The ultrashort flare GnRH-agonist/GnRH-antagonist protocol enables cycle programming and may overcome the “detrimental effect” of the oral contraceptive

29 06 2012

To the Editor:

I read with interest the recently published Reflections paper by Bosch (1) on the ongoing debate entitled: “Can we skip weekends in GnRH antagonist cycles without compromising the final outcome?” This article comprehensively covered the role of oral contraceptive (OC) pretreatment in patients undergoing the GnRH-antagonist controlled ovarian hyperstimulation (COH) protocol for in vitro fertilization–embryo transfer (IVF-ET) cycle.

To summarize, while OC pretreatment results in “dual benefit”–a better synchronized response and a scheduled cycle–it was associated with a significantly lower ongoing pregnancy rate, longer duration of the stimulation, and higher gonadotropin consumption. The detrimental effect of OC pretreatment was related to the potential negative effect of the gestagen component on the endometrium, or the low endogenous LH levels induced by OCs with their deleterious impact on oocyte competence or endometrial receptivity. Regarding the latter, Bosch suggested the addition of LH or the use of hMG during COH, in order to overcome the negative influence of low LH.

Bosch concluded that since the most extended approach of OC pretreatment has been shown to be probably harmful for cycle outcome, programming of GnRH antagonist cycles continues to be a challenge, and further studies evaluating the importance of scheduling IVF cycles while maintaining a friendly approach and without compromising the final outcome are required.
Contrary to the aforementioned observations, which relate a negative impact of OC pretreatment on IVF outcome, for almost three decades the combination of OC pretreatment with the microdose flare protocol has been offered to poor-responder patients (2), demonstrating similar results when compared with various other COH protocols, with improved cycle parameters and decreased cancellation rates (3). Moreover, the introduction of GnRH antagonists to the COH armamentarium has raised interest in their potential application for poor responders, however, with no compelling advantage over the microdose flare protocol.

Prompted by this information, we introduced the combined ultrashort flare GnRH-agonist/GnRH-antagonist (ultrashort GnRH-ag/GnRH-ant) protocol to our COH armamentarium. This protocol is performed by the administration of OC, started at the prior menses and administered for at least 10 days. Ovulation induction is performed with triptorelin 0.1 mg/day for 3 consecutive days, started 3 days after the cessation of the OC, followed by gonadotropins which are initiated 2 days later. GnRH antagonist is added according to the individual program policy (fixed or flexible), and continued until the day of HCG trigger for final oocytes maturation.

The ultrashort GnRH-ag/GnRH-ant protocol combines the beneficial effects of OC pretreatment and the GnRH-agonist flare with that of the GnRH-antagonist protocol (4): (a) Pretreatment with OCs allows flexible treatment scheduling and may suppress pre-GnRH-agonist FSH without blunting the FSH flare, but with blunting LH flare and early follicular progesterone levels; (b) The ultrashort flare GnRH-ag/GnRH-antag protocol further combines the benefit of the stimulatory effect of microdose flare on early follicular phase endogenous FSH release without the concomitant deleterious rises in androgen levels or corpus luteum rescue; and (c) The GnRH antagonist provides immediate LH suppression with the possible improvement of the quality of the blastocysts generated.

Thus, the ultrashort flare GnRH-ag/GnRH-antag protocol allows cycle programming and overcomes the “detrimental effect” of the OC pretreatment by the ultrashort GnRH-agonist flare, as seen in poor responders using the microdose-flare protocol. It was successfully used in poor responder patients (5), those with embryos of poor quality (4), and those with repeated IVF failure (6).

Another issue that was raised by Bosch is the importance of hCG triggering day. Delay or early administration of hCG, with respect to the theoretically proposed fixed criterion of “as soon as 3 follicles are of 17 mm of diameter,” did not alter IVF cycle outcome. Contrary to Bosch’s opinion, we believe that in patients undergoing the GnRH antagonist, but not the long suppressive GnRH-agonist protocols, day of HCG trigger is crucial for IVF success. When we aimed to clarify the contribution of “physicians’ experience” on IVF outcome in patients undergoing GnRH-antagonists COH protocols, we observed that patients achieving, on the day of hCG administration, a ratio of E2 level to number of follicles of >14 mm lower than 100 pg/mL (7-8) had the highest pregnancy rates. Moreover, practically speaking, our criteria for the day of HCG trigger reliably and more precisely reflects the routine clinical practice, compared with the theoretically proposed fixed criterion of “as soon as 3 follicles are of 17 mm of diameter,” which is difficult to implement.

In conclusion, in our opinion, OC pretreatment combined with the ultrashort flare GnRH-ag/GnRH-antag protocol and HCG trigger, when the ratio of E2 level to number of follicles of >14 mm is lower than 100 pg/mL, allow cycle programming and may optimize IVF outcome.

Professor Raoul Orvieto M.D.
Infertility and IVF Unit, Department of Obstetrics and Gynecology,
Barzilai Medical Center, Ashkelon; and
Ben Gurion University of the Negev, Beer Sheva, Israel

References

1. Bosch E. Can we skip weekends in GnRH antagonist cycles without compromising the final outcome? Fertil Steril 2012;97:1299-1300.

2. Scott RT, Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization. Fertil Steril 1994;61:880-5.

3. Surrey ES, Bower J, Hill DM, Ramsey J, Surrey MW. Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil Steril 1998;69:419-24.

4. Orvieto R, Nahum R, Rabinson J, Gemer O, Anteby EY, Meltcer S. Ultrashort flare GnRH agonist combined with flexible multidose GnRH antagonist for patients with repeated IVF failures and poor embryo quality. Fertil Steril 2009;91:S1398-400.

5. Orvieto R, Kruchkovich J, Rabinson J, Zohav E, Anteby EY, Meltcer S. Ultrashort gonadotropin-releasing hormone agonist combined with flexible multidose gonadotropin-releasing hormone antagonist for poor responders in in vitro fertilization/embryo transfer programs. Fertil Steril 2008;90:228-30.

6. Orvieto R, Meltcer S, Liberty G, Rabinson J, Anteby EY, Nahum R. A combined approach to patients with repeated IVF failures. Fertil Steril 2010;94:2462-4.

7. Orvieto R, Zohav E, Scharf S, Rabinson J, Meltcer S, Anteby E, et al. The influence of E2/follicle and E2/oocyte ratios on the outcome of controlled ovarian stimulation for in-vitro fertiliztion Gynecol Endocrinol 2007;23:72-5.

8. Orvieto R, Rabinson J, Meltcer S, Gemer O, Anteby EY, Zohav E. Does physicians’ experience influence IVF success in patients undergoing controlled ovarian stimulation with GnRH-antagonists? Fertil Steril 2008;89(3):736-7.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.06.053

The author responds:

To the Editor:

I read with interest the letter by Dr. Orvieto on my Reflections paper entitled “Can we skip weekends in GnRH antagonist cycles without compromising the final outcome?” (1)

In the letter, Orvieto questions a potential detrimental effect of oral contraceptive (OC) pretreatment in GnRH antagonist cycles, based on the successful use of these compounds in the microflare and the ultrashort flare GnRH agonist/GnRH antagonist protocols in poor responders.

However, the impact of OC pretreatment in IVF outcome has been analyzed properly, that is, through randomized controlled trials, in patients with normal ovarian function following the conventional GnRH antagonist protocol and recombinant (r) FSH for controlled ovarian stimulation (COS). When these trials have been pooled out in two meta-analyses, both have reported a significantly lower ongoing pregnancy rate when the OCs were given as pretreatment (2, 3).

On the other hand, no comparison between OC versus no-OC pretreatment has been reported under any other type of protocol, or in different patient subpopulations. Therefore, the only good quality evidence available suggests a harmful effect of OC pretreatment in COS for IVF, while any other advantage has not been documented yet with the same level of evidence. Anyhow, it still remains unknown if this impact is present when any other type of COS protocol is used, or a different patient subpopulation is considered, such as poor responders. Moreover, although numerous strategies have been proposed to improve ovarian stimulation in poor responders, none of them is the ideal for all such patients (4).

Orvieto affirms that the day of hCG trigger is crucial for IVF success in GnRH antagonist cycles. I fully agree with this assumption, especially when poor and high responders are concerned. Again, the possibility of advancing or delaying for one day hCG triggering is restricted to normal responders. While in poor responders advancing hCG could result in a shorter number of oocytes retrieved, delaying it would increase the risk of ovarian hyperstimulation syndrome, and/or increase progesterone in high responders (5). Whether the criteria for choosing the day of hCG triggering should be based on the E2/follicles ratio needs further research, as it has been shown that this ratio may vary depending on the gonadotropins used for stimulation (6).

In summary, there is strong evidence suggesting a detrimental effect of OC pretreatment in GnRH antagonist cycles. While this is an extended practice among IVF physicians, if this finding is not present under different protocols and in different patient subpopulations, it needs to be shown with properly designed randomized controlled trials. In the meantime, available data shouldn’t be ignored. Flexibility on the day of hCG triggering seems to be an option in normal responder patients, but it should be used with caution under any other circumstance.

Ernesto Bosch, M.D.
Instituto Valenciano de Infertilidad
Valencia, Spain

References

1. Bosch E. Can we skip weekends in GnRH antagonist cycles without compromising the final outcome? Fertil Steril 2012;97:1299-300.

2. Griesinger G, Kolibianakis EM, 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;94:2382-4.

3. Smulders B, van Oirschot SM, Farquhar C, Rombauts L, Kremer JA. Oral contraceptive pill, progestogen or estrogen pre-treatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques. Cochrane Database Syst Rev 2010;Jan 20(1).

4. Loutradis D, Vomvolaki E, Drakakis P. Poor responder protocols for in-vitro fertilization: options and results. Curr Opin Obstet Gynecol 2008;20:374-8.

5. Bosch E, Labarta E, Crespo J, Simón C, Remohí J, Jenkins J, Pellicer A. Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles. Hum Reprod 2010;25:2092-100.

6. Smitz J, Andersen AN, Devroey P, Arce JC, MERIT Group. Endocrine profile in serum and follicular fluid differs after ovarian stimulation with HP-hMG or recombinant FSH in IVF patients. Hum Reprod 2007;22:676-87.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.06.054

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One response

11 07 2012
Raoul Orvieto

I would like to thank Dr. Bosch for is reply. However, there are 2 points that I would like to clarify.
I do accept and did not question the potential detrimental effect of OC pretreatment in GnRH antagonist cycles. I only offered and tried to explain why the ultrashort flare GnRH-ag/GnRH-antag protocol may serve as an alternative, by allowing cycle programming and overcoming the “detrimental effect” of the OC pretreatment.

The second point is the importance of hCG triggering day. I stated that the theoretically proposed fixed criterion of “as soon as 3 follicles are of 17 mm of diameter” is imprecise, difficult to implement, and does not reflect routine clinical practice. A patient with 3 follicles >17 mm in diameter and 7 more follicles of 15 mm, for example, will not be triggered on this day, but 1 to 2 days later. That is why we suggested a different triggering criterion: “patients achieving, on the day of hCG administration, a ratio of E2 level to number of follicles of >14 mm lower than 100 pg/mL” (1). This unnoticed criterion is more precise and reflects routine clinical practice, compared with the theoretically proposed fixed criterion of “as soon as 3 follicles are of 17 mm of diameter.”

Professor Raoul Orvieto M.D.
Director
Infertility and IVF Unit, Department of Obstetrics and Gynecology,
Barzilai Medical Center, Ashkelon; and
Ben Gurion University of the Negev, Beer Sheva, Israel

References
1. Orvieto R, Rabinson J, Meltcer S, Gemer O, Anteby EY, Zohav E. Does physicians’ experience influence IVF success in patients undergoing controlled ovarian stimulation with GnRH-antagonists? Fertil Steril 2008;89:736-7.

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