This cross-sectional clinical study was designed to explore the impact of tryptophan-kynurenine and tryptophan-serotonin (5 HT) pathways on reproductive performance during in vitro fertilization (IVF). Paired serum and follicular fluid (FF) samples were obtained from 64 consecutive IVF patients. The analysis was done by using LC-MS/MS. Ovarian hyperstimulation resulted in decreased serum tryptophan (p<0.004), 5-HT (p<0.049) and kynurenine (p<0.001). FF levels of tryptophan (R=0.245, p<0.051), kynurenine (R=0.556, p<0.001) and 5-HT (R=0.523, p<0.001) were positively related to their respective serum levels. Clinical pregnancy was associated with higher serum 5-HT (p<0.045) and FF 5-HT (p<0.020) and lower kynurenine to 5-HT ratio (p<0.024). Chemical pregnancy was also positively related to FF 5-HT (R=0.362, p<0.024). Moreover, there was a direct relationship of the number of mature oocytes to the FF 5-HT (R=0.363, p<0.020) but it was inversely related to FF tryptophan to 5-HT and FF kynurenine to 5-HT ratios (R=-0.389, p<0.016 and R=-0.337, p<0.036, respectively). Multivariate logistic regression revealed that the number of mature oocytes was significantly influenced by FF 5-HT (?=0.473, p<0.001). In IVF patients ovarian hyperstimulation results in a reduction of the availability of tryptophan to catabolic pathways to kynurenine and 5-HT. Outcome measures improved significantly when 5-HT predominated over kynurenine.

Department of Obstetrics and Gynaecology Medical School University of Pécs Pécs Hungary

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AMIREAULT P, DUBE F. Intracellular cAMP and calcium signaling by serotonin in mouse cumulus-oocyte complexes. Mol Pharmacol. 2005;68:1678–1687. doi: 10.1124/mol.104.010124. PubMed DOI

AMIREAULT P, DUBE F. Serotonin and its antidepressant-sensitive transport in mouse cumulus-oocyte complexes and early embryos. Biol Reprod. 2005;73:358–365. doi: 10.1095/biolreprod.104.039313. PubMed DOI

BADAWY AA. Effects of pregnancy on tryptophan metabolism and disposition in the rat. Biochem J. 1988;255:369–372. PubMed PMC

BADAWY AA. Tryptophan metabolism, disposition and utilization in pregnancy. Biosci Rep. 2015;35 doi: 10.1042/BSR20150197. PubMed DOI PMC

BODIS J, TOROK A, TINNEBERG HR, HANF V, PAPENFUSS F, SCHWARZ H. Serotonin induces progesterone release from human granulosa cells in a superfused granulosa cell system. Arch Gynecol Obstet. 1993;253:59–64. doi: 10.1007/BF02768730. PubMed DOI

BONNIN A, LEVITT P. Placental Source for 5-HT that tunes fetal brain development. Neuropsychopharmacology. 2012;37:299–300. doi: 10.1038/npp.2011.194. PubMed DOI PMC

BRITAN A, MAFFRE V, TONE S, DREVET JR. Quantitative and spatial differences in the expression of tryptophan-metabolizing enzymes in mouse epididymis. Cell Tissue Res. 2006;324:301–310. doi: 10.1007/s00441-005-0151-7. PubMed DOI

BUZNIKOV GA, SHMUKLER YB, LAUDER JM. From oocyte to neuron: do neurotransmitters function in the same way throughout development? Cell Mol Neurobiol. 1996;16:537–559. doi: 10.1007/BF02152056. PubMed DOI PMC

CHEN Y, GUILLEMIN GJ. Kynurenine pathway metabolites in humans: disease and healthy states. Int J Tryptophan Res. 2009;2:1–19. doi: 10.4137/IJTR.S2097. PubMed DOI PMC

CHRISTEN S, PETERHANS E, STOCKER R. Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases. Proc Natl Acad Sci. 1990;87:2506–2510. doi: 10.1073/pnas.87.7.2506. PubMed DOI PMC

COTE F, FLIGNY C, BAYARD E, LAUNAY JM, GERSHON MD, MALLET J, VODJDANI G. Maternal serotonin is crucial for murine embryonic development. Proc Natl Acad Sci. 2007;104:329–334. doi: 10.1073/pnas.0606722104. PubMed DOI PMC

DAFOPOULOS K, MESSINI CI, ANIFANDIS G, GEORGOULIAS P, SOURLAS D, MESSINIS IE. Blood ghrelin, adiponectin and resistin levels during controlled ovarian stimulation in IVF cycles. Physiol Res. 2016;65:809–814. doi: 10.33549/physiolres.933295. PubMed DOI

DOHERTY LF, KWON HE, TAYLOR HS. Regulation of tryptophan 2,3-dioxygenase by HOXA10 enhances embryo viability through serotonin signaling. Am J Physiol Endocrinol Metab. 2011;300:E86–93. doi: 10.1152/ajpendo.00439.2010. PubMed DOI PMC

DRÁBKOVÁ P, ANDRLOVÁ L, HAMPL R, KANĎÁR R. Amino acid metabolism in human embryos. Physiol Res. 2016;65:823–832. doi: 10.33549/physiolres.933240. PubMed DOI

FABJAN T, EVRTAČNIK-BOKAL E, KUMER K, OSREDKAR J. Determination of oxidative stress balance in follicular fluid. J Lab Med. 2018;42:51–58. doi: 10.1515/labmed-2017-0106. DOI

FORREST CM, KHALIL OS, PISAR M, DARLINGTON LG, STONE TW. Prenatal inhibition of the tryptophan-kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus. Brain Res. 2013;1504:1–15. doi: 10.1016/j.brainres.2013.01.031. PubMed DOI

FTUKIJWATARI T, MURAKAMI M, OHTA M, KIMURA N, JIN-NO Y, SASAKI R, SHIBATA K. Changes in the urinary excretion of the metabolites of the tryptophan-niacin pathway during pregnancy in Japanese women and rats. J Nutr Sci Vitaminol. 2004;50:392–398. doi: 10.3177/jnsv.50.392. PubMed DOI

GROEBNER AE, SCHULKE K, SCHEFOLD JC, FUSCH G, SINOWATZ F, REICHENBACH HD, WOLF E, MEYER HH, ULBRICH SE. Immunological mechanisms to establish embryo tolerance in early bovine pregnancy. Reprod Fertil Dev. 2011a;23:619–632. doi: 10.1071/RD10230. PubMed DOI

GROEBNER AE, RUBIO-ALIAGA I, SCHULKE K, REICHENBACH HD, DANIEL H, WOLF E, MEYER HH, ULBRICH SE. Increase of essential amino acids in the bovine uterine lumen during preimplantation development. Reproduction. 2011b;141:685–695. doi: 10.1071/RD10230. PubMed DOI

GROZDICS E, BERTA L, BAJNOK A, VERES G, ILISZ I, KLIVENYI P, RIGO J, JR, VECSEI L, TULASSAY T, TOLDI G. B7 costimulation and intracellular indoleamine-2,3-dioxygenase (IDO) expression in peripheral blood of healthy pregnant and non-pregnant women. BMC Pregnancy Childbirth. 2014;14(306):1–9. doi: 10.1186/1471-2393-14-306. PubMed DOI PMC

HANNAN NJ, BAMBANG K, KAITU’U-LINO TJ, KONJE JC, TONG S. A bioplex analysis of cytokines and chemokines in first trimester maternal plasma to screen for predictors of miscarriage. PLoS ONE. 2014;9:e93320. doi: 10.1371/journal.pone.0093320. PubMed DOI PMC

HERY M, FRANCOIS-BELLAN AM, HERY F, DEPREZ P, BECQUET D. Serotonin directly stimulates luteinizing hormone-releasing hormone release from GT1 cells via 5-HT7 receptors. Endocrine. 1997;7:261–265. doi: 10.1007/BF02778149. PubMed DOI

HOLTAN SG, CHEN Y, KAIMAL R, CREEDON DJ, ENNINGA EAL, NEVALA WK, MARKOVIC SN. Growth modelling of the maternal cytokine milieu throughout normal pregnancy: macrophage-derived chemokine decreases as inflammation/counterregulation increases. J Immunol Res. 2015;2015:1–11. doi: 10.1155/2015/952571. PubMed DOI PMC

IL’KOVA G, REHAK P, VESELA J, CIKOS S, FABIAN D, CZIKKOVA S, KOPPEL J. Serotonin localization and its functional significance during mouse preimplantation embryo development. Zygote. 2004;12:205–213. doi: 10.1017/S0967199404002862. PubMed DOI

KISS J, HALASZ B. Demonstration of serotoninergic axons terminating on luteinizing hormone-releasing hormone neurons in the preoptic area of the rat using a combination of immunocytochemistry and high resolution autoradiography. Neuroscience. 1985;14:69–78. doi: 10.1016/0306-4522(85)90164-2. PubMed DOI

KUDO Y, BOYD CA, SPYROPOULOU I, REDMAN CW, TAKIKAWA O, KATSUKI T, HARA T, OHAMA K, SARGENT IL. Indoleamine 2,3-dioxygenase: distribution and function in the developing human placenta. J Reprod Immunol. 2004a;61:87–98. doi: 10.1016/j.jri.2003.11.004. PubMed DOI

KUDO Y, HARA T, KATSUKI T, TOYOFUKU A, KATSURA Y, TAKIKAWA O, FUJII T, OHAMA K. Mechanisms regulating the expression of indoleamine 2,3-dioxygenase during decidualization of human endometrium. Hum Reprod. 2004b;19:1222–1230. doi: 10.1093/humrep/deh218. PubMed DOI

LEE GK, PARK HJ, MACLEOD M, CHANDLER P, MUNN DH, MELLOR AL. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology. 2002;107:452–460. doi: 10.1046/j.1365-2567.2002.01526.x. PubMed DOI PMC

LE FLOC’H N, OTTEN W, MERLOT E. Tryptophan metabolism, from nutrition to potential therapeutic application. Amino Acids. 2011;41:1195–1205. doi: 10.1007/s00726-010-0752-7. PubMed DOI

LI S, PELLETIER G. Involvement of serotonin in the regulation of GnRH gene expression in the male rat brain. Neuropeptides. 1995;29:21–25. doi: 10.1016/0143-4179(95)90052-7. PubMed DOI

LIGAM P, MANUELPILLAI U, WALLACE EM, WALKER D. Localisation of indoleamine 2,3-dioxygenase and kynurenine hydroxylase in the human placenta and decidua: implications for role of the kynurenine pathway in pregnancy. Placenta. 2005;26:498–504. doi: 10.1016/j.placenta.2004.08.009. PubMed DOI

MANUELPILLAI U, LIGAM P, SMYTHE G, WALLACE EM, HIRST J, WALKER DW. Identification of kynurenine pathway enzyme mRNAs and metabolites in human placenta: up-regulation by inflammatory stimuli and with clinical infection. Am J Obstet Gynecol. 2005;192:280–288. doi: 10.1016/j.ajog.2004.06.090. PubMed DOI

MELLOR AL, MUNN DH. Tryptophan catabolism prevents maternal T cells from activating lethal anti-fetal immune responses. J Reprod Immunol. 2001;52:5–13. doi: 10.1016/S0165-0378(01)00118-8. PubMed DOI

MUNN DH, SHAFIZADEH E, ATTWOOD JT, BONDAREV I, PASHINE A, MELLOR AL. Inhibition of T Cell Proliferation by Macrophage Tryptophan Catabolism. J Exp Med. 1999;189:1363–1372. doi: 10.1084/jem.189.9.1363. PubMed DOI PMC

MUNN DH, ZHOU M, ATTWOOD JT, BONDAREV I, CONWAY SJ, MARSHALL B, BROWN C, MELLOR AL. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191–1193. doi: 10.1126/science.281.5380.1191. PubMed DOI

SAINIO EL, PULKKI K, YOUNG SN. L-tryptophan: biochemical, nutritional and pharmacological aspects. Amino Acids. 1996;10:21–47. doi: 10.1007/BF00806091. PubMed DOI

SANTILLAN MK, PELHAM CJ, KETSAWATSOMKRON P, SANTILLAN DA, DAVIS DR, DEVOR EJ, GIBSON-CORLEY KN, SCROGGINS SM, GROBE JL, YANG B, HUNTER SK, SIGMUND CD. Pregnant mice lacking indoleamine 2,3-dioxygenase exhibit preeclampsia phenotypes. Physiol Rep. 2015;3:1–9. doi: 10.14814/phy2.12257. PubMed DOI PMC

SCHROCKSNADEL H, BAIER-BITTERLICH G, DAPUNT O, WACHTER H, FUCHS D. Decreased plasma tryptophan in pregnancy. Obstet Gynecol. 1996;88:47–50. doi: 10.1016/0029-7844(96)00084-1. PubMed DOI

STONE TW, STOY N, DARLINGTON LG. An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci. 2013;34:136–143. doi: 10.1016/j.tips.2012.09.006. PubMed DOI

SUZUKI S, TONE S, TAKIKAWA O, KUBO T, KOHNO I, MINATOGAWA Y. Expression of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase in early concepti. Biochem J. 2001;355:425–429. doi: 10.1042/bj3550425. PubMed DOI PMC

VÁRNAGY Á, BÓDIS J, KOVÁCS GL, SULYOK E, RAUH M, RASCHER W. Metabolic hormones in follicular fluid in women undergoing in vitro fertilization. J Reprod Med: 2013;58:305–311. PubMed

VÁRNAGY Á, KŐSZEGI T, GYÖRGYI E, SULYOK E, PRÉMUSZ V, BÓDIS J. Levels of total antioxidant capacity and 8-hydroxy-2′-deoxyguanosine of serum and follicular fluid in women undergoing in vitro fertilization: Focusing on endometriosis. Hum Fertil. 2018:1–9. PubMed

VESELA J, REHAK P, MIHALIK J, CZIKKOVA S, POKORNY J, KOPPEL J. Expression of serotonin receptors in mouse oocytes and preimplantation embryos. Physiol Res. 2003;52:223–228. PubMed

WEISS G, DIEZ-RUIZ A, MURR C, THEUR I, FUCHS D. Tryptophan metabolites as scavengers of reactive oxygen and chlorine species. Pteridines. 2002;13:140–143. doi: 10.1515/pteridines.2002.13.4.140. DOI

WICHERS MC, KOEK GH, ROBAEYS G, VERKERK R, SCHARPE S, MAES M. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry. 2005;10:538–544. doi: 10.1038/sj.mp.4001600. PubMed DOI

WOLF H, BROWN RR, PRICE JM, MADSEN PO. Studies on tryptophan metabolism in male subjects treated with female sex hormones. J Clin Endocrinol Metab. 1970;31:397–408. doi: 10.1210/jcem-31-4-397. PubMed DOI

WOLF H. Studies on tryptophan metabolism in man. Scand J Clin Lab Invest. 1974;136:1–186. PubMed

XU K, LIU G, FU C. The tryptophan pathway targeting antioxidant capacity in the placenta. Oxid Med Cell Longev. 2018;2018:1–8. doi: 10.1155/2018/1054797. PubMed DOI PMC

YUE CY, ZHANG B, YING CM. Elevated serum level of IL-35 associated with the maintenance of maternal-fetal immune tolerance in normal pregnancy. PLoS One. 2015;10:e0128219. doi: 10.1371/journal.pone.0128219. PubMed DOI PMC