The potential role of incretin-based therapies for polycystic ovary syndrome: a narrative review of the current evidence

Mohammed Altigani Abdalla, Harshal Deshmukh, Stephen Atkin, Thozhukat Sathyapalan, Mohammed Altigani Abdalla, Harshal Deshmukh, Stephen Atkin, Thozhukat Sathyapalan

Abstract

Introduction: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Metabolic consequences associated with PCOS include, but are not limited to, insulin resistance (IR), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). This narrative review aims to provide a comprehensive overview of the potential therapeutic roles of the incretin-based therapies in the management of PCOS.

Methods: We performed a systematic search of databases including PubMed, MEDLINE and EMBASE up to 1 October 2020. We developed a search string of medical subject headings (MeSH) including the terms PCOS, incretin mimetics, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-1 receptor antagonists (GLP-1 RAs), liraglutide, exenatide, semaglutide, dipeptidyl peptidase-4 (DPP-4) inhibitors, combined with IR, testosterone and sex hormone-binding globulin (SHBG).

Results: We identified 854 relevant articles and, after the initial screening, eight interventional animal studies, one observational animal study, 14 interventional human studies, two case-control studies and one systematic review were included. These studies showed the potential significant roles of GLP-1 RAs and DPP-4 inhibitors in the management of PCOS, with significant improvements in the metabolic parameters, including substantial weight reduction and improved insulin sensitivity. These agents also improved the hormonal parameters through decreased free androgen and increased SHBG. Moreover, they improved menstrual regularity, increased fertility with enhanced ovulation and pregnancy in obese women with PCOS.

Conclusion: GLP-1 RAs and DPP-4 inhibitors have a promising therapeutic role in PCOS; however, larger clinical trials are needed to establish the role of incretin-based therapies in the management of PCOS.

Keywords: DPP-4; GLP-1 RAs; PCOS; dipeptidyl peptidase-4 inhibitors; exenatide; glucagon-like peptide-1; infertility; insulin resistance; liraglutide; obesity; polycystic ovary syndrome; sitagliptin; vildagliptin.

Conflict of interest statement

Conflict of interest: The authors declare that there is no conflict of interest.

© The Author(s), 2021.

Figures

Figure 1.
Figure 1.
The mechanism by which glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (RAs) enhance insulin sensitivity and weight loss.
Figure 2.
Figure 2.
Flowchart for the method of study selection.

References

    1. March WA, Moore VM, Willson KJ, et al. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010; 25: 544–551.
    1. Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab 2006; 91: 781–785.
    1. Azziz R, Carmina E, Dewailly D, et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91: 4237–4245.
    1. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018; 110: 364–379.
    1. Goodarzi MO, Dumesic DA, Chazenbalk G, et al. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011; 7: 219–231.
    1. Apridonidze T, Essah PA, Iuorno MJ, et al. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90: 1929–1935.
    1. Boyle JA, Teede HJ. PCOS: refining diagnostic features in PCOS to optimize health outcomes. Nat Rev Endocrinol 2016; 12: 630–631.
    1. Moran LJ, Hutchison SK, Norman RJ, et al. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2011; CD007506.
    1. Creutzfeldt W. The incretin concept today. Diabetologia 1979; 16: 75–85.
    1. Papaetis GS. Incretin-based therapies in prediabetes: current evidence and future perspectives. World J Diabetes 2014; 5: 817–834.
    1. Tzotzas T, Karras SN, Katsiki N. Glucagon-Like Peptide-1 (GLP-1) receptor agonists in the treatment of obese women with polycystic ovary syndrome. Curr Vasc Pharmacol 2017; 15: 218–229.
    1. Madsbad S. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes Obes Metab 2014; 16: 9–21.
    1. Ferjan S, Jensterle M, Oblak T, et al. An impaired glucagon-like peptide-1 response is associated with prediabetes in polycystic ovary syndrome with obesity. J Int Med Res 2019; 47: 4691–4700.
    1. Vrbikova J, Hill M, Bendlova B, et al. Incretin levels in polycystic ovary syndrome. Eur J Endocrinol 2008; 159: 121–127.
    1. Zhang F, Tang X, Cao H, et al. Impaired secretion of total glucagon-like peptide-1 in people with impaired fasting glucose combined impaired glucose tolerance. Int J Med Sci 2012; 9: 574–581.
    1. Garber AJ. Incretin effects on beta-cell function, replication, and mass: the human perspective. Diabetes Care 2011; 34 (Suppl. 2): S258–S263.
    1. Byrne MM, Gliem K, Wank U, et al. Glucagon-like peptide 1 improves the ability of the beta-cell to sense and respond to glucose in subjects with impaired glucose tolerance. Diabetes 1998; 47: 1259–1265.
    1. Yabe D, Seino Y, Seino Y. Incretin concept revised: the origin of the insulinotropic function of glucagon-like peptide-1 – the gut, the islets or both? J Diabetes Investig 2018; 9: 21–24.
    1. Crepaldi G, Carruba M, Comaschi M, et al. Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in type 2 diabetes management. J Endocrinol Invest 2007; 30: 610–614.
    1. Hjerpsted JB, Flint A, Brooks A, et al. Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity. Diabetes Obes Metab 2018; 20: 610–619.
    1. Triplitt C, Solis-Herrera C. GLP-1 receptor agonists: practical considerations for clinical practice. Diabetes Educ 2015; 41: 32S–46S.
    1. Abdalla MA, Deshmukh H, Atkin S, et al. A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome. Ther Adv Endocrinol Metab 2020; 11: 2042018820938305.
    1. Alvarez E, Martinez MD, Roncero I, et al. The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. J Neurochem 2005; 92: 798–806.
    1. Farkas I, Vastagh C, Farkas E, et al. Glucagon-like peptide-1 excites firing and increases GABAergic miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) neurons of the male mice via activation of Nitric Oxide (NO) and suppression of endocannabinoid signaling pathways. Front Cell Neurosci 2016; 10: 214.
    1. Ma X, Bruning J, Ashcroft FM. Glucagon-like peptide 1 stimulates hypothalamic proopiomelanocortin neurons. J Neurosci 2007; 27: 7125–7129.
    1. Lopez-Ferreras L, Richard JE, Noble EE, et al. Lateral hypothalamic GLP-1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight. Mol Psychiatry 2018; 23: 1157–1168.
    1. Beiroa D, Imbernon M, Gallego R, et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 2014; 63: 3346–3358.
    1. Heppner KM, Baquero AF, Bennett CM, et al. GLP-1R signaling directly activates arcuate nucleus kisspeptin action in brain slices but does not rescue luteinizing hormone inhibition in ovariectomized mice during negative energy balance. eNeuro 2017; 4: ENEURO.0198-16.2016.
    1. Outeirino-Iglesias V, Romani-Perez M, Gonzalez-Matias LC, et al. GLP-1 increases preovulatory LH source and the number of mature follicles, as well as synchronizing the onset of puberty in female rats. Endocrinology 2015; 156: 4226–4237.
    1. Nishiyama Y, Hasegawa T, Fujita S, et al. Incretins modulate progesterone biosynthesis by regulating bone morphogenetic protein activity in rat granulosa cells. J Steroid Biochem Mol Biol 2018; 178: 82–88.
    1. Jensterle M, Salamun V, Kocjan T, et al. Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study. J Ovarian Res 2015; 8: 32.
    1. McClenaghan NH. Physiological regulation of the pancreatic {beta}-cell: functional insights for understanding and therapy of diabetes. Exp Physiol 2007; 92: 481–496.
    1. Drucker DJ. Minireview: the glucagon-like peptides. Endocrinology 2001; 142: 521–527.
    1. Guo C, Huang T, Chen A, et al. Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages. Braz J Med Biol Res 2016; 49: e5826.
    1. Jiang Y, Wang Z, Ma B, et al. GLP-1 improves adipocyte insulin sensitivity following induction of endoplasmic reticulum stress. Front Pharmacol 2018; 9: 1168.
    1. Parlevliet ET, de Leeuw van Weenen JE, Romijn JA, et al. GLP-1 treatment reduces endogenous insulin resistance via activation of central GLP-1 receptors in mice fed a high-fat diet. Am J Physiol Endocrinol Metab 2010; 299: E318–E324.
    1. MacDonald PE, El-Kholy W, Riedel MJ, et al. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 2002; 51 (Suppl. 3): S434–S442.
    1. Smits MM, Tonneijck L, Muskiet MH, et al. Gastrointestinal actions of glucagon-like peptide-1-based therapies: glycaemic control beyond the pancreas. Diabetes Obes Metab 2016; 18: 224–235.
    1. Meloni AR, DeYoung MB, Lowe C, et al. GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence. Diabetes Obes Metab 2013; 15: 15–27.
    1. Buteau J, Roduit R, Susini S, et al. Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells. Diabetologia 1999; 42: 856–864.
    1. Buteau J, Foisy S, Rhodes CJ, et al. Protein kinase Czeta activation mediates glucagon-like peptide-1-induced pancreatic beta-cell proliferation. Diabetes 2001; 50: 2237–2243.
    1. Buteau J, Foisy S, Joly E, et al. Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 2003; 52: 124–132.
    1. He Junxian, Cai Lisi, Li Jing, Li Yunhui, Tao Xin, Zhang Yu. Exenatide Improves Endometrial Glands in PCOS Rats through AMPKα-SIRT1. 2020. 10.21203/-28388/v1.
    1. Tao X, Cai L, Chen L, et al. Effects of metformin and exenatide on insulin resistance and AMPKα-SIRT1 molecular pathway in PCOS rats. J Ovarian Res 2019; 12: 86.
    1. Sun L, Ji C, Jin L, et al. Effects of exenatide on metabolic changes, sexual hormones, inflammatory cytokines, adipokines, and weight change in a DHEA-treated rat model. Reprod Sci 2016; 23: 1242–1249.
    1. Elkind-Hirsch K, Marrioneaux O, Bhushan M, et al. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93: 2670–2678.
    1. Liu X, Zhang Y, Zheng S-Y, et al. Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome. Clin Endocrinol (Oxf) 2017; 87: 767–774.
    1. Rasmussen CB, Lindenberg S. The effect of liraglutide on weight loss in women with polycystic ovary syndrome: an observational study. Front Endocrinol (Lausanne) 2014; 5: 140.
    1. Frossing S, Nylander M, Chabanova E, et al. Effect of liraglutide on ectopic fat in polycystic ovary syndrome: a randomized clinical trial. Diabetes Obes Metab 2018; 20: 215–218.
    1. Jensterle M, Kocjan T, Kravos NA, et al. Short-term intervention with liraglutide improved eating behavior in obese women with polycystic ovary syndrome. Endocr Res 2015; 40: 133–138.
    1. Jensterle M, Kravos NA, Goricar K, et al. Short-term effectiveness of low dose liraglutide in combination with metformin versus high dose liraglutide alone in treatment of obese PCOS: randomized trial. BMC Endocr Disord 2017; 17: 5.
    1. Kahal H, Abouda G, Rigby AS, et al. Glucagon-like peptide-1 analogue, liraglutide, improves liver fibrosis markers in obese women with polycystic ovary syndrome and nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 2014; 81: 523–528.
    1. Kahal H, Kilpatrick E, Rigby A, et al. The effects of treatment with liraglutide on quality of life and depression in young obese women with PCOS and controls. Gynecol Endocrinol 2019; 35: 142–145.
    1. Nylander M, Frossing S, Clausen HV, et al. Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a randomized clinical trial. Reprod Biomed Online 2017; 35: 121–127.
    1. Salamun V, Jensterle M, Janez A, et al. 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: 1–11.
    1. Dawson AJ, Sathyapalan T, Vince R, et al. The effect of exenatide on cardiovascular risk markers in women with polycystic ovary syndrome. Front Endocrinol (Lausanne) 2019; 10: 189.
    1. Tang L, Yuan L, Yang G, et al. Changes in whole metabolites after exenatide treatment in overweight/obese polycystic ovary syndrome patients. Clin Endocrinol (Oxf) 2019; 91: 508–516.
    1. Zheng S, Liu E, Zhang Y, et al. Circulating zinc-alpha2-glycoprotein is reduced in women with polycystic ovary syndrome, but can be increased by exenatide or metformin treatment. Endocr J 2019; 66: 555–562.
    1. Sekar R, Singh K, Arokiaraj AW, et al. Pharmacological actions of glucagon-like peptide-1, gastric inhibitory polypeptide, and glucagon. Int Rev Cell Mol Biol 2016; 326: 279–341.
    1. Ladenheim EE. Liraglutide and obesity: a review of the data so far. Drug Des Devel Ther 2015; 9: 1867–1875.
    1. Papaetis GS, Filippou PK, Constantinidou KG, et al. Liraglutide: new perspectives for the treatment of polycystic ovary syndrome. Clin Drug Investig 2020; 40: 695–713.
    1. 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; 2020: 1484321.
    1. Singh A, Fernandes JRD, Chhabra G, et al. Liraglutide modulates adipokine expression during adipogenesis, ameliorating obesity, and polycystic ovary syndrome in mice. Endocrine 2019; 64: 349–366.
    1. Niafar M, Pourafkari L, Porhomayon J, et al. A systematic review of GLP-1 agonists on the metabolic syndrome in women with polycystic ovaries. Arch Gynecol Obstet 2016; 293: 509–515.
    1. Hughes S, Neumiller JJ. Oral semaglutide. Clin Diabetes 2020; 38: 109–111.
    1. Chen B, Moore A, Escobedo LV, et al. Sitagliptin lowers glucagon and improves glucose tolerance in prediabetic obese SHROB rats. Exp Biol Med (Maywood) 2011; 236: 309–314.
    1. Dobrian AD, Ma Q, Lindsay JW, et al. Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am J Physiol Endocrinol Metab 2011; 300: E410–E421.
    1. Mu J, Woods J, Zhou YP, et al. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes 2006; 55: 1695–1704.
    1. Wang Q, Shang J, Zhang Y, et al. Metformin and sitagliptin combination therapy ameliorates polycystic ovary syndrome with insulin resistance through upregulation of lncRNA H19. Cell Cycle 2019; 18: 2538–2549.
    1. Wang F, Zhang ZF, He YR, et al. Effects of dipeptidyl peptidase-4 inhibitors on transforming growth factor-beta1 signal transduction pathways in the ovarian fibrosis of polycystic ovary syndrome rats. J Obstet Gynaecol Res 2019; 45: 600–608.
    1. Dumesic DA, Phan JD, Leung KL, et al. Adipose insulin resistance in normal-weight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2019; 104: 2171–2183.
    1. Xu N, Kwon S, Abbott DH, et al. Epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS)-like phenotypes in prenatally androgenized rhesus monkeys. PLoS One 2011; 6: e27286.
    1. Devin JK, Nian H, Celedonio JE, et al. Sitagliptin decreases visceral fat and blood glucose in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2020; 105: dgz028.
    1. Devin J, Nian H, Wright P, et al. MON-474 Dipeptidyl Peptidase-4 (DPP4) inhibition decreases visceral fat and improves glucose metabolism in overweight women with polycystic ovarian syndrome. J Endocr Soc 2019; 3 (Suppl. 1): MON-474.
    1. Ferjan S, Janez A, Jensterle M. Dpp4 inhibitor sitagliptin as a potential treatment option in metformin-intolerant obese women with polycystic ovary syndrome: a pilot randomized study. Endocr Pract 2018; 24: 69–77.
    1. Ferjan S, Janez A, Jensterle M. Dipeptidyl peptidase-4 inhibitor sitagliptin prevented weight regain in obese women with polycystic ovary syndrome previously treated with liraglutide: a pilot randomized study. Metab Syndr Relat Disord 2017; 15: 515–520.
    1. Jensterle M, Goricar K, Janez A. Add on DPP-4 inhibitor alogliptin alone or in combination with pioglitazone improved beta-cell function and insulin sensitivity in metformin treated PCOS. Endocr Res 2017; 42: 261–268.
    1. El-Halwagy AS, Al-Gergawy AA, Eleslam ES, et al. Clinical and biochemical changes in polycystic ovarian syndrome patients in response to 3 different oral hypoglycemic drugs: a double blind randomized controlled study. Open J Obstet Gynecol 2016; 7: 117–128.
    1. Foley JE, Jordan J. Weight neutrality with the DPP-4 inhibitor, vildagliptin: mechanistic basis and clinical experience. Vasc Health Risk Manag 2010; 6: 541–548.
    1. Dineen L, Law C, Scher R, et al. Alogliptin (nesina) for adults with type-2 diabetes. P T 2014; 39: 186–202.
    1. Elkind-Hirsch KE, Paterson MS, Seidemann EL, et al. Short-term therapy with combination dipeptidyl peptidase-4 inhibitor saxagliptin/metformin extended release (XR) is superior to saxagliptin or metformin XR monotherapy in prediabetic women with polycystic ovary syndrome: a single-blind, randomized, pilot study. Fertil Steril 2017; 107: 253–260e251.
    1. Tao T, Wu P, Wang Y, et al. Comparison of glycemic control and beta-cell function in new onset T2DM patients with PCOS of metformin and saxagliptin monotherapy or combination treatment. BMC Endocr Disord 2018; 18: 14.

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