PErsonalized Addition of Recombinant LH in Ovarian Stimulation

NCT04719000 | Recruiting Phase 4

• 1 other identifier: FSD-RHLH-2019-08
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

Different ovarian stimulation regimens have shown to modify late follicular phase hormonal profiles. Besides, recent studies confirm that progesterone levels and their variation in the last day of oocyte maturation are affected by the dose of gonadotropins administered and by other factors. Progesterone elevation in late follicular phase of in vitro fertilization/intracytoplasmatic sperm injection (IVF/ICSI) cycles under ovarian stimulation compromises implantation rates due to a negative effect on the endometrium. However, there is still conflict in the literature questioning whether progesterone levels alone on the triggering day is a sufficient indicator as progesterone does not give the full picture of the ovarian functions, number of follicles as well as estrogen production that facilitate endometrial growth, thus some studies suggest that especially in aged and poor responders Progesterone/Estrogen (P4/E2) ratio has a better reflection (Progesterone (ng/mL) ×1,000/estradiol(pg/mL)) on the ovarian function. The scope of the current pilot study is to compare serum progesterone levels as well as P4/E2 ratio on the day of ovulation triggering of women belonging to POSEIDON category group 2 who undergo a new ovarian stimulation with a dose of rhFSH 300 IU or 300 IU rhFSH plus 150 IU recombinant human luteinizing hormone (rhLH) in a gonadotropin-releasing hormone (GnRH) antagonist protocol.

Conditions

Infertility

Outcome Measures

Primary Outcomes (2)

• Serum progesterone levels on the day of ovulation triggering.

  The outcome will be evaluated on the day of ovulation triggering

  5 -20 days from initiation of ovarian stimulation

• P/E2 ratio

  Progesterone / estradiol ratio

  5 -20 days from initiation of ovarian stimulation

Secondary Outcomes (17)

• Progesterone Profile

  days 1, 6, 8, 10 and the day of ovulation triggering

• Estradiol Profile

  days 1, 6, 8, 10 and the day of ovulation triggering

• FSH Profile

  days 1, 6, 8, 10 and the day of ovulation triggering

• Testosterone Profile

  days 1, 6, 8, 10 and the day of ovulation triggering

• LH Profile

  days 1, 6, 8, 10 and the day of ovulation triggering

Other Outcomes (4)

• Ovarian hyperstimulation syndrome (OHSS) (percent).

  Until 15 days after the end of ovarian stimulation

• Miscarriages

  before completion of 12 weeks of gestation

• Cycle cancelation

  Until 15 days after the beginning of ovarian stimulation

Study Arms (2)

rhFSH+rhLH

EXPERIMENTAL

Ovarian Stimulation with rhFSH+rhLH

Drug: rhFSH+rhLH

rhFSH

ACTIVE COMPARATOR

Ovarian Stimulation with rhFSH

Drug: rhFSH

Interventions

rhFSH+rhLH DRUG

300 IU of rhFSH and 150 IU of rhLH (Pergoveris®) GnRH antagonist: cetrorelix 0.25 mg (Cetrotide® - Merck) GnRH antagonist: cetrorelix 0.25 mg (Cetrotide® - Merck) Recombinant human chorionic gonadotropin (rhCG) 6500 IU (Ovitrelle® - Merck) micronized progesterone 90 mg (Crinone 8% ® - Merck)

rhFSH+rhLH

rhFSH DRUG

300 IU rhFSH (Gonal-F®- Merck) GnRH antagonist: cetrorelix 0.25 mg (Cetrotide® - Merck) GnRH antagonist: cetrorelix 0.25 mg (Cetrotide® - Merck) rhCG 6500 IU (Ovitrelle® - Merck) micronized progesterone 90 mg (Crinone 8% ® - Merck)

rhFSH

Eligibility Criteria

• Age: 35 Years - 40 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Able and willing to sign the Patient Consent Form and adhere to study visitation schedule.
• ≥ 35 years ≤40 years old.
• AFC ≥5 and or AMH ≥1.2 ng/mL.
• \<4 or 4-9 oocytes retrieved in a previous IVF/ICSI cycle with a starting dose of ≤225 IU with any gonadotropin under a GnRH antagonist protocol.
• Up to 3 previous ovarian stimulation cycles with a starting dose of ≤225 IU in which dose adjustments during stimulation did not exceed 300 IU.
• Ovarian stimulation for IVF/ICSI

You may not qualify if:

• Poor ovarian responders according to the Bologna criteria.
• Polycystic ovary syndrome (PCOS) patients according to the Rotterdam criteria.
• AFC\>20.
• Age \>40 or \<35 years old.
• Women with \>10 oocytes retrieved in a previous IVF/ICSI cycle with 150-225 IU starting dose.
• Women who required dose adjustments during stimulation \>300 IU with any gonadotropin in their previous cycle
• Uterine abnormalities.
• Recent history of any current untreated endocrine abnormality.
• Unilateral or bilateral hydrosalpinx (visible on ultrasound scan (USS), unless clipped).
• Contraindications for the use of medicine used for ovarian stimulation (gonadotropins, GnRH antagonist, progesterone vaginal gel)
• Recent history of severe disease requiring regular treatment (Clinically significant concurrent medical condition that could compromise subject safety or interfered with the trial assessment and patients with any contraindication to pregnancy).
• Preimplantation Genetic Testing for Aneuploidies (PGT-a).
• Testicular Sperm Aspiration or Testicular Sperm Extraction (TESA or TESE)

Sponsors & Collaborators

• Fundación Santiago Dexeus Font: lead
• Merck, S.L., Spain: collaborator

Study Sites (1)

Hospital Universitario Quiron Dexeus

Barcelona, 08028, Spain

RECRUITING

Related Publications (26)

• Esteves SC, Khastgir G, Shah J, Murdia K, Gupta SM, Rao DG, Dash S, Ingale K, Patil M, Moideen K, Thakor P, Dewda P. Association Between Progesterone Elevation on the Day of Human Chronic Gonadotropin Trigger and Pregnancy Outcomes After Fresh Embryo Transfer in In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles. Front Endocrinol (Lausanne). 2018 Apr 26;9:201. doi: 10.3389/fendo.2018.00201. eCollection 2018.

  PMID: 29755412 BACKGROUND

• Fatemi HM, Van Vaerenbergh I. Significance of premature progesterone rise in IVF. Curr Opin Obstet Gynecol. 2015 Jun;27(3):242-8. doi: 10.1097/GCO.0000000000000172.

  PMID: 25811257 BACKGROUND

• Huang Y, Wang EY, Du QY, Xiong YJ, Guo XY, Yu YP, Sun YP. Progesterone elevation on the day of human chorionic gonadotropin administration adversely affects the outcome of IVF with transferred embryos at different developmental stages. Reprod Biol Endocrinol. 2015 Aug 4;13:82. doi: 10.1186/s12958-015-0075-3.

  PMID: 26238449 BACKGROUND

• Joo BS, Park SH, An BM, Kim KS, Moon SE, Moon HS. Serum estradiol levels during controlled ovarian hyperstimulation influence the pregnancy outcome of in vitro fertilization in a concentration-dependent manner. Fertil Steril. 2010 Feb;93(2):442-6. doi: 10.1016/j.fertnstert.2009.02.066. Epub 2009 Apr 25.

  PMID: 19394001 BACKGROUND

• Lawrenz B, Fatemi HM. Effect of progesterone elevation in follicular phase of IVF-cycles on the endometrial receptivity. Reprod Biomed Online. 2017 Apr;34(4):422-428. doi: 10.1016/j.rbmo.2017.01.011. Epub 2017 Jan 24.

  PMID: 28162937 BACKGROUND

• Mitwally MF, Bhakoo HS, Crickard K, Sullivan MW, Batt RE, Yeh J. Estradiol production during controlled ovarian hyperstimulation correlates with treatment outcome in women undergoing in vitro fertilization-embryo transfer. Fertil Steril. 2006 Sep;86(3):588-96. doi: 10.1016/j.fertnstert.2006.02.086. Epub 2006 Jun 30.

  PMID: 16814289 BACKGROUND

• Valbuena D, Martin J, de Pablo JL, Remohi J, Pellicer A, Simon C. Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo. Fertil Steril. 2001 Nov;76(5):962-8. doi: 10.1016/s0015-0282(01)02018-0.

  PMID: 11704118 BACKGROUND

• Racca A, De Munck N, Santos-Ribeiro S, Drakopoulos P, Errazuriz J, Galvao A, Popovic-Todorovic B, Mackens S, De Vos M, Verheyen G, Tournaye H, Blockeel C. Do we need to measure progesterone in oocyte donation cycles? A retrospective analysis evaluating cumulative live birth rates and embryo quality. Hum Reprod. 2020 Jan 1;35(1):167-174. doi: 10.1093/humrep/dez238.

  PMID: 31953546 BACKGROUND

• Younis JS. The role of progesterone/estradiol ratio in exploring the mechanism of late follicular progesterone elevation in low ovarian reserve women. Med Hypotheses. 2019 Apr;125:126-128. doi: 10.1016/j.mehy.2019.02.047. Epub 2019 Feb 28.

  PMID: 30902140 BACKGROUND

• Lin YJ, Lan KC, Huang FJ, Lin PY, Chiang HJ, Kung FT. Reproducibility and clinical significance of pre-ovulatory serum progesterone level and progesterone/estradiol ratio on the day of human chorionic gonadotropin administration in infertile women undergoing repeated in vitro fertilization cycles. Reprod Biol Endocrinol. 2015 May 13;13:41. doi: 10.1186/s12958-015-0037-9.

  PMID: 25967104 BACKGROUND

• Grynberg M, Labrosse J. Understanding Follicular Output Rate (FORT) and its Implications for POSEIDON Criteria. Front Endocrinol (Lausanne). 2019 Apr 16;10:246. doi: 10.3389/fendo.2019.00246. eCollection 2019.

  PMID: 31040828 BACKGROUND

• Polyzos NP, Nwoye M, Corona R, Blockeel C, Stoop D, Haentjens P, Camus M, Tournaye H. Live birth rates in Bologna poor responders treated with ovarian stimulation for IVF/ICSI. Reprod Biomed Online. 2014 Apr;28(4):469-74. doi: 10.1016/j.rbmo.2013.11.010. Epub 2013 Dec 4.

  PMID: 24581984 BACKGROUND

• Polyzos NP, Sunkara SK. Sub-optimal responders following controlled ovarian stimulation: an overlooked group? Hum Reprod. 2015 Sep;30(9):2005-8. doi: 10.1093/humrep/dev149. Epub 2015 Jul 21.

  PMID: 26202582 BACKGROUND

• Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011 Jul;26(7):1768-74. doi: 10.1093/humrep/der106. Epub 2011 May 10.

  PMID: 21558332 BACKGROUND

• Poseidon Group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number); Alviggi C, Andersen CY, Buehler K, Conforti A, De Placido G, Esteves SC, Fischer R, Galliano D, Polyzos NP, Sunkara SK, Ubaldi FM, Humaidan P. A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril. 2016 Jun;105(6):1452-3. doi: 10.1016/j.fertnstert.2016.02.005. Epub 2016 Feb 26. No abstract available.

  PMID: 26921622 BACKGROUND

• Humaidan P, Alviggi C, Fischer R, Esteves SC. The novel POSEIDON stratification of 'Low prognosis patients in Assisted Reproductive Technology' and its proposed marker of successful outcome. F1000Res. 2016 Dec 23;5:2911. doi: 10.12688/f1000research.10382.1. eCollection 2016.

  PMID: 28232864 BACKGROUND

• Andersen AN, Devroey P, Arce JC. Clinical outcome following stimulation with highly purified hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled trial. Hum Reprod. 2006 Dec;21(12):3217-27. doi: 10.1093/humrep/del284. Epub 2006 Jul 27.

  PMID: 16873892 BACKGROUND

• Smitz J, Andersen AN, Devroey P, Arce JC; MERIT Group. Endocrine profile in serum and follicular fluid differs after ovarian stimulation with HP-hMG or recombinant FSH in IVF patients. Hum Reprod. 2007 Mar;22(3):676-87. doi: 10.1093/humrep/del445. Epub 2006 Nov 16.

  PMID: 17110397 BACKGROUND

• Vuong TN, Phung HT, Ho MT. Recombinant follicle-stimulating hormone and recombinant luteinizing hormone versus recombinant follicle-stimulating hormone alone during GnRH antagonist ovarian stimulation in patients aged >/=35 years: a randomized controlled trial. Hum Reprod. 2015 May;30(5):1188-95. doi: 10.1093/humrep/dev038. Epub 2015 Mar 3.

  PMID: 25740882 BACKGROUND

• Al-Azemi M, Kyrou D, Kolibianakis EM, Humaidan P, Van Vaerenbergh I, Devroey P, Fatemi HM. Elevated progesterone during ovarian stimulation for IVF. Reprod Biomed Online. 2012 Apr;24(4):381-8. doi: 10.1016/j.rbmo.2012.01.010. Epub 2012 Jan 24.

  PMID: 22377153 BACKGROUND

• Bungum L, Franssohn F, Bungum M, Humaidan P, Giwercman A. The circadian variation in Anti-Mullerian hormone in patients with polycystic ovary syndrome differs significantly from normally ovulating women. PLoS One. 2013 Sep 4;8(9):e68223. doi: 10.1371/journal.pone.0068223. eCollection 2013.

  PMID: 24023708 BACKGROUND

• Gonzalez-Foruria I, Rodriguez I, Martinez F, Rodriguez-Purata J, Montoya P, Rodriguez D, Nicolau J, Coroleu B, Barri PN, Polyzos NP. Clinically significant intra-day variability of serum progesterone levels during the final day of oocyte maturation: a prospective study with repeated measurements. Hum Reprod. 2019 Aug 1;34(8):1551-1558. doi: 10.1093/humrep/dez091.

  PMID: 31334546 BACKGROUND

• Griesinger G, Mannaerts B, Andersen CY, Witjes H, Kolibianakis EM, Gordon K. Progesterone elevation does not compromise pregnancy rates in high responders: a pooled analysis of in vitro fertilization patients treated with recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in six trials. Fertil Steril. 2013 Dec;100(6):1622-8.e1-3. doi: 10.1016/j.fertnstert.2013.08.045. Epub 2013 Sep 29.

  PMID: 24083873 BACKGROUND

• 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.

  PMID: 25985996 BACKGROUND

• Golan A, Weissman A. Symposium: Update on prediction and management of OHSS. A modern classification of OHSS. Reprod Biomed Online. 2009 Jul;19(1):28-32. doi: 10.1016/s1472-6483(10)60042-9.

  PMID: 19573287 BACKGROUND

• Bosch E, Vidal C, Labarta E, Simon C, Remohi J, Pellicer A. Highly purified hMG versus recombinant FSH in ovarian hyperstimulation with GnRH antagonists--a randomized study. Hum Reprod. 2008 Oct;23(10):2346-51. doi: 10.1093/humrep/den220. Epub 2008 Jun 25.

  PMID: 18583332 BACKGROUND

Related Links

• Department of Obstetrics, Gynaecology and Reproduction Hospital Universitari Quirón Dexeus

MeSH Terms

Conditions

Infertility

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases

Study Officials

• Nikolaos P Polyzos, MD PhD

  Hospital Universitari Dexeus

  STUDY CHAIR

Central Study Contacts

Nikolaos P Polyzos, MD PhD

CONTACT

0034932274700; nikpol@dexeus.com

Ignacio Rodríguez, MSc

CONTACT

0034932274700; nacrod@dexeus.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 14, 2021
• First Posted: January 22, 2021
• Study Start: February 4, 2021
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): November 1, 2027
• Last Updated: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)