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Retrieving oocytes from small non-stimulated follicles in polycystic ovary syndrome (PCOS): in vitro maturation (IVM) is not indicated in the new GnRH antagonist era
CONCEPTIONS
Retrieving oocytes from small non-stimulated follicles in polycystic ovary syndrome (PCOS): in vitro maturation (IVM) is not indicated in the new GnRH antagonist era Dominique de Ziegler, M.D.,a Isabelle Streuli, M.D.,a Vanessa Gayet, M.D.,a Nelly Frydman, M.D.,a,b Osama Bajouh, M.D.,a and Charles Chapron, M.D.a a Paris Descartes, Paris Sorbonne Cite — Department of Obstetrics, Gynecology and Reproductive Medicine, Universite ^ pitaux de Paris, CHU Cochin, Paris; and b Department of Obstetrics, Gynecology and Reproductive Assistance Publique Ho Paris-Sud—Assistance Publique Ho ^ pitaux de Paris, CHU Antoine Be cle re, Clamart, France Medicine, Universite
It has been two decades since pregnancies have been obtained through in vitro maturation (IVM) of germinal vesicle-stage oocytes retrieved from non-stimulated ovaries. This technique first offered in PCOS cannot be recommended today in this indication because the results do not match those of regular ART, and new GnRH antagonist and agonist-trigger protocols reliably prevent OHSS. (Fertil SterilÒ 2012;98:290–3. Ó2012 by American Society for Reproductive Medicine.) Use your smartphone Key Words: In vitro maturation, IVM, assisted reproductive treatments, ART, polycystic ovary to scan this QR code syndrome, PCOS Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/de-zieglerd-polycystic-ovary-syndrome-pcos-in-vitro-maturation/
and connect to the discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
T
he first pregnancies resulting from in vitro maturation (IVM) of germinal-vesicle stage oocytes retrieved from non-stimulated ovaries were reported two decades ago (1). These early successes having been confirmed and expended (2, 3), IVM became part of assisted reproduction technologies (ART), having its dedicated section in the reports of the ESHRE's registry (4). From inception, the possibility of obtaining embryos from oocytes harvested from non-stimulated ovaries appeared particularly interesting in the
case of polycystic ovary syndrome (PCOS). In PCOS indeed, controlled ovarian stimulation (COS) needed in regular ART may be at times difficult to manage and carry undue risks of ovarian hyperstimulation syndrome (OHSS), a dreadful complication of ART (5).
IVM, A DECEIVING ALTERNATIVE TO COS-BASED ART IN PCOS COS responses in PCOS are characterized by a reduced therapeutic margin
Received April 30, 2012; revised June 18, 2012; accepted June 22, 2012. D.d.Z. has nothing to disclose. I.S. has nothing to disclose. V.G. has nothing to disclose. N.F. has nothing to disclose. O.B. has nothing to disclose. C.C. has nothing to disclose. Reprint requests: Dominique de Ziegler, M.D., Professor and Head, Reproductive Endocrinology and cologie Obste trique II, Groupe d'ho ^ pitaux Paris centre Cochin Broca Infertility, Service de Gyne ^ tel Dieu, Ho ^ pital Cochin, 53, Avenue de l'Observatoire, 75014 Paris, France (E-mail: Ho [email protected]). Fertility and Sterility® Vol. 98, No. 2, August 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.06.043 290
between the doses of gonadotropin that produce insufficient or excessive responses (E2 levels and number of oocytes obtained) (6). Such brittle responses to COS are also encountered in regularly ovulating women whose ovaries fulfill the echo graphic criteria of PCOS, R12 antral follicles/side (7), or more recent definitions based on AMH levels >5 ng/mL (8). While special protocols (dual suppression [9]) and/or measures during COS (withholding gonadotropin administration, or ‘coasting’ [10]) reduce the risk, they do not totally prevent OHSS. Until recently therefore, there remained subgroups of PCOS patients who are hard manage and at high risk of OHSS, in case of past OHSS or very high antral follicle counts (AFC) and/or AMH levels (11–14). For the reasons described above, IVM stood as a therapeutic alternative VOL. 98 NO. 2 / AUGUST 2012
Fertility and Sterility® for women with PCOS or PCO in whom COS is unmanageable or bound to result in OHSS (15). Practically speaking, IVM was also seen as possibly providing better yields in women with large AFC scores, as in PCOS and PCO. The latter was confirmed by Child et al. (2) who obtained more oocytes from women with PCOS (11.3 þ 9.0, mean þ SD) or PCO (10.0 þ 5.1) than from cycling women (5.1 þ 3.7). In this trial, implantation, pregnancy, and live birth rates were also higher in women with PCOS (9.6%, 29.9%, and 14.9%, respectively) or PCO (8.9%, 23.1%, and 17.3%, respectively), as compared with cycling women (1.5%, 4.0%, and 2.0%, respectively) (2). The results of IVM in PCOS, higher than in cycling women, do not match however those of regular COS-based ART in these women. In a case-control trial, the results of 107 PCOS women undergoing IVM were compared to those of 107 other PCOS women treated by regular COS-associated ART (3). The mature oocyte and embryo yields were of 7.8 and 12.0 oocytes and 6.1 and 9.3 embryos in the IVM and regular ART groups, respectively (3). Likewise, pregnancy and live birth rates were lower at 26.2% and 15.9%, respectively in IVM, as compared to 38.3% and 26.2%, respectively in regular ART (3). A French team with an early involvement in IVM also reported deceiving results in 45 consecutive cycles conducted in 33 women fulfilling the Rotterdam criteria for PCOS (16). Women had an ultrasound on day 6–8 of naturally occurring or induced menses (dydrogesterone, 10 mg/day for 10 days). Oocytes were collected 33–36 hours after administration of 10,000 IU of hCG (17) and handled as previously described (18). Cumulus-oocyte complexes were decoronated with hyaluronidase 24 hours later and inseminated by ICSI after witnessing extrusion of the first polar body. Oocytes that were still immature were kept for an extra 24 hours in maturation culture medium before insemination and discarded if not matured after 48 hours in culture. Of 509 oocytes retrieved (mean SD/patient: 11.4 6.9), 276 (4.8 3.2/patient, 54.2%) and 45 (1.5 1.7/patient, 8.8%) matured after 24 and 48 hours, respectively. The clinical pregnancy (cPR) and live birth rates were a mediocre 22.5% and 13.5% per retrieval, respectively with an embryo implantation rate of 10.9% (16).
ART OUTCOME IN PCOS It was originally feared that ART outcome might be poorer in PCOS because of decreased oocyte quality and/or altered endometrial receptivity. The former was rooted in beliefs that the disorderly responses to COS often seen in PCOS yielded crops of numerous but poorly performing oocytes (19). The latter stemmed from speculations that the androgen elevation seen in COS (20) might be exacerbated in PCOS (21) and alter endometrial receptivity, including by hampering the expression of HOX genes (22, 23). The fears of decreased ART outcome in PCOS mentioned above are clearly not supported by recent facts. On the contrary, a meta-analysis retaining 9 of 920 reports on ART in PCOS that had matched controls receiving similar COS regimens reported equal if not better ART outcome in PCOS. The PCOS group totaled 458 women undergoing 793 cycles, while there were 694 matched controls undergoing 1,116 ART cycles (24). The study found that PCOS women were at VOL. 98 NO. 2 / AUGUST 2012
higher risk (12.8%) than controls (4.1%) of being cancelled during the course of COS (OR: 0.5; 95% CI: 0.2–1.0), had longer stimulations (mean: 1.2 days; 95% CI: 0.9, 1.5), produced on average 2.9 more oocytes (95%CI: 2.2–3.6), but had similar numbers of embryos and similar clinical pregnancy and live birth rates per initiated cycle (24). In agreement with these findings, Holte et al. reported that pregnancy and live-birth rates are log-linearly related to antral follicle count (AFC), with PCOS at the far end of the AFC spectrum having superior outcome (25). In a challenging concept, Mellembakken et al. suggested that the age-related decrease in ART outcome is delayed in PCOS as compared to age-matched women suffering from tubal infertility (26). Finally, population-based studies indicated that PCOS women ultimately achieve normal if not superior fertility scores (27). Moreover simple treatments such as metformin are likely to further improve the reproductive outcome of women with PCOS (28).
GnRH-a TRIGGER CONTROLS THE RISK OF OHSS IN PCOS Recent developments in COS protocols have upended the OHSS problem by offering effective ways of preventing OHSS in PCOS (29). First, the risk of OHSS is reduced in COS protocols using GnRH antagonists for preventing premature luteinization as compared with the classical GnRH-a protocols (30). Second, the antagonists protocols have revived the possibility of triggering ovulation with GnRH-a (31) instead of hCG, as first reported two decades ago in non-suppressed cycles (32–35). Using GnRH-a for triggering ovulation effectively prevents OHSS. In a retrospective study, Manzanares et al. (36) observed no case of OHSS in 42 women who previously experienced OHSS when they received an antagonist protocol with GnRH-a trigger. Questions were soon raised however about the quality of ART outcome following GnRH-a trigger. In a meta-analysis retaining 8 RCTs, OHSS risks were profoundly reduced following GnRH-a triggering, but so were pregnancy chances (37). In an RCT, Humaidan et al. (38) found more matured (MII) oocytes in women (n ¼ 55) undergoing GnRHa trigger as opposed to receiving hCG for ovulation induction (n ¼ 67), possibly an effect of the FSH elevation induced by GnRH-a. Yet, these authors also observed lower implantation (P< .001) and clinical pregnancy rates at 6% and 36% (P¼ .002) topped by higher pregnancy losses at 79% and 4% (P¼ .005) in the GnRH-a trigger and hCG groups, respectively (38). In contrast with the lower pregnancy chances observed in regular ART, there were no differences in recipient outcome when antagonist and GnRH-a trigger were used in oocyte donors in whom they effectively prevent OHSS (39, 40). The fact that GnRH trigger reduces regular ART outcome without affecting the results of donor-egg ART points at a negative impact on endometrial receptivity. Confronting the mounting evidence of decreased live birth rates when GnRH-a trigger is used for preventing OHSS, certain authors have advocated a ‘freeze-all’ strategy in these cases (41, 42). These authors reported good outcomes following systematic cryopreservation at the 2PN stage (41). 291
CONCEPTIONS Demarking from the freeze-all recommendation, Humaidan et al. (43, 44) claimed that proper endometrial receptivity can be restored following GnRH-a trigger by a single 1,500 IU hCG bolus at the time of oocyte retrieval, while the risk of OHSS remained minimal. In a slightly different paradigm, Griffin et al. reported good general ART outcome when 1,000 IU of hCG were co-administered with GnRH-a trigger in a so-called ‘dual-trigger’ approach (45). Finally, Engmann et al. (46) reported normalizing pregnancy chances after GnRH-a trigger by providing ‘‘intensive luteal support.’’ The latter consisted of 50 mg of IM progesterone starting on the evening of oocyte retrieval and continued until 11 weeks of gestation together with 0.1 mg of E2 administered transdermally, starting one day after oocyte retrieval (46). In certain cases, the doses of IM progesterone and E2 were increased in order to maintain the circulating levels of progesterone and E2 above 20 ng/mL and 200 pg/mL, respectively (47). The fact that luteal support using IM progesterone is more effective than vaginal progesterone at normalizing receptivity in case of GnRH trigger suggests the possibility of a nonuterine effect. Indeed, uterine tissue concentrations of progesterone are higher in case of vaginal administration (48) because of a first uterine pass effect (49, 50). In contrast, the benefit of IM over vaginal progesterone seen after GnRH-a trigger appears to be dependent on circulating levels of progesterone, not uterine tissue concentration (51). The value of intensive luteal support in GnRH-a trigger cycles was also supported by Imbar et al. (52) who stressed the financial advantage of this approach over the freeze-all option. Finally, as recently published in this journal, an ideal compromise might be to provide the dual-trigger approach (45) associating GnRH-a and 1,000 IU of hCG when peak E2 is <4,000 pg/mL; and intensive luteal support alone when E2 is >4,000 pg/mL (51).
CONCLUSION Evidence indicates the original interest for treating certain PCOS patients with COS-less IVM in order to avoid the risk of OHSS has been superseded by new effective means of avoiding OHSS. Indeed, antagonist and GnRH-a trigger protocols— using the dual-trigger, intense luteal support, or freeze-all approaches—offer the high yield of regular ART while avoiding the risk of OHSS. Moreover, evidence that ART outcome is not diminished in PCOS (contrary to what was originally feared) while the results of IVM are markedly lower, further stresses the fact that IVM is not a viable option in PCOS. Conversely, IVM should be seen as a procedure that is more appropriate when no other option exists, as for example in certain cancer cases. Acknowledgments: The expert assistance of Ms. Nadine Cointot for preparing this manuscript was greatly appreciated and is acknowledged.
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Retrieving oocytes from small non-stimulated follicles in polycystic ovary syndrome (PCOS): in vitro maturation (IVM) is not indicated in the new GnRH antagonist era Dominique de Ziegler, M.D.,a Isabelle Streuli, M.D.,a Vanessa Gayet, M.D.,a Nelly Frydman, M.D.,a,b Osama Bajouh, M.D.,a and Charles Chapron, M.D.a a Paris Descartes, Paris Sorbonne Cite — Department of Obstetrics, Gynecology and Reproductive Medicine, Universite ^ pitaux de Paris, CHU Cochin, Paris; and b Department of Obstetrics, Gynecology and Reproductive Assistance Publique Ho Paris-Sud—Assistance Publique Ho ^ pitaux de Paris, CHU Antoine Be cle re, Clamart, France Medicine, Universite
It has been two decades since pregnancies have been obtained through in vitro maturation (IVM) of germinal vesicle-stage oocytes retrieved from non-stimulated ovaries. This technique first offered in PCOS cannot be recommended today in this indication because the results do not match those of regular ART, and new GnRH antagonist and agonist-trigger protocols reliably prevent OHSS. (Fertil SterilÒ 2012;98:290–3. Ó2012 by American Society for Reproductive Medicine.) Use your smartphone Key Words: In vitro maturation, IVM, assisted reproductive treatments, ART, polycystic ovary to scan this QR code syndrome, PCOS Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/de-zieglerd-polycystic-ovary-syndrome-pcos-in-vitro-maturation/
and connect to the discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
T
he first pregnancies resulting from in vitro maturation (IVM) of germinal-vesicle stage oocytes retrieved from non-stimulated ovaries were reported two decades ago (1). These early successes having been confirmed and expended (2, 3), IVM became part of assisted reproduction technologies (ART), having its dedicated section in the reports of the ESHRE's registry (4). From inception, the possibility of obtaining embryos from oocytes harvested from non-stimulated ovaries appeared particularly interesting in the
case of polycystic ovary syndrome (PCOS). In PCOS indeed, controlled ovarian stimulation (COS) needed in regular ART may be at times difficult to manage and carry undue risks of ovarian hyperstimulation syndrome (OHSS), a dreadful complication of ART (5).
IVM, A DECEIVING ALTERNATIVE TO COS-BASED ART IN PCOS COS responses in PCOS are characterized by a reduced therapeutic margin
Received April 30, 2012; revised June 18, 2012; accepted June 22, 2012. D.d.Z. has nothing to disclose. I.S. has nothing to disclose. V.G. has nothing to disclose. N.F. has nothing to disclose. O.B. has nothing to disclose. C.C. has nothing to disclose. Reprint requests: Dominique de Ziegler, M.D., Professor and Head, Reproductive Endocrinology and cologie Obste trique II, Groupe d'ho ^ pitaux Paris centre Cochin Broca Infertility, Service de Gyne ^ tel Dieu, Ho ^ pital Cochin, 53, Avenue de l'Observatoire, 75014 Paris, France (E-mail: Ho [email protected]). Fertility and Sterility® Vol. 98, No. 2, August 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.06.043 290
between the doses of gonadotropin that produce insufficient or excessive responses (E2 levels and number of oocytes obtained) (6). Such brittle responses to COS are also encountered in regularly ovulating women whose ovaries fulfill the echo graphic criteria of PCOS, R12 antral follicles/side (7), or more recent definitions based on AMH levels >5 ng/mL (8). While special protocols (dual suppression [9]) and/or measures during COS (withholding gonadotropin administration, or ‘coasting’ [10]) reduce the risk, they do not totally prevent OHSS. Until recently therefore, there remained subgroups of PCOS patients who are hard manage and at high risk of OHSS, in case of past OHSS or very high antral follicle counts (AFC) and/or AMH levels (11–14). For the reasons described above, IVM stood as a therapeutic alternative VOL. 98 NO. 2 / AUGUST 2012
Fertility and Sterility® for women with PCOS or PCO in whom COS is unmanageable or bound to result in OHSS (15). Practically speaking, IVM was also seen as possibly providing better yields in women with large AFC scores, as in PCOS and PCO. The latter was confirmed by Child et al. (2) who obtained more oocytes from women with PCOS (11.3 þ 9.0, mean þ SD) or PCO (10.0 þ 5.1) than from cycling women (5.1 þ 3.7). In this trial, implantation, pregnancy, and live birth rates were also higher in women with PCOS (9.6%, 29.9%, and 14.9%, respectively) or PCO (8.9%, 23.1%, and 17.3%, respectively), as compared with cycling women (1.5%, 4.0%, and 2.0%, respectively) (2). The results of IVM in PCOS, higher than in cycling women, do not match however those of regular COS-based ART in these women. In a case-control trial, the results of 107 PCOS women undergoing IVM were compared to those of 107 other PCOS women treated by regular COS-associated ART (3). The mature oocyte and embryo yields were of 7.8 and 12.0 oocytes and 6.1 and 9.3 embryos in the IVM and regular ART groups, respectively (3). Likewise, pregnancy and live birth rates were lower at 26.2% and 15.9%, respectively in IVM, as compared to 38.3% and 26.2%, respectively in regular ART (3). A French team with an early involvement in IVM also reported deceiving results in 45 consecutive cycles conducted in 33 women fulfilling the Rotterdam criteria for PCOS (16). Women had an ultrasound on day 6–8 of naturally occurring or induced menses (dydrogesterone, 10 mg/day for 10 days). Oocytes were collected 33–36 hours after administration of 10,000 IU of hCG (17) and handled as previously described (18). Cumulus-oocyte complexes were decoronated with hyaluronidase 24 hours later and inseminated by ICSI after witnessing extrusion of the first polar body. Oocytes that were still immature were kept for an extra 24 hours in maturation culture medium before insemination and discarded if not matured after 48 hours in culture. Of 509 oocytes retrieved (mean SD/patient: 11.4 6.9), 276 (4.8 3.2/patient, 54.2%) and 45 (1.5 1.7/patient, 8.8%) matured after 24 and 48 hours, respectively. The clinical pregnancy (cPR) and live birth rates were a mediocre 22.5% and 13.5% per retrieval, respectively with an embryo implantation rate of 10.9% (16).
ART OUTCOME IN PCOS It was originally feared that ART outcome might be poorer in PCOS because of decreased oocyte quality and/or altered endometrial receptivity. The former was rooted in beliefs that the disorderly responses to COS often seen in PCOS yielded crops of numerous but poorly performing oocytes (19). The latter stemmed from speculations that the androgen elevation seen in COS (20) might be exacerbated in PCOS (21) and alter endometrial receptivity, including by hampering the expression of HOX genes (22, 23). The fears of decreased ART outcome in PCOS mentioned above are clearly not supported by recent facts. On the contrary, a meta-analysis retaining 9 of 920 reports on ART in PCOS that had matched controls receiving similar COS regimens reported equal if not better ART outcome in PCOS. The PCOS group totaled 458 women undergoing 793 cycles, while there were 694 matched controls undergoing 1,116 ART cycles (24). The study found that PCOS women were at VOL. 98 NO. 2 / AUGUST 2012
higher risk (12.8%) than controls (4.1%) of being cancelled during the course of COS (OR: 0.5; 95% CI: 0.2–1.0), had longer stimulations (mean: 1.2 days; 95% CI: 0.9, 1.5), produced on average 2.9 more oocytes (95%CI: 2.2–3.6), but had similar numbers of embryos and similar clinical pregnancy and live birth rates per initiated cycle (24). In agreement with these findings, Holte et al. reported that pregnancy and live-birth rates are log-linearly related to antral follicle count (AFC), with PCOS at the far end of the AFC spectrum having superior outcome (25). In a challenging concept, Mellembakken et al. suggested that the age-related decrease in ART outcome is delayed in PCOS as compared to age-matched women suffering from tubal infertility (26). Finally, population-based studies indicated that PCOS women ultimately achieve normal if not superior fertility scores (27). Moreover simple treatments such as metformin are likely to further improve the reproductive outcome of women with PCOS (28).
GnRH-a TRIGGER CONTROLS THE RISK OF OHSS IN PCOS Recent developments in COS protocols have upended the OHSS problem by offering effective ways of preventing OHSS in PCOS (29). First, the risk of OHSS is reduced in COS protocols using GnRH antagonists for preventing premature luteinization as compared with the classical GnRH-a protocols (30). Second, the antagonists protocols have revived the possibility of triggering ovulation with GnRH-a (31) instead of hCG, as first reported two decades ago in non-suppressed cycles (32–35). Using GnRH-a for triggering ovulation effectively prevents OHSS. In a retrospective study, Manzanares et al. (36) observed no case of OHSS in 42 women who previously experienced OHSS when they received an antagonist protocol with GnRH-a trigger. Questions were soon raised however about the quality of ART outcome following GnRH-a trigger. In a meta-analysis retaining 8 RCTs, OHSS risks were profoundly reduced following GnRH-a triggering, but so were pregnancy chances (37). In an RCT, Humaidan et al. (38) found more matured (MII) oocytes in women (n ¼ 55) undergoing GnRHa trigger as opposed to receiving hCG for ovulation induction (n ¼ 67), possibly an effect of the FSH elevation induced by GnRH-a. Yet, these authors also observed lower implantation (P< .001) and clinical pregnancy rates at 6% and 36% (P¼ .002) topped by higher pregnancy losses at 79% and 4% (P¼ .005) in the GnRH-a trigger and hCG groups, respectively (38). In contrast with the lower pregnancy chances observed in regular ART, there were no differences in recipient outcome when antagonist and GnRH-a trigger were used in oocyte donors in whom they effectively prevent OHSS (39, 40). The fact that GnRH trigger reduces regular ART outcome without affecting the results of donor-egg ART points at a negative impact on endometrial receptivity. Confronting the mounting evidence of decreased live birth rates when GnRH-a trigger is used for preventing OHSS, certain authors have advocated a ‘freeze-all’ strategy in these cases (41, 42). These authors reported good outcomes following systematic cryopreservation at the 2PN stage (41). 291
CONCEPTIONS Demarking from the freeze-all recommendation, Humaidan et al. (43, 44) claimed that proper endometrial receptivity can be restored following GnRH-a trigger by a single 1,500 IU hCG bolus at the time of oocyte retrieval, while the risk of OHSS remained minimal. In a slightly different paradigm, Griffin et al. reported good general ART outcome when 1,000 IU of hCG were co-administered with GnRH-a trigger in a so-called ‘dual-trigger’ approach (45). Finally, Engmann et al. (46) reported normalizing pregnancy chances after GnRH-a trigger by providing ‘‘intensive luteal support.’’ The latter consisted of 50 mg of IM progesterone starting on the evening of oocyte retrieval and continued until 11 weeks of gestation together with 0.1 mg of E2 administered transdermally, starting one day after oocyte retrieval (46). In certain cases, the doses of IM progesterone and E2 were increased in order to maintain the circulating levels of progesterone and E2 above 20 ng/mL and 200 pg/mL, respectively (47). The fact that luteal support using IM progesterone is more effective than vaginal progesterone at normalizing receptivity in case of GnRH trigger suggests the possibility of a nonuterine effect. Indeed, uterine tissue concentrations of progesterone are higher in case of vaginal administration (48) because of a first uterine pass effect (49, 50). In contrast, the benefit of IM over vaginal progesterone seen after GnRH-a trigger appears to be dependent on circulating levels of progesterone, not uterine tissue concentration (51). The value of intensive luteal support in GnRH-a trigger cycles was also supported by Imbar et al. (52) who stressed the financial advantage of this approach over the freeze-all option. Finally, as recently published in this journal, an ideal compromise might be to provide the dual-trigger approach (45) associating GnRH-a and 1,000 IU of hCG when peak E2 is <4,000 pg/mL; and intensive luteal support alone when E2 is >4,000 pg/mL (51).
CONCLUSION Evidence indicates the original interest for treating certain PCOS patients with COS-less IVM in order to avoid the risk of OHSS has been superseded by new effective means of avoiding OHSS. Indeed, antagonist and GnRH-a trigger protocols— using the dual-trigger, intense luteal support, or freeze-all approaches—offer the high yield of regular ART while avoiding the risk of OHSS. Moreover, evidence that ART outcome is not diminished in PCOS (contrary to what was originally feared) while the results of IVM are markedly lower, further stresses the fact that IVM is not a viable option in PCOS. Conversely, IVM should be seen as a procedure that is more appropriate when no other option exists, as for example in certain cancer cases. Acknowledgments: The expert assistance of Ms. Nadine Cointot for preparing this manuscript was greatly appreciated and is acknowledged.
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