Assisted reproductive technology: looking beyond the era of gonadotropin-releasing hormone analogues

Reflections

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VOLUME 116, ISSUE 2, P343-344

Authors:

Paul Pirtea, M.D., Dominique de Ziegler, M.D., Jean Marc Ayoubi, M.D., Ph.D.

Abstract:

Reflections on "Medroxiprgesterona acetate is a useful alternative to a GnRH antagonist in oocyte donation: a randomized control trial" by Giles et al.

Read the full text here. 

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. 

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Go to the profile of Juan Giles
5 months ago

Towards the progestogen era

Juan Giles M.D., Ph.D. 1, 2

Pilar Alama M.D., Ph.D.1, 2

Carmen Vidal M.D., Ph.D.1, 2

Ernesto Bosch M.D., Ph.D.1, 2

 

1IVI-RMA, Valencia, Spain,  2IVI Foundation, Instituto de Investigacion Sanitaria Hospital Universitario y Politecnico La Fe, Valencia, Spain.

 

A trend in current society is personalization, and this includes assisted reproduction, whether it be in the IVF laboratory or ovarian stimulation protocols (OS).  In relation to the latter, several protocols have been employed in order to maximize live birth rates, mitigate risks and reduce cancellation and dropout rates. To this end, the choice of gonadotropin, as well as the starting dose, is fundamental and should be in accordance with the patient’s characteristics, especially markers of ovarian reserve, such as serum anti-Müllerian hormone (AMH) and ultrasound antral follicular count (AFC).

In addition to selecting the adequate therapy, the drug used to prevent early luteinization is key to success. GnRH analogs have traditionally been employed, but they have some disadvantages, such as the formation of functional follicular cysts, the need for a prolonged period of down-regulation, and increased cancelation rates. These undesirable effects have fueled an interest in finding alternatives to prevent a premature peak in the luteinizing hormone (LH) level, as  described brilliantly by Pirtea et al. (see  Editorial).

The realization that most patients undergo two and even three waves of follicular development - in contrast to the theory of a single wave - together with knowledge of the local inhibitory effects of the corpus luteum and progesterone (P4), has challenged the traditional concept of folliculogenesis and has inspired current luteal phase OS protocols. Thus, we now know that the ovary can be stimulated in a progesterone-enriched environment, which implies initiating OS in outside the follicular phase, for example in the luteal phase.

Based on the ability of P4 to inhibit ovulation, progestins have been used in OS follicular protocols to prevent the LH surge in patients undergoing IVF, as a safe alternative to GnRH analogue administration. This new approach is referred to as progestin-primed ovarian stimulation (PPOS).

Together with the acquisition of new knowledge on ovarian physiopathology, the evolution of vitrification techniques has been an essential element in the development of novel OS protocols that have improved the individualization of fertility treatments, but which require oocyte or embryo vitrification because the endometrium is out of phase when embryo transfer (ET) is performed.

Until now, protocols that include the administration of progestins in the follicular phase have been successfully used in normally ovulating patients, those with polycystic ovary syndrome or endometriosis, and low responders (1). 

Currently, for professional, economic or personal/relation-based reasons, there is a gradual increase in the age at which women choose to become mothers and at which they seek assisted reproductive techniques (ART). This situation has increased the demand for procedures in which PPOS can play an important role, such as oocyte donation, fertility preservation and preimplantation genetic testing for aneuploid (PGT-A), as none of them involve fresh embryo transfer.

Pituitary suppression with PPOS not only has a similar efficacy to that obtained with GnRH antagonists, but also does not adversely affect pregnancy outcome or the number of euploid embryos, and has not been associated with an increase in adverse neonatal outcomes or congenital malformations (2). Data in the literature, including those published in our study (3), do not support a negative effect of progestins on oocyte quality. We analyzed embryo quality using timelapse technology and observed a very similar initial embryonic growth pattern with both protocols; embryos initiated division and developed at a similar rate until the compaction/blastulation stage, at which time no differences were observed (unpublished data).

An additional aspect of the PPOS protocol we evaluated for the first time is donor satisfaction. Following oocyte retrieval, a questionnaire was offered to all participants to assess their satisfaction with the information provided by staff and with the medication administered for ovarian stimulation.

In all the responses directly related to medication, the results were more positive among the donors receiving medroxiprogesterone acetate (MPA). The importance of non-injectable medical treatment was paramount for 79% of the donors in the MPA group and for 70% in the antagonist group.  Donors in the MPA group who had previously been stimulated with the antagonist were asked some additional questions to compare the two treatments. The satisfaction level was much higher than the previous cycle among 63.54% of donors and higher among 30.2% (a total of 92.74%; unpublished data). These results are in accordance with those of another study conducted by our group to evaluate the degree of satisfaction among oocyte donors undergoing treatment with corifollitropin α versus daily FSH injections for the first week of ovarian stimulation (6). The findings clearly showed a positive trend towards corifollitropin α, confirming that reduction of subcutaneous medication can decrease treatment burden and increase donor compliance.

In cycles with fresh embryo transfer, progestogins are not cost-effective, since embryo vitrification and a subsequent cycle to transfer the vitrified embryos are required, and less so if additional transfers are necessary due to lack of gestation.  Cycles in which fresh transfer is not performed, such as PGT or oocyte donation, are more cost-effective than GnRH antagonists, but not short protocols with GnRH agonists (5). The higher cost of PPOS protocols with respect to short agonist protocols is due to the fact that these drugs do not produce endogenous gonadotropin release. Our data regarding the duration of OS and gonadotropin dose are in line with other studies performed in oocyte donors, all of which suggest that MPA does not induce stronger pituitary suppression than conventional protocols in this population. A further aspect to take into account is that this type of protocol reduces the number of ultrasound and analytical controls that are necessary to monitor follicular development, which indirectly reduces costs.

 Another critical advantage of progestin cycles is that GnRH agonists can be used to trigger oocyte maturation, thus avoiding the risk of ovarian hyperstimulation syndrome, which is of special relevance in this population, who are usually high responders.

Despite the studies carried out to date, the progestogin of choice and the most suitable dose at which it should be administered are yet to be defined. Moreover, other routes of administration, such as transdermal or vaginal options, need to be explored. Likewise, the subcutaneous route suggested by Pirtea is certainly worthy of exploration, though one of the aspects that make it more attractive, namely the convenience of the route of administration, would be lost in the donor population. In the same way, there should be further investigation about the usefulness of initiating PPOS either on stimulation day 7 or when the leading follicle reaches a diameter of 14 mm, similarly to GnRH antagonist protocols.

Future research on this topic should compare the efficacy of different progestins, as well as the minimum effective dose of each of them, possible side effects (since only our study has reported on this aspect), and degree of patient satisfaction. 

In summary, progestins have proven their effectiveness as a gonadotropin adjuvant in terms of ovarian response, reproductive outcome and security. Thus, they should be considered a useful tool in cycles that do not require fresh embryo transfer, such as the oocyte donation cycles analyzed in our randomized control trial (RCT), in order to allow greater personalization of treatment and a more friendly approach to OS.

 

 

REFERENCES

 

  1. Ata B, Capuzzo M, Turkgeldi E, Yildiz S, La Marca A. Progestins for pituitary suppression during ovarian stimulation for ART: a comprehensive and systematic review including meta-analyses. Hum Reprod Update. 2021 Jan 4;27(1):48-66.
  2. Zolfaroli I, Ferriol GA, Mora JH, Cano A. Impact of progestin ovarian stimulation on newborn outcomes: a meta-analysis. J Assist Reprod Genet 2020;37:1203–12
  3. Giles J, Alama P, Gamiz P, Vidal C, Badia P, Pellicer A, Bosch E. Medroxyprogesterone acetate is a useful alternative to a gonadotropin-releasing hormone antagonist in oocyte donation: a randomized, controlled trial. Fertil Steril. 2021 Apr 1:S0015-0282(21).
  4. Evans MB, Parikh T, DeCherney AH, Csokmay JM, Healy MW, Hill MJ. Evaluation of the cost-effectiveness of ovulation suppression with progestins compared with GnRH analogs in assisted reproduction cycles. Reprod Biomed Online 2019;38: 691-698.
  5. Requena A, Cruz M, Collado D, Izquierdo A, Ballesteros A, Muñoz M, García-Velasco JA. Evaluation of the degree of satisfaction in oocyte donors using sustained-release FSH corifollitropin α. Reprod Biomed Online. 2013 Mar;26(3):253-9