Background. The natural cycle is the prototype to which we aspire to emulate in assisted reproduction techniques. Increasing evidence is emerging that controlled ovarian hyperstimulation (COH) with exogenous gonadotropins may be detrimental to oogenesis, embryo quality, and endometrial receptivity. This research aimed at assessing the impact of COH on the intrafollicular milieu by comparing follicular fluid (FF) cytokine profiles during stimulated in vitro fertilization (IVF) and modified natural cycle (MNC) IVF. Methods. Ten women undergoing COH IVF and 10 matched women undergoing MNC IVF were recruited for this pilot study. 40 FF cytokine concentrations from individual follicles and plasma were measured by fluid-phase multiplex immunoassay. Demographic/cycle/cytokine data were compared and correlations between cytokines were computed. Results. No significant differences were found between COH and MNC groups for patient and cycle demographics, including outcome. Overall mean FF cytokine levels were higher in the MNC group for 29/40 cytokines, significantly so for leukaemia inhibitory factor and stromal cell-derived factor-1α. Furthermore, FF MNC cytokine correlations were significantly stronger than for COH data. Conclusions. These findings suggest that COH perturbs intrafollicular cytokine networks, in terms of both cytokine levels and their interrelationships. This may impact oocyte maturation/fertilization and embryo developmental competence. 1. Introduction Controlled ovarian hyperstimulation (COH) with gonadotropins has improved success rates of in vitro fertilization (IVF) by increasing the number and opportunity for selection of embryos before transfer [1–3] as well as permitting the cryopreservation of supernumerary embryos for further fertility treatment [4, 5]. The basis of COH is to support the growth of multiple follicles to the preovulatory stage, a process achieved by bypassing physiological regulatory mechanisms. Urinary-derived or recombinant follicle stimulating hormone (FSH) is administered to increase serum concentrations above the threshold required for dominant follicle selection, thus enabling the entire cohort of recruited follicles to develop and attain preovulatory status [4]. Luteinising hormone (LH) is often coadministered although, following pituitary downregulation, this is not essential for follicular development as remnant basal LH levels are sufficient to stimulate the theca cells. Administration of a GnRH analogue (long protocol) or an antagonist (short protocol) that desensitizes the pituitary is primarily used to
References
[1]
M. J. Pelinck, A. Hoek, A. H. M. Simons, and M. J. Heineman, “Efficacy of natural cycle IVF: a review of the literature,” Human Reproduction Update, vol. 8, no. 2, pp. 129–139, 2002.
[2]
M. P. Rosen, S. Shen, A. T. Dobson, P. F. Rinaudo, C. E. McCulloch, and M. I. Cedars, “A quantitative assessment of follicle size on oocyte developmental competence,” Fertility and Sterility, vol. 90, no. 3, pp. 684–690, 2008.
[3]
S. X. Y. Wang, “The past, present, and future of embryo selection in in vitro fertilization: frontiers in reproduction conference,” The Yale Journal of Biology and Medicine, vol. 84, no. 4, pp. 487–490, 2011.
[4]
N. S. Macklon, R. L. Stouffer, L. C. Giudice, and B. C. J. M. Fauser, “The science behind 25 years of ovarian stimulation for in vitro fertilization,” Endocrine Reviews, vol. 27, no. 2, pp. 170–207, 2006.
[5]
J. P. Geraedts and L. Gianaroli, “Embryo selection and IVF,” Human Reproduction, vol. 27, no. 9, pp. 2876–2877, 2012.
[6]
E. H. Y. Ng, E. Y. L. Lau, W. S. B. Yeung, and P. C. Ho, “Oocyte and embryo quality in patients with excessive ovarian response during in vitro fertilization treatment,” Journal of Assisted Reproduction and Genetics, vol. 20, no. 5, pp. 186–191, 2003.
[7]
V. Sharma, J. Williams, W. Collins, A. Riddle, B. Mason, and M. Whitehead, “A comparison of treatments with exogenous FSH to promote folliculogenesis in patients with quiescent ovaries due to the continued administration of an LH-RH agonist,” Human Reproduction, vol. 2, no. 7, pp. 553–556, 1987.
[8]
V. Sharma, M. Whitehead, B. Mason et al., “Influence of superovulation on endometrial and embryonic development,” Fertility and Sterility, vol. 53, no. 5, pp. 822–829, 1990.
[9]
J. A. Horcajadas, A. Riesewijk, J. Polman et al., “Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles,” Molecular Human Reproduction, vol. 11, no. 3, pp. 195–205, 2005.
[10]
E. B. Baart, E. Martini, M. J. Eijkemans et al., “Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial,” Human Reproduction, vol. 22, no. 4, pp. 980–988, 2007.
[11]
J. A. Horcajadas, P. Díaz-Gimeno, A. Pellicer, and C. Simón, “Uterine receptivity and the ramifications of ovarian stimulation on endometrial function,” Seminars in Reproductive Medicine, vol. 25, no. 6, pp. 454–460, 2007.
[12]
J. A. Horcajadas, P. Mínguez, J. Dopazo et al., “Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 11, pp. 4500–4510, 2008.
[13]
M. A. Santos, E. W. Kuijk, and N. S. Macklon, “The impact of ovarian stimulation for IVF on the developing embryo,” Reproduction, vol. 139, no. 1, pp. 23–34, 2010.
[14]
A. Pellicer, A. Ruiz, R. M. Castellvi et al., “Is the retrieval of high numbers of oocytes desirable in patients treated with gonadotrophin-releasing hormone analogues (GnRHa) and gonadotrophins?” Human Reproduction, vol. 4, no. 5, pp. 536–540, 1989.
[15]
M. H. van der Gaast, M. J. C. Eijkemans, J. B. van der Net, et al., “Optimum number of oocytes for a successful first IVF treatment cycle,” Reproductive BioMedicine Online, vol. 13, pp. 476–480, 2006.
[16]
M. A. Aboulghar, A. M. Ramzy, R. T. Mansour, Y. M. Amin, and G. I. Serour, “Oocyte quality in patients with severe ovarian hyperstimulation syndrome,” Fertility and Sterility, vol. 68, no. 6, pp. 1017–1021, 1997.
[17]
G. Ertzeid and R. Storeng, “Adverse effects of gonadotrophin treatment on pre- and postimplantation development in mice,” Journal of Reproduction and Fertility, vol. 96, no. 2, pp. 649–655, 1992.
[18]
I. Van Der Auwera and T. D'Hooghe, “Superovulation of female mice delays embryonic and fetal development,” Human Reproduction, vol. 16, no. 6, pp. 1237–1243, 2001.
[19]
C. A. Hodges, A. Ilagan, D. Jennings, R. Keri, J. Nilson, and P. A. Hunt, “Experimental evidence that changes in oocyte growth influence meiotic chromosome segregation,” Human Reproduction, vol. 17, no. 5, pp. 1171–1180, 2002.
[20]
Y. Li, H.-L. Feng, Y.-J. Cao et al., “Confocal microscopic analysis of the spindle and chromosome configurations of human oocytes matured in vitro,” Fertility and Sterility, vol. 85, no. 4, pp. 827–832, 2006.
[21]
M. Von Wolff, Z. Kollmann, C. E. Flück et al., “Gonadotrophin stimulation for in vitro fertilization significantly alters the hormone milieu in follicular fluid: a comparative study between natural cycle IVF and conventional IVF,” Human Reproduction, vol. 29, no. 5, pp. 1049–1057, 2014.
[22]
A. N. Andersen, P. Devroey, and J.-C. Arce, “Clinical outcome following stimulation with highly purified hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled trial,” Human Reproduction, vol. 21, no. 12, pp. 3217–3227, 2006.
[23]
A. Weghofer, S. Munné, W. Brannath et al., “The impact of LH-containing gonadotropin stimulation on euploidy rates in preimplantation embryos: antagonist cycles,” Fertility and Sterility, vol. 92, no. 3, pp. 937–942, 2009.
[24]
L. Regan, E. J. Owen, and H. S. Jacobs, “Hypersecretion of luteinising hormone, infertility, and miscarriage,” The Lancet, vol. 336, no. 8724, pp. 1141–1144, 1990.
[25]
J. N. Hugues, J. Soussis, I. Calderon, et al., “Does the addition of recombinant LH in WHO group II anovulatory women over-responding to FSH treatment reduce the number of developing follicles? A dose-finding study,” Human Reproduction, vol. 20, no. 3, pp. 629–635, 2005.
[26]
Z. Shoham, “The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation,” Fertility and Sterility, vol. 77, no. 6, pp. 1170–1177, 2002.
[27]
M. Schimberni, F. Morgia, J. Colabianchi et al., “Natural-cycle in vitro fertilization in poor responder patients: a survey of 500 consecutive cycles,” Fertility and Sterility, vol. 92, no. 4, pp. 1297–1301, 2009.
[28]
K.-G. Nygren, “Single embryo transfer: the role of natural cycle/minimal stimulation IVF in the future,” Reproductive BioMedicine Online, vol. 14, no. 5, article 2841, 2007.
[29]
R. Cutting, D. Morroll, S. Roberts, S. Pickering, and A. Rutherford, “Elective single embryo transfer: guidelines for practice British fertility society and association of clinical embryologists,” Human Fertility, vol. 11, no. 3, pp. 131–146, 2008.
[30]
Joint SOGC-CFAS, “Guidelines for the number of embryos to transfer following in vitro fertilization no. 182, September 2006,” International Journal of Gynecology & Obstetrics, vol. 102, pp. 203–216, 2008.
[31]
J. D. Gordon, M. Dimattina, A. Reh, A. Botes, G. Celia, and M. Payson, “Utilization and success rates of unstimulated in vitro fertilization in the United States: an analysis of the Society for Assisted Reproductive Technology database,” Fertility and Sterility, vol. 100, no. 2, pp. 392–395, 2013.
[32]
B. C. Fauser, G. Nargund, A. N. Andersen et al., “Mild ovarian stimulation for IVF: 10 years later,” Human Reproduction, vol. 25, no. 11, pp. 2678–2684, 2010.
[33]
G. Nargund, B. C. J. M. Fauser, N. Macklon, W. Ombelet, K. Nygren, and R. Frydman, “The ISMAAR proposal on terminology for ovarian stimulation for IVF,” Human Reproduction, vol. 22, no. 11, pp. 2801–2804, 2007.
[34]
W. M. Enien, S. El Sahwy, C. P. Harris, M. W. Seif, and M. Elstein, “Human chorionic gonadotrophin and steroid concentrations in follicular fluid: the relationship to oocyte maturity and fertilization rates in stimulated and natural in-vitro fertilization cycles,” Human Reproduction, vol. 10, no. 11, pp. 2840–2844, 1995.
[35]
M. J. De Los Santos, V. Garca-Lez, D. Beltrn-Torregrosa et al., “Hormonal and molecular characterization of follicular fluid, cumulus cells and oocytes from pre-ovulatory follicles in stimulated and unstimulated cycles,” Human Reproduction, vol. 27, no. 6, pp. 1596–1605, 2012.
[36]
D. Vinatier, C. Lefebvre-Maunoury, and C. Bernardi, “The ovaries, the immune system, cytokines: physiology,” Journal de Gynecologie Obstetrique et Biologie de la Reproduction, vol. 22, no. 6, pp. 581–591, 1993.
[37]
C. L. Best and J. A. Hill, “Interleukin-1α and -β modulation of luteinized human granulosa cell oestrogen and progesterone biosynthesis,” Human Reproduction, vol. 10, no. 12, pp. 3206–3210, 1995.
[38]
V. Machelon and D. Emilie, “Production of ovarian cytokines and their role in ovulation in the mammalian ovary,” European Cytokine Network, vol. 8, no. 2, pp. 137–143, 1997.
[39]
D. F. Albertini, C. M. H. Combelles, E. Benecchi, and M. J. Carabatsos, “Cellular basis for paracrine regulation of ovarian follicle development,” Reproduction, vol. 121, no. 5, pp. 647–653, 2001.
[40]
J. J. Eppig, “Oocyte control of ovarian follicular development and function in mammals,” Reproduction, vol. 122, no. 6, pp. 829–838, 2001.
[41]
M. K. Skinner, “Regulation of primordial follicle assembly and development,” Human Reproduction Update, vol. 11, no. 5, pp. 461–471, 2005.
[42]
S. Vujisi？, S. ？. Lepej, I. Emedi, R. Bauman, A. Remenar, and M. K. Tiljak, “Ovarian follicular concentration of IL-12, IL-15, IL-18 and p40 subunit of IL-12 and IL-23,” Human Reproduction, vol. 21, no. 10, pp. 2650–2655, 2006.
[43]
S. Vujisic and S. Zidovec, “Follicular immunology environment and the influence on in-vitro fertilization outcome,” Current Women's Health Reviews, vol. 1, pp. 49–60, 2005.
[44]
C. Mendoza, N. Cremades, E. Ruiz-Requena et al., “Relationship between fertilization results after intracytoplasmic sperm injection, and intrafollicular steroid, pituitary hormone and cytokine concentrations,” Human Reproduction, vol. 14, no. 3, pp. 628–635, 1999.
[45]
M. E. Hammadeh, A. K. Ertan, M. Baltes, et al., “Immunoglobulins and cytokines level in follicular fluid in relation to etiology of infertility and their relevance to IVF outcome,” American Journal of Reproductive Immunology, vol. 47, no. 2, pp. 82–90, 2002.
[46]
C. Mendoza, E. Ruiz-Requena, E. Ortega et al., “Follicular fluid markers of oocyte developmental potential,” Human Reproduction, vol. 17, no. 4, pp. 1017–1022, 2002.
[47]
M. E. Hammadeh, C. Fischer-Hammadeh, A. S. Amer, P. Rosenbaum, and W. Schmidt, “Relationship between cytokine concentration in serum and preovulatory follicular fluid and in vitro fertilization/intracytoplasmic sperm injection outcome,” Chemical Immunology and Allergy, vol. 88, pp. 80–97, 2005.
[48]
M. Bedaiwy, A. Y. Shahin, A. M. AbulHassan et al., “Differential expression of follicular fluid cytokines: relationship to subsequent pregnancy in IVF cycles,” Reproductive BioMedicine Online, vol. 15, no. 3, pp. 321–325, 2007.
[49]
N. Lédée, R. Lombroso, L. Lombardelli, et al., “Cytokines and chemokines in follicular fluids and potential of the corresponding embryo: the role of granulocyte colony-stimulating factor,” Human Reproduction, vol. 23, no. 9, pp. 2001–2009, 2008.
[50]
A. Revelli, L. D. Piane, S. Casano, E. Molinari, M. Massobrio, and P. Rinaudo, “Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics,” Reproductive Biology and Endocrinology, vol. 7, article 40, 2009.
[51]
N. Lédée, M. Petitbarat, M. Rahmati et al., “New pre-conception immune biomarkers for clinical practice: interleukin-18, interleukin-15 and TWEAK on the endometrial side, G-CSF on the follicular side,” Journal of Reproductive Immunology, vol. 88, no. 2, pp. 118–123, 2011.
[52]
A. Sarapik, A. Velthut, K. Haller-Kikkatalo, et al., “Follicular proinflammatory cytokines and chemokines as markers of IVF success,” Clinical and Developmental Immunology, vol. 2012, Article ID 606459, 10 pages, 2012.
[53]
H. Hagberg, C. Mallard, and B. Jacobsson, “Role of cytokines in preterm labour and brain injury,” British Journal of Obstetrics and Gynaecology, vol. 112, supplement 1, pp. 16–18, 2005.
[54]
A. Agic, H. Xu, D. Finas, C. Banz, K. Diedrich, and D. Hornung, “Is endometriosis associated with systemic subclinical inflammation?” Gynecologic and Obstetric Investigation, vol. 62, no. 3, pp. 139–147, 2006.
[55]
O. B. Christiansen, H. S. Nielsen, and A. M. Kolte, “Inflammation and miscarriage,” Seminars in Fetal and Neonatal Medicine, vol. 11, no. 5, pp. 302–308, 2006.
[56]
A. Arici, E. Oral, O. Bukulmez, S. Buradagunta, O. Engin, and D. L. Olive, “Interleukin-8 expression and modulation in human preovulatory follicles and ovarian cells,” Endocrinology, vol. 137, no. 9, pp. 3762–3769, 1996.
[57]
E. Runesson, K. Ivarsson, P. O. Janson, and M. Br？nnstr？m, “Gonadotropin- and cytokin-regulated expression of the chemokine interleukin 8 in the human preovulatory follicle of the menstrual cycle,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 11, pp. 4387–4395, 2000.
[58]
V. Baud and M. Karin, “Signal transduction by tumor necrosis factor and its relatives,” Trends in Cell Biology, vol. 11, no. 9, pp. 372–377, 2001.
[59]
R. P. Numerof and K. Asadullah, “Cytokine and anti-cytokine therapies for psoriasis and atopic dermatitis,” BioDrugs, vol. 20, no. 2, pp. 93–103, 2006.
[60]
S. Weiser, J. Miu, H. J. Ball, and N. H. Hunt, “Interferon-γ synergises with tumour necrosis factor and lymphotoxin-α to enhance the mRNA and protein expression of adhesion molecules in mouse brain endothelial cells,” Cytokine, vol. 37, no. 1, pp. 84–91, 2007.
[61]
N. A. Bersinger, Z. Kollmann, and M. von Wolff, “Serum but not follicular fluid cytokine levels are increased in stimulated versus natural cycle IVF: a multiplexed assay study,” Journal of Reproductive Immunology, vol. 106, pp. 27–33, 2014.
[62]
O. Tokuyama, Y. Nakamura, A. Muso, Y. Fujino, O. Ishiko, and S. Ogita, “Vascular endothelial growth factor concentrations in follicular fluid obtained from IVF-ET patients: a comparison of hMG, clomiphene citrate, and natural cycle,” Journal of Assisted Reproduction and Genetics, vol. 19, no. 1, pp. 19–23, 2002.
[63]
J. S. Cunha-Filho, N. Lemos, N. Stein, A. Laranjeira, and E. P. Passos, “Vascular endothelial growth factor and inhibin A in follicular fluid of infertile patients who underwent in vitro fertilization with a gonadotropin-releasing hormone antagonist,” Fertility and Sterility, vol. 83, no. 4, pp. 902–907, 2005.
[64]
C. McRae, N. E. Baskind, N. M. Orsi, V. Sharma, and J. Fisher, “Metabolic profiling of follicular fluid and plasma from natural cycle in vitro fertilization patients—a pilot study,” Fertility and Sterility, vol. 98, no. 6, pp. 1449.e6–1457.e6, 2012.
[65]
N. M. Orsi, N. Gopichandran, U. V. Ekbote, and J. J. Walker, “Murine serum cytokines throughout the estrous cycle, pregnancy and post partum period,” Animal Reproduction Science, vol. 96, no. 1-2, pp. 54–65, 2006.
[66]
P. F. Levay, C. Huyser, F. L. Fourie, and D. J. Rossouw, “The detection of blood contamination in human follicular fluid,” Journal of Assisted Reproduction and Genetics, vol. 14, no. 4, pp. 212–217, 1997.
[67]
C. Huyser, F. L. R. Fourie, and L. Wolmarans, “Spectrophotometric absorbance of follicular fluid: a selection criterion,” Journal of Assisted Reproduction and Genetics, vol. 9, no. 6, pp. 539–544, 1992.
[68]
C. M. Boomsma, A. Kavelaars, M. J. C. Eijkemans, B. C. J. M. Fauser, C. J. Heijnen, and N. S. MacKlon, “Ovarian stimulation for in vitro fertilization alters the intrauterine cytokine, chemokine, and growth factor milieu encountered by the embryo,” Fertility and Sterility, vol. 94, no. 5, pp. 1764–1768, 2010.
[69]
J. R. L. de Mola, J. M. Goldfarb, B. R. Hecht, G. P. Baumgardner, C. J. Babbo, and M. A. Friedlander, “Gonadotropins induce the release of interleukin-1β, interleukin-6 and tumor necrosis factor-α from the human preovulatory follicle,” American Journal of Reproductive Immunology, vol. 39, no. 6, pp. 387–390, 1998.
[70]
M. J. de Los Santos, V. Garca-Lez, D. Beltrn-Torregrosa et al., “Hormonal and molecular characterization of follicular fluid, cumulus cells and oocytes from pre-ovulatory follicles in stimulated and unstimulated cycles,” Human Reproduction, vol. 27, no. 6, pp. 1596–1605, 2012.
[71]
A. Arici, E. Oral, O. Bahtiyar, O. Engin, E. Seli, and E. E. Jones, “Leukaemia inhibitory factor expression in human follicular fluid and ovarian cells,” Human Reproduction, vol. 12, no. 6, pp. 1233–1239, 1997.
[72]
S. Coskun, M. Uzumcu, K. Jaroudi, J. M. G. Hollanders, R. S. Parhar, and S. T. Al-Sedairy, “Presence of leukemia inhibitory factor and interleukin-12 in human follicular fluid during follicular growth,” The American Journal of Reproductive Immunology, vol. 40, no. 1, pp. 13–18, 1998.
[73]
M. Jean, S. Mirallie, P. Barriere et al., “Leukaemia inhibitory factor expression in human follicular fluid,” Human Reproduction, vol. 14, no. 2, article 571, 1999.
[74]
Y. Zhao, J. E. Nichols, S. E. Bulun, C. R. Mendelson, and E. R. Simpson, “Aromatase P450 gene expression in human adipose tissue: role of a Jak/STAT pathway in regulation of the adipose-specific promoter,” The Journal of Biological Chemistry, vol. 270, no. 27, pp. 16449–16457, 1995.
[75]
O. Bukulmez and A. Arici, “Leukocytes in ovarian function,” Human Reproduction Update, vol. 6, no. 1, pp. 1–15, 2000.
[76]
K. C. Reinhart, R. K. Dubey, C. L. Mummery, M. Van Rooijen, P. J. Keller, and R. Marinella, “Synthesis and regulation of leukaemia inhibitory factor in cultured bovine oviduct cells by hormones,” Molecular Human Reproduction, vol. 4, no. 3, pp. 301–308, 1998.
[77]
J. E. Holt, A. Jackson, S. D. Roman, R. J. Aitken, P. Koopman, and E. A. McLaughlin, “CXCR4/SDF1 interaction inhibits the primordial to primary follicle transition in the neonatal mouse ovary,” Developmental Biology, vol. 293, no. 2, pp. 449–460, 2006.
[78]
A. Nishigaki, H. Okada, R. Okamoto et al., “Concentrations of stromal cell-derived factor-1 and vascular endothelial growth factor in relation to the diameter of human follicles,” Fertility and Sterility, vol. 95, no. 2, pp. 742–746, 2011.
[79]
T. Hamza, J. B. Barnett, and B. Li, “Interleukin 12 a key immunoregulatory cytokine in infection applications,” International Journal of Molecular Sciences, vol. 11, no. 3, pp. 789–806, 2010.
[80]
G. Trinchieri, “Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity,” Annual Review of Immunology, vol. 13, pp. 251–276, 1995.
[81]
J. Hodge-Dufour, M. W. Marino, M. R. Horton et al., “Inhibition of interferon γ induced interleukin 12 production: a potential mechanism for the anti-inflammatory activities of tumor necrosis factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 23, pp. 13806–13811, 1998.
[82]
A. Giuliani, W. Schoell, J. Auner, and W. Urdl, “Controlled ovarian hyperstimulation in assisted reproduction: effect on the immune system,” Fertility and Sterility, vol. 70, no. 5, pp. 831–815, 1998.
[83]
A. Hoek, J. Schoemaker, and H. A. Drexhage, “Premature ovarian failure and ovarian autoimmunity,” Endocrine Reviews, vol. 18, no. 1, pp. 107–134, 1997.
