Micronized Progesterone vs Gonadotropin-releasing Hormone (GnRH) Antagonist in Freeze-all IVF Cycles.

Study Overview
=================
Brief Summary
-----------------
To examine whether the number of euploid embryos following ovarian stimulation with micronized progesterone is equivalent as compared with the number of embryos after ovarian stimulation with the use of a GnRH antagonist in patients undergoing ovarian stimulation for IVF or intracytoplasmatic sperm injection (ICSI).

Detailed Description
-----------------
The pre-ovulatory surges of GnRH and LH are activated by increased concentrations of circulating estradiol, but ovulation is blocked when progesterone concentrations are elevated, due to a central inhibition of the GnRH surge. Although traditionally GnRH has been traditionally considered the drug of choice to control endogenous LH in controlled ovarian stimulation (COS) cycles, recently, micronized progesterone has been shown to be an effective oral alternative for preventing premature LH surges during COS in women undergoing IVF/ICSI treatments, with excellent results, whereas their safety during pregnancy is well-established. This novel protocol, has several advantages (good tolerance, user convenience, and cost reduction), that are very attractive when it comes to establishing a convenient user regimen in combination with a ''freeze all'' strategy. However, the comparative efficacy of this novel protocol with the more universal use of GnRH-antagonist protocol for the treatment of IVF patients in terms of embryo ploidy has never been evaluated up to date. The current study aims, for the first time, to examine whether the number of euploid embryos following ovarian stimulation with micronized progesterone is equivalent as compared with the number of embryos after ovarian stimulation with the use of a GnRH antagonist in patients undergoing ovarian stimulation for IVF/ICSI. If efficacy would prove to be similar, with no impact on the chromosomal constitution of embryos, there will be obvious advantages for the preferential use of micronized progesterone over the antagonist protocol: oral administration is preferred over subcutaneous injection, and total cost of medication would be lower. This would be particularly interesting for the future in all freeze all protocols such as women undergoing ovarian stimulation for fertility preservation, preimplantation genetic screening and oocyte donation programs.

Official Title
-----------------
Suppression of Endogenous Luteinizing Hormone (LH) Surge With Progesterone vs GnRH Antagonist in Freeze-all IVF Cycles. A Prospective Equivalence Study With Repeated Ovarian Stimulation Cycles.

Conditions
-----------------
Infertility, IVF, Preimplantation Diagnosis

Intervention / Treatment
-----------------
* Drug: GnRh antagonist
* Drug: Micronized progesterone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Infertile patients Age 36-40 years old BMI 18-30 kg/m2 Undergoing preimplantation genetic screening cycles Planned to undergo at least two treatment cycles, to accumulate embryos to increase the chance of obtaining euploid embryos for transfer Willing to participate in the study Exclusion Criteria: Age> 41 Severe male factor requiring TESE (testicular sperm extraction) Low ovarian reserve (AMH < 1.2 ng/ml) Administration of any other drug potentially interfering with the treatment.

Ages Eligible for Study
-----------------
Minimum Age: 36 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 44 women undergoing IVF treatments due to infertility, will be asked to participate in a trial in which they will undergo 2 ovarian stimulation protocols with recombinant follicle stimulating hormone (rFSH): the first one using a flexible antagonist protocol to suppress the endogenous LH rise and the second using oral micronized progesterone 200 mg/day from day 1 of stimulation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GnRH antagonist<br>In the antagonist cycle, LH suppression will be accomplished by subcutaneous (SC) injections of 0.25 mg of Cetrorelix or Ganirelix starting in the presence of follicles >14mm or E2 levels >400 pg/ml and continuing until ovulation triggering. | Drug: GnRh antagonist<br>* In the antagonist cycle, LH suppression will be accomplished by subcutaneous (SC) injections of 0.25 mg of Cetrorelix or Ganirelix starting in the presence of follicles >14mm or E2 levels >400 pg/ml and continuing until ovulation triggering to avoid LH surge in COS<br>* Other names: Cetrorelix or Ganirelix;|
| Experimental: Micronized progesterone<br>In the progesterone cycle, endogenous LH suppression will be accomplished by oral administration of micronized progesterone (200 mg) once a day at bed time, from stimulation day 1 and continuing until ovulation triggering. | Drug: Micronized progesterone<br>* Micronized progesterone protocol to avoid LH surge in COS, from stimulation day 1 and continuing until ovulation triggering.<br>* Other names: Utrogestan;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of euploid embryos as compared between the 2 ovarian stimulation cycles | Number of euploid embryos between oocytes received from the antagonist GnRh protocol or the micronized progesterone protocol. | 15-45 days following oocyte retrieval procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endocrine profile at specific intervals | To evaluate the difference in the mean serum estradiol (E2) levels (measured in pg/mL) at the predefined intervals treatment days. | Stimulation day 0, day 6, day 8, day of final oocyte maturation and day +1 after oocyte maturation (actual day may vary between 9-15) | 
| Endocrine profile at specific intervals | To evaluate the difference in the mean serum follicle stimulating hormone levels (FSH, measured in IU/mL) at the predefined intervals treatment days. | Stimulation day 0, day 6, day 8, day of final oocyte maturation and day +1 after oocyte maturation (actual day may vary between 9-15) | 
| Endocrine profile at specific intervals | To evaluate the difference in the mean serum progesterone levels (measured in ng/mL) at the predefined intervals treatment days. | Stimulation day 0, day 6, day 8, day of final oocyte maturation and day +1 after oocyte maturation (actual day may vary between 9-15) | 
| Duration of stimulation | Total days of ovarian stimulation. The outcome will be evaluated on the of final oocyte maturation. | 9-20 days from initiation of ovarian stimulation | 
| Incidence of premature LH rise |  | 9-20 days from initiation of ovarian stimulation | 
| Total dose of gonadotropins | Total units of recombinant FSH. The outcome will be evaluated on the day of final oocyte maturation. | 9-20 days from initiation of ovarian stimulation | 
| Number of mature oocytes | The outcome will be evaluated on the day of oocyte retrieval | 9-20 days from initiation of ovarian stimulation | 
| Ultrasound ovarian follicles diameter measurement | During the regular follicular scan, two diameters of each ovarian follicle will be recorded: the maximum diameters in the transverse and longitudinal scan planes. | 9-20 days from initiation of ovarian stimulation | 
| Fertilization rate | The outcome will be evaluated the day after the of oocyte retrieval | 1 day after oocyte retrieval |