Androgenic Profile Following Controlled Ovarian Stimulation

Infertility, Female Clinical Trial

Official title:

Follicular Fluid, Serum Endocrine Profile Following Stimulation With Recombinant Gonadotropins or Highly Purified Human Menopausal Gonadotropin During GnRH-antagonist Protocol

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02992808
• Other study ID #: SHEBA-16-3516-EZ-CTIL
• Status: Not yet recruiting
• Phase: Phase 4
• First received: December 11, 2016
• Last updated: December 18, 2016
• Start date: December 2016
• Est. completion date: January 2020

Study information

• Verified date: December 2016
• Source: Sheba Medical Center
• Contact: Eran Zilberberg, MD
• Phone: +97235302882
• Is FDA regulated: No
• Health authority: Israel: Ethics Commission
• Study type: Interventional

Clinical Trial Summary

In this study the investigators will try to discover whether there is a difference for any of the stimulation preparations - recombinant FSH + recombinant LH (pergoveris & luveris) vs. human menopausal gonadotropin (menopur) during GnRH-antagonist cycles in the meaning of androgenic hormones profile. The study question is whether using recombinant LH will result in different follicular hormonal milieu, serum endocrine profile or IVF outcomes than using highly purified urinary gonadotropins with hCG mimicking LH activity.

Description:

ABSTRACT:

The optimal controlled ovarian stimulation (COH) protocol is yet to be decided and most probably there is no right protocol that is optimal for all patients.

The role of luteinizing hormone (LH) administration during controlled ovarian stimulation (COH) is widely debated in the current medical literature.

Until recently the only source for exogenous LH activity was HMG preparations, however, in the past few years an advancement in the field of recombinant technology resulted in recombinant preparations of LH. In contrast to LH activity in HMG which is mainly due to hCG rather than from LH, using r-LH provides true, consistent and precise LH activity.

In the past years few papers were published about the difference between recombinant follicle stimulating hormone (r-FSH) and menotropins but there is still a need for researching the different effects of gonadotropins preparations and in particular the effect of LH administration during COH in the manner of follicular endocrine characteristics, embryo quality and pregnancy outcomes.

In the present study the investigators aim to elucidate whether there is a difference for any of the stimulation preparations - recombinant FSH + recombinant LH (pergoveris & luveris) vs. human menopausal gonadotropin (menopur) during GnRH-antagonist cycles. The study question is whether using recombinant LH will result in different follicular hormonal milieu, serum endocrine profile or IVF outcomes than using highly purified urinary gonadotropins with hCG mimicking LH activity.

In the relevant medical literature there is one prospective study dealing with the same question, but, during long-GnRH-agonist cycles. In the aforementioned paper there were no significant differences between the two stimulation preparations.

MATERIALS & METHODS:

Study design - A non-intervention observational trial. Primary endpoint - Serum & follicular fluid hormonal profile during COH (FSH, LH, progesterone, estradiol, testosterone, androstendione, 17-OH progesterone) Secondary endpoints - Implantation rate, clinical pregnancy, # of follicles, # of oocytes, # of embryos, top quality embryos.

Study sample - 100 patients undergoing COH for IVF using the GnRH-antagonist protocol Inclusion criteria - 20-40 years old IVF patients, BMI 19-35 undergoing their 1-4 IVF cycle.

Exclusion criteria - Suspected PCOS, history of OHSS, Patients who had a chronic illness or were receiving chronic medical treatment will be excluded.

Gonadotropin preparations -

1. As HP-HMG we will use Menopur© (menotropins for injection, FERRING) which contains equal amount of FSH & LH.

2. As the recombinant preparation we will use Pergoveris© (follitropin alfa/lutropin alfa, MERCK SERONO) which contains 150 units of FSH + 75 units of LH and Luveris© (lutropin alfa, MERCK SERONO) which is LH only preparation.

The patients - The study population will consist of all consecutive eligible patients attending the IVF unit of our department for treatment of infertility. The study required no modification of our routine, flexible, multi-dose GnRH antagonist protocol.

Briefly, after the presence of quiescent ovaries on transvaginal ultrasound and low serum E2 level were confirmed on day 2/3 of menstruation, recombinant FSH - Gonal-F© (follitropin alfa; MERCK SERONO) will be administered subcutaneously at a starting dose of 150-300 IU, depending on patient's age and/or ovarian responsiveness in previous cycles. The gonadotropin dosage will be adjusted individually according to serum E2 levels and vaginal ultrasound measurements of follicular diameter, obtained every one or two days. LH will be added to the protocol as urinary preparation Menopur© (menotropins for injection, FERRING) or as recombinant preparations - Pergoveris© (follitropin alfa/lutropin alfa, MERCK SERONO) with or without Luveris© (lutropin alfa, MERCK SERONO). GnRH-antagonist - Cetrotide© (cetrorelix, MERCK SERONO), 0.25 mg daily subcutaneously, will be added when the leading follicle reached 14-16 mm diameter, and will be continued until the day of ovulation triggering. When at least three mature (>17 mm) follicles will be obtained, patients will receive an injection of either Ovitrelle© 250 mcg (Choriogonadotropin alfa, MERCK SERONO) or GnRH-agonist - Decapeptyl© 0.2 mg (Triptorelin acetate, FERRING).

In summary, for the purpose of the study, in addition to the routine monitoring during the COH cycle, blood samples will be drawn to determine the hormonal profile (E2, progesterone), levels of serum androgens, namely, testosterone, androstendione, 17-OH progesterone and LH and FSH: (1) day 1-3 of menstruation (Day-S); (2) day of or prior to hCG administration (Day-hCG); and (3) day of ovum pick-up (Day-OPU).

Moreover, pooled follicular fluid will be collected after oocytes retrieval (fluid destined to be discarded) and will be examined for hormonal profile (FSH, LH, progesterone, estradiol, testosterone, androstendione, 17-OH progesterone).

To note - participation in this study WILL NOT change the COH treatment.

Statistics - The chi-squared test and analysis of variance (ANOVA) will be applied to detect statistically significant differences among the groups with regard to proportions or means. A two-sided P < 0.05 was considered statistically significant.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: January 2020
• Est. primary completion date: January 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 20 Years to 40 Years

Eligibility

Inclusion Criteria:

• Infertile women between 20-40 years of age

• BMI 19-35

• undergoing their 1-4 IVF cycle

Exclusion Criteria:

• Suspected PCOS

• History of OHSS

• Patients who had a chronic illness or were receiving chronic medical treatment

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Infertility
• Infertility, Female

Intervention

Drug:
• recombinant gonadotropins

• HP-HMG

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Sheba Medical Center

References & Publications (5)

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. — View Citation

Devroey P, Pellicer A, Nyboe Andersen A, Arce JC; Menopur in GnRH Antagonist Cycles with Single Embryo Transfer Trial Group.. A randomized assessor-blind trial comparing highly purified hMG and recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer. Fertil Steril. 2012 Mar;97(3):561-71. doi: 10.1016/j.fertnstert.2011.12.016. — View Citation

Requena A, Cruz M, Ruiz FJ, García-Velasco JA. Endocrine profile following stimulation with recombinant follicle stimulating hormone and luteinizing hormone versus highly purified human menopausal gonadotropin. Reprod Biol Endocrinol. 2014 Jan 29;12:10. doi: 10.1186/1477-7827-12-10. — View Citation

Revelli A, Pettinau G, Basso G, Carosso A, Ferrero A, Dallan C, Canosa S, Gennarelli G, Guidetti D, Filippini C, Benedetto C. Controlled Ovarian Stimulation with recombinant-FSH plus recombinant-LH vs. human Menopausal Gonadotropin based on the number of retrieved oocytes: results from a routine clinical practice in a real-life population. Reprod Biol Endocrinol. 2015 Jul 25;13:77. doi: 10.1186/s12958-015-0080-6. — View Citation

Van Wely M, Westergaard LG, Bossuyt PM, Van der Veen F. Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles. Cochrane Database Syst Rev. 2003;(1):CD003973. Review. Update in: Cochrane Database Syst Rev. 2011;(2):CD003973. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum hormonal profile	Hormonal profile = FSH, LH, progesterone, estradiol, testosterone, androstendione, 17-OH progesterone	(1) day 1-3 of menstruation (Day-S); (2) day of or prior to hCG administration (Day-hCG); and (3) day of ovum pick-up (Day-OPU).	No
Primary	Follicular fluid hormonal profile	Hormonal profile = FSH, LH, progesterone, estradiol, testosterone, androstendione, 17-OH progesterone	Ovum pick up day	No
Secondary	Implantation rate	Number of gestational sacs on US exam / number of retrieved embryos	About three weeks after embryo transfer	No
Secondary	Clinical pregnancy	Number of cases with gestational sac per US exam / cases of embryo transfer	About three weeks after embryo transfer	No
Secondary	Biochemical pregnancy	Positive BHCG test	About two weeks after embryo tranfer	No
Secondary	Ongoing pregnancy	Number of viable pregnancies at about 10-12 weeks of gestation	10-12 weeks after embryo tranfer	No
Secondary	Live birth rate	Number of pregnancies ended in a live birth	Until about 40 weeks after embryo transfer	No
Secondary	Number of follicles	Larger than 14 mm follicles per US	During stimulation - one-two dayes before ovum pick-up	No
Secondary	Number of oocytes retrieved	Number of oocytes retrieved during ovarian pick-up	1 day right after ovarian pick-up	No
Secondary	Number of embryos	Number of developing embryos in the laboratory	About 3 days after OPU (ovum pick-up)	No
Secondary	Number of top quality embryos	The number of day 3 embryos with 7-8 cells with less than 15% fragmentation	3 days after OPU	No