Regimen of ovarian stimulation affects oocyte and therefore embryo quality
2016; Elsevier BV; Volume: 105; Issue: 3 Linguagem: Inglês
10.1016/j.fertnstert.2016.01.022
ISSN1556-5653
AutoresErnesto Bosch, Elena Labarta, Efstratios M. Κolibianakis, Mitchell P. Rosen, David R. Meldrum,
Tópico(s)Assisted Reproductive Technology and Twin Pregnancy
ResumoWithout any doubt the regimen used to mature multiple capable oocytes for IVF impacts IVF outcomes. Studies have indicated that the inclusion of LH activity, adjuvant agents such as growth hormone (GH), and regimens providing for simultaneous action of both LH and FSH during final oocyte maturation may have beneficial effects on IVF outcomes. Because of the difficulty in improving IVF outcomes in poor responders, the studies on GH are of particular interest. As pointed out in this review, the apparent beneficial effects of GH on oocyte competence may also apply to older women or to normal responders with reduced embryo quality. A much more difficult question is whether and how much ovarian stimulation impacts on oocyte competence. Paradoxically it seems that there are not demonstrated differences between the stimulated and the natural unstimulated cycle, whereas studies in laboratory animals and IVF patients have shown deleterious effects of higher compared with lower doses of gonadotropins. Recent studies suggest that the use of high doses of gonadotropins as an independent factor correlates negatively with the probability of live birth, whereas a high ovarian response per se is associated with better cumulative pregnancy rates, owing to the availability of more euploid and good-quality embryos. Although adjunctive use of androgens has not been discussed here, it is briefly covered in the first review of this series. Without any doubt the regimen used to mature multiple capable oocytes for IVF impacts IVF outcomes. Studies have indicated that the inclusion of LH activity, adjuvant agents such as growth hormone (GH), and regimens providing for simultaneous action of both LH and FSH during final oocyte maturation may have beneficial effects on IVF outcomes. Because of the difficulty in improving IVF outcomes in poor responders, the studies on GH are of particular interest. As pointed out in this review, the apparent beneficial effects of GH on oocyte competence may also apply to older women or to normal responders with reduced embryo quality. A much more difficult question is whether and how much ovarian stimulation impacts on oocyte competence. Paradoxically it seems that there are not demonstrated differences between the stimulated and the natural unstimulated cycle, whereas studies in laboratory animals and IVF patients have shown deleterious effects of higher compared with lower doses of gonadotropins. Recent studies suggest that the use of high doses of gonadotropins as an independent factor correlates negatively with the probability of live birth, whereas a high ovarian response per se is associated with better cumulative pregnancy rates, owing to the availability of more euploid and good-quality embryos. Although adjunctive use of androgens has not been discussed here, it is briefly covered in the first review of this series. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/bosche-ovarian-stimulation-embryo-quality/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/bosche-ovarian-stimulation-embryo-quality/ Follicular development and oocyte maturation are two intimately related processes. Although the oocyte was previously considered only a passive recipient of signals for maturation from the granulosa cells, it is now well known that communication between oocytes and granulosa cells is bidirectional (1Eppig J.J. Oocyte control of ovarian follicular development and function in mammals.Reproduction. 2001; 122: 829-838Crossref PubMed Google Scholar). Moreover, this interplay is essential for both follicular differentiation but also for the production of an oocyte competent to undergo fertilization and embryogenesis. The communication between granulosa cells and the oocyte is controlled by gonadotropins and the oocyte itself. Both gonadotropins influence oocyte competence through the two main local growth factor systems: the bone morphogenetic system and the insulin-like growth factors (IGF) system. It has been observed in the animal model that modification of these systems influences ovulation rates, oocyte competence, and resulting embryo quality (2Webb R. Garnsworthy P.C. Campbell B.K. Hunter M.G. Intra-ovarian regulation of follicular development and oocyte competence in farm animals.Theriogenology. 2007; 68: S22-S29Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Inevitably, controlled ovarian stimulation (COS) for IVF entails variations in theca and granulosa cell functions that may affect oocyte quality. Multiple follicular development causes the growth of follicles of different sizes and functional activity that will contain oocytes at different maturation stages (3Lindner C. Lichtenberg V. Westhof G. Braendle W. Bettendorf G. Endocrine parameters of human follicular fluid and fertilization capacity of oocytes.Horm Metab Res. 1988; 20: 243-246Crossref PubMed Google Scholar). On the other hand, success of IVF is clearly dependent on the size and quality of the oocyte cohort (4Sunkara S.K. Rittenberg V. Raine-Fenning N. Bhattacharya S. Zamora J. Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles.Hum Reprod. 2011; 26: 1768-1774Crossref PubMed Scopus (199) Google Scholar, 5Fatemi H.M. Doody K. Griesinger G. Witjes H. Mannaerts B. High ovarian response does not jeopardize ongoing pregnancy rates and increases cumulative pregnancy rates in a GnRH-antagonist protocol.Hum Reprod. 2013; 28: 442-452Crossref PubMed Scopus (21) Google Scholar, 6Ji J. Liu Y. Tong X.H. Luo L. Ma J. Chen Z. The optimum number of oocytes in IVF treatment: an analysis of 2455 cycles in China.Hum Reprod. 2013; 28: 2728-2734Crossref PubMed Scopus (40) Google Scholar). Today the therapeutic arsenal for COS includes many possibilities, depending on the type of gonadotrophins given, their doses, the regimen of pituitary suppression used, and the administration or not of adjuvant agents (7Bosch E. Ezcurra D. Individualised controlled ovarian stimulation (iCOS): maximising success rates for assisted reproductive technology patients.Reprod Biol Endocrinol. 2011; 9: 82Crossref PubMed Scopus (36) Google Scholar). The effects of each of these combinations on follicular growth and oocyte maturation may be different. The impact of ovarian stimulation on oocyte and embryo quality is still unclear. Most of the studies performed in animals show a deleterious effect of ovarian stimulation on oocyte quality and embryo development throughout different stages. Although in humans this issue has not been thoroughly studied owing to ethical reasons, pregnancy rates are still lower in stimulated IVF cycles than one might predict, and the proportion of embryo loss is more than desired. It has been hypothesized that ovarian stimulation treatments could explain these findings, but also high ovarian response after the use of gonadotropins. The use of GnRH agonists (GnRHas) in IVF practice led to lower cancellation rates, an increased number of oocytes, and higher pregnancy rates (8Hughes E.G. Fedorkow D.M. Daya S. Sagle M.A. Van de Koppel P. Collins J.A. The routine use of gonadotropin-releasing hormone agonists prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized controlled trials.Fertil Steril. 1992; 58: 888-896Abstract Full Text PDF PubMed Google Scholar). Later the introduction of GnRH antagonists, which cause profound and immediate pituitary suppression (9Frydman R. Cornel C. de Ziegler D. Taieb J. Spitz I.M. Bouchard P. Prevention of premature luteinizing hormone and progesterone rise with a gonadotropin-releasing hormone antagonist, Nal-Glu, in controlled ovarian hyperstimulation.Fertil Steril. 1991; 56: 923-927Abstract Full Text PDF PubMed Google Scholar), allowed for less aggressive and more individualized protocols and also avoided the initial flare-up and subsequent estrogen deprivation symptoms (10Diedrich K. Diedrich C. Santos E. Zoll C. al-Hasani S. Reissmann T. et al.Suppression of the endogenous luteinizing hormone surge by the gonadotrophin-releasing hormone antagonist Cetrorelix during ovarian stimulation.Hum Reprod. 1994; 9: 788-791Crossref PubMed Google Scholar). Initial trials comparing GnRHa and GnRH antagonist cycles reported slightly but consistently lower pregnancy rates when antagonists were used (11Olivennes F. [LH and GnRH antagonists].J Gynecol Obstet Biol Reprod (Paris). 2002; 31 (1S25–1S7)Google Scholar). The action of antagonists inhibiting the cellular cycle via the decrease of growth factors was suggested as a putative cause of this poorer outcome (12Hernandez E.R. Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists.Hum Reprod. 2000; 15: 1211-1216Crossref PubMed Google Scholar). However, to date it has been clearly shown that GnRH antagonist cycles obtain similar live birth rates compared with the GnRHa long protocol (13Al-Inany H.G. Youssef M.A. Aboulghar M. Broekmans F. Sterrenburg M. Smit J. et al.Gonadotrophin-releasing hormone antagonists for assisted reproductive technology.Cochrane Database Syst Rev. 2011; : CD001750PubMed Google Scholar), and therefore no impact on oocyte quality has been observed. Nevertheless, patients with endometriosis (14Barnhart K. Dunsmoor-Su R. Coutifaris C. Effect of endometriosis on in vitro fertilization.Fertil Steril. 2002; 77: 1148-1155Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar), or those with accelerated folliculogenesis, could benefit from a GnRHa long protocol, owing to the better control of endogenous gonadotropins (15Huirne J.A. Homburg R. Lambalk C.B. Are GnRH antagonists comparable to agonists for use in IVF?.Hum Reprod. 2007; 22: 2805-2813Crossref PubMed Scopus (0) Google Scholar). Although the physiologic role of LH during the follicular phase of a natural cycle is unquestionable (16Balasch J. Miro F. Burzaco I. Casamitjana R. Civico S. Ballesca J.L. et al.The role of luteinizing hormone in human follicle development and oocyte fertility: evidence from in-vitro fertilization in a woman with long-standing hypogonadotrophic hypogonadism and using recombinant human follicle stimulating hormone.Hum Reprod. 1995; 10: 1678-1683Crossref PubMed Google Scholar, 17Recombinant human luteinizing hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study. The European Recombinant Human LH Study Group.J Clin Endocrinol Metab. 1998; 83: 1507-1514Crossref PubMed Scopus (0) Google Scholar), its impact during a COS cycle remains controversial. The administration of LH activity in COS induces several differences in the synthesis of follicular steroids, which may have an impact on oocyte maturation and competence. Using recombinant LH, our group has shown that there is an LH-dose-dependent increase of follicular fluid E2, androstenedione (A), and T (18Bosch E. Pau E. Albert C. Zuzuarregui J.L. Remohí J. Pellicer A. Impact of different amounts of LH in controlled ovarian hyperstimulation oocyte donation cycles.Fertil Steril. 2006; 86: S425Abstract Full Text Full Text PDF Google Scholar). Metaphase I oocytes were obtained from follicles that had significantly lower E2 concentrations and higher T and A levels, whereas oocytes with multiple anomalies were recovered from follicles with significantly higher LH levels. Together, this suggests there is an optimal level of LH action on the follicle through which the oocyte achieves adequate maturation and maximal competence. These findings of steroids in follicular fluid are consistent with those observed in the MERIT study (19Smitz J. Andersen A.N. Devroey P. Arce J.C. MERIT GroupEndocrine profile in serum and follicular fluid differs after ovarian stimulation with HP-hMG or recombinant FSH in IVF patients.Hum Reprod. 2007; 22: 676-687Crossref PubMed Scopus (115) Google Scholar), in which patients who received highly purified hMG for stimulation showed higher concentrations of E2, A, and T than those who were stimulated with recombinant FSH (rFSH). Interestingly, more good-quality embryos were observed in the highly purfied (hp)-hMG group, although pregnancy rates were comparable. These studies suggest that the action of LH may be helpful for patients with low serum androgen levels. It has been shown that serum androgens decline steeply with age, with a decrease from menarche to menopause that ranges from 49% for free T to 77% DHEAS (20Davison S.L. Bell R. Donath S. Montalto J.G. Davis S.R. Androgen levels in adult females: changes with age, menopause, and oophorectomy.J Clin Endocrinol Metab. 2005; 90: 3847-3853Crossref PubMed Scopus (487) Google Scholar). Moreover, it has been demonstrated that whereas the synthesis of E2 in response to rFSH stimulation is preserved in older women, there is a significant decrease in the synthesis of A when rFSH alone is given for stimulation (21Welt C.K. Jimenez Y. Sluss P.M. Smith P.C. Hall J.E. Control of estradiol secretion in reproductive ageing.Hum Reprod. 2006; 21: 2189-2193Crossref PubMed Scopus (0) Google Scholar). Indeed, in a prospective, randomized study we observed that in patients with basal T below the mean (0.45 ng/mL), there was a strong trend toward a better ongoing pregnancy rate when LH was added to rFSH, compared with rFSH alone in a GnRHa long protocol (22Bosch E. Labarta E. Vidal C. Giles J. Bellver J. Zuzuarregui J.L. et al.The relationship between serum androgen levels and the need of LH administration during controlled ovarian stimulation for in vitro fertilization: an explorative study.Hum Reprod. 2011; 26: i26Crossref Google Scholar), whereas no differences were observed when both protocols were compared in women with T above the mean. No other differences were observed with respect to other androgen serum levels. Together, this supports a potential benefit of LH administration in older women, in whom basal androgens and their synthesis in response to rFSH in the absence of LH are diminished. To date there seems to be no clear benefit obtained by combining LH and FSH in unselected normogonadotrophic patients (23Kolibianakis E.M. Collins J. Tarlatzis B.C. Devroey P. Diedrich K. Griesinger G. Among patients treated for IVF with gonadotrophins and GnRH analogues, is the probability of live birth dependent on the type of analogue used? A systematic review and meta-analysis.Hum Reprod Update. 2006; 12: 651-671Crossref PubMed Scopus (0) Google Scholar, 24Mochtar M.H. Van der Veen F. Ziech M. van Wely M. Recombinant Luteinizing Hormone (rLH) for controlled ovarian hyperstimulation in assisted reproductive cycles.Cochrane Database Syst Rev. 2007; : CD005070PubMed Google Scholar). On the other hand, the potential benefit of LH administration in patients of advanced reproductive age (i.e., >35 years) has been evaluated in a systematic review and meta-analysis (25Hill M.J. Levens E.D. Levy G. Ryan M.E. Csokmay J.M. DeCherney A.H. et al.The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and meta-analysis.Fertil Steril. 2012; 97: 1108-1114.e1Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). In that group of women it was clearly shown that LH administration led to significantly better implantation and clinical pregnancy rates than rFSH alone. Moreover, it was demonstrated that although rFSH led to a higher oocyte yield, there were no differences in metaphase II oocytes, and the fertilization rate was better in patients receiving LH. These were also our findings in an age-adjusted randomized, controlled trial performed in normogonadotrophic patients after COS using a GnRH antagonist protocol (26Bosch E. Labarta E. Crespo J. Simon C. Remohi J. Pellicer A. Impact of luteinizing hormone administration on gonadotropin-releasing hormone antagonist cycles: an age-adjusted analysis.Fertil Steril. 2011; 95: 1031-1036Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). It was observed that whereas in patients under 35 year old, results were virtually the same in both stimulation groups (rFSH vs. rFSH + recombinant LH [rLH]), the implantation rate was significantly higher in women receiving rFSH and rLH in the 36–39-year-old group, with a clinically relevant increase in ongoing pregnancy rate. These findings seem to conflict with those published more recently in a similar trial in which patients aged 35 years or more were stimulated with the GnRH antagonist protocol and randomized to receive either rFSH alone across the cycle, together with 150 IU of rLH from day 6 of stimulation (27Konig T.E. van der Houwen L.E. Overbeek A. Hendriks M.L. Beutler-Beemsterboer S.N. Kuchenbecker W.K. et al.Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years or older undergoing IVF/ICSI: a randomized controlled multicentre study.Hum Reprod. 2013; 28: 2804-2812Crossref PubMed Scopus (0) Google Scholar). In this study no benefits of rLH administration were observed. Nevertheless, an analysis of the differences between the studies allows drawing interesting and complementary conclusions about the possible role of LH in the treatment of this particular population (28Bosch E. Comment on 'Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years old or older undergoing IVF/ICSI: a randomized controlled multicentre study'.Hum Reprod. 2014; 29: 636-637Crossref PubMed Scopus (0) Google Scholar). In our study we used a contraceptive pill (CP) the cycle before stimulation, and we substituted 75 IU of rFSH per day with 75 IU of rLH from stimulation day 1 in the study group. Although in our study hormonal determinations before starting stimulation are not available, it is very likely that after a cycle of CP, hormone values (E2, FSH, LH, P, and T) were lower than in the subsequent study. This would explain a slower response for the group receiving rFSH alone at the beginning of stimulation, due to ovarian suppression. In this scenario, LH administration aids steroidogenesis, with a greater androgen synthesis as substrate for aromatization to estrogen. This may also explain why in GnRH antagonist IVF cycles stimulated with rFSH alone the administration of a CP in the prior cycle is associated with a lower pregnancy rate (29Griesinger G. Kolibianakis E.M. Venetis C. Diedrich K. Tarlatzis B. Oral contraceptive pretreatment significantly reduces ongoing pregnancy likelihood in gonadotropin-releasing hormone antagonist cycles: an updated meta-analysis.Fertil Steril. 2010; 94: 2382-2384Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). Therefore, it seems that the beneficial effect of LH suppression in this specific population is only observed when given from the first day of stimulation, and it might be more crucial when a CP is given for pretreatment. The substitution of 75 IU of rFSH by 75 IU of rLH from the beginning of stimulation may explain the lower P levels observed on the day of hCG administration. Through its action at the theca layer, LH enhances the conversion of pregnenolone into androgens, whereas FSH enhances its conversion into P in the granulosa cells. This P cannot be converted into androgens in humans (30Yding Andersen C. Bungum L. Nyboe Andersen A. Humaidan P. Preovulatory progesterone concentration associates significantly to follicle number and LH concentration but not to pregnancy rate.Reprod Biomed Online. 2011; 23: 187-195Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), so if its production is excessive it raises circulating levels (31Fleming R. Jenkins J. The source and implications of progesterone rise during the follicular phase of assisted reproduction cycles.Reprod Biomed Online. 2010; 21: 446-449Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). In fact, in a multivariate analysis of more than 4,000 cycles, we observed that a P increase at the end of stimulation was significantly related to the daily dose of FSH but not of LH (32Bosch E. Labarta E. Crespo J. Simon C. Remohi J. Jenkins J. et al.Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles.Hum Reprod. 2010; 25: 2092-2100Crossref PubMed Scopus (184) Google Scholar). Recently, a large retrospective cohort study showed that the lowest risk of having high P levels at the end of stimulation is achieved when LH is administered in a ratio of 0.3–0.6 with respect to the dose of FSH (33Werner M.D. Forman E.J. Hong K.H. Franasiak J.M. Molinaro T.A. Scott Jr., R.T. Defining the "sweet spot" for administered luteinizing hormone-to-follicle-stimulating hormone gonadotropin ratios during ovarian stimulation to protect against a clinically significant late follicular increase in progesterone: an analysis of 10,280 first in vitro fertilization cycles.Fertil Steril. 2014; 102: 1312-1317Abstract Full Text Full Text PDF PubMed Google Scholar). Effects of ovarian stimulation on oocyte and embryo quality have been well characterized in animals, showing that aggressive stimulation leads to poorer embryo development potential and could increase the rate of chromosomal abnormalities (34Chang M.C. Digynic triploidy after superovulation.Nature. 1977; 266: 382-383Crossref PubMed Google Scholar, 35Ertzeid G. Storeng R. The impact of ovarian stimulation on implantation and fetal development in mice.Hum Reprod. 2001; 16: 221-225Crossref PubMed Google Scholar, 36Van der Auwera I. D'Hooghe T. Superovulation of female mice delays embryonic and fetal development.Hum Reprod. 2001; 16: 1237-1243Crossref PubMed Google Scholar). Later studies in animals suggested that embryo development seems to be adversely affected in a dose-dependent manner (37Edwards L.J. Kind K.L. Armstrong D.T. Thompson J.G. Effects of recombinant human follicle-stimulating hormone on embryo development in mice.Am J Physiol Endocrinol Metab. 2005; 288: E845-E851Crossref PubMed Scopus (17) Google Scholar, 38Lee S.T. Kim T.M. Cho M.Y. Moon S.Y. Han J.Y. Lim J.M. Development of a hamster superovulation program and adverse effects of gonadotropins on microfilament formation during oocyte development.Fertil Steril. 2005; 83: 1264-1274Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). In humans, studies are limited and less conclusive. In fact, when natural and stimulated cycles are compared, no differences have been observed in terms of embryo cleavage capacity (39Ziebe S. Bangsboll S. Schmidt K.L. Loft A. Lindhard A. Nyboe Andersen A. Embryo quality in natural versus stimulated IVF cycles.Hum Reprod. 2004; 19: 1457-1460Crossref PubMed Scopus (0) Google Scholar), oocyte (40Gras L. McBain J. Trounson A. Kola I. The incidence of chromosomal aneuploidy in stimulated and unstimulated (natural) uninseminated human oocytes.Hum Reprod. 1992; 7: 1396-1401Crossref PubMed Google Scholar) and embryo aneuploidy rate (41Labarta E. Bosch E. Alama P. Rubio C. Rodrigo L. Pellicer A. Moderate ovarian stimulation does not increase the incidence of human embryo chromosomal abnormalities in in vitro fertilization cycles.J Clin Endocrinol Metab. 2012; 97: E1987-E1994Crossref PubMed Scopus (20) Google Scholar), or incidence of aneuploidy in aborted fetuses (42Qin J.Z. Pang L.H. Li M.Q. Xu J. Zhou X. Risk of chromosomal abnormalities in early spontaneous abortion after assisted reproductive technology: a meta-analysis.PLoS One. 2013; 8: e75953Crossref PubMed Scopus (0) Google Scholar) or in chorionic villus sampling in the late first trimester of pregnancy (43Conway D.A. Patel S.S. Liem J. Fan K.J. Jalian R. Williams 3rd, J. et al.The risk of cytogenetic abnormalities in the late first trimester of pregnancies conceived through assisted reproduction.Fertil Steril. 2011; 95: 503-506Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). A significantly different follicular endocrine milieu has been detected when natural cycle mature follicles and stimulated follicles have been compared (44von Wolff M. Kollmann Z. Fluck C.E. Stute P. Marti U. Weiss B. 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.Hum Reprod. 2014; 29: 1049-1057Crossref PubMed Scopus (0) Google Scholar), although our group could not detect a relationship between this modification in follicular physiology and embryo morphology or even oocyte meiotic spindle structure (45de los Santos M.J. Garcia-Laez V. Beltran-Torregrosa D. Horcajadas J.A. Martinez-Conejero J.A. Esteban F.J. et al.Hormonal and molecular characterization of follicular fluid, cumulus cells and oocytes from pre-ovulatory follicles in stimulated and unstimulated cycles.Hum Reprod. 2012; 27: 1596-1605Crossref PubMed Scopus (0) Google Scholar). Most of the studies in humans designed to evaluate the impact of gonadotropins on oocyte quality have compared different doses of gonadotropins. When mild and conventional stimulation are compared, a higher proportion of good morphologic quality embryos is observed in the former (46Hohmann F.P. Macklon N.S. Fauser B.C. A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol.J Clin Endocrinol Metab. 2003; 88: 166-173Crossref PubMed Scopus (192) Google Scholar, 47Baart E.B. Martini E. Eijkemans M.J. Van Opstal D. Beckers N.G. Verhoeff A. et al.Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial.Hum Reprod. 2007; 22: 980-988Crossref PubMed Scopus (280) Google Scholar). Additionally, a positive relationship between doses of gonadotropins and aneuploidy rate was found, either in the embryo (47Baart E.B. Martini E. Eijkemans M.J. Van Opstal D. Beckers N.G. Verhoeff A. et al.Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial.Hum Reprod. 2007; 22: 980-988Crossref PubMed Scopus (280) Google Scholar) or in granulosa cells (48Kaleli S. Yanikkaya-Demirel G. Erel C.T. Senturk L.M. Topcuoglu A. Irez T. High rate of aneuploidy in luteinized granulosa cells obtained from follicular fluid in women who underwent controlled ovarian hyperstimulation.Fertil Steril. 2005; 84: 802-804Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). Conversely, we showed that ovarian stimulation does not significantly raise the embryo aneuploidy rate in IVF-derived human embryos when compared with an unstimulated cycle and that ovarian response was not positively related to aneuploidy (49Labarta E. Bosch E. Pellicer A. Impact of ovarian stimulation with gonadotrophins on embryo aneuploidy.Hum Reprod Update. 2014; 20: 964Crossref PubMed Google Scholar). The proportion of euploid oocytes is directly related to the number of mature oocytes, and inversely related to the number of units of FSH per oocyte and per mature oocyte obtained (50Haaf T. Hahn A. Lambrecht A. Grossmann B. Schwaab E. Khanaga O. et al.A high oocyte yield for intracytoplasmic sperm injection treatment is associated with an increased chromosome error rate.Fertil Steril. 2009; 91: 733-738Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 51Gianaroli L. Magli M.C. Cavallini G. Crippa A. Capoti A. Resta S. et al.Predicting aneuploidy in human oocytes: key factors which affect the meiotic process.Hum Reprod. 2010; 25: 2374-2386Crossref PubMed Scopus (0) Google Scholar). This is in line with recent studies, which do not support the idea that ovarian stimulation is so detrimental to oocyte and embryo quality. In fact, it has been shown that high ovarian response to conventional ovarian stimulation does not increase embryo aneuploidy rates in preimplantational genetic screening (PGS) cycles using array comparative genomic hybridization, either in infertile patients or in oocyte donors (52Ata B. Kaplan B. Danzer H. Glassner M. Opsahl M. Tan S.L. et al.Array CGH analysis shows that aneuploidy is not related to the number of embryos generated.Reprod Biomed Online. 2012; 24: 614-620Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 53Labarta E. Bosch E. Mercader A. Alamá P. Mateu E. Pellicer A. Relationship between ovarian response and number of euploid embryos in oocyte donor cycles.Fertil Steril. 2012; 98: S282Abstract Full Text Full Text PDF Google Scholar). Moreover, the more euploid blastocysts that are available, the higher the clinical pregnancy rate, even in fresh cycles (54Morin S. Melzer-Ross K. McCulloh D. Grifo J. Munne S. A greater number of euploid blastocysts in a given cohort predicts excellent outcomes in single embryo transfer cycles.J Assist Reprod Genet. 2014; 31: 667-673Crossref PubMed Google Scholar, 55Gleicher N. Kim A. Weghofer A. Barad D.H. Lessons from elective in vitro fertilization (IVF) in, principally, non-infertile women.Reprod Biol Endocrinol. 2012; 10: 48Crossref PubMed Scopus (0) Google Scholar), and the higher the ovarian response, the higher the cumulative pregnancy rate after including thawed embryo transfers (5Fatemi H.M. Doody K. Griesinger G. Witjes H. Mannaerts B. High ovarian response does not jeopardize ongoing pregnancy rates and increases cumulative pregnancy rates in a GnRH-antagonist protocol.Hum Reprod. 2013; 28: 442-452Crossref PubMed Scopus (21) Google Scholar, 6Ji J. Liu Y. Tong X.H. Luo L. Ma J. Chen Z. The optimum number of oocytes in IVF
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