The Effect of n-3 Polyunsaturated Fatty Acid Supplementation on Androgen Status in Patients with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Clinical Trials

Abstract

The anti-androgenic role of n-3 polyunsaturated fatty acids (PUFAs) among patients with polycystic ovary syndrome (PCOS) has recently been proposed. The present study aimed to systematically review clinical trials assessing the effects of n-3 PUFAs consumption on androgen status among adult females with PCOS. PubMed, ISI Web of Science, Google Scholar, and Scopus were searched up to December 2015. Clinical investigations assessing the effect of n-3 PUFAs on adult females with PCOS were included. Mean±standard deviation of change in serum total testosterone, sex hormone binding globulin (SHBG), and dehydroepiandrostrone sulfate (DHEAS) were extracted. Eight clinical trials with 298 participants were eligible. Meta-analysis showed that n-3 PUFAs supplementation marginally reduces total testosterone (mean difference [MD]: − 0.19 nmol/l; 95% CI: − 0.39 to 0.00; p=0.054), but not SHBG (MD: 1.75 nmol/l; 95% CI: −0.51 to 4.01; p=0.129) or serum DHEAS levels (Hedes’ g: −0.11 nmol/l; 95% CI: −0.29 to 0.06; p=0.19) among adult females with PCOS. Subgroup analyses showed that only before-after studies (Hedges’ g: 0.15; 95% CI: −0.27 to −0.04; p=0.01) and long-term interventions (>6 weeks) (Hedges’ g: −0.17; 95% CI, −0.29 to −0.05; p=0.004) had reducing effects on serum DHEAS levels. The majority of long-term trials utilized a single group design (no control group). It does not appear that n-3 PUFAs supplementation significantly affects the androgenic profile of females with PCOS; however, some before-after and long-term intervention studies show reduced DHEAS levels. Future studies incorporating double blinded placebo controlled clinical trials with long follow-up periods are warranted.

Key words

n-3 polyunsaturated fatty acids - polycystic ovary syndrome - systematic review - meta-analysis

• References

• 1 Lorenz LB, Wild RA. Polycystic ovarian syndrome: an evidence-based approach to evaluation and management of diabetes and cardiovascular risks for today’s clinician. Clin Obstetr Gynecol 2007; 50: 226-243
• 2 Liepa GU, Sengupta A, Karsies D. Polycystic ovary syndrome (PCOS) and other androgen excess-related conditions: can changes in dietary intake make a difference?. Nutr Clin Pract 2008; 23: 63-71
• 3 McGowan MP. Polycystic ovary syndrome: a common endocrine disorder and risk factor for vascular disease. Current treatment options in cardiovascular medicine 2011; 13: 289-301
• 4 O’Connor A, Gibney J, Roche HM. Metabolic and hormonal aspects of polycystic ovary syndrome: the impact of diet. Proc Nutr Soc 2010; 69: 628-635
• 5 Sartor BM, Dickey RP. Polycystic ovarian syndrome and the metabolic syndrome. The Am J Med Sci 2005; 330: 336-342
• 6 Tomlinson J, Millward A, Stenhouse E, Pinkney J. Type 2 diabetes and cardiovascular disease in polycystic ovary syndrome: what are the risks and can they be reduced?. Diabet Med 2010; 27: 498-515
• 7 Wild RA. Dyslipidemia in PCOS. Steroids 2012; 77: 295-299
• 8 Hart R, Norman R. Polycystic ovarian syndrome–prognosis and outcomes. Best Pract Res Clin Obstet Gynaecol 2006; 20: 751-778
• 9 Moran LJ, Lombard CB, Lim S, Noakes M, Teede HJ. Polycystic ovary syndrome and weight management. Womens Health (Lond Engl) 2010; 6: 271-283
• 10 Jeanes YM, Barr S, Smith K, Hart KH. Dietary management of women with polycystic ovary syndrome in the United Kingdom: the role of dietitians. J Hum Nutr Diet 2009; 22: 551-558
• 11 Phelan N, O’Connor A, Kyaw Tun T, Correia N, Boran G, Roche HM, Gibney J. Hormonal and metabolic effects of polyunsaturated fatty acids in young women with polycystic ovary syndrome: results from a cross-sectional analysis and a randomized, placebo-controlled, crossover trial. Am J Clin Nutr 2011; 93: 652-662
• 12 Barr S, Hart K, Reeves S, Sharp K, Jeanes YM. Habitual dietary intake, eating pattern and physical activity of women with polycystic ovary syndrome. Eur J Clin Nutr 2011; 65: 1126-1132
• 13 Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011; 7: 219-231
• 14 Asemi Z, Esmaillzadeh A. DASH diet, insulin resistance, and serum hs-CRP in polycystic ovary syndrome: a randomized controlled clinical trial. Horm Metab Res 2015; 47: 232-238
• 15 Marsh K, Brand-Miller J. The optimal diet for women with polycystic ovary syndrome?. Br J Nutr 2005; 94: 154-165
• 16 Farshchi H, Rane A, Love A, Kennedy RL. Diet and nutrition in polycystic ovary syndrome (PCOS): pointers for nutritional management. J Obstet Gynaecol 2007; 27: 762-773
• 17 Moran LJ, Ko H, Misso M, Marsh K, Noakes M, Talbot M, Frearson M, Thondan M, Stepto N, Teede HJ. Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines. J Acad Nutr Diet 2013; 113: 520-545
• 18 Sonnenstuhl P. More on PCOS. Adv Nurse Pract 2001; 9: 18
• 19 Kalgaonkar S, Almario RU, Gurusinghe D, Garamendi EM, Buchan W, Kim K, Karakas SE. Differential effects of walnuts vs almonds on improving metabolic and endocrine parameters in PCOS. Eur J Clin Nutr 2011; 65: 386-393
• 20 Kasim-Karakas SE, Almario RU, Gregory L, Wong R, Todd H, Lasley BL. Metabolic and endocrine effects of a polyunsaturated fatty acid-rich diet in polycystic ovary syndrome. J Clin Endocrinol Metab 2004; 89: 615-620
• 21 Poudyal H, Panchal SK, Diwan V, Brown L. Omega-3 fatty acids and metabolic syndrome: effects and emerging mechanisms of action. Progress in lipid research 2011; 50: 372-387
• 22 Risérus U. Fatty acids and insulin sensitivity. Curr Opin Clin Nutr Metab Care 2008; 11: 100
• 23 Saldeen P, Saldeen T. Women and omega-3 fatty acids. Obstetr Gynecol Survey 2004; 59: 722-730
• 24 Cussons AJ, Watts GF, Mori TA, Stuckey BGA. Omega-3 Fatty Acid Supplementation Decreases Liver Fat Content in Polycystic Ovary Syndrome: A Randomized Controlled Trial Employing Proton Magnetic Resonance Spectroscopy. J Clin Endocrinol Metab 2009; 94: 3842-3848
• 25 Alvheim AR, Malde MK, Osei-Hyiaman D, Hong Lin Y, Pawlosky RJ, Madsen L, Kristiansen K, Frøyland L, Hibbeln JR. Dietary Linoleic Acid Elevates Endogenous 2-AG and Anandamide and Induces Obesity. Obesity (Silver Spring) 2012; 20: 1984-1994
• 26 Vargas ML, Almario RU, Buchan W, Kim K, Karakas SE. Metabolic and endocrine effects of long-chain versus essential omega-3 polyunsaturated fatty acids in polycystic ovary syndrome. Metabolism 2011; 60: 1711-1718
• 27 Shapiro H, Tehilla M, Attal-Singer J, Bruck R, Luzzatti R, Singer P. The therapeutic potential of long-chain omega-3 fatty acids in nonalcoholic fatty liver disease. Clin Nutr 2011; 30: 6-19
• 28 Kuzmanov A, Broughton KS. Role of marine omega-3 fatty acids in PCOS cancer risk. 13th World Congress on Controversies in Obsterics, Gynecology, and Infertility (COGI) 2010; 349-354
• 29 Oner G, Muderris II. Efficacy of omega-3 in the treatment of polycystic ovary syndrome. J Obstet Gynaecol 2013; 33: 289-291
• 30 Phelan N, Gibney J. What is the potential role of polyunsaturated fatty acids in controlling dyslipidemia in patients with polycystic ovary syndrome?. Clin Lipidol 2012; 7: 5-8
• 31 Moher D, Cook DJ, Jadad AR, Tugwell P, Moher M, Jones A, Pham B, Klassen TP. Assessing the quality of reports of randomised trials: implications for the conduct of meta-analyses. Health Technol Assess 1999; 3 (i–iv) 1-98
• 32 Nadjarzadeh A, Dehghani Firouzabadi R, Vaziri N, Daneshbodi H, Lotfi MH, Mozaffari-Khosravi H. The effect of omega-3 supplementation on androgen profile and menstrual status in women with polycystic ovary syndrome: A randomized clinical trial. Iran J Reprod Med 2013; 11: 665-672
• 33 Chalmers I, Hedges LV, Cooper H. A brief history of research synthesis. Eval Health Prof 2002; 25: 12-37
• 34 Hedges LV, Pigott TD. The power of statistical tests for moderators in meta-analysis. Psychol Meth 2004; 9: 426-445
• 35 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177-188
• 36 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539-1558
• 37 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629-634
• 38 Sterne JA, Egger M, Smith GD. Systematic reviews in health care: Investigating and dealing with publication and other biases in meta-analysis. BMJ 2001; 323: 101-105
• 39 Mohammadi E, Rafraf M. Benefits of omega-3 fatty acids supplementation on serum paraoxonase 1 activity and lipids ratios in polycystic ovary syndrome People’s. Health Promot Perspect 2012; 2: 197-204
• 40 Mohammadi E, Rafraf M, Farzadi L, Asghari-Jafarabadi M, Sabour S. Effects of omega-3 fatty acids supplementation on serum adiponectin levels and some metabolic risk factors in women with polycystic ovary syndrome. Asia Pac J Clin Nutr 2012; 21: 511-518
• 41 Platt J, Kuzmanov A, Halliday T, Lindmier M, Peterson N, Broughton KS. Omega-3 fatty acid and vitamin D ingestion and leptin and adiponectin in PCOS. 13th World Congress on Controversies in Obsterics, Gynecology, and Infertility (COGI) 2010; 355-359
• 42 Rafraf M, Mohammadi E, Asghari-Jafarabadi M, Farzadi L. Omega-3 fatty acids improve glucose metabolism without effects on obesity values and serum visfatin levels in women with polycystic ovary syndrome. J Am Coll Nutr 2012; 31: 361-368
• 43 Rafraf M, Mohammadi E, Farzadi L, Asghari-Jafarabadi M, Sabour S. Effects of ω-3 Fatty Acid Supplementation on Glycemic Status and High Sensitive C-Reactive Protein in Women with Polycystic Ovary Syndrome. J Ardabil Univ Med Sci 2012; 12: 373-383
• 44 Kohama T, Kobayashi H, Inoue M. The effect of soybeans on the anovulatory cycle. J Med Food 2005; 8: 550-551
• 45 Yoon JW, Kim CH, Ahn JW, Kang HJ, Song HJ, Kang BM. Effect of Omega-3-polyunsaturated fatty acids and metfromin on ovarian morphology and Intraovarian blood flow in patients with polycystic ovary sandromne. Fertil Steril 2010; 94: S194-S194
• 46 Dayspring TD. Understanding hypertriglyceridemia in women: clinical impact and management with prescription omega-3-acid ethyl esters. Int J Womens Health 2011; 3: 87-97
• 47 Epstein FH, Moller DE, Flier JS. Insulin resistance—mechanisms, syndromes, and implications. N Eng J Med 1991; 325: 938-948
• 48 Franks S, Robinson S, Willis DS. Nutrition, insulin and polycystic ovary syndrome. Rev Reprod 1996; 1: 47-53
• 49 Kien CL. Dietary interventions for metabolic syndrome: role of modifying dietary fats. Curr Diabetes Rep 2009; 9: 43-50
• 50 Bruni V, Dei M, Pontello V, Vangelisti P. The management of polycystic ovary syndrome. Ann N Y Acad Sci 2003; 997: 307-321
• 51 Cussons AJ, Stuckey BG, Walsh JP, Burke V, Norman RJ. Polycystic ovarian syndrome. marked differences between endocrinologists and gynaecologists in diagnosis and management. Clin Endocrinol (Oxf) 2005; 62: 289-295
• 52 Franks S, Robinson S, Willis DS. Nutrition, insulin and polycystic ovary syndrome. Rev Reprod 1996; 1: 47-53
• 53 Goldenberg N, Glueck C. Medical therapy in women with polycystic ovarian syndrome before and during pregnancy and lactation. Minerva Ginecol 2008; 60: 63-75
• 54 Gonzalez F. Inflammation in Polycystic Ovary Syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids 2012; 77: 300-305
• 55 Loria P, Lonardo A, Carulli L, Verrone A, Ricchi M, Lombardini S, Rudilosso A, Ballestri S, Carulli N. Review article: the metabolic syndrome and non-alcoholic fatty liver disease. Aliment Pharmacol Therap 2005; 22: 31-36
• 56 Sathyapalan T, Atkin SL. Recent advances in cardiovascular aspects of polycystic ovary syndrome. Eur J Endocrinol 2012; 166: 575-583
• 57 Azadbakht L, Rouhani MH, Surkan PJ. Omega-3 fatty acids, insulin resistance and type 2 diabetes. J Res Med Sci 2011; 16: 1259-1260
• 58 Brostow DP, Odegaard AO, Koh WP, Duval S, Gross MD, Yuan JM, Pereira MA. Omega-3 fatty acids and incident type 2 diabetes: the Singapore Chinese Health Study. Am J Clin Nutr 2011; 94: 520-526
• 59 Djousse L, Gaziano JM, Buring JE, Lee IM. Dietary omega-3 fatty acids and fish consumption and risk of type 2 diabetes. Am J Clin Nutr 2011; 93: 143-150
• 60 Kaushik M, Mozaffarian D, Spiegelman D, Manson JE, Willett WC, Hu FB. Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. Am J Clin Nutr 2009; 90: 613-620
• 61 Horikawa C, Yoshimura Y, Kamada C, Tanaka S, Tanaka S, Hanyu O, Araki A, Ito H, Tanaka A, Ohashi Y, Akanuma Y, Yamada N, Sone H. Dietary intake in Japanese patients with type 2 diabetes: Analysis from Japan Diabetes Complications Study. J Diabetes Investig 2014; 5: 176-187
• 62 Kondo K, Morino K, Nishio Y, Kondo M, Nakao K, Nakagawa F, Ishikado A, Sekine O, Yoshizaki T, Kashiwagi A, Ugi S, Maegawa H. A fish-based diet intervention improves endothelial function in postmenopausal women with type 2 diabetes mellitus: A randomized crossover trial. Metabolism 2014; 63: 930-940
• 63 Muley A, Muley P, Shah M. ALA, Fatty Fish or Marine n-3 Fatty Acids for Preventing DM?: A Systematic Review and Meta-Analysis. Curr Diabetes Rev 2014; 10: 158-165
• 64 Stirban A, Nandrean S, Gotting C, Stratmann B, Tschoepe D. Effects of n-3 polyunsaturated fatty acids (PUFAs) on circulating adiponectin and leptin in subjects with type 2 diabetes mellitus. Horm Metab Res 2014; 46: 490-492
• 65 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997; 18: 774-800
• 66 Martinez-Bermejo E, Luque-Ramirez M, Escobar-Morreale HF. Obesity and the polycystic ovary syndrome. Minerva Endocrinol 2007; 32: 129-140
• 67 Moran LJ, Brinkworth G, Noakes M, Norman RJ. Effects of lifestyle modification in polycystic ovarian syndrome. Reprod Biomed Online 2006; 12: 569-578
• 68 Botwood N, Hamilton-Fairley D, Kiddy D, Robinson S, Franks S. Sex hormone-binding globulin and female reproductive function. J Steroid Biochem Mol Biol 1995; 53: 529-531
• 69 Bays HE, Tighe AP, Sadovsky R, Davidson MH. Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovascul Therap 2008; 6: 391-409
• 70 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC. Diagnosis and management of the metabolic syndrome an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005; 112: 2735-2752
• 71 Hauner H, Bender M, Haastert B, Hube F. Plasma concentrations of soluble TNF-alpha receptors in obese subjects. Int J Obes Relat Metab Disord 1998; 22: 1239-1243
• 72 Liu LS, Spelleken M, Rohrig K, Hauner H, Eckel J. Tumor necrosis factor-alpha acutely inhibits insulin signaling in human adipocytes: implication of the p80 tumor necrosis factor receptor. Diabetes 1998; 47: 515-522
• 73 Davis MB, Duvernoy CS. How to stay heart healthy in 2011: considerations for the primary prevention of cardiovascular disease in women. Womens Health (Lond Engl) 2011; 7: 433-451