Feasibility and Efficacy of a New Ovarian Stimulation Regimen With RANDom Start, Use of Corifollitropin Alpha and Progestin Protocol for Oocyte donorS

Medically assisted procreation can help infertile patients with a panel of techniques adapted to various causes of infertility. In most cases, these techniques use patients' own gametes. However, despite the medical advances, it is still impossible today to regenerate gametic cells when they have disappeared from the gonads. Especially for women with premature ovarian failure, the only feasible option is to receive oocytes from a third-party donor. In France, the principle of free and anonymous applies to the donation and no compensation is allowed outside the reimbursement of expenses incurred. Oocyte donors are women volunteers who agree to undergo heavy medical treatment to help other women, without any other consideration so that the recognition of their donation. It is important for these women to minimize the risks involved, to simplify and minimize ovarian stimulation treatments, which are generally injections and to offer maximum flexibility, without reducing the quality of the donation.

The advent of oocyte and embryo vitrification has opened up new opportunities for reproductive scientists to improve the practice and results of IVF attempts. It is now established that vitrification of whole oocyte cohorts does not compromise, and may even improve, the results of IVF attempts. In addition, it is now clear that progesterone modulates the frequency of Gonadotropin-Releasing Hormone (GnRH) pulses and can strongly inhibit the pulsatile secretion of GnRH and LH and thereby inhibit the LH peak induced by increased plasma concentrations of GnRH and LH. estradiol. And, in the context of oocyte donation, the deleterious effects of ovarian stimulation on endometrial receptivity have no impact: the increase in progesterone levels during stimulation is not a concern in this group who will not benefit from an embryonic transfer.

Initially, progesterone stimulation protocols were performed during the luteal phase as part of the urgent preservation of fertility in cancer patients. The first European feasibility study was conducted and published in 2013 in normotensive patients. While the preliminary findings were not optimistic, many publications, from 2013, showed that this luteal strategy is effective without the addition of a GnRH antagonist, but imposes a freeze all strategy. In all these studies, whether it is luteal phase stimulation schemes, strategies of 2 consecutive stimulations, in the follicular and then luteal phase, or random-start stimulation protocol, the quality of the oocytes does not seem to be impacted, with identical implantation and birth rates in the control groups (conventional ovarian stimulation). The state of health of newborns and malformation rates are also identical to those of conventional protocols.

Although luteal phase endogenous progesterone levels appear to be sufficient to block the LH surge, recent publications have also shown the efficacy of exogenous progesterone, which can, without compromising the oocyte's competence, replace the use of an agonist or antagonist during the follicular phase. The advantages are oral administration and the reduction of potential costs, without any secondary effect on the competence of oocytes.

Different progestins were used. Kuang et al (2015) report the first randomized study studying an exogenous progestogen-based ovarian stimulation protocol using medroxyprogesterone acetate (MPA). Compared to a standard short protocol, with embryonic vitrification in both groups, the number of mature oocytes and the number of frozen embryos, the implantation and pregnancy rates after thawed embryo transfers were not significantly different. The same group published between 2015 and 2017, 4 studies validating micronized progesterone as an effective oral alternative to treatment with GnRH agonists for the prevention of premature LH surge during controlled ovarian stimulation for intracytoplasmic sperm injection (IVF-ICSI). Recently, the same group compared dydrogesterone and micronized progesterone with the same results. More recently, another progestogen, desogestrel, has been used in addition to corifollitropin alpha in an oocyte donation program, compared to a conventional antagonist protocol. The authors reported the same number of oocytes in both groups, with better tolerance of treatment in the desogestrel group. In the same way as for luteal phase stimulation protocols, exogenous progestin-exogenous ovarian stimulation protocols have similar neonatal outcomes, compared to "standard" protocols, for birth weight, gestational age, and Congenital malformation rate.