Long-term Endogenous Androgen Priming in Bologna Criteria Poor Responder Patients - A Pilot Study

Will Long-term Endogenous Androgen Priming, Using a Combination of Low Dose HCG and Aromatase Inhibitor in Bologna Criteria Poor Responder Patients Increase Ovarian Reserve Parameters - A Pilot Study

Until now no scientific clinical evidence exists regarding the possible impact of long term endogenous androgen priming in IVF patients aligned with the Bologna Criteria, in specific the impact of priming on serum parameters correlated with the ovarian reserve, antral follicle count, and the number of retrievable follicles. Thus, this pilot-study will explore a new suggested protocol for the Bologna criteria patient developed from basic physiology, and will if successful result in a subsequent randomized controlled trial in the same subset of patients, enabling a possible paradigm shift in the treatment of poor ovarian response (POR).

Study Overview

• Status: Completed
• Conditions: Poor Ovarian Response
• Intervention / Treatment: Drug: Androgen priming

Detailed Description

A single center study pilot study in 30 IVF Bologna criteria POR patients. All patients fulfilling the ESHRE Bologna criteria will be eligible for inclusion.

Eight weeks prior to stimulation for IVF, patients will start treatment with a low dose of rhCG (Ovitrelle). At the same time daily treatment with the aromatase inhibitor daily will commence, concomitantly with GnRHa down-regulation with a depot GnRHa.

After 8 weeks, stimulation will be performed with a fixed dose of 300 IU rFSH (Gonal F, Merck) for the first 5 days in patients ≤ 34 years of age and 300 IU Pergoveris (Merck) in patients ≥ 35 years of age. The use of hCG and aromatase inhibitor will stop on the first day of stimulation.

Monitoring will be performed according to the standard procedure of the clinic. Patients will receive a bolus of 6.500 IU rhCG (Ovitrelle, Merck) for triggering of final oocyte maturation. Oocyte pick-up and embryo transfer will be performed according to the policy of the clinic. Oocyte pick-up (OPU) and embryo transfer will be performed according to standard procedures.

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• Vietnam
  • Ho Chi Minh City, Vietnam
    • Lan N Vuong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 41 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Bologna poor responders: At least two of the following three features present:

• Advanced maternal age (≥40 years) or any other risk factor for POR
• A previous POR (≤3 oocytes with a conventional stimulation protocol)
• An abnormal ovarian reserve test (i.e. antral follicle count < 5-7 follicles or AMH< 0.5 - 1.1 ng/mL)
• Poor responder if - Two previous episodes of POR after maximal stimulation (300 IU)

Description

Inclusion Criteria:

• Age 18 - 41 years
• BMI < 30 kg/m2
• Ovarian reserve, according to the ESHRE Bologna Criteria measured within two months prior to stimulation start

Bologna criteria: At least two of the following three features present:

• Advanced maternal age (≥40 years) or any other risk factor for POR
• A previous POR (≤3 oocytes with a conventional stimulation protocol)
• An abnormal ovarian reserve test (i.e. antral follicle count < 5-7 follicles or AMH< 0.5 - 1.1 ng/mL)

• Poor responder if - Two previous episodes of POR after maximal stimulation (300 IU)

  • Receiving GnRH-antagonist co-treatment during ovarian stimulation
  • Agreement to participate in the study, and to disclose any medical events to the investigator. The subject must be willing and able to comply with the protocol requirements for the duration of the study.
  • Have given written informed consent with the understanding that the subject may withdraw consent at any time without prejudice to future medical care.

Exclusion Criteria:

• Chronical medical conditions like Diabetes, Crohns disease, Thyroid disease, Hepatitis B and Sexually Transmitted Diseases Simultaneous participation in an interventional clinical trial.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Androgen priming; Eight weeks prior to stimulation for IVF - at the onset of menses, patients will start treatment with a low dose of rhCG (Ovitrelle). At the same time daily treatment with the aromatase inhibitor will commence, concomitantly with GnRHa down-regulation with a depot GnRHa (28days). After 8 weeks, a standard rFSH stimulation with either 300 IU rFSH or 300 IU rFSH+rLH will start. The androgen priming (hCG and aromatase inhibitor) will stop on the first day of stimulation.

Drug: Androgen priming; Androgen priming: with a low dose of recombinant hCG, aromatase inhibitor, and a depot GnRHa for 8 weeks Stimulation: a standard rFSH stimulation with either 300 IU rFSH or 300 IU (rFSH + rLH) Blood sampling: 6 blood samples to measure FSH, LH, E2, testosterone, and AMH Ultrasound examination: to count all antral follicles, 2-10 mm in each ovary Follicular fluid: to analyze E2, androstenedione, testosterone, progesterone, inhibin B. Granulosa cells: to analyze gene expression in cumulus and mural granulosa cells of Luteinising hormone receptor (LHR), 3β-hydroxy-steroid-dehydrogenase (3ßHSD), inhibin-Ba (INHB-A) receptor, androgen and FSH receptor; Other Names: low dose hCG and aromatase inhibitor priming

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum concentrations of AMH	Blood sampling	8 weeks after starting androgen priming

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of antral follicles	Follicles 2-10mm on ultrasound	8 weeks after starting androgen priming
Serum concentrations of testosterone	Blood sampling	Up to 2 weeks after starting FSH stimulation
Serum concentrations of hCG	Blood sampling	Up to 2 weeks after starting FSH stimulation
Serum concentrations of progesterone	Blood sampling	Up to 2 weeks after starting FSH stimulation
Number of antral follicles	Follicles 2-10 mm on ultrasound	Up to 2 weeks after starting FSH stimulation
Number of pre-ovulatory follicles	Follicles >/= 14 mm on ultrasound	Up to 2 weeks after starting FSH stimulation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Follicular fluid concentration of estradiol	Aspiration of follicular fluid while doing ovum pick-up	Up to one hour after ovum pick-up
Follicular fluid concentration of androstenedione	Aspiration of follicular fluid while doing ovum pick-up	Up to one hour after ovum pick-up
Follicular fluid concentration of testosterone	Aspiration of follicular fluid while doing ovum pick-up	Up to one hour after ovum pick-up
Follicular fluid concentration of progesterone	Aspiration of follicular fluid while doing ovum pick-up	Up to one hour after ovum pick-up
Follicular fluid concentration of inhibin B	Aspiration of follicular fluid while doing ovum pick-up	Up to one hour after ovum pick-up
Cumulus and mural Luteinising hormone receptor (LHR) gene expression	Cumulus and mural granulosa cells from oocyte from the first follicle in each women were isolated immediately after ovum pick-up and snap frozen for analysis of LHR gene expression. qPCR was performed and calculation of the expression level of the gene of interest was carried out according to the comparative method, normalised to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for relative quantification of gene expression.	Up to one hour after ovum pick-up
Cumulus and mural 3β-hydroxy-steroid-dehydrogenase (3ßHSD) gene expression	Cumulus and mural granulosa cells from oocyte from the first follicle in each women were isolated immediately after ovum pick-up and snap frozen for analysis of 3ßHSD gene expression. qPCR was performed and calculation of the expression level of the gene of interest was carried out according to the comparative method, normalised to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for relative quantification of gene expression.	Up to one hour after ovum pick-up
Cumulus and mural inhibin-Ba (INHB-A) receptor gene expression	Cumulus and mural granulosa cells from oocyte from the first follicle in each women were isolated immediately after ovum pick-up and snap frozen for analysis of INHB-A gene expression. qPCR was performed and calculation of the expression level of the gene of interest was carried out according to the comparative method, normalised to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for relative quantification of gene expression.	Up to one hour after ovum pick-up
Cumulus and mural androgen receptor gene expression	Cumulus and mural granulosa cells from oocyte from the first follicle in each women were isolated immediately after ovum pick-up and snap frozen for analysis of androgen receptor gene expression. qPCR was performed and calculation of the expression level of the gene of interest was carried out according to the comparative method, normalised to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for relative quantification of gene expression.	Up to one hour after ovum pick-up
Cumulus and mural FSH receptor gene expression	Cumulus and mural granulosa cells from oocyte from the first follicle in each women were isolated immediately after ovum pick-up and snap frozen for analysis of FSH receptor gene expression. qPCR was performed and calculation of the expression level of the gene of interest was carried out according to the comparative method, normalised to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for relative quantification of gene expression.	Up to one hour after ovum pick-up

Collaborators and Investigators

• Sponsor: Mỹ Đức Hospital
• Investigators: Principal Investigator: Tuong M Ho, MD, Mỹ Đức Hospital

Publications and helpful links

General Publications

• Vuong TNL, Ho MT, Ha TQ, Jensen MB, Andersen CY, Humaidan P. Effect of GnRHa ovulation trigger dose on follicular fluid characteristics and granulosa cell gene expression profiles. J Assist Reprod Genet. 2017 Apr;34(4):471-478. doi: 10.1007/s10815-017-0891-9. Epub 2017 Feb 14.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 26, 2018
• Primary Completion (ACTUAL): February 18, 2019
• Study Completion (ACTUAL): March 1, 2019

Study Registration Dates

• First Submitted: January 23, 2018
• First Submitted That Met QC Criteria: February 25, 2018
• First Posted (ACTUAL): February 27, 2018

Study Record Updates

• Last Update Posted (ACTUAL): July 5, 2019
• Last Update Submitted That Met QC Criteria: July 2, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Steroid Synthesis Inhibitors; Estrogen Antagonists; Androgens; Aromatase Inhibitors
• Other Study ID Numbers: CS/BVMD/18/01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No