Triptophan metabolism in patients with different body-weighted polycystic over syndrome

Aim: Polycystic ovary syndrome(PCOS) is a common gynecological and endocrinological disorder that affects women in the reproductive period, has many genetic and environmental factors in its etiology, is characterized by chronic anovulation and hyperandrogenism. Its etiopathogenesis involves impaired metabolism of steroid hormones, amino acids, carbohydrates, lipids, purines and the citric acid cycle. Tryptophan amino acid is converted to kynurenine and its sub-metabolites in the kynurenine pathway initiated by tryptophan(2,3)-dioxygenase(TDO) and indolamine(2,3)-dioxygenase(IDO) enzymes. These metabolites may exhibit neurotoxic or neuroprotective properties as well as various functions such as controlling inflammation, regulating energy homeostasis and metabolism. Activation of the kynurenine pathway indicates the body's defense against the immune response. It is thought that causes such as insulin resistance, abnormal amino acid metabolism, chronic low-grade systemic inflammation, and TCA cycle changes seen in the pathophysiology of PCOS may be related to changes in tryptophan metabolism. There is no previous study investigating tryptophan metabolism metabolites related to PCOS. Therefore, in this study, it was aimed to investigate tryptophan metabolism in PCOS patients with different body weights. The relationship between tryptophan metabolism in PCOS patients with obesity and insulin resistance is studied for the first time. A new hypothesis for the etiopathogenesis of PCOS is put forward by investigating the possible role of tryptophan metabolism in PCOS patients. The second goal is to examine the possible between tryptophan metabolism and disease severity. The results of the study will also help develop new strategies for the treatment of PCOS. Material and Method: The study consisted of normal-weight PCOS, overweight-obese PCOS patients, and control groups with similar body weights. In addition to routinely requested biochemistry and hormone tests for diagnosis and follow-up of PCOS patients, IL-6 and CRP and tryptophan and its metabolites, measured in LC-MS/MS, were examined to evaluate the presence of inflammation. The results obtained from the patient and control groups were statistically analyzed with Jamovi (Version 2.2.5.0) and JASP (Version 0.16.1). Results: Glucose, ALT, TG, VLDL, HbA1c, fasting insulin, HOMA-IR, CRP, FSH, E2, fT and QUIN were statistically (p<0,05) higher in the overweight-obese PCOS group; than the normal weight PCOS group. AMH, androstenedione, LH, 17 OH P and SHBG were found to be higher in the normal weight PCOS group than the overweight-obese PCOS group. In the PCOS patient group, there were negative correlations between DHEA-S and kynurenine/tryptophan ratio, kynurenic acid and PICA, total testosterone and kynurenic acid, 3-HK and BMI, glucose and CRP. There were positive correlations between kynurenine and CRP and IL-6, between kynurenine/tryptophan ratio and CRP and IL-6, and between picolinic acid and SHBG. There was an inverse relationship between tryptophan and kynurea, kynurea and kyn/trp, and an inverse relationship between tryptophan and kyn/trp in normal weight and overweight-obese PCOS patient groups. If we seperate participants according to presence of IR, 3-HK values of HOMA-IR negative PCOS patients were significantly higher than HOMA-IR positive PCOS patients. And in general 3-HK values were higher in the PCOS group than the controls when grouping according to IR. Kynurenine predicted the development of PCOS (AUC=0.596, p=0.049) with 68.37% sensitivity and 54.0% specificity. For 3-HK the sensitivity and specificity rates in predicting the development of PCOS were found to be 37.76% and 96.0% respectively (AUC=0.680, p<0.001). Conclusion: Our study results showed that obesity, insulin resistance, chronic low-grade inflammation, hyperandrogenism affect the pathogenesis of PCOS via tryptophan metabolism and kynurenine pathway. The tryptophan metabolism pathway in PCOS patients is promising in diagnosing the disease, guiding treatment and preventive measures from the disease. Key Words: Indolamine (2,3)-dioxygenase, Insulin resistance, Kynurenin, Obesity, Polycystic Ovary Syndrome, Tryptophan