Rezvan N, Moini A, Janani L, et al. Effects of quercetin on adiponectin-mediated insulin sensitivity in polycystic ovary syndrome: a randomized placebo-controlled double-blind clinical trial. Horm Metab Res. 2017;49:115-121.
A 12-week randomized placebo-controlled double-blind clinical trial was conducted to determine the effect of quercetin supplementation on serum adiponectin levels in women with polycystic ovary syndrome (PCOS).
A total of 84 women with PCOS diagnosed by the Rotterdam Criteria, aged 20 to 40 years, with a BMI between 25 and 40 kg/m2 were enrolled in the study. Those with concomitant endocrine or metabolic diseases (hypothyroidism, hyperthyroidism, androgen-secreting tumors, diabetes mellitus, adrenal hyperplasia, Cushing’s syndrome) and those taking interfering medications (metformin, contraceptive, antihypertensive, fat-lowering, anti-inflammatory) were excluded.
Participants in the experimental group (n=42) received a total of 1 g of quercetin (Jarrow, USA) daily, with one 500 mg capsule taken orally after breakfast and lunch. The control group (n=42) followed the same dosing schedule, but with placebo capsules containing starch. Adherence was monitored by weekly phone check-ins and by counting the number of capsules returned every 2 weeks.
Primary outcome measures included changes in serum levels of total and high molecular weight (HMW) adiponectin. Also assessed were the following anthropometric, metabolic, and hormonal measures: weight, BMI, waist to hip ratio (WHR), serum testosterone, luteinizing hormone (LH), sex hormone–binding globulin (SHBG), and homeostatic model assessment of insulin resistance (HOMA-IR). Assessments were performed at baseline and week 12.
Of the 84 enrolled, only 2 participants, both in the control group, failed to complete the trial. One discontinued the intervention due to reported diarrhea and the other was lost to follow-up.
While this study’s findings have elucidated the role of adiponectin in insulin resistance, it is still unclear if and how PCOS symptomology will be affected by increasing levels.
In the experimental group, total and HMW adiponectin levels were significantly higher (8.6% and 7.4%; P<0.001 for both) at the end of the trial compared to baseline. Notable and significant improvements in HOMA-IR (17.5%; P<0.001), serum testosterone, and LH were also observed. Quercetin had a marginal effect on SHBG. Placebo failed to produce any therapeutic benefit regarding these same measures. Changes in weight, BMI, and WHR were not significantly different between the 2 groups. An inverse correlation between adiponectin levels and HOMA-IR, BMI, and WC was noted and deemed statistically significant.
Insulin resistance and subsequent hyperinsulinemia are common clinical features of PCOS. With an estimated prevalence of 50% to 70%, insulin resistance is considered a significant contributory factor in the pathophysiology of the condition.1 One proposed mechanism of PCOS involves stimulation of ovarian theca cells by insulin, resulting in testosterone production and eventual androgen excess.1 Treatment protocols for PCOS, both conventional and naturopathic, typically include insulin sensitization as a primary goal. At the least, lowering insulin will lessen risk of type 2 diabetes mellitus and cardiovascular disease. At most, it may help control the symptomology as well.
The gold standard for diagnosing insulin resistance is hyperinsulinemic-euglycemic clamp, though it is not commonly used. Instead, diagnosis and management are typically guided by clinical presentation and fasting blood glucose and hemoglobin A1c levels. Measurement of adiponectin, a protein derived from adipose tissue, may strengthen diagnostic accuracy given that it is a strong predictor of insulin resistance.2 Unlike other adipokines, its effects are protective (antiinflammatory, antidiabetic, antiatherogenic, cardioprotective) and levels are inversely associated with metabolic dysregulation.3
The first clinical trial to study adiponectin and its role in PCOS-related metabolic syndrome was published in 2003. It identified a direct correlation between adiponectin levels and glucose disposal rate (P=0.043) and an inverse correlation with WHR (P=0.024). It also recognized adiponectin level as a valid indicator of abdominal fat mass.4
Trolle et al confirmed the inverse correlation between adiponectin levels and WHR, and found the same to be true for insulin and HOMA-IR. Also within this study, metformin was tested to determine its ability to increase adiponectin levels.5 No significant changes were observed, and several other papers documented the same outcome.6,7 Conversely, there are multiple reports of success with other insulin sensitizing medications such as pioglitazone,8 rosiglitazone,9 and the combination of flutamide plus metformin.10
In the studies involving the aforementioned medications, researchers also reported significantly lower baseline adiponectin levels in those with PCOS compared to non-PCOS weight-matched individuals. Findings suggest that adiposity, even in the absence of obesity, leads to alterations in levels. That said, lean PCOS patients might still be at risk for low levels of adiponectin and insulin resistance depending on their body composition.
This study was the first to assess the effect of quercetin on PCOS, though past research reveals therapeutic benefit for numerous conditions and highlight quercetin’s antioxidative11 and anti-inflammatory12 properties. A paper published in September 2017 revealed that women with PCOS have greater levels of oxidative stress and inflammation than those without PCOS, so it is not surprising that quercetin is currently of interest among researchers.13 It is also worth noting that PCOS may put women at greater risk for ovarian cancer.14 In vitro and animal studies suggest that quercetin may have a protective effect against ovarian cancer development.15
While the findings of this study have elucidated the role of adiponectin in insulin resistance, it is still unclear if and how PCOS symptomology will be affected by increasing levels. Further research investigating long-term outcomes of supplementation is needed to better understand its use in the treatment of PCOS. Until then, quercetin is a low-risk intervention that may serve as a beneficial adjunctive treatment.
- Bednarska S, Siejka A. The pathogenesis and treatment of polycystic ovary syndrome: what’s new? Adv Clin Exp Med. 2017;26(2):359-367
- Park SE, Park CY, Sweeney G. Biomarkers of insulin sensitivity and insulin resistance: past, present and future. Crit Rev Clin Lab Sci. 2015;52(4):180-190.
- Nigro E, Scudiero O, Monaco ML, et al. New insight into adiponectin role in obesity and obesity-related diseases. BioMed Res Int. 2014;2014. Article ID: 658913.
- Ducluzeau P, Cousin P, Malvoisin E, et al. Glucose-to-insulin ratio rather than sex hormone-binding globulin and adiponectin levels is the best predictor of insulin resistance in nonobese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(8):3626-3631.
- Trolle B, Lauszus FF, Frystyk J, et al. Adiponectin levels in women with polycystic ovary syndrome: impact of metformin treatment in a randomized controlled study. Fertil Steril. 2010;94(6):2234-2238.
- Luque-Ramírez M, Alvarez-Blasco F, Escobar-Morreale HF. Antiandrogenic contraceptives increase serum adiponectin in obese polycystic ovary syndrome patients. Obesity (Silver Spring). 2009;17(1):3-9.
- Kruszyńska A, Słowińska-Srzednicka J, Jeske W, et al. Proinsulin, adiponectin and hsCRP in reproductive age women with polycystic ovary syndrome (PCOS)--the effect of metformin treatment. Endokrynol Pol. 2014;65(1):2-10.
- Glintborg D, Frystyk J, Højlund K, et al. Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo-controlled study in polycystic ovary syndrome. Clin Endocrinol (Oxf). 2008;68(2):165-174.
- Majuri A, Santaniemi M, Rautio K, et al. Rosiglitazone treatment increases plasma levels of adiponectin and decreases levels of resistin in overweight women with PCOS: a randomized placebo-controlled study. Eur J Endocrinol. 2007;156(2):263-269.
- Ibáñez L, de Zegher F. Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: opposite effects on adipocytokines and body adiposity. J Clin Endocrinol Metab. 2004;89(4):1592-1597.
- Najafzadeh M, Reynolds PD, Baumgartner A, Anderson D. Flavonoids inhibit the genotoxicity of hydrogen peroxide (H(2)O(2)) and of the food mutagen 2-amino-3-methylimadazo[4,5-f]-quinoline (IQ) in lymphocytes from patients with inflammatory bowel disease (IBD). Mutagenesis. 2009;(5):405-411.
- Nair MP, Mahajan S, Reynolds JL, et al. The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-kappa beta system. Clin Vaccine Immunol. 2006;13(3):319-328.
- Artimani T, Karimi J, Mehdizadeh M, et al. Evaluation of pro-oxidant-antioxidant balance (PAB) and its association with inflammatory cytokines in polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2017;Sep 4:1-5.
- Harris HR, Terry KL. Polycystic ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review. Fertil Res Pract. 2016;2:14.
- Parvaresh A, Razavi R, Rafie N, Ghiasvand R, Pourmasoumi M, Miraghajani M. Quercetin and ovarian cancer: an evaluation based on a systematic review. J Res Med Sci. 2016;21:34.