Effect of Different Ovarian Stimulation Protocols on Endometrial Receptivity
Effect of Different Ovarian Stimulation Protocols on Endometrial Receptivity
This study will assess the change in endometrial gene expression signature on the day of
 embryo transfer according to the type of exogenous gonadotropins administered.
Late-follicular elevated progesterone (LFEP) following ovarian stimulation for assisted
 reproductive technologies (ART) has been linked to abnormal endometrial receptivity
 expression profiles and lower pregnancy rates. For this reason, physicians frequently propose
 that patients with LFEP avoid performing a fresh embryo transfer, postponing instead it to a
 subsequent unstimulated cycle. Although this strategy may reduce the detrimental effect LFEP
 may have on cumulative ART pregnancy rates, it may also frustrate couples who wish to become
 pregnant as soon as possible.

 With the intent of minimizing potentially-avoidable treatment delays, an increasing number of
 researchers are proposing that physicians revisit their current ovarian stimulation regimens.
 One strategy which may reduce the incidence of LFEP is to decrease the dose of gonadotropins
 administered at the end of stimulation (i.e. a stepdown protocol). A similar approach, using
 corifollitropin alpha (CFA), has also been recently advanced, taking advantage of the
 stepdown-like pharmacodynamic profile of this compound.

 In order to assess the clinical usefulness of these strategies, the investigators propose a
 single-center, open-label, paired, randomized trial. The main objective of this study is to
 assess the changes in the endometrial gene expression profile on the day of fresh embryo
 transfer according to the type of gonadotropins administered for ovarian stimulation. In
 summary, all consenting subjects will first undergo an endometrial biopsy seven days after
 the luteinizing hormone peak in an unmedicated natural cycle. This biopsy will serve as the
 baseline endometrial biopsy (natural cycle biopsy) for a gene expression analysis. Following
 this baseline biopsy, subjects will be randomly allocated to a specific type of ovarian
 stimulation regimen in order to later perform a second endometrial biopsy, this time five
 days after oocyte retrieval (stimulated cycle biopsy). Subjects will be randomized to
 administer, on the third day of their menstrual cycle, either a single dose of 150 IU of CFA
 (study arms 1A and 1B) or a fixed daily dose of 200 IU of recombinant follicle stimulating
 (rFSH, study arm 2). On the eighth day of stimulation, it is expected that 15% to 30% of all
 subjects who performed CFA will have reached the follicular development criteria for final
 oocyte maturation and ovulation triggering.
Inclusion Criteria:

 1. Informed consent form (ICF) dated and signed.

 2. Age: ≥18 and <40 years old.

 3. AFC ≥5 and <20.

 4. AMH ≥1.1 ng/mL and <2.5 ng/mL, performed in the 12 months prior to inclusion.

 5. Body Mass Index (BMI): ≥18.5 Kg/m2 and <30 Kg/m2.

 6. Weight: ≥50 kg and <80 kg.

 7. First or second ART cycle or fertility preservation cycle.

 8. Regular menstrual cycles (between 22 and 35 days).

 9. Two ovaries present.

 10. Pregnancy-wish.

 11. Planned for single blastocyst transfer.

 Exclusion Criteria:

 1. Simultaneous participation in another clinical study.

 2. Previous history of poor ovarian response (<4 oocytes retrieved) with a maximal dose
 of OS (≥300 IU/day) or OHSS, regardless of gonadotropin dose.

 3. Known reasons for impaired implantation (i.e. hydrosalpinx, fibroid distorting the
 endometrial cavity, Asherman's syndrome, thrombophilia or endometrial tuberculosis).

 4. Repeated miscarriages (>2 previous biochemical pregnancies or >2 spontaneous
 miscarriages).

 5. Recurrent implantation failure (>3 failed cycles with good quality embryos).

 6. Polycystic ovary syndrome (PCOS).

 7. Tumours of the ovary, breast, uterus, pituitary or hypothalamus.

 8. Abnormal (not menstrual) vaginal bleeding without a known/diagnosed cause.

 9. Ovarian cysts or enlarged ovaries.

 10. Fibroid tumours of the uterus incompatible with pregnancy.

 11. Malformations of the reproductive organs incompatible with pregnancy.

 12. Primary gonadal failure.

 13. Renal impairment defined as estimated glomerular filtration rate of 90 ml/min/1.73 m2
 determined by the Modified Diet and Renal Disease (MDRD) equation at screening.

 14. Previous antibiotic hypersensitivity reactions (streptomycin and/or neomycin).

 15. Risk factors for thromboembolic events, such as a personal or family history, severe
 obesity or thrombophilia.

 16. Moderate or severe hepatic impairment.

 17. Untreated and uncontrolled thyroid dysfunction.

 18. Current use of oral contraceptive, anti-depressants, anti-psychotics, steroids,
 anti-epileptics or chemotherapy.

 19. Administration of exogenous Estradiol (E2), Progesterone (P4) or gonadotropins in the
 preceding menstrual cycle.

 20. Active female smoking.

 21. Acceptors of donated oocytes/embryos.

 22. Ongoing pregnancy.

 23. Women who have previously enrolled in the trial.

 24. Those unable to comprehend the investigational nature of the proposed study.