The Comparison of Granulosa Cell Apoptosis Rates With or Without Luteinizing Hormone Administration in Poor Responders.

Fertilization in Vitro Clinical Trial

Official title:

The Comparison of Granulosa Cell Apoptosis Rates on Microdose Flare up GnRH Analog Protocol Versus Luteinizing Hormone Administrated Microdose Flare up GnRH Analog Protocol in Poor Ovarian Responders Undergoing in Vitro Fertilization.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03527823
• Other study ID #: GranulosaApoptosis
• Secondary ID: 123
• Status: Completed
• Start date: October 17, 2018
• Est. completion date: January 10, 2019

Study information

• Verified date: June 2020
• Source: Giresun University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

In Zeynep Kamil Women and Children's Education and Research Hospital which is a tertiary referral hospital, the investigators perform microdose flare-up gonadotropin-releasing hormone (GNRH) analogue or GNRH antagonist protocol to the poor responders. The investigators may or may not supplement luteinizing hormone (LH). Human chorionic gonadotropin (hCG) triggering is performed when at least 2 follicles diameter are above 17 mm and the serum estradiol level is above 500 pg / ml. 36 hours after hCG, ovarian aspiration is performed by the guidance of transvaginal ultrasound. Normally after oocyte separation process, the remaining follicle aspiration fluid is destroyed.

n the present study, the follicle aspiration fluid is planned to be used with the patient's permission. The investigators are going to examine the granulosa cell apoptosis rate by using annexin-5 antibody in both groups 1 (LH added) and 2 (without LH).

For this purpose, a total of 40 volunteer patients are planned to involve, the groups are designed as 20 LH added and 20 LH added women.

In the present study, the investigators hypothesis that the rates of granulosa cell apoptosis in poor responders may be different between the group 1 (with LH) and group 2 (without LH), this will lead to IVF therapy in the near future.

Description:

The supplementation of human menopausal gonadotropin (HMG) in terms of luteinizing hormone (LH) support in controlled ovarian stimulation (COS) is a controversial issue. Follicle stimulating hormone (FSH) and LH are required for ovarian steroidogenesis in anovulatory women with gonadotropin deficiency according to the two cell-two gonadotropin hypothesis. LH supplementation is needed to ensure adequate follicular estradiol (E2) production during the follicular phase, completion of oocyte maturation and development in the endometrium. Despite, the need for LH for ovarian stimulation in normogonadotropic women is controversial. Additional LH supplementation during stimulation with FSH may provide an advantage in increasing follicle development and thus may be shortening the duration of treatment. It has been suggested that the change of gonadotropins from FSH to LH in the presence of ovarian stimulation is beneficial in the development of a more homogeneous follicular cohort [1] [2]. However, contrary opinions have reported that LH supplementation does not bring any additional benefit [3].

In recent years, studies have been done to investigate the utility of the addition of LH as well as FSH to the cycle outcome. In a Cochrane review, the combination of recombinant follicle stimulating hormone (r-FSH) and recombinant luteinizing hormone (r-LH) administration in in vitro fertilization/intracytoplasmic sperm injection (IVF / ICSI) cycles compared to only r-FSH cycles in 14 randomized controlled trials [4]. When r-LH was added, there was no statistical difference in terms of pregnancy outcomes. However, due to the small size of the work, the net result was not achieved. The other study supported the treatment of rFSH alone, while the addition of r-LH was found to be beneficial only in one of the studies [5, 6] . As a result, there is no significant difference in live birth rates.

However, the studies in only poor responders showed a significant increase in pregnancy rates with the addition of r-LH [5, 7]. In contrast, recently Bosch et al. reported that the addition of r-LH in the 36-39 age group of patients with GnRH antagonist protocol benefit from LH support, while patients under the age of 36 do not [8]. In conclusion, there is no consensus to administrate r-LH to the protocols of poor responders. Our hypothesis is LH administration may decrease granulosa apoptosis rate in follicular fluids and may be beneficial to poor responders and over age of 35.

In Zeynep Kamil Women and Children's Education and Research Hospital where the data of study patients is going to be collected, the investigators are applying microdose flare-up GNRH analogue or GNRH antagonist protocol to the poor responders. The investigators may or may not supplement LH. hCG is performed when at least 2 follicles are 17 mm and the serum estradiol level is above 500 pg / ml. 36 hours after hCG, ovarian aspiration is performed by the guidance of transvaginal ultrasound. Normally after oocyte separation process, the remaining follicle aspiration fluid is destroyed.

The follicle aspiration fluid is planned to be used within the permission of the patient in the present study. The investigators are going to examine the granulosa cell apoptosis rate with using annexin-5 antibody in group 1 (LH added) and group 2 (without LH).

For this purpose, a total of 40 volunteer patients are planned to have 20 LH added and 20 LH added patient groups.

Statistical analysis is going to be performed using SPSS 11 program. p <0.05 will be considered significant.

In the present study, the investigators hypothesis that comparing the rates of granulosa cell apoptosis in poor responders as two different groups (with and without addition of LH) will lead to IVF therapy in the near future.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: January 10, 2019
• Est. primary completion date: December 1, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 49 Years

Eligibility

Inclusion Criteria:

• 18-49 aged female

• poor ovarian responders

• undergoing treatment for primary/secondary infertility

Exclusion Criteria:

• endocrinologic or metabolic disorders

Related Conditions & MeSH terms

• Fertilization in Vitro

Locations

Country	Name	City	State
Turkey	Sebnem Alanya Tosun	Giresun

Sponsors (2)

Lead Sponsor	Collaborator
Sebnem Alanya Tosun	Giresun University Funding for Scientific Research Project

Country where clinical trial is conducted

Turkey, 

References & Publications (9)

Balasch J, Vidal E, Peñarrubia J, Casamitjana R, Carmona F, Creus M, Fábregues F, Vanrell JA. Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH. Hum Reprod. 2001 Aug;16(8):1636-43. — View Citation

Bosch E, Labarta E, Crespo J, Simón C, Remohí J, Pellicer A. Impact of luteinizing hormone administration on gonadotropin-releasing hormone antagonist cycles: an age-adjusted analysis. Fertil Steril. 2011 Mar 1;95(3):1031-6. doi: 10.1016/j.fertnstert.2010.10.021. Epub 2010 Nov 10. — View Citation

De Placido G, Alviggi C, Perino A, Strina I, Lisi F, Fasolino A, De Palo R, Ranieri A, Colacurci N, Mollo A; Italian Collaborative Group on Recombinant Human Luteinizing Hormone. Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum Reprod. 2005 Feb;20(2):390-6. Epub 2004 Dec 2. — View Citation

Ferraretti AP, Gianaroli L, Magli MC, D'angelo A, Farfalli V, Montanaro N. Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. Fertil Steril. 2004 Dec;82(6):1521-6. — View Citation

Filicori M, Cognigni GE, Samara A, Melappioni S, Perri T, Cantelli B, Parmegiani L, Pelusi G, DeAloysio D. The use of LH activity to drive folliculogenesis: exploring uncharted territories in ovulation induction. Hum Reprod Update. 2002 Nov-Dec;8(6):543-57. Review. — View Citation

Kaleli S, Yanikkaya-Demirel G, Erel CT, Senturk LM, Topçuoglu A, Irez T. High rate of aneuploidy in luteinized granulosa cells obtained from follicular fluid in women who underwent controlled ovarian hyperstimulation. Fertil Steril. 2005 Sep;84(3):802-4. — View Citation

Mochtar MH, Van der Veen, Ziech M, van Wely M. Recombinant Luteinizing Hormone (rLH) for controlled ovarian hyperstimulation in assisted reproductive cycles. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005070. Review. Update in: Cochrane Database Syst Rev. 2017 May 24;5:CD005070. — View Citation

Sullivan MW, Stewart-Akers A, Krasnow JS, Berga SL, Zeleznik AJ. Ovarian responses in women to recombinant follicle-stimulating hormone and luteinizing hormone (LH): a role for LH in the final stages of follicular maturation. J Clin Endocrinol Metab. 1999 Jan;84(1):228-32. — View Citation

Tarlatzis B, Tavmergen E, Szamatowicz M, Barash A, Amit A, Levitas E, Shoham Z. The use of recombinant human LH (lutropin alfa) in the late stimulation phase of assisted reproduction cycles: a double-blind, randomized, prospective study. Hum Reprod. 2006 Jan;21(1):90-4. Epub 2005 Sep 19. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the comparison of granulosa cell apoptosis rate with or without LH supplementation in poor responders	the investigators hypothesized that granulosa cell apoptosis rate on luteinizing hormone supplemented microdose flare up GnRH analog protocol in poor ovarian responders undergoing in vitro fertilization would be lower than not administered protocol	June 2018-August 2018