Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation

Follicular and luteal phase stimulations show similar in vitro fertilization performance which may lead to a novel strategy to increase the chances of pregnancy in reduced ovarian reserve patient populations.

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Authors

Filippo Maria Ubaldi, M.D., M.Sc., Antonio Capalbo, Ph.D., Alberto Vaiarelli, M.D., Ph.D., Danilo Cimadomo, M.Sc., Silvia Colamaria, M.D., Carlo Alviggi, M.D., Ph.D., Elisabetta Trabucco, M.D., Roberta Venturella, M.D., Gábor Vajta, Ph.D., Laura Rienzi, M.Sc.

Volume 105, Issue 6, Pages 1488-1495

Abstract

Objective:

To compare the euploid blastocyst formation rates obtained after follicular phase (FP) versus luteal phase (LP) stimulation performed in the same menstrual cycle in a preimplantation genetic diagnosis for aneuploidy testing (PGD-A) program in patients with reduced ovarian reserve.

Design:

Prospective paired noninferiority observational study.

Setting:

Private infertility program.

Patient(s):

Forty-three reduced ovarian reserve patients undergoing a PGD-A.

Intervention(s):

Both FP and LP stimulations using follicle-stimulating hormone and luteinizing hormone in combination with gonadotropin-releasing hormone (GnRH) antagonist starting on day 2 of the cycle and 5 days after the first oocyte retrieval, respectively, where GnRH agonist was used for both FP and LP ovulation triggering; a trophectoderm biopsy quantitative polymerase chain reaction–based PGD-A strategy; and single euploid blastocyst transfers during a subsequent natural cycle.

Main Outcome Measure(s):

Primary outcome measure: euploid blastocyst rate per injected metaphase 2 (MII) oocyte; secondary outcome measures: number of cumulus-oocyte complexes (COCs), MII oocytes, and blastocysts.

Result(s):

Patients with an antimüllerian hormone level of <1.5 ng/mL, antral follicle count of <6 follicles, and/or <5 oocytes retrieved in a previous cycle were included. No statistically significant differences were found in the number of retrieved COCs (5.1 ± 3.4 vs. 5.7 ± 3.3), MII oocytes (3.4 ± 1.9 vs. 4.1 ± 2.5), or biopsied blastocysts per stimulated cycle (1.2 ± 1.2 vs. 1.4 ± 1.7) from FP versus LP stimulation, respectively. No differences were observed in the euploid blastocyst rate calculated either per biopsied blastocyst (46.9% vs. 44.8%) or injected MII oocyte (16.2% vs. 15.0%). Conclusion(s):

Stimulation with an identical protocol in the FP and LP of the same menstrual cycle resulted in a similar number of blastocysts in patients with reduced ovarian response. The LP stimulation statistically significantly contributed to the final transferable blastocyst yield, thus increasing the number of patients undergoing transfer per menstrual cycle.

Read the full text at: http://www.fertstert.org/article/S0015-0282(16)30002-4/fulltext

Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

1 Comments

Go to the profile of Raoul Orvieto
Raoul Orvieto about 4 years ago

We read with interest the recent clinical review by Ubaldi et al, "Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation" (1) and congratulate them on their effort. At the same time we, however, are troubeled by the design of the study and, therefore, have to question some of the authors’ conclusions.

A very obvious issue is the description of the study as a poor responder study. It enrolled 51 patients, alleged to be poor responders and, indeed, 8 among them (15.6%) did not respond to stimulation. The remaining 43 patients, however, underwent 86 oocyte pick-ups (OPUs), of which 84 resulted in retrieval of at least one oocyte, in either follicular or luteal phase stimulations (or both). Out of 84 cycles, 64 yielded at least one blastocyst for a 76.2% blastocyst formation rate per successful OPU. Of notice, 26 of the OPUs (9 in the follicular and 17 in the luteal stimulation) resulted in 5 or more MII oocytes (31%). Furthermore, 38/43 patients (88.4%) produced at least on blastocyst in either follicular or luteal phase stimulation (or both), or in another way, 20 out of 84 OPUs (23.8%) and 5 of the 43 patients (11.6%) yielded a blastocyst. Lastly, the ranges of COCs retrieved were 1–22 and 1–17 in the follicular and luteal phase stimulation patients , respectively, actually reflecting the inclusion of patients with polycystic ovarian morphology. All of these outcome characteristics call into question the definition of this patient population as poor responders.

Such a definition is also difficult to defend since patient selection allowed for entry of patients up to an AMH level of 1.49ng/ml, 5 follicles and 4 oocyte retrieved in prior cycles. While these may be criteria that define functional ovarian reserve as poor in young patients, they very obviously are anything but poor in older patients. Interestingly, the investigated patient population was, however, of rather advance age (39.2±3.4 years). We would argue that at that age above noted functional ovarian reserve parameters are anything but low.

The literature also supports our interpretation: In a randomized clinical trial (RCT) of 253 poor responder patients who reached the OPU stage by Lanias et al (2), 44 were cancelled due to failed fertilizations or failure to reach day-2/3 embryo transfer (17.4%). Also, the mean number of embryos transferred was only 1, with a range of 1–2, and no embryos cryopreserved.

Taking further into consideration that blastocyst formation rates across studies range between 28 -97%, with a mean blastulation rate of 47% (3), and that and that alleged euploidy rates of embryos among women ages 32 -44 have been suggested to range between 45.7-55.7% (4), cancellation rate per successful OPU in poor responders should be much higher than the 17.4% the authors report in patients undergoing non-screened (PGS) day 2-3 embryo transfers.

Turning to the, in itself, especially in poor prognosis patients highly controversial issue of PGS utilization, which of course includes poor responders, utilization of PGS has been repeatedly proven outright harmful (5-6), notwithstanding that biological realities recently have lead to the conclusion that reliable determinations of embryo ploidy from single trophectoderm biopsies are impossible (7-9). Since poor prognosis patients reach embryo transfer at greatly reduced rates, “enrollment of
consecutive patients with reduced ovarian reserve… undergoing a preimplantation genetic diagnosis," virtually secures biased patient selection toward good prognosis patients.

We have recently pointed out the unfortunate increase in studies published in reproductive medicine which include exactly such biases, and the detrimental effects publications of such biased studies have had on the worldwide practice of in vitro fertilization (IVF) (5). The study by Ubaldi et al, a highly reputable group of investigators, is, therefore, one more example of yet another proposed alleged improvement to standard IVF practice, which is based on very obvious statistical biases that were not detected by peer review. Suffice it to say that the peer review process also did not detect that outcomes were not adjusted for repeat events (many patients underwent multiple repeat cycles, which, of course, also biases outcomes). We, therefore, caution colleagues who, based on the title of this study and, maybe the abstract, are considering a practice change by switching to DuoStim in poor responders (with and without PGS). Ideally, such studies, of course, also should, when possible, be RCTs, and assess cumulative births, including fresh as well as frozen-thawed cycles.

Raoul Orvieto, MD1 and Norbert Gleicher, MD2
1Infertility and IVF Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center (Tel Hashomer), Ramat Gan, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. E-mail : raoul.orvieto@sheba.health.gov.il
2Center for Human Reproduction, New York, NY; Foundation for Reproductive Medicine, New York, NY; Rockefeller University, New York, NY and Department of Obstetrics and Gynecology, University of Vienna, Vienna, Austria.

References
1.Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, Trabucco E, Venturella R, Vajta G, Rienzi L. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertil Steril. 2016;105(6):1488-1495.
2.Lainas TG, Sfontouris IA, Papanikolaou EG, Zorzovilis JZ, Petsas GK, Lainas GT, Kolibianakis EM. Flexible GnRH antagonist versus flare-up GnRH agonist protocol in poor responders treated by IVF: a randomized controlled trial.Hum Reprod 2008;23:1355-8.
3. Glujovsky D, Blake D, Bardach A, Farquhar C. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology.
Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD002118.

4. Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, Scott RT Jr.The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril 2014;101:656-663.

5. Gleicher N, Kushnir VA, Barad DH. The impact of patient preselection on reported IVF outcomes. J Assist Reprod Genet. 2016 Apr;33(4):455-9 6 .Paulson RJ. Every last baby out of every last egg: the appropriate goal for fertility treatment in women older than 40 years. Fertile Steril 2016;105:1443-1444.

7. Orvieto R, Shuly Y, Brengauz M, Feldman B.Should pre-implantation genetic screening be implemented to routine clinical practice? Gynecol Endocrinol 2016 Feb 12:1-3. [Epub ahead of print]

8. Gleicher N Gleicher N, Vidali A, Braverman J, Kushnir VA, Albertini DF, Barad DH. Further evidence against use of PGS in poor prognosis patients: report of normal births after transfer of embryos reported as aneuploid. Fertil Steril. 2015 ;104(Suppl 3) e59; O-151

9. Greco E, Minasi MG, Fiorentino F. Healthy Babies after Intrauterine Transfer of Mosaic Aneuploid Blastocysts. N Engl J Med 2015;73:2089-90.