestin-only pills or cyclical progestins are recommended for those with contraindications to OCs. Metformin is also considered a second-line choice for improving menstrual cycles in women presenting insulin-resistance and dysglicemia. Hirsutism requires cosmetic procedures and medical treatment with OCs. More severe cases may need anti-androgen drugs added to the OCs. In conclusion, strategies regarding the management of reproductive issues in PCOS encompass a tailored approach to individual needs of each patient.
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Effects of low-dose versus placebo or conventional-dose postmenopausal hormone therapy on variables related to cardiovascular risk: a systematic review and meta-analyses of randomized clinical trials.
Casanova, G, Bossardi Ramos, R, Ziegelmann, P, Spritzer, PM
The Journal of clinical endocrinology and metabolism. 2015;(3):1028-37
Abstract
CONTEXT Hormone therapy (HT), the most efficient treatment for menopausal symptoms, might have deleterious cardiovascular (CV) effects. OBJECTIVE This study aimed to evaluate the effects of low-dose estrogen HT on CV risk factors vs conventional-dose HT and placebo in postmenopausal women with no established CV disease. DATA SOURCES MEDLINE, Cochrane Central, and EMBASE were searched for trials published in 1990-2013; a hand search of reference lists of selected articles was performed; and ClinicalTrials.gov was searched for unpublished trials. STUDY SELECTION Within randomized controlled trials of healthy postmenopausal women comparing low-dose HT to placebo or conventional-dose HT, 11 418 studies were initially identified. DATA EXTRACTION Data were independently extracted by two investigators. Disagreements were resolved by a third author. DATA SYNTHESIS Twenty-eight trials (3360 patients) were included. Low-dose HT vs placebo or conventional-dose HT did not effect weight, body mass index (BMI), blood pressure, C-reactive protein, or high-density lipoprotein cholesterol (HDL-C). Low-dose HT was associated with lower levels of total cholesterol (-12.16 mg/dL, 95% confidence interval [CI], -17.41 - -6.92) and low-density lipoprotein cholesterol (LDL-C) (-12.16 mg/dL; 95% CI, -16.55 - -7.77) vs placebo. Compared with conventional-dose HT, low-dose HT was associated with higher total cholesterol (5.05 mg/dL; 95% CI, 0.88-9.21) and LDL-C (4.49 mg/dL; 95% CI, 0.59-8.39). Low-dose HT was not associated with differences in triglycerides vs placebo. Oral, low-dose HT was associated with lower triglycerides vs conventional-dose HT (-14.09 mg/dL; 95% CI, -24.2 - -3.93). CONCLUSION In this population of apparently healthy postmenopausal women, the effect of low-dose HT did not differ from that of placebo or conventional-dose HT regarding weight, BMI, blood pressure, CRP, or HDL-C. In contrast, low-dose HT was associated with better lipid profile vs placebo, and induced higher total and LDL-C and lower triglycerides vs conventional-dose HT.