Instituto Valenciano de Infertilidad SL

IVF patients frequently experience physical, emotional or physicological burden; this is particularly relevant in the case of oocyte donors, since young women undergo a procedure that is of no health benefit to them. One of the phases of the treatment that contributes most to this situation is ovarian stimulation; as it involves the administration of daily injections which, in addition to the discomfort of administration, causes anxiety to the patient about its correct administration and possible side effects and to physicians concerns about patient compliance.
Advances in pharmacology and knowledge of ovarian pathophysiology have led to the development of new protocols that simplify and reduce drug administration, decrease the potential risk of misapplication and contribute to an improved patient experience. In this context, Corifollitropin α, a long-acting recombinant FSH (rFSH) molecule, provides with a single subcutaneous injection similar results as daily administration of rFSH during a week.
On the other hand, conventional stimulation protocols used in ART resort to using a GnRH analogue (agonist or antagonist) to prevent early luteinization, which is defined as the presence of a progesterone value of > 1.5 ng/ml on the day of induced ovulation. Nevertheless, its use presents some disadvantages, such as it being sometimes complex to achieve desensitization or consistent hypothalamic block, risk of OHS when ovulation is triggered with HCG or its cost. Hence the interest in exploring new options to prevent a premature peak in LH. Nowadays, the oral administration of progestagens (progesterone-primed ovarian stimulation [PPOS]) during the follicular phase of ovarian stimulation (OS) has emerged as an attractive alternative to conventional protocols for preventing early luteinization. Moreover, PPOS produces a similar or even better, in some subgroups, response to OS (length of treatment, number of MII, cancelation rate, etc.), reproductive outcomes (pregnancy rate, live birth rate, etc) and safety (rate of ovarian hyperstimulation [OHSS] or congenital malformations).
Thus, PPOS would seem to be an effective option for personalized protocols, particularly when fresh embryo transfer (FET) is not to be performed, a circumstance that is likely to rise in frequency given the progressive increase in women's age at childbearing; for example, in oocyte donation, or in fertility preservation (FP) and preimplantation genetic testing for aneuploidy (PGT-A). However, very little data are available regarding cycle outcome following Corifollitropin α and PPOS as pituitary suppressor.
The present study, a prospective RCT, was designed to evaluate cycle characteristics (MII oocytes as the primary objective) and endocrinologic profiles of oocyte donors receiving Corifollitropin α and MPA as co-treatment compared with those receiving a daily dose of rFSH (follitropin β) as a control.

Both controlled ovarian stimulation (COS) and frozen embryo transfer has become an integral part of in vitro fertilization (IVF) treatment. Fresh embryo transfer is usually performed by providing Luteal Phase Support (LPS) with progesterone after COS. Frozen embryo transfer (FET) is usually performed in artificial cycles with hormone replacement treatment (HRT), in which exogenous progesterone is administered, although it can also be performed in a Natural Cycle (without hormone supplementation) (NC). There is evidence that the supraphysiologic levels of estradiol and progesterone during COS+LPS and HRT could lead to morphologic and biochemical endometrial modifications, altering endometrial receptivity and lowering implantation and pregnancy rates.
We hypothesize that the supraphysiologic hormone levels required for both COS+LPS, and HRT may be inducing alterations in endometrial composition and function, specifically the chronic accumulation of senescent cells; either due to an excessive hormonal induction, a lack of clearance due to a deficit of uNKs, or a combination of both, ultimately affecting both endometrial receptivity and decidualization, worsening IVF outcomes.
The in vitro clearance of endometrial senescent cells by selective induction of apoptosis has been found to enhance the decidualization capacity of the rest of Endometrial Stromal Cells (EnSC), which could represent in a future adjuvant strategy to reduce the potentially deleterious effects of supraphysiologic hormone levels and improve reproductive outcomes in IVF patients.
The results derived from this project would have a direct impact on clinical practice. First, the results would allow us to evaluate, based on experimental data, potential endometrial side effects of stimulation protocols commonly used in IVF treatments. In addition, in the case of finding a pathological accumulation of senescent cells affecting endometrial receptivity, we will be able to in vitro evaluate the effectiveness of adjuvant senolytic (drugs designed to specifically remove senescent cells) compounds to in vitro improve the expression of endometrial receptivity markers, as a first step to demonstrate the effectiveness of their use in improving the reproductive outcomes of IVF patients.

This study is a prospective ranzomized analysis including 372 human oocytes from 44 women. Half of the oocytes from the same patient will be randomly allocated to induce oocyte activation using two protocols: in protocol nº 1 we will use ionomycin (prepared solution), protocol nª2 A23187 (GM508 CultActive Gynemed) will be applied. Non treated oocytes will serve as control. Oocyte fertilization rates, embryo development and embryo quality will be analyzed. Obstetrics variables of offspring will be also followed and compared.