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Small follicles may be a promising source of oocytes in modified natural cycle in vitro fertilization–embryo transfer
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Small follicles may be a promising source of oocytes in modified natural cycle in vitro fertilization–embryo transfer The recent study by Teramoto et al. (1) has shown that nondominant small follicles are a promising supplementary source of in vivo matured oocytes, and their use may increase the live-birth rate in natural cycle in vitro fertilization (IVF). The investigators have retrospectively evaluated 771 infertile patients who underwent natural cycle IVF during a 2-year period. When the leading, dominant follicle reached a diameter of 16–18 mm, they triggered an endogenous luteinizing hormone (LH) surge via a nasally administered gonadotropinreleasing hormone (GnRH) agonist (buserelin) and aspirated all the follicles of 3-mm diameter or larger after aspirating the dominant follicle. After fertilization, they cultured the embryos to the blastocyst stage and cryopreserved all the goodquality blastocysts. Single-thawed embryo transfer (ET) was performed in subsequent cycles. Aspiration of the small, 3–10 mm follicles yielded 902 metaphase 2 (MII) oocytes and generated 78 live births whereas aspiration of follicles of 11 mm or larger yielded 466 MII oocytes and 90 live births. An average of 12.8 small follicles were aspirated from their patients, yielding 5.3 oocytes per patient (1). The success of retrieving oocytes and generating live births resulting from small follicle aspirations was correlated with ovarian reserve but not with the outcomes of the dominant follicle aspiration because they were successful in ova pickup from the very small follicles, even in cases where the dominant follicles did not generate mature oocytes. The authors concluded that follicles that are 3–10 mm are a promising supplementary source of mature oocytes in natural cycle IVF. It is interesting that aspiration of small, 3–10 mm follicles resulted in live births in >10% of the patients whose dominant follicle did not yield oocytes (1). The combination of natural cycle IVF with in vitro maturation (IVM) of immature oocytes may enhance the pregnancy rate for natural cycle IVF by 36% compared with the rate for natural cycle IVF using only dominant-follicle oocytes (1). The rationale for IVM–IVF is the retrieval of immature oocytes from nonselected small follicles before the oocytes have lost their developmental competency (1). The optimal timing for collection has been empirically determined to be when the dominant follicle reaches 12–14 mm diameter, which is around day 10 of the cycle (1). The ET of a thawed blastocyst was performed 5 days after spontaneous ovulation in the natural cycle after the IVF cycle (1). However, in cases where the endometrial thickness was below 6 mm, the ET was cancelled, and in the next cycle the endometrium prepared with estrogen and progestin supplementation (1). The authors must be congratulated for their fine results. However, their study raises several questions. They correctly claim that a natural cycle is more ‘‘patient friendly’’ than the conventional controlled ovarian stimulation attempting to retrieve 10 to 15 oocytes. In this context, many IVF patients
may prefer to have a fresh single ET rather than having their blastocysts frozen and having to return for another thawed ET cycle, where monitoring the endometrial width and measuring hormones for timing the spontaneous ovulation is necessary at least once, and in some cases several times. In cases of fresh blastocyst transfer, using a GnRH-agonist trigger would deteriorate the luteal secretion of hormones, necessitating massive luteal support with estrogen and progesterone. To overcome this problem, triggering with human chorionic gonadotropin (hCG) may be preferable to GnRHagonist triggering in a natural or very mild stimulation cycle. The agonist trigger is usually used in cases where late follicular high estradiol levels are measured and/or many follicles are visualized on ultrasound to minimize the risk of ovarian hyperstimulation syndrome (OHSS) (2, 3). Its advantage in a natural cycle has not been unequivocally demonstrated. Although follicles of 11–15 mm diameter are closer to the size of the dominant follicles (R16 mm) as compared with the smaller follicles (%10 mm) in terms of oocyte maturity and competency, the authors combined the 11–15 mm follicles and the R16 mm follicles into one group, addressing them equally as ‘‘dominant’’ follicles (1). However, 11–15 mm follicles are not identical to dominant follicles and should not be treated as such. Four possible mechanisms can be put forward to explain the apparent paradox of ‘‘less is more’’ (2): 1. In natural or mild stimulation cycles, the healthiest follicles are selected by the principle of ‘‘quality for quantity’’ (2). 2. High estradiol (E2) levels in the late follicular phase significantly correlate with higher rates of small for gestational age and low-birth-weight neonates (2). 3. Antim€ ullerian hormone, LH, testosterone, and E2 are significantly higher in natural-cycle IVF than in stimulated IVF follicles, suggesting an alteration of the follicular metabolism in stimulated cycles (2). 4. Supraphysiologic E2 levels may increase the growth hormone-binding protein (GH-BP) bioneutralizing growth hormone, diminishing the resultant insulin-like growth factor levels necessary for optimal synergism with follicle-stimulating hormone (2). Thus, the recommendation is to aim to retrieve six to eight oocytes. Mild stimulation should be the common practice for IVF. In cases where more than 10 ova are retrieved or high E2 levels are reached, either intentionally or unintentionally, a freeze-all policy may be considered and ET postponed to a subsequent natural cycle (2). At present, the field of IVF has two main goals: retrieving high-quality oocytes and achieving high pregnancy rates without jeopardizing the patient's well-being and while minimizing assisted reproduction–associated risks such as OHSS and multiple pregnancy (4). However, regarding IVF–ET, two different perspectives seem to be working in parallel. The first group contends that it is more cost effective to stimulate the ovaries to obtain 10 to 15 retrievable MII ova; this maximizes the cumulative pregnancy rate because the embryos can be cryopreserved, enabling several more ETs after
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one follicular aspiration. The second group advocates a natural or modified natural cycle as more patient friendly: it minimizes the risk of OHSS, minimizes medication use, and achieves lower costs for assisted reproduction technology/ IVF. Indeed, the first successful IVF newborn, Louise Brown, was generated in a natural cycle. The main drawback of the natural cycle is its low cumulative pregnancy rate due to the very limited number of retrievable ova. The article by Teramoto et al. (1) shows that the aspiration of small, 3–10 mm diameter follicles and IVM may almost double the cumulative pregnancy rate. A prospective randomized study between the two modes is needed to determine which represents the better method: freezing all retrieved ova, as was done by Teramoto et al. (1), after triggering ovulation with GnRH agonist then postponing ET to future cycle(s), or alternatively using an hCG trigger 34 to 36 hours before follicular aspiration and performing fresh single ET (blastocyst). Several investigators have linked the risk of implantation failure to poor endometrial receptivity during fresh ET, which can be associated with more than 60% of conventionally stimulated IVF cycles (4, 5). In a meta-analysis comparing fresh to thawed ET (4, 5), including 633 cycles in either normal or hyperresponders, it was shown that the freeze-all two-step approach yielded a higher pregnancy rate compared with fresh ET (risk ratio 1.32; 95% CI, 1.10–1.59) (4, 5). However, this was demonstrated in conventional controlled ovarian stimulation IVF, not in natural or modified natural cycles as in Teramoto et al. (1). A prospective randomized study between two arms is needed to decide whether to freeze all the generated blastocysts, as was done by the Teramoto study, after triggering ovulation with a GnRH agonist and postponing ET to future cycle(s), or alternatively to use a hCG trigger 34 to 36 hours before follicular aspiration and performing fresh single ET (blastocyst). On the one hand, retrieval of many oocytes may be associated with higher rates of embryos aneuploidy, OHSS, and a high rate of oocyte abnormalities such as an abnormal zona pellucida, wide perivitelline space, abnormally granular cytoplasm and vacuoles, refractile bodies, aggregations in the
endoplasmic reticulum, or fragmentation or degeneration of the first polar body (2, 4). On the other hand, it has been shown that the pregnancy rate increases up to retrieval of 10 oocytes, plateaus between 10 and 15, and decreases thereafter when more than 15 oocytes are retrieved (2, 4). A possible compromise would be retrieval of four to six oocytes, which will enable a good pregnancy rate and minimize the risk of OHSS and patient discomfort, while keeping the endometrium in phase and enabling fresh single blastocyst transfer with a high implantation rate (2–4). Zeev Blumenfeld, M.D. Reproductive Endocrinology, Department of Obstetrics and Gynecology, RAMBAM Health Care Campus, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel
Q3
http://dx.doi.org/10.1016/j.fertnstert.2016.03.028 You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/blumenfeldz-modified-naturalcycle-ivf/ Use your smartphone to scan this QR code 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.
REFERENCES 1.
2. 3. 4. 5.
Teramoto S, Osada H, Sato Y, Shozu M. Non-dominant small follicles are a promising source of mature oocytes in modified natural cycle in vitro fertilization and embryo transfer. Fertil Steril 2016. in press. Blumenfeld Z. Why more is less and less is more when it comes to ovarian stimulation. J Assist Reprod Genet 2015;32:1713–9. Blumenfeld Z. Does freeze all policy eliminate OHSS??? ‘‘It ain't necessarily so.’’. J Assist Reprod Genet 2015;32:1571. Merviel P, LE Martelot MT, Roche S, Lelievre C, Menard M, Auget S, et al. Challenges in ovarian stimulation. Minerva Ginecol 2016. Roque M, Lattes K, Serra S, Sola I, Geber S, Carreras R, et al. Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril 2013;99:156–62.
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Small follicles may be a promising source of oocytes in modified natural cycle in vitro fertilization–embryo transfer The recent study by Teramoto et al. (1) has shown that nondominant small follicles are a promising supplementary source of in vivo matured oocytes, and their use may increase the live-birth rate in natural cycle in vitro fertilization (IVF). The investigators have retrospectively evaluated 771 infertile patients who underwent natural cycle IVF during a 2-year period. When the leading, dominant follicle reached a diameter of 16–18 mm, they triggered an endogenous luteinizing hormone (LH) surge via a nasally administered gonadotropinreleasing hormone (GnRH) agonist (buserelin) and aspirated all the follicles of 3-mm diameter or larger after aspirating the dominant follicle. After fertilization, they cultured the embryos to the blastocyst stage and cryopreserved all the goodquality blastocysts. Single-thawed embryo transfer (ET) was performed in subsequent cycles. Aspiration of the small, 3–10 mm follicles yielded 902 metaphase 2 (MII) oocytes and generated 78 live births whereas aspiration of follicles of 11 mm or larger yielded 466 MII oocytes and 90 live births. An average of 12.8 small follicles were aspirated from their patients, yielding 5.3 oocytes per patient (1). The success of retrieving oocytes and generating live births resulting from small follicle aspirations was correlated with ovarian reserve but not with the outcomes of the dominant follicle aspiration because they were successful in ova pickup from the very small follicles, even in cases where the dominant follicles did not generate mature oocytes. The authors concluded that follicles that are 3–10 mm are a promising supplementary source of mature oocytes in natural cycle IVF. It is interesting that aspiration of small, 3–10 mm follicles resulted in live births in >10% of the patients whose dominant follicle did not yield oocytes (1). The combination of natural cycle IVF with in vitro maturation (IVM) of immature oocytes may enhance the pregnancy rate for natural cycle IVF by 36% compared with the rate for natural cycle IVF using only dominant-follicle oocytes (1). The rationale for IVM–IVF is the retrieval of immature oocytes from nonselected small follicles before the oocytes have lost their developmental competency (1). The optimal timing for collection has been empirically determined to be when the dominant follicle reaches 12–14 mm diameter, which is around day 10 of the cycle (1). The ET of a thawed blastocyst was performed 5 days after spontaneous ovulation in the natural cycle after the IVF cycle (1). However, in cases where the endometrial thickness was below 6 mm, the ET was cancelled, and in the next cycle the endometrium prepared with estrogen and progestin supplementation (1). The authors must be congratulated for their fine results. However, their study raises several questions. They correctly claim that a natural cycle is more ‘‘patient friendly’’ than the conventional controlled ovarian stimulation attempting to retrieve 10 to 15 oocytes. In this context, many IVF patients
may prefer to have a fresh single ET rather than having their blastocysts frozen and having to return for another thawed ET cycle, where monitoring the endometrial width and measuring hormones for timing the spontaneous ovulation is necessary at least once, and in some cases several times. In cases of fresh blastocyst transfer, using a GnRH-agonist trigger would deteriorate the luteal secretion of hormones, necessitating massive luteal support with estrogen and progesterone. To overcome this problem, triggering with human chorionic gonadotropin (hCG) may be preferable to GnRHagonist triggering in a natural or very mild stimulation cycle. The agonist trigger is usually used in cases where late follicular high estradiol levels are measured and/or many follicles are visualized on ultrasound to minimize the risk of ovarian hyperstimulation syndrome (OHSS) (2, 3). Its advantage in a natural cycle has not been unequivocally demonstrated. Although follicles of 11–15 mm diameter are closer to the size of the dominant follicles (R16 mm) as compared with the smaller follicles (%10 mm) in terms of oocyte maturity and competency, the authors combined the 11–15 mm follicles and the R16 mm follicles into one group, addressing them equally as ‘‘dominant’’ follicles (1). However, 11–15 mm follicles are not identical to dominant follicles and should not be treated as such. Four possible mechanisms can be put forward to explain the apparent paradox of ‘‘less is more’’ (2): 1. In natural or mild stimulation cycles, the healthiest follicles are selected by the principle of ‘‘quality for quantity’’ (2). 2. High estradiol (E2) levels in the late follicular phase significantly correlate with higher rates of small for gestational age and low-birth-weight neonates (2). 3. Antim€ ullerian hormone, LH, testosterone, and E2 are significantly higher in natural-cycle IVF than in stimulated IVF follicles, suggesting an alteration of the follicular metabolism in stimulated cycles (2). 4. Supraphysiologic E2 levels may increase the growth hormone-binding protein (GH-BP) bioneutralizing growth hormone, diminishing the resultant insulin-like growth factor levels necessary for optimal synergism with follicle-stimulating hormone (2). Thus, the recommendation is to aim to retrieve six to eight oocytes. Mild stimulation should be the common practice for IVF. In cases where more than 10 ova are retrieved or high E2 levels are reached, either intentionally or unintentionally, a freeze-all policy may be considered and ET postponed to a subsequent natural cycle (2). At present, the field of IVF has two main goals: retrieving high-quality oocytes and achieving high pregnancy rates without jeopardizing the patient's well-being and while minimizing assisted reproduction–associated risks such as OHSS and multiple pregnancy (4). However, regarding IVF–ET, two different perspectives seem to be working in parallel. The first group contends that it is more cost effective to stimulate the ovaries to obtain 10 to 15 retrievable MII ova; this maximizes the cumulative pregnancy rate because the embryos can be cryopreserved, enabling several more ETs after
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REFLECTIONS 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168
one follicular aspiration. The second group advocates a natural or modified natural cycle as more patient friendly: it minimizes the risk of OHSS, minimizes medication use, and achieves lower costs for assisted reproduction technology/ IVF. Indeed, the first successful IVF newborn, Louise Brown, was generated in a natural cycle. The main drawback of the natural cycle is its low cumulative pregnancy rate due to the very limited number of retrievable ova. The article by Teramoto et al. (1) shows that the aspiration of small, 3–10 mm diameter follicles and IVM may almost double the cumulative pregnancy rate. A prospective randomized study between the two modes is needed to determine which represents the better method: freezing all retrieved ova, as was done by Teramoto et al. (1), after triggering ovulation with GnRH agonist then postponing ET to future cycle(s), or alternatively using an hCG trigger 34 to 36 hours before follicular aspiration and performing fresh single ET (blastocyst). Several investigators have linked the risk of implantation failure to poor endometrial receptivity during fresh ET, which can be associated with more than 60% of conventionally stimulated IVF cycles (4, 5). In a meta-analysis comparing fresh to thawed ET (4, 5), including 633 cycles in either normal or hyperresponders, it was shown that the freeze-all two-step approach yielded a higher pregnancy rate compared with fresh ET (risk ratio 1.32; 95% CI, 1.10–1.59) (4, 5). However, this was demonstrated in conventional controlled ovarian stimulation IVF, not in natural or modified natural cycles as in Teramoto et al. (1). A prospective randomized study between two arms is needed to decide whether to freeze all the generated blastocysts, as was done by the Teramoto study, after triggering ovulation with a GnRH agonist and postponing ET to future cycle(s), or alternatively to use a hCG trigger 34 to 36 hours before follicular aspiration and performing fresh single ET (blastocyst). On the one hand, retrieval of many oocytes may be associated with higher rates of embryos aneuploidy, OHSS, and a high rate of oocyte abnormalities such as an abnormal zona pellucida, wide perivitelline space, abnormally granular cytoplasm and vacuoles, refractile bodies, aggregations in the
endoplasmic reticulum, or fragmentation or degeneration of the first polar body (2, 4). On the other hand, it has been shown that the pregnancy rate increases up to retrieval of 10 oocytes, plateaus between 10 and 15, and decreases thereafter when more than 15 oocytes are retrieved (2, 4). A possible compromise would be retrieval of four to six oocytes, which will enable a good pregnancy rate and minimize the risk of OHSS and patient discomfort, while keeping the endometrium in phase and enabling fresh single blastocyst transfer with a high implantation rate (2–4). Zeev Blumenfeld, M.D. Reproductive Endocrinology, Department of Obstetrics and Gynecology, RAMBAM Health Care Campus, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel
Q3
http://dx.doi.org/10.1016/j.fertnstert.2016.03.028 You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/blumenfeldz-modified-naturalcycle-ivf/ Use your smartphone to scan this QR code 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.
REFERENCES 1.
2. 3. 4. 5.
Teramoto S, Osada H, Sato Y, Shozu M. Non-dominant small follicles are a promising source of mature oocytes in modified natural cycle in vitro fertilization and embryo transfer. Fertil Steril 2016. in press. Blumenfeld Z. Why more is less and less is more when it comes to ovarian stimulation. J Assist Reprod Genet 2015;32:1713–9. Blumenfeld Z. Does freeze all policy eliminate OHSS??? ‘‘It ain't necessarily so.’’. J Assist Reprod Genet 2015;32:1571. Merviel P, LE Martelot MT, Roche S, Lelievre C, Menard M, Auget S, et al. Challenges in ovarian stimulation. Minerva Ginecol 2016. Roque M, Lattes K, Serra S, Sola I, Geber S, Carreras R, et al. Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril 2013;99:156–62.
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