Skip to main content

Serum uric acid/creatinine ratio and free androgen index are synergistically associated with increased risk of polycystic ovary syndrome in obese women

Abstract

Background

Features of metabolic syndrome such as abdominal obesity, insulin resistance, hypertension and dyslipidemia are commonly encountered in polycystic ovary syndrome (PCOS). Recent evidence has suggested an association between high serum uric acid/creatinine (UA/Cr) ratio and metabolic syndrome however, no studies have investigated this association in PCOS. The current study was conducted to investigate the relationship between UA/Cr ratio and PCOS and to identify whether UA/Cr ratio and free androgen index (FAI) have an additive interaction for detection of PCOS risk in obese women.

Methods

This study enrolled 40 obese women with PCOS and 40 control women with regular menstrual cycles matched for age and body mass index (BMI). Anthropometric measurements, fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), lipids profile, luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), total testosterone, free androgen index (FAI), UA/Cr ratio were assessed.

Results

Serum UA/Cr ratio was significantly higher in obese women with PCOS than in non-PCOS women. UA/Cr ratio was correlated with BMI, waist and neck circumferences, blood pressure, fasting insulin, HOMA-IR, lipids, LH/FSH, estradiol, DHEAS, total testosterone, FAI and SHBG. UA/Cr ratio and FAI were independent risk factors for PCOS in obese women however, the addictive interaction between UA/Cr ratio and FAI had a higher fold risk (OR: 4.3, 95% CI, 3.4–7.58) and a more significance (P = 0.002) for determination of PCOS.

Conclusion

Serum UA/Cr ratio combined with FAI can exert an additive or synergistic impact on prediction of PCOS in obese women.

Peer Review reports

Background

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age [1] affecting 5–20% [2]. It is a multi-factorial complex disorder with genetic and environmental background [3]. PCOS is characterized by hyperandrogenism, chronic anovulation and polycystic ovaries after exclusion of related disorders [4]. Beyond infertility, women with PCOS are prone to many complications such as increased risk of type 2 diabetes (T2D), cardiovascular disease, sleep apnea syndrome, endometrial cancer in addition to mood disorders [5, 6] therefore, early diagnosis and treatment is of a great importance.

Hyperandrogenemia is one of the most important features of PCOS and the key point in its diagnosis [7]. Total testosterone level in women may not be a sensitive marker for the detection of androgen excess on the other side, routine measurement of free testosterone is challenging [8, 9]. Accordingly, free androgen index (FAI), calculated by total testosterone and sex hormone binding globulin (SHBG), indirectly reflects the free androgen levels [10]. FAI is considered to be the single most-useful test of hyperandrogenemia in women [11].

Women with PCOS frequently exhibit features of metabolic syndrome (MS) such as abdominal obesity, insulin resistance, hypertension and dyslipidemia [1, 12, 13]. Besides that, MS is highly prevalent in women with PCOS [14]. Recently, an increasing evidence indicates that elevated serum uric acid/creatinine (UA/Cr) ratio, a new biomarker reflecting endogenous uric acid levels more precisely than serum uric acid, is related to MS [15,16,17,18]. PCOS is a complex endocrine-metabolic disorder in which serum uric acid is closely related to androgen excess [19]. It is unknown whether the obese women with PCOS have an elevated UA/Cr ratio, and if so, whether the link between UA/Cr ratio and FAI provides a benefit to predict PCOS in obese women. This study was conducted to explore the relationship between UA/Cr ratio and PCOS and to identify whether UA/Cr ratio and FAI have an additive interaction for detection of PCOS risk in obese women.

Methods

This case control study comprised 40 obese women with PCOS and 40 control women matched for age and body mass index (BMI). Obesity was defined as a BMI  30 Kg/m2. Healthy controls had regular menstrual cycles and no family history of PCOS. Women with PCOS were recruited from the Fertility Outpatient Clinic at Mansoura University Hospital, Mansoura University, Egypt.

All participants were subjected to a thorough medical history and underwent a clinical examination with stress on signs of hyperandrogenism (acne, hirsutism, and/or acanthosis nigricans). Systolic and diastolic blood pressure (SBP & DBP) were taken in the sitting position after 10 min of rest using a random-zero sphygmomanometer. Anthropometric measurements including height, body weight, BMI and waist circumference (WC) were obtained with standardized techniques. BMI was calculated as weight/height2 [kg/m2] and WC was measured at the level of the iliac crest at the end of normal expiration. Neck circumference, as an indicator for upper-body subcutaneous fat, was measured at the level of the thyroid cartilage in the standing position with erect head.

Diagnosis of PCOS was based on the Rotterdam revised criteria [4]; at least 2 of the 3 following criteria after exclusion of other causes of hyperandrogenism and menstrual irregularities:

  1. 1)

    Oligomenorrhea (intermenstrual interval of > 35 days and < 8 menstrual bleeds in a year) or amenorrhea (absent menstrual bleeding in the past 90 days).

  2. 2)

    Clinical hyperandrogenism (Ferriman Gallwey score ≥ 8 [20] and/or biochemical hyperandrogenism (increased total testosterone levels or dehydroepiandrosterone sulfate (DHEAS).

  3. 3)

    Polycystic ovaries on ultrasound scan (at least one ovary contains 12 follicles or more with 2 to 9 mm in diameters and/or ovarian volume > 10 mm).

In eumenorrheic women with clinical signs of hyperandrogenism, normal ovulation was assessed by a progesterone level on days 20–24 of 1 or 2 consecutive cycles.

None of the participants had thyroid disorders, hyperprolactinemia, non-classical congenital adrenal hyperplasia, T2D, hepatic or renal failure, connective tissue disorders, malignancy, pregnancy, taking birth control pills or hormone replacement therapy, anti-androgens, ovulation-inducing agents, steroids, lipid lowering drugs or insulin sensitizers for at least 3 months before the study. We also excluded women who were taking medications affecting the circulating uric acid levels such as aspirin and thiazide diuretics.

Laboratory assay

Fasting plasma glucose, serum uric acid, creatinine, total cholesterol (TC), triglycerides (TGs) and high density lipoprotein cholesterol (HDL-C) were measured by automated chemistry analyzer (cobas c311) using its commercial kits supplied by Roche Diagnostic Germany. Low density lipoprotein cholesterol (LDL-C) was calculated according to Friedewald formula [21]. Fasting insulin was estimated by a solid phase enzyme-linked immunosorbent assay supplied by (BIOS) kits. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated with the formula: HOMA-IR= [fasting insulin (µU/mL) × fasting glucose (mmol/L)/22.5] [22]. Serum luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, testosterone, DHEAS and SHBG were measured by automated chemistry analyzer (Cobas 411) using a potential electrochemiluminescence technology for immune assay analysis. Serum UA/Cr ratio was calculated as uric acid (mmol/l)/creatinine (µmol/l). FAI was calculated with the formula: total testosterone (nmol/L)/SHBG (nmol/L) ×100 [10].

Statistical analysis

Data entry and analysis were done by the SPSS statistical package (version 22, Armonk, NY: IBM Corp). The data were expressed as mean ± SD for continuous data, number and percent for categorical data and median (minimum-maximum) for skewed data. Student´s t and Mann-Whitney U tests were used to compare the 2 studied groups for parametric and non-parametric data, respectively. The correlations of UA/Cr ratio and FAI with all other studied variables were analyzed by the Pearson and Spearman correlations analysis. Binary stepwise logistic regression analysis was performed to predict the independent variables of binary outcome; significant predictors in the univariate analysis were entered into regression model. P ≤ 0.05 was considered to be significant.

Results

Obese women with PCOS had significantly higher SBP, DBP, FPG, fasting insulin, HOMA-IR, LH/FSH, DHEAS, total testosterone, FAI, uric acid and lower SHBG compared with non-PCOS obese women. No significant differences between obese women with and without PCOS with regard to TC, TGs, LDL, HDL, estradiol and creatinine Table 1. UA/Cr ratio was significantly higher in obese women with PCOS than in non-PCOS women (4.38 ± 0.69 vs. 3.94 ± 0.88, P < 0.001) Fig. 1.

Table 1 Baseline characteristics of the study subjects
Fig. 1
figure 1

UA/Cr ratio in obese women with and without PCOS

UA/Cr ratio was positively correlated with BMI, WC, neck circumference, SBP, DBP, fasting insulin, HOMA-IR, TC, TGs, LDL-C, LH/FSH, estradiol, DHEAS, total testosterone and FAI (Fig. 2) and negatively correlated with HDL-C and SHBG. FAI was positively correlated with BMI, WC, neck circumference, fasting insulin, HOMA-IR, TC, TGs, LDL-C, LH/FSH, estradiol and DHEAS and negatively correlated with HDL-C Table 2.

Fig. 2
figure 2

Correlation between UA/Cr ratio and FAI in obese women with PCOS

Table 2 Correlations between UA/Cr ratio and FAI with other variables in obese women with PCOS

After adjustments for confounding factors, the UA/Cr ratio and FAI were independent risk factors for PCOS in obese women; the OR (95% CI) were 1.62 (1.13–4.58) and 3.12 (1.28–8.25), respectively. Furthermore, the addictive interaction between UA/Cr ratio and FAI was an independent determinant for PCOS with a higher fold risk (OR: 4.3, 95% CI: 3.4–7.58) and a more significance (P = 0.002) Table 3.

Table 3 Associations of UA/Cr ratio, FAI and combined UA/Cr ratio & FAI with PCOS

Discussion

In the current study, obese women with PCOS had a significantly higher UA/Cr ratio than those without PCOS. UA/Cr ratio was significantly correlated with BMI, WC, neck circumference, blood pressure, fasting insulin, HOMA-IR and lipids profile. Additionally, UA/Cr ratio was associated with PCOS risk in obese women after adjusting for confounding factors.

Our results are in accordance with Al-Daghri et al. [15] who noticed significant correlations between serum UA/Cr ratio and BMI, WC and HDL-C in patients with T2D. Our findings are also in parallel with Moriyama [16], who found significant associations between increased UA/Cr quartiles and anthropometric measures, blood pressure, insulin resistance, lipids and number of MS components in healthy Japanese subjects. UA/Cr ratio was positively correlated with BMI, WC, TG, LDL-C, HOMA-IR, and negatively correlated with HDL-C even in subjects with normal serum uric acid levels and different glucose tolerance states [23]. We found a positive correlation between UA/Cr ratio and neck circumference, this is in parallel with Yang et al. [24] who identified a positive correlation between neck circumference and hyperuricemia in women with PCOS. Upper body adiposity leads to excess free fatty acid release and high airway pressure with consequent oxidative stress and insulin resistance [25].

The close association between elevated serum uric acid, the end product of purine metabolism, and PCOS has been previously reported [19, 26] on the other hand, obesity is thought to be the driver of renal disease in women with PCOS [27]. Uric acid and creatinine levels are positively associated with the most metabolic disorders related to PCOS such as obesity, dyslipidemia and hypertension [28,29,30,31,32]. Additionally, a relationship between serum creatinine and hyperuricemia in both men and women has been previously established [30, 33] thus, the application of the UA/Cr ratio reduces the interference due to sex and renal function [34]. Indeed, serum UA/Cr ratio reflects the endogenous uric acid levels more precisely than uric acid and is closely related to metabolic disorders [35]. The association of UA/Cr ratio with MS and its components has been recently proposed [15,16,17,18]; the UA/Cr may be a useful marker in the pathogenesis and prognosis of MS [15] and a good indicator for components of MS even in healthy subjects [16]. MS and PCOS are almost the two sides of the same coin thus, the association between high UA/Cr ratio and PCOS in obese women is an expected finding.

In the present study, FAI was significantly higher in obese women with PCOS than in those without PCOS. FAI was significantly correlated with most of PCOS worse metabolic profiles. FAI was an independent risk factors for PCOS in obese women with adjusted OR 3.12.

Our findings are in agreement with the previous reports investigating the relationship between FAI and PCOS [36,37,38,39]. We found a significant correlation between FAI and metabolic disorders related to PCOS. In an earlier study conducted by Kauffman et al. [40], FAI was correlated with fasting insulin, HOMA-IR, TC, LDL in PCOS women with NFLD. Our results also go in line with Cai et al. [41] who observed that FAI was positively associated with WC, BMI, TG, TC and LDL-C and negatively associated with HDL-C. Recently, de Medeiros et al. [42] reported a positive association of FAI with most anthropometric and metabolic biomarkers in PCOS women. Al Kindi et al. [43] recommended the use of FAI than testosterone alone in the routine investigation for hyperandrogenism in women. Despite FAI was speculated to be more accurate than total testosterone to evaluate androgen excess in women with PCOS [44, 45], a recent meta-analysis revealed that FAI has a moderate diagnostic value for PCOS [46]. Of interest, we observed a significant positive association between UA/Cr ratio and FAI. Our study also revealed a new combined index composed of FAI and UA/Cr ratio; this combination was an independent significant risk factor for PCOS in obese women with a 4.3-fold risk.

Serum uric acid is closely related to androgen excess which is the clue criterion of PCOS [19]: hyperandrogenemia increases serum uric acid by inducing hepatic metabolism of purine nucleotides and enhancing purine renewal in the kidney [47, 48]. Indeed, hyperandrogenemia is associated with visceral obesity, insulin resistance and low inflammatory state [49,50,51]. Accumulation of visceral adipose tissue stimulates uric acid synthesis through de novo purine synthesis in the pentose phosphate pathway [52] in turn, uric acid induces intracellular and mitochondrial oxidative stress leading to increased fat synthesis and impaired fatty acid oxidation through disturbances in the Krebs cycle [53, 54]. Furthermore, hyperinsulinemia reduces renal uric acid clearance by activation of GLUT 9 leading to hyperuricemia [55]. On the other hand, hyperuricemia induces insulin resistance through suppression of both basal and glucose-stimulated insulin secretion [56], induction of β-cell dysfunction through NF-κB signaling pathway [57], reduction of serum nitric oxide levels [58] and bioavailability [59].

To our knowledge, this is the first study to indicate the association of UA/Cr ratio with PCOS. In addition to the direct individual association of UA/Cr ratio and FAI with PCOS risk in obese women, we found that the combined UA/Cr ratio and FAI had an additive interaction for the detection of PCOS.

Conclusion

Serum UA/Cr ratio combined with FAI can exert an additive or synergistic impact on prediction of PCOS in obese women. However, large-scale prospective studies of different ethnicities are needed to confirm our results.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

References

  1. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011;7:219–31.

    Article  CAS  Google Scholar 

  2. Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2016;31:2841–55.

    Article  Google Scholar 

  3. Kosova G, Urbanek M. Genetics of the polycystic ovary syndrome. Mol Cell Endocrinol. 2013;373:29–38.

    Article  CAS  Google Scholar 

  4. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004, 81:19–25.

    Article  Google Scholar 

  5. Randeva HS, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, et al. Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev. 2012;33:812–41.

    Article  CAS  Google Scholar 

  6. Barry JA, Kuczmierczyk AR. Anxiety and depression in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2011;26:2442–5.

    Article  CAS  Google Scholar 

  7. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. J Clin Endocrinol Metab. 2006;91:4237–45.

    Article  CAS  Google Scholar 

  8. Vermeulen A, Verdonck L, Kaufman J. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666–72.

    Article  CAS  Google Scholar 

  9. Taieb J, Mathian B, Millot F, Patricot MC, Mathieu M, Queyrel N, et al. Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women and children. Clin Chem. 2003;49:1381–95.

    Article  CAS  Google Scholar 

  10. Ly LP, Handelsman DJ. Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays. Eur J Endocrinol. 2005;152:471–8.

    Article  CAS  Google Scholar 

  11. Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4565–92.

    Article  CAS  Google Scholar 

  12. Elting MW, Korsen TJ, Bezemer PD, Schoemaker J. Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a dutch PCOS population. Hum Reprod. 2001;16:556–60.

    Article  CAS  Google Scholar 

  13. Wild RA, Rizzo M, Clifton S, Carmina E. Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. Fertil Steril. 2011;95:1073–9.e1-11.

    Article  CAS  Google Scholar 

  14. Chan JL, Kar S, Vanky E, Morin-Papunen L, Piltonen T, Puurunen J, et al. Racial and ethnic differences in the prevalence of metabolic syndrome and its components of metabolic syndrome in women with polycystic ovary syndrome: a regional cross-sectional study. Am J Obstet Gynecol. 2017;217(2):189.e1-9.e8.

    Article  Google Scholar 

  15. Al-Daghri NM, Al-Attas OS, Wani K, Sabico S, Alokail MS. Serum uric acid to creatinine ratio and risk of metabolic syndrome in saudi type 2 Diabetic patients. Sci Rep. 2017;7:12104.

    Article  Google Scholar 

  16. Moriyama K. The Association between the serum uric acid to creatinine ratio and metabolic syndrome, liver function, and Alcohol Intake in healthy japanese subjects. Metab Syndr Relat Disord. 2019;17:380–7.

    Article  CAS  Google Scholar 

  17. Kawamoto R, Ninomiya D, Akase T, Kikuchi A, Kasai Y, Kusunoki T, et al. Serum uric acid to creatinine ratio independently predicts Incident Metabolic Syndrome among Community-Dwelling Persons. Metab Syndr Relat Disord. 2019;17:81–9.

    Article  CAS  Google Scholar 

  18. Li R, Luo SY, Zuo ZG, Yu Z, Chen WN, Ye YX, et al. Association between serum uric acid to creatinine ratio and metabolic syndrome based on community residents in Chashan town, Dongguan city. Zhonghua Yu Fang Yi Xue Za Zhi. 2021;55:1449–55.

    CAS  Google Scholar 

  19. Mu L, Pan J, Yang L, Chen Q, Chen Y, Teng Y, et al. Association between the prevalence of hyperuricemia and reproductive hormones in polycystic ovary syndrome. Reprod Biol Endocrinol. 2018;16:104.

    Article  CAS  Google Scholar 

  20. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1996;21:1440–7.

    Article  Google Scholar 

  21. Friedewald WT, Levy RT, Fredrickson DS. Estimation of the concentration of low- density lipoprotein cholesterol without the use of preparative ultracentrifuge. Clin Chem. 1972;18:499–502.

    Article  CAS  Google Scholar 

  22. Mathews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis Model Assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28:412–9.

    Article  Google Scholar 

  23. Ma C, Liu Y, He S, Zeng J, Li P, Ma C, et al. C-Peptide: a Mediator of the Association between serum uric acid to creatinine ratio and non-alcoholic fatty liver disease in a Chinese Population with normal serum uric acid levels. Front Endocrinol (Lausanne). 2020;11:600472.

    Article  Google Scholar 

  24. Yang H, Liu C, Jin C, Yu R, Ding L, Mu L. Neck Circumference Is Associated with Hyperuricemia in Women with Polycystic Ovary Syndrome. Front Endocrinol (Lausanne). 2021;12:712855.

  25. Shen X, Wu S, Xu R, Wu Y, Li J, Cui L, et al. Neck circumference is Associated with Hyperuricemia: a cross-sectional study. Clin Rheumatol. 2019;38:2373–81.

    Article  Google Scholar 

  26. Durmus U, Duran C, Ecirli S. Visceral adiposity index levels in overweight and/or obese, and non-obese patients with polycystic ovary syndrome and its relationship with metabolic and inflammatory parameters. J Endocrinol Invest. 2017;40:487–97.

    Article  CAS  Google Scholar 

  27. Lakkis JI, Weir MR. Obesity and kidney disease. Prog Cardiovasc Dis. 2018;61:157–67.

    Article  Google Scholar 

  28. Qi D, Liu J, Wang C, Wang L, Zhang X, Lin Q, et al. Sex-specific differences in the prevalence of and risk factors for hyperuricemia among a low-income population in China: a cross-sectional study. Postgrad Med. 2020;132:559–67.

    Article  Google Scholar 

  29. Meherubin I, Nessa A, Huda MN, Yeasmin F, Afroz L, Mumu NS. Level of serum creatinine and creatinine clearance rate in obese female. Mymensingh Med J. 2021;30:991–6.

    CAS  Google Scholar 

  30. Eljaaly Z, Mujammami M, Nawaz SS, Rafiullah M, Siddiqui K. Risk predictors of high uric acid levels among patients with Type-2 diabetes. Diabetes Metab Syndr Obes. 2021;14:4911–20.

    Article  CAS  Google Scholar 

  31. Firoz S, Nessa A, Islam MF, Sharmin A, Israt S, Akter N, et al. Evaluation of serum uric acid and serum creatinine in male hypertensive patients. Mymensingh Med J. 2020;29:273–8.

    CAS  Google Scholar 

  32. Gyebi L, Soltani Z, Reisin E. Lipid nephrotoxicity: new concept for an old disease. Curr Hypertens Rep. 2012;14:177–81.

    Article  CAS  Google Scholar 

  33. Ni Q, Lu X, Chen C, Du H, Zhang R. Risk factors for the development of hyperuricemia: a STROBE-compliant cross-sectional and longitudinal study. Medicine. 2019;98:e17597.

    Article  Google Scholar 

  34. Lolekha P, Wongwan P, Kulkantrakorn K. Association between serum uric acid and motor subtypes of Parkinson’s disease. J Clin Neurosci. 2015;22:1264–7.

    Article  CAS  Google Scholar 

  35. Li M, Gu L, Yang J, Lou Q. Serum uric acid to creatinine ratio correlates with β-cell function in type 2 diabetes. Diabetes Metab Res Rev. 2018;34:e3001.

    Article  Google Scholar 

  36. Hahn S, Kuehnel W, Tan S, Kramer K, Schmidt M, Roesler S, et al. Diagnostic value of calculated testosterone indices in the assessment of polycystic ovary syndrome. Clin Chem Lab Med. 2007;45:202–7.

    Article  CAS  Google Scholar 

  37. Mueller A, Cupisti S, Binder H, Hoffmann I, Kiesewetter F, Beckmann MV, et al. Endocrinological markers for assessment of hyperandrogenemia in hirsute women. Horm Res. 2007;67:35–41.

    CAS  Google Scholar 

  38. Ożga K, Krzyczkowska-Sendrakowska M, Hubalewska-Dydejczyk A, Gilis-Januszewska A, Ratajczak M, Ratajczak M, et al. The value of the free androgen index depends on the phenotype of polycystic ovary syndrome - a single-centre experience. Endokrynol Pol. 2019;70:330–5.

    Article  Google Scholar 

  39. Khattak M, Usman R, Sultana N, Khattak A. Comparison of free androgen index in polycystic ovary syndrome and non-polycystic ovary syndrome infertile patients. J Ayub Med Coll Abbottabad. 2021;33:577–81.

    Google Scholar 

  40. Kauffman RP, Baker TE, Baker V, Kauffman MM, Castracane VD. Endocrine factors associated with non-alcoholic fatty liver disease in women with polycystic ovary syndrome: do androgens play a role? Gynecol Endocrinol. 2010;26:39–46.

    Article  CAS  Google Scholar 

  41. Cai J, Wu CH, Zhang Y, Wang YY, Xu WD, Lin TC, et al. High-free androgen index is associated with increased risk of non-alcoholic fatty liver disease in women with polycystic ovary syndrome, independent of obesity and insulin resistance. Int J Obes (Lond). 2017;41:1341–7.

    Article  CAS  Google Scholar 

  42. de Medeiros SF, Barbosa BB, de Medeiros AKLWY, de Medeiros MAS, Yamamoto MMW. Differential Effects of various androgens on polycystic ovary syndrome. Horm Metab Res. 2021;53:341–9.

    Article  Google Scholar 

  43. Al Kindi MK, Al Essry FS, Al Essry FS, Mula-Abed WA. Validity of serum testosterone, free androgen index, and calculated free testosterone in women with suspected hyperandrogenism. Oman Med J. 2012;27:471–4.

    Article  CAS  Google Scholar 

  44. Escobar-Morreale HF, Asuncion M, Calvo RM, Sancho J, SanMillán JL. Receiver operating characteristic analysis of the performance of basal serum hormone profiles for the diagnosis of polycystic ovary syndrome in epidemiological studies. Eur J Endocrinol. 2001;145:619–24.

    Article  CAS  Google Scholar 

  45. Chanukvadze D, Kristesashvili J. Effectiveness of different diagnostic methods for assessment of hyperandrogenism in young women with hirsutism. Georgian Med News. 2011;11:25–9.

    CAS  Google Scholar 

  46. Wang L, Li J. The value of serum-free androgen index in the diagnosis of polycystic ovary syndrome: a systematic review and meta-analysis. J Obstet Gynaecol Res. 2021;47:1221–31.

    Article  CAS  Google Scholar 

  47. Pizzichini M, Di Stefano A, Resconi G, Pompucci G, Marinello E. Influence of testosterone on purine nucleotide turnover in rat kidney. Horm Metab Res. 1990;22:334–8.

    Article  CAS  Google Scholar 

  48. Marinello E, Leoncini R, Terzuoli L, Vannoni D, Porcelli B, Resconi G. Effect of testosterone on purine nucleotide metabolism in rat liver. Horm Metab Res. 2004;36:614–9.

    Article  CAS  Google Scholar 

  49. Schiffer L, Arlt W, O’Reilly MW. Understanding the role of Androgen Action in female adipose tissue. Front Horm Res. 2019;53:33–49.

    Article  CAS  Google Scholar 

  50. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33:981–1030.

    Article  CAS  Google Scholar 

  51. Kabakchieva P, Gateva A, Velikova T, Georgiev T, Yamanishi K, Okamura H, et al. Elevated levels of interleukin-18 are associated with several indices of general and visceral adiposity and insulin resistance in women with polycystic ovary syndrome. Arch Endocrinol Metab. 2022;66:3–11.

    Article  Google Scholar 

  52. Santos RD. Elevated uric acid, the metabolic syndrome and cardiovascular disease: cause, consequence, or just a not so innocent bystander? Endocrine. 2012;41:350–2.

    Article  CAS  Google Scholar 

  53. Baldwin W, McRae S, Marek G, Wymer D, Pannu V, Baylis C, et al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes. 2011;60:1258–69.

    Article  CAS  Google Scholar 

  54. Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classical antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol. 2007;293:C584-96.

    Article  Google Scholar 

  55. Perez-Ruiz F, Aniel-Quiroga MA, Herrero-Beites AM, Chinchilla SP, Erauskin GG, Merriman T. Renal clearance of uric acid is linked to insulin resistance and lower excretion of sodium in gout patients. Rheumatol Int. 2015;35:1519–24.

    Article  CAS  Google Scholar 

  56. Rocic B, Vucic-Lovrencic M, Poje N, Poje M, Bertuzzi F. Uric acid may inhibit glucose-induced insulin secretion via binding to an essential arginine residue in rat pancreatic beta-cells. Bioorg Med Chem Lett. 2005;15:1181–4.

    Article  CAS  Google Scholar 

  57. Jia L, Xing J, Ding Y, Shen Y, Shi X, Ren W, et al. Hyperuricemia causes pancreatic beta-cell death and dysfunction through NF-kappaB signaling pathway. PLoS ONE. 2013;8:e78284.

    Article  CAS  Google Scholar 

  58. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67:1739–42.

    Article  Google Scholar 

  59. Lee TS, Lu TM, Chen CH, Guo BC, Hsu CP. Hyperuricemia induces endothelial dysfunction and accelerates atherosclerosis by disturbing the asymmetric dimethylarginine/dimethylarginine dimethylaminotransferase 2 pathway. Redox Biol. 2021;46:102108.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank all sample donors for their contribution to this study and all members of the Endocrinology Unit, Specialized Medical Hospital, Mansoura, Egypt.

Funding

Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author information

Authors and Affiliations

Authors

Contributions

MME, AI, RB and NS wrote the manuscript text and prepared figures, NM carried out the laboratory studies. All authors reviewed the manuscript. The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Mervat M El-Eshmawy.

Ethics declarations

Ethics approval and consent to participate

All procedures performed in the study were in accordance with Mansoura university institution and the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study complies with current research ethics standards and was approved by the Institutional Research Ethics Board of the Faculty of Medicine, Mansoura University, Egypt (Approval no: MS.19.11.883). A written informed consent was obtained from all women participants.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El-Eshmawy, M.M., Ibrahim, A., Bahriz, R. et al. Serum uric acid/creatinine ratio and free androgen index are synergistically associated with increased risk of polycystic ovary syndrome in obese women. BMC Endocr Disord 22, 315 (2022). https://doi.org/10.1186/s12902-022-01240-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12902-022-01240-y

Keywords