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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Insights into New Therapeutic Approaches for the Treatment and Management of Polycystic Ovary Syndrome: An Updated Review

Author(s): Rohina Bashir, Imtiyaz Ahmad Wani and Mohd. Ashraf Ganie*

Volume 28, Issue 18, 2022

Published on: 21 July, 2022

Page: [1493 - 1500] Pages: 8

DOI: 10.2174/1381612828666220518150754

Price: $65

Abstract

Background: Polycystic ovary syndrome (PCOS) is a long-term, highly prevalent, complex heterogeneous, polygenic endocrine disorder characterized by both metabolic and reproductive disorders. It affects 6-23% of reproductive-age women globally.

Objective: This review aims to facilitate an understanding of novel PCOS management approaches and highlight the results from relevant interventional animal and human studies.

Methods: Manual search on PubMed, Cochrane, and Scopus databases was performed for relevant articles, preclinical and clinical trials based on related keywords.

Results: According to a multitude of studies, PCOS has evolved over time, but a substantial lag remains in management approaches. New insights into the cross-talk between muscle, brain, fat, and ovaries pointed out new therapeutic targets. This review has highlighted the efficacy of a wide spectrum of novel therapeutic agents [Phosphodiesterase-4 Inhibitors, Glucagon-like peptide-1 receptor agonists, nutritional supplements (Vitamins D and K, omega-3, prebiotics, probiotics and synbiotics), fecal microbiota transplantation (FMT) and intestinal cytokine IL-22] as PCOS therapeutic options. These novel therapies combine anti-inflammatory, insulinsensitizing, and anti-obesity activities, along with the restoration of the gut microbiota and thus hold the potential to address the basic pathogenic mechanisms of PCOS.

Conclusion: Exhaustive, multicentric and multiethnic studies are vital to generating a network of normative data to better figure out the PCOS trajectory and change prognostic outcomes. Preclinical and clinical data are warranted to corroborate the new therapeutics and direct health care resources accordingly.

Keywords: Polycystic ovary syndrome, phosphodiesterase 4 inhibitors, IL-22, probiotics, fecal microbiota transplantation, gut microbiome.

[1]
Bulsara JP, Patel P, Soni A, Acharya S. A review on brief insight into polycystic ovarian syndrome. Endocrine Metab Sci 2021; 3: 100085.
[2]
Deswal R, Narwal V, Dang A, Pundir CS. The prevalence of polycystic ovary syndrome: a brief systematic review. J Hum Reprod Sci 2020; 13(4): 261-71.
[http://dx.doi.org/10.4103/jhrs.JHRS_95_18] [PMID: 33627974]
[3]
Costello M, Garad R, Hart R, et al. A review of first line infertility treatments and supporting evidence in women with polycystic ovary syndrome. Med Sci (Basel) 2019; 7(9): 95.
[http://dx.doi.org/10.3390/medsci7090095] [PMID: 31510088]
[4]
White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab 1996; 81(11): 3821-4.
[PMID: 8923819]
[5]
Palomba S, Falbo A, Zullo F, Orio F Jr. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a com-prehensive review. Endocr Rev 2009; 30(1): 1-50.
[http://dx.doi.org/10.1210/er.2008-0030] [PMID: 19056992]
[6]
Bubna AK. Metformin - For the dermatologist. Indian J Pharmacol 2016; 48(1): 4-10.
[http://dx.doi.org/10.4103/0253-7613.174388] [PMID: 26997714]
[7]
Du Q, Yang S, Wang Y-J, Wu B, Zhao Y-Y, Fan B. Effects of thiazolidinediones on polycystic ovary syndrome: a meta-analysis of ran-domized placebo-controlled trials. Adv Ther 2012; 29(9): 763-74.
[http://dx.doi.org/10.1007/s12325-012-0044-6] [PMID: 22932791]
[8]
Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E. American association of clinical endocrinologists, american college of endocrinology, and androgen excess and PCOS society disease state clinical review: guide to the best practices in the evalua-tion and treatment of polycystic ovary syndrome-part 1. Endocr Pract 2015; 21(11): 1291-300.
[http://dx.doi.org/10.4158/EP15748.DSC] [PMID: 26509855]
[9]
Mazza A, Fruci B, Guzzi P, et al. In PCOS patients the addition of low-dose spironolactone induces a more marked reduction of clinical and biochemical hyperandrogenism than metformin alone. Nutr Metab Cardiovasc Dis 2014; 24(2): 132-9.
[http://dx.doi.org/10.1016/j.numecd.2013.04.016] [PMID: 23845740]
[10]
Jensterle M, Kocjan T, Janez A. Phosphodiesterase 4 inhibition as a potential new therapeutic target in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 2014; 99(8): E1476-81.
[http://dx.doi.org/10.1210/jc.2014-1430] [PMID: 24823465]
[11]
Tohma YA, Onalan G, Tepeoglu M, et al. Phosphodiesterase 4 inhibitor plus metformin is superior to metformin alone for the treatment of polycystic ovary syndrome: A rat model study. Exp Ther Med 2019; 17(5): 4013-22.
[http://dx.doi.org/10.3892/etm.2019.7428] [PMID: 30988783]
[12]
Wouters EF, Bredenbröker D, Teichmann P, et al. Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in pa-tients with treatment-naive, newly diagnosed type 2 diabetes mellitus. J Clin Endocrinol Metab 2012; 97(9): E1720-5.
[http://dx.doi.org/10.1210/jc.2011-2886] [PMID: 22723325]
[13]
Nakamura J, Okamura N, Kawakami Y. Augmentation of lipolysis in adipocytes from fed rats, but not from starved rats, by inhibition of rolipram-sensitive phosphodiesterase 4. Arch Biochem Biophys 2004; 425(1): 106-14.
[http://dx.doi.org/10.1016/j.abb.2004.02.036] [PMID: 15081899]
[14]
Zhang R, Maratos-Flier E, Flier JS. Reduced adiposity and high-fat diet-induced adipose inflammation in mice deficient for phos-phodiesterase 4B. Endocrinology 2009; 150(7): 3076-82.
[http://dx.doi.org/10.1210/en.2009-0108] [PMID: 19359377]
[15]
Andersen A, Lund A, Knop FK, Vilsbøll T. Glucagon-like peptide 1 in health and disease. Nat Rev Endocrinol 2018; 14(7): 390-403.
[http://dx.doi.org/10.1038/s41574-018-0016-2] [PMID: 29728598]
[16]
van der Steeg JW, Steures P, Eijkemans MJ, et al. Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Hum Reprod 2008; 23(2): 324-8.
[http://dx.doi.org/10.1093/humrep/dem371] [PMID: 18077317]
[17]
Nylander M, Frøssing S, Clausen HV, Kistorp C, Faber J, Skouby SO. Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a randomized clinical trial. Reprod Biomed Online 2017; 35(1): 121-7.
[http://dx.doi.org/10.1016/j.rbmo.2017.03.023] [PMID: 28479118]
[18]
Kahal H, Aburima A, Ungvari T, et al. The effects of treatment with liraglutide on atherothrombotic risk in obese young women with polycystic ovary syndrome and controls. BMC Endocr Disord 2015; 15(1): 14.
[http://dx.doi.org/10.1186/s12902-015-0005-6] [PMID: 25880805]
[19]
Salamun V, Jensterle M, Janez A, Vrtacnik Bokal E. Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study. Eur J Endocrinol 2018; 179(1): 1-11.
[http://dx.doi.org/10.1530/EJE-18-0175] [PMID: 29703793]
[20]
Sun Z, Li P, Wang X, et al. GLP-1/GLP-1R signaling regulates ovarian PCOS-associated granulosa cells proliferation and antiapoptosis by modification of forkhead box protein O1 phosphorylation sites. Int J Endocrinol 2020; 2000: 1484321.
[21]
Fernandez EDT, Huffman AM, Syed M, Romero DG, Yanes Cardozo LL. Effect of GLP-1 receptor agonists in the cardiometabolic com-plications in a rat model of postmenopausal PCOS. Endocrinology 2019; 160(12): 2787-99.
[http://dx.doi.org/10.1210/en.2019-00450] [PMID: 31593246]
[22]
Liu X, Zhang Y, Zheng SY, et al. Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese poly-cystic ovary syndrome. Clin Endocrinol (Oxf) 2017; 87(6): 767-74.
[http://dx.doi.org/10.1111/cen.13454] [PMID: 28834553]
[23]
Günalan E, Yaba A. Y&lmaz B. The effect of nutrient supplementation in the management of polycystic ovary syndrome-associated met-abolic dysfunctions: A critical review. J Turk Ger Gynecol Assoc 2018; 19(4): 220-32.
[http://dx.doi.org/10.4274/jtgga.2018.0077] [PMID: 30299265]
[24]
de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B12 deficiency: randomised placebo controlled trial BMJ 2010; 340: (may 19 4): c2181.
[http://dx.doi.org/10.1136/bmj.c2181] [PMID: 20488910]
[25]
Izadi A, Ebrahimi S, Shirazi S, et al. Hormonal and metabolic effects of coenzyme Q10 and/or vitamin E in patients with polycystic ova-ry syndrome. J Clin Endocrinol Metab 2019; 104(2): 319-27.
[PMID: 30202998]
[26]
Ebrahimi FA, Samimi M, Foroozanfard F, et al. The effects of omega-3 fatty acids and vitamin E co-supplementation on indices of insu-lin resistance and hormonal parameters in patients with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled tri-al. Exp Clin Endocrinol Diabetes 2017; 125(6): 353-9.
[http://dx.doi.org/10.1055/s-0042-117773] [PMID: 28407657]
[27]
Tarkesh F, Namavar Jahromi B, Hejazi N, Tabatabaee H. Beneficial health effects of Menaquinone-7 on body composition, glycemic indices, lipid profile, and endocrine markers in polycystic ovary syndrome patients. Food Sci Nutr 2020; 8(10): 5612-21.
[http://dx.doi.org/10.1002/fsn3.1837] [PMID: 33133563]
[28]
Choi HJ, Yu J, Choi H, et al. Vitamin K2 supplementation improves insulin sensitivity via osteocalcin metabolism: a placebo-controlled trial. Diabetes Care 2011; 34(9): e147-7.
[http://dx.doi.org/10.2337/dc11-0551] [PMID: 21868771]
[29]
Varsha MK, Thiagarajan R, Manikandan R, Dhanasekaran G. Vitamin K1 alleviates streptozotocin-induced type 1 diabetes by mitigating free radical stress, as well as inhibiting NF-&B activation and iNOS expression in rat pancreas. Nutr 2015; 31(1): 214-22.
[http://dx.doi.org/10.1016/j.nut.2014.05.012] [PMID: 25466668]
[30]
Dihingia A, Ozah D, Baruah PK, Kalita J, Manna P. Prophylactic role of vitamin K supplementation on vascular inflammation in type 2 diabetes by regulating the NF-&B/Nrf2 pathway via activating Gla proteins. Food Funct 2018; 9(1): 450-62.
[http://dx.doi.org/10.1039/C7FO01491K] [PMID: 29227493]
[31]
Dihingia A, Ozah D, Ghosh S, et al. Vitamin K1 inversely correlates with glycemia and insulin resistance in patients with type 2 diabetes (T2D) and positively regulates SIRT1/AMPK pathway of glucose metabolism in liver of T2D mice and hepatocytes cultured in high glu-cose. J Nutr Biochem 2018; 52: 103-14.
[http://dx.doi.org/10.1016/j.jnutbio.2017.09.022] [PMID: 29175667]
[32]
Shea MK, Booth SL, Gundberg CM, et al. Adulthood obesity is positively associated with adipose tissue concentrations of vitamin K and inversely associated with circulating indicators of vitamin K status in men and women. J Nutr 2010; 140(5): 1029-34.
[http://dx.doi.org/10.3945/jn.109.118380] [PMID: 20237066]
[33]
Joham AE, Teede HJ, Cassar S, et al. Vitamin D in polycystic ovary syndrome: Relationship to obesity and insulin resistance. Mol Nutr Food Res 2016; 60(1): 110-8.
[http://dx.doi.org/10.1002/mnfr.201500259] [PMID: 26255991]
[34]
Rashidi B, Haghollahi F, Shariat M, Zayerii F. The effects of calcium-vitamin D and metformin on polycystic ovary syndrome: a pilot study. Taiwan J Obstet Gynecol 2009; 48(2): 142-7.
[http://dx.doi.org/10.1016/S1028-4559(09)60275-8] [PMID: 19574176]
[35]
Reis GVOP, Gontijo NA, Rodrigues KF, Alves MT, Ferreira CN, Gomes KB. Vitamin D receptor polymorphisms and the polycystic ovary syndrome: A systematic review. J Obstet Gynaecol Res 2017; 43(3): 436-46.
[http://dx.doi.org/10.1111/jog.13250]
[36]
Wehr E, Pieber TR, Obermayer-Pietsch B. Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. J Endocrinol Invest 2011; 34(10): 757-63.
[PMID: 21613813]
[37]
Lerchbaum E, Theiler-Schwetz V, Kollmann M, et al. Effects of vitamin D supplementation on surrogate markers of fertility in PCOS women: A randomized controlled trial. Nutrients 2021; 13(2): 547.
[http://dx.doi.org/10.3390/nu13020547] [PMID: 33562394]
[38]
Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352(12): 1223-36.
[http://dx.doi.org/10.1056/NEJMra041536] [PMID: 15788499]
[39]
Khani B, Mardanian F, Fesharaki SJ. Omega-3 supplementation effects on polycystic ovary syndrome symptoms and metabolic syn-drome. J Res Med Sci 2017; 22(1): 64.
[http://dx.doi.org/10.4103/jrms.JRMS_644_16] [PMID: 28616051]
[40]
Qi K, Fan C, Jiang J, et al. Omega-3 fatty acid containing diets decrease plasma triglyceride concentrations in mice by reducing endoge-nous triglyceride synthesis and enhancing the blood clearance of triglyceride-rich particles. Clin Nutr 2008; 27(3): 424-30.
[http://dx.doi.org/10.1016/j.clnu.2008.02.001] [PMID: 18362042]
[41]
Cussons AJ, Watts GF, Mori TA, Stuckey BG. Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syn-drome: a randomized controlled trial employing proton magnetic resonance spectroscopy. J Clin Endocrinol Metab 2009; 94(10): 3842-8.
[http://dx.doi.org/10.1210/jc.2009-0870] [PMID: 19622617]
[42]
Mazloomi S, Sheikh N, Farimani MS, Pilehvari S. Association of Prx4, total oxidant status, and inflammatory factors with insulin re-sistance in polycystic ovary syndrome. Int J Endocrinol 2021; 2021: 9949753.
[43]
Singh RK, Chang H-W, Yan D, et al. Influence of diet on the gut microbiome and implications for human health. J Transl Med 2017; 15(1): 73.
[http://dx.doi.org/10.1186/s12967-017-1175-y] [PMID: 28388917]
[44]
Cammarota G, Ianiro G, Tilg H, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 2017; 66(4): 569-80.
[http://dx.doi.org/10.1136/gutjnl-2016-313017] [PMID: 28087657]
[45]
Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013; 341(6150): 1241214.
[http://dx.doi.org/10.1126/science.1241214] [PMID: 24009397]
[46]
Guo Y, Qi Y, Yang X, et al. Association between polycystic ovary syndrome and gut microbiota. PLoS One 2016; 11(4): e0153196.
[http://dx.doi.org/10.1371/journal.pone.0153196] [PMID: 27093642]
[47]
Torres PJ, Skarra DV, Ho BS, et al. Letrozole treatment of adult female mice results in a similar reproductive phenotype but distinct changes in metabolism and the gut microbiome compared to pubertal mice. BMC Microbiol 2019; 19(1): 57.
[http://dx.doi.org/10.1186/s12866-019-1425-7] [PMID: 30871463]
[48]
Qi X, Yun C, Sun L, et al. Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med 2019; 25(8): 1225-33.
[http://dx.doi.org/10.1038/s41591-019-0509-0] [PMID: 31332392]
[49]
Qi X, Yun C, Liao B, Qiao J, Pang Y. The therapeutic effect of interleukin-22 in high androgen-induced polycystic ovary syndrome. J Endocrinol 2020; 245(2): 281-9.
[http://dx.doi.org/10.1530/JOE-19-0589] [PMID: 32163914]
[50]
Sabat R, Wolk K. Deciphering the role of interleukin-22 in metabolic alterations. Cell Biosci 2015; 5(1): 68.
[http://dx.doi.org/10.1186/s13578-015-0060-8] [PMID: 26674616]
[51]
Wang X, Ota N, Manzanillo P, et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 2014; 514(7521): 237-41.
[http://dx.doi.org/10.1038/nature13564] [PMID: 25119041]
[52]
Shamasbi SG, Dehgan P, Mohammad-Alizadeh Charandabi S, Aliasgarzadeh A, Mirghafourvand M. The effect of resistant dextrin as a prebiotic on metabolic parameters and androgen level in women with polycystic ovarian syndrome: a randomized, triple-blind, con-trolled, clinical trial. Eur J Nutr 2019; 58(2): 629-40.
[http://dx.doi.org/10.1007/s00394-018-1648-7] [PMID: 29480399]
[53]
Xue J, Li X, Liu P, et al. Inulin and metformin ameliorate polycystic ovary syndrome via anti-inflammation and modulating gut microbi-ota in mice. Endocr J 2019; 66(10): 859-70.
[http://dx.doi.org/10.1507/endocrj.EJ18-0567] [PMID: 31270279]
[54]
Ahmadi S, Jamilian M, Karamali M, et al. Probiotic supplementation and the effects on weight loss, glycaemia and lipid profiles in wom-en with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Hum Fertil (Camb) 2017; 20(4): 254-61.
[http://dx.doi.org/10.1080/14647273.2017.1283446] [PMID: 28142296]
[55]
Shoaei T, Heidari-Beni M, Tehrani HG, Feizi A, Esmaillzadeh A, Askari G. Effects of probiotic supplementation on pancreatic &-cell function and c-reactive protein in women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial. Int J Prev Med 2015; 6(1): 27.
[http://dx.doi.org/10.4103/2008-7802.153866] [PMID: 25949777]
[56]
Karamali M, Eghbalpour S, Rajabi S, et al. Effects of probiotic supplementation on hormonal profiles, biomarkers of inflammation and oxidative stress in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Arch Iran Med 2018; 21(1): 1-7.
[PMID: 29664663]
[57]
Ghanei N, Rezaei N, Amiri GA, Zayeri F, Makki G, Nasseri E. The probiotic supplementation reduced inflammation in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. J Funct Foods 2018; 42: 306-11.
[http://dx.doi.org/10.1016/j.jff.2017.12.047]
[58]
Zhang H, Wen W, Shen J, Wei L. Effect of microecological preparation supplementation on woman with polycystic ovary syndrome: A meta-analysis protocol. Medicine (Baltimore) 2018; 97(44): e13040.
[http://dx.doi.org/10.1097/MD.0000000000013040] [PMID: 30383670]
[59]
Ohshima T, Kojima Y, Seneviratne CJ, Maeda N. Therapeutic application of synbiotics, a fusion of probiotics and prebiotics, and bio-genics as a new concept for oral Candida infections: a mini review. Front Microbiol 2016; 7: 10.
[http://dx.doi.org/10.3389/fmicb.2016.00010] [PMID: 26834728]
[60]
Olas B. Probiotics, prebiotics and synbiotics—A promising strategy in prevention and treatment of cardiovascular diseases? Int J Mol Sci 2020; 21(24): 9737.
[http://dx.doi.org/10.3390/ijms21249737] [PMID: 33419368]
[61]
Karimi E, Moini A, Yaseri M, et al. Effects of synbiotic supplementation on metabolic parameters and apelin in women with polycystic ovary syndrome: a randomised double-blind placebo-controlled trial. Br J Nutr 2018; 119(4): 398-406.
[http://dx.doi.org/10.1017/S0007114517003920] [PMID: 29498342]
[62]
Nasri K, Jamilian M, Rahmani E, Bahmani F, Tajabadi-Ebrahimi M, Asemi Z. The effects of synbiotic supplementation on hormonal status, biomarkers of inflammation and oxidative stress in subjects with polycystic ovary syndrome: a randomized, double-blind, place-bo-controlled trial. BMC Endocr Disord 2018; 18(1): 21.
[http://dx.doi.org/10.1186/s12902-018-0248-0] [PMID: 29649996]
[63]
Shamasbi SG, Dehghan P, Charandabi SM-A, Aliasgarzadeh A, Mirghafourvand M. Effect of prebiotic on anthropometric indices in women with polycystic ovarian syndrome: a triple-blind, randomized, controlled clinical trial. Iran Red Crescent Med J 2018; 20: e67270.
[64]
Darvishi S, Rafraf M, Asghari-Jafarabadi M, Farzadi L. Synbiotic supplementation improves metabolic factors and obesity values in women with polycystic ovary syndrome independent of affecting apelin Levels: a randomized double-blind placebo-controlled clinical trial. Int J Fertil Steril 2021; 15(1): 51-9.
[PMID: 33497048]
[65]
Shabani A, Noshadian M, Jamilian M, Chamani M, Mohammadi S, Asemi Z. The effects of a novel combination of selenium and probi-otic on weight loss, glycemic control and markers of cardio-metabolic risk in women with polycystic ovary syndrome. J Funct Foods 2018; 46: 329-34.
[http://dx.doi.org/10.1016/j.jff.2018.04.071]
[66]
Karimi E, Heshmati J, Shirzad N, et al. The effect of synbiotics supplementation on anthropometric indicators and lipid profiles in wom-en with polycystic ovary syndrome: a randomized controlled trial. Lipids Health Dis 2020; 19(1): 60.
[http://dx.doi.org/10.1186/s12944-020-01244-4] [PMID: 32248805]
[67]
Samimi M, Dadkhah A, Haddad Kashani H, Tajabadi-Ebrahimi M, Seyed Hosseini E, Asemi Z. The effects of synbiotic supplementation on metabolic status in women with polycystic ovary syndrome: a randomized double-blind clinical trial. Probiotics Antimicrob Proteins 2019; 11(4): 1355-61.
[http://dx.doi.org/10.1007/s12602-018-9405-z] [PMID: 29532416]

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