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

Infertility Clinical Trial

— Prog_STIM  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04108039
• Other study ID #: FSD-PRG-2019-02
• Status: Completed
• Phase: N/A
• Start date: September 25, 2019
• Est. completion date: May 15, 2022

Study information

• Verified date: May 2023
• Source: Institut Universitari Dexeus
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: May 15, 2022
• Est. primary completion date: January 15, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 36 Years to 40 Years

Eligibility

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.

Related Conditions & MeSH terms

• Infertility
• IVF
• Preimplantation Diagnosis

Intervention

Drug:
• GnRh antagonist
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
• Micronized progesterone
Micronized progesterone protocol to avoid LH surge in COS, from stimulation day 1 and continuing until ovulation triggering.

Locations

Country	Name	City	State
Spain	Institut Universitari Dexeus	Barcelona	Catalunya

Sponsors (1)

Lead Sponsor	Collaborator
Institut Universitari Dexeus

Country where clinical trial is conducted

Spain, 

References & Publications (11)

Cedrin-Durnerin I, Bstandig B, Parneix I, Bied-Damon V, Avril C, Decanter C, Hugues JN. Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol. Hum Reprod. 2007 Jan;22(1):109-16. doi: 10.1093/humrep/del340. Epub 2006 Aug 26. — View Citation

Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum Reprod. 2011 Oct;26(10):2593-7. doi: 10.1093/humrep/der251. Epub 2011 Aug 9. — View Citation

Dong J, Wang Y, Chai WR, Hong QQ, Wang NL, Sun LH, Long H, Wang L, Tian H, Lyu QF, Lu XF, Chen QJ, Kuang YP. The pregnancy outcome of progestin-primed ovarian stimulation using 4 versus 10 mg of medroxyprogesterone acetate per day in infertile women undergoing in vitro fertilisation: a randomised controlled trial. BJOG. 2017 Jun;124(7):1048-1055. doi: 10.1111/1471-0528.14622. — View Citation

Griesinger G, Venetis CA, Tarlatzis B, Kolibianakis EM. To pill or not to pill in GnRH-antagonist cycles: the answer is in the data already! Reprod Biomed Online. 2015 Jul;31(1):6-8. doi: 10.1016/j.rbmo.2015.04.001. Epub 2015 Apr 9. — View Citation

Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, Ai A, Shoham Z. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril. 2015 Jul;104(1):62-70.e3. doi: 10.1016/j.fertnstert.2015.03.022. Epub 2015 May 5. — View Citation

Lambalk CB, Banga FR, Huirne JA, Toftager M, Pinborg A, Homburg R, van der Veen F, van Wely M. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type. Hum Reprod Update. 2017 Sep 1;23(5):560-579. doi: 10.1093/humupd/dmx017. — View Citation

Richter TA, Robinson JE, Lozano JM, Evans NP. Progesterone can block the preovulatory gonadotropin-releasing hormone/luteinising hormone surge in the ewe by a direct inhibitory action on oestradiol-responsive cells within the hypothalamus. J Neuroendocrinol. 2005 Mar;17(3):161-9. doi: 10.1111/j.1365-2826.2005.01287.x. — View Citation

Verberg MF, Eijkemans MJ, Heijnen EM, Broekmans FJ, de Klerk C, Fauser BC, Macklon NS. Why do couples drop-out from IVF treatment? A prospective cohort study. Hum Reprod. 2008 Sep;23(9):2050-5. doi: 10.1093/humrep/den219. Epub 2008 Jun 10. — View Citation

Zhang J, Mao X, Wang Y, Chen Q, Lu X, Hong Q, Kuang Y. Neonatal outcomes and congenital malformations in children born after human menopausal gonadotropin and medroxyprogesterone acetate treatment cycles. Arch Gynecol Obstet. 2017 Dec;296(6):1207-1217. doi: 10.1007/s00404-017-4537-z. Epub 2017 Sep 25. — View Citation

Zhu X, Ye H, Fu Y. Use of Utrogestan during controlled ovarian hyperstimulation in normally ovulating women undergoing in vitro fertilization or intracytoplasmic sperm injection treatments in combination with a "freeze all" strategy: a randomized controlled dose-finding study of 100 mg versus 200 mg. Fertil Steril. 2017 Feb;107(2):379-386.e4. doi: 10.1016/j.fertnstert.2016.10.030. Epub 2016 Nov 16. — View Citation

Zhu X, Zhang X, Fu Y. Utrogestan as an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Medicine (Baltimore). 2015 May;94(21):e909. doi: 10.1097/MD.0000000000000909. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	Incidence of premature LH rise		9-20 days from initiation of ovarian stimulation
Secondary	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
Secondary	Number of mature oocytes	The outcome will be evaluated on the day of oocyte retrieval	9-20 days from initiation of ovarian stimulation
Secondary	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
Secondary	Fertilization rate	The outcome will be evaluated the day after the of oocyte retrieval	1 day after oocyte retrieval