Összefoglaló. A szerzők ismertetik vizsgálataik eredményeit, melyeket a közelmúltban az in vitro fertilizációs kezelésben részesülő betegeikben a tüszőfolyadék biomarkereinek analízisével értek el. A vizsgálatok célja annak feltárása volt, hogy az in vitro fertilizációs eljárás során a petesejtek aspirációjakor nyert tüszőfolyadék-biomarkerek lokális/ovarialis vagy szisztémás eredetűek, és milyen összefüggést mutatnak az in vitro fertilizáció eredményességét jelző paraméterekkel. Megerősítettük, hogy az autokrin/parakrin szerotoninrendszer már a fejlődés legkorábbi időszakában is működőképes, és mind az anyai szérum, mind a tüszőfolyadék szerotoninszintje szignifikáns pozitív összefüggést mutatott az érett petesejtek számával és a klinikai terhességgel (β = 0,447, p = 0,015, illetve β = 0,443, p = 0,016). Az agyi eredetű neurotrofikus faktor (BDNF) esetében ilyen kapcsolat nem volt igazolható, de a tüszőfolyadék BDNF- és szerotoninszintjei közötti pozitív korreláció (r = 0,377, p = 0,040) azt mutatja, hogy a két neurohormon ’feed-forward’ (előrecsatoló ) szabályozása ovarialis szinten is működik. A hypothalamicus kisspeptin esetében csupán a posztstimulációs anyai szérumhormonszint befolyásolta az érett petesejtek számát (β = 0,398, p = 0,029). A triptofán–kinurenin–szerotonin rendszer elemzése azt mutatta, hogy kedvezőbb in vitro fertilizációs kimenetel várható, ha a szerotonin–kinurenin egyensúly a szerotonin javára tolódik el. Az oxidatívstressz-markerek közül vizsgálták a DNS-károsodás biomarkerét, a 8-hidroxi-2’-deoxiguanozin és a totális antioxidáns-kapacitás szérum- és tüszőfolyadékszintjeit, és megállapították, hogy mindkét marker kedvezőtlenül befolyásolja az életképes embriók számát (r = 0,302, p = 0,027 és r = 0,268, p = 0,039). A protektív hatású szirtuinok – nikotinamid-adenin-dinukleotid-függő hiszton-deacetiláz fehérjék – közül a vizsgált szirtuin-1 és szirtuin-6 a szérumszintektől függetlenül kimutatható a tüszőfolyadékban. Szignifikáns pozitív korreláció van a tüszőfolyadék-szirtuin-6 és az érettpetesejt-szám (F = 6,609, p = 0,016), valamint a szérum-szirtuin-1 (F = 10,008, p = 0,005) és a szérum-szirtuin-6 (F = 5,268, p = 0,031) és a klinikai terhesség gyakorisága között. Eredményeink alapján megállapítható, hogy a tüszőfolyadék biomarkereinek vizsgálata javíthatja az in vitro fertilizáció kimenetelének megítélését. Orv Hetil. 2021; 162(14): 523–529.
Summary. This article outlines the result of recent studies on several follicular fluid biomarkers in patients undergoing in vitro fertilization. The aim of these studies was to investigate whether 1) the follicular fluid biomarkers in question are produced locally by the ovaries or they originate from the circulating plasma, 2) and to establish their association with parameters of in vitro fertilization outcome. It was confirmed that the autocrine/paracrine serotonin system is functional already at the earliest stage of development and both maternal serum and follicular fluid serotonin levels were positively related to the number of mature oocytes (β = 0.447, p = 0.015 and β = 0.443, p = 0.016, respectively) and clinical pregnancy (β = 1.028, p = 0.047). Such associations for brain-derived neurotrophic factor (BDNF) could not be found, but BDNF and serotonin in the follicular fluid were closely related (r = 0.377, p<0.040) suggesting that the feed-forward regulation of these neurohormones is activated at ovarian level. The hypothalamic kisspeptin in the post-stimulation maternal serum also increased the number of mature oocytes (β = 0.398, p = 0.029). Analysis of the tryptophan–kynurenine–serotonin system showed a more favourable in vitro fertilization outcome when the serotonin–kynurenine balance was shifted and serotonin predominated over kynurenine. The oxidative stress markers, 8-hydroxy-2’-deoxyguanosine, an indicator of DNA damage and the total antioxidant capacity in follicular fluid and maternal serum had negative impact on the number of viable embryos (r = 0.302, p = 0.027 and r = 0.268, p = 0.039), respectively. The protective sirtuins – the nicotinamide adenine dinucleotide-dependent histone deacetylase proteins – could be detected in follicular fluid irrespective of their maternal serum levels. Significant positive relationship was demonstrated between follicular fluid sirtuin 6 and mature oocytes (F = 6.609, p = 0.016) as well as between serum sirtuin 1 (F = 10.008, p = 0.005) and serum sirtuin 6 (F = 5.268, p = 0.031) and the rate of clinical pregnancy, respectively. On the basis of these results, it can be concluded that measuring several follicular fluid biomarkers may improve the prediction of the outcome of in vitro fertilization. Orv Hetil. 2021; 162(14): 523–529.
Fülöp V, Vermes G, Demeter J. The relationship between inflammatory and immunological processes during pregnancy. Practical aspects. [A gyulladásos és immunológiai folyamatok kapcsolata a várandósság alatt. Gyakorlati vonatkozások.] Orv Hetil. 2019; 160: 1247–1259. [Hungarian]
Brubel R, Dobó N, Csibi N, et al. The effect of surgical treatment of bowel endometriosis on fertility. [A bélendometriosis miatt végzett műtétek hatása a fertilitásra.] Orv Hetil. 2019; 160: 1633–1638. [Hungarian]
Várnagy A, Bódis J, Kovács GL, et al. Metabolic hormones in follicular fluid in women undergoing in vitro fertilization. J Reprod Med. 2013; 58: 305–311.
Wada K, Hu L, Mores N, et al. Serotonin (5-HT) receptor subtypes mediate specific modes of 5-HT-induced signaling and regulation of neurosecretion in gonadotropin-releasing hormone neurons. Mol Endocrinol. 2006; 20: 125–135.
Bódis J, Török A, Tinneberg HR, et al. Serotonin induces progesterone release from human granulosa cells in a superfused granulosa cell system. Arch Gynecol Obstet. 1993; 253: 59–64.
Il’ková G, Rehák P, Veselá J, et al. Serotonin localization and its functional significance during mouse preimplantation embryo development. Zygote 2004; 12: 205–213.
Veselá J, Rehák P, Mihalik J, et al. Expression of serotonin receptors in mouse oocytes and preimplantation embryos. Physiol Res. 2003; 52: 223–228.
Bódis J, Sulyok E, Kőszegi T, et al. Serum and follicular fluid levels of serotonin, kisspeptin and brain-derived neurotrophic factor in patients undergoing in vitro fertilization: an observational study. Neurohormones in patients receiving IVF. J Int Med Res. 2020; 48(4) . [Epub 2019 Dec 23]
Kawamura K, Kawamura N, Mulders SM, et al. Ovarian brain-derived neurotrophic factor (BDNF) promotes the development of oocytes into preimplantation embryos. Proc Natl Acad Sci USA 2005; 102: 9206–9211.
Feng B, Chen S, Shelden RM, et al. Effect of gonadotropins on brain-derived neurotrophic factor secretion by human follicular cumulus cells. Fertil Steril. 2003; 80: 658–659.
Zhao P, Qiao J, Huang S, et al. Gonadotrophin-induced paracrine regulation of human oocyte maturation by BDNF and GDNF secreted by granulosa cells. Hum Reprod. 2011; 26: 695–702.
Ramer I, Kanninen TT, Sisti G, et al. The serum brain-derived neurotrophic factor concentration prior to initiation of an in vitro fertilization cycle predicts outcome. J Reprod Immunol. 2016; 116: 46–49.
de Roux N, Genin E, Carel JC, et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003; 100: 10972–10976.
Bhattacharya M, Babwah AV. Kisspeptin: beyond the brain. Endocrinology 2015; 156: 1218–1227.
Dorfman MD, Garcia-Rudaz C, Alderman Z, et al. Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure. Endocrinology 2014; 155: 3098–3111.
Abbara A, Jayasena CN, Christopoulos G, et al. Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization (IVF) therapy. J Clin Endocrinol Metab. 2015; 100: 3322–3331.
Badaway AA. Tryptophan metabolism, disposition and utilization in pregnancy. Biosci Rep. 2015; 35: e00261.
Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998; 281: 1191–1193.
Groebner AE, Schulke K, Schefold JC, et al. Immunological mechanisms to establish embryo tolerance in early bovine pregnancy. Reprod Fertil Dev. 2011; 23: 619–632.
Christen S, Peterhans E, Stocker R. Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases. Proc Natl Acad Sci USA 1990; 87: 2506–2510.
Weiss G, Diez-Ruiz A, Murr C, et al. Tryptophan metabolites as scavengers of reactive oxygen and chlorine species. Pteridines 2002; 13: 140–145.
Bódis J, Sulyok E, Koppán M, et al. Tryptophan catabolism to serotonin and kynurenine in women undergoing in vitro fertilization. Physiol Res. 2020; 69: 1113–1124.
Agarwal A, Gupta S, Sekhon L, et al. Redox considerations in female reproductive function and assisted reproduction: from molecular mechanisms to health implications. Antioxid Redox Signaling 2008; 10: 1375–1403.
Attaran M, Pasqualotto E, Falcone T, et al. The effect of follicular fluid reactive oxygen species on the outcome of in vitro fertilization. Int J Fertil Womens Med. 2000; 45: 314–320.
Gardner DK, Wale PL. Analysis of metabolism to select viable human embryos for transfer. Fertil Steril. 2013; 99: 1062–1072.
Seino T, Saito H, Kaneko T, et al. Eight-hydroxy-2’-deoxyguanosine in granulosa cells is correlated with the quality of oocytes and embryos in an in vitro fertilization–embryo transfer program. Fertil Steril. 2002; 77: 1184–1190.
Tamura H, Takasaki A, Miwa I, et al. Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res. 2008; 44: 280–287.
Várnagy Á, Kőszegi T, Györgyi E, et al. Levels of total antioxidant capacity and 8-hydroxy-2’-deoxyguanosine of serum and follicular fluid in women undergoing in vitro fertilization: focusing on endometriosis. Human Fertil. 2020; 23: 200–208.
Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and phyisiology of sirtuins. Nature 2009; 460: 587–591.
Zhang J, Fang L, Lu Z, et al. Are sirtuins markers of ovarian aging? Gene 2016; 575: 680–686.
Bordone L, Cohen D, Robinson A, et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 2007; 6: 759–767.
Zhao HC, Ding T, Ren Y, et al. Role of Sirt3 in mitochondrial biogenesis and developmental competence of human in vitro matured oocytes. Hum Reprod. 2016; 31: 607–622.
Palacios JA, Herranz D, De Bonis MI, et al. SIRT1 contributes to telomere maintenance and augments global homologous recombination. J Cell 2010; 191: 1299–1313.
Liu M, Yin Y, Ye X, et al. Resveratrol protects against age-associated infertility in mice. Hum Reprod. 2013; 28: 707–717.
Bódis J, Sulyok E, Kőszegi T, et al. Serum and follucular fluid levels of sirtuin 1, sirtuin 6, and resveratrol in women undergoing in vitro fertilization: an observational, clinical study. J Int Med Res. 2019; 47: 772–782.