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

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ClinicalTrials.gov Identifier: NCT03447184
Recruitment Status : Completed
First Posted : February 27, 2018
Last Update Posted : July 4, 2019
Sponsor:
Information provided by (Responsible Party):
Mỹ Đức Hospital

Brief Summary:
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).

Condition or disease Intervention/treatment
Poor Ovarian Response 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.


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Study Type : Observational
Actual Enrollment : 30 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: 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
Actual Study Start Date : March 26, 2018
Actual Primary Completion Date : February 18, 2019
Actual Study Completion Date : March 1, 2019

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 Name: low dose hCG and aromatase inhibitor priming




Primary Outcome Measures :
  1. Serum concentrations of AMH [ Time Frame: 8 weeks after starting androgen priming ]
    Blood sampling


Secondary Outcome Measures :
  1. Number of antral follicles [ Time Frame: 8 weeks after starting androgen priming ]
    Follicles 2-10mm on ultrasound

  2. Serum concentrations of testosterone [ Time Frame: Up to 2 weeks after starting FSH stimulation ]
    Blood sampling

  3. Serum concentrations of hCG [ Time Frame: Up to 2 weeks after starting FSH stimulation ]
    Blood sampling

  4. Serum concentrations of progesterone [ Time Frame: Up to 2 weeks after starting FSH stimulation ]
    Blood sampling

  5. Number of antral follicles [ Time Frame: Up to 2 weeks after starting FSH stimulation ]
    Follicles 2-10 mm on ultrasound

  6. Number of pre-ovulatory follicles [ Time Frame: Up to 2 weeks after starting FSH stimulation ]
    Follicles >/= 14 mm on ultrasound


Other Outcome Measures:
  1. Follicular fluid concentration of estradiol [ Time Frame: Up to one hour after ovum pick-up ]
    Aspiration of follicular fluid while doing ovum pick-up

  2. Follicular fluid concentration of androstenedione [ Time Frame: Up to one hour after ovum pick-up ]
    Aspiration of follicular fluid while doing ovum pick-up

  3. Follicular fluid concentration of testosterone [ Time Frame: Up to one hour after ovum pick-up ]
    Aspiration of follicular fluid while doing ovum pick-up

  4. Follicular fluid concentration of progesterone [ Time Frame: Up to one hour after ovum pick-up ]
    Aspiration of follicular fluid while doing ovum pick-up

  5. Follicular fluid concentration of inhibin B [ Time Frame: Up to one hour after ovum pick-up ]
    Aspiration of follicular fluid while doing ovum pick-up

  6. Cumulus and mural Luteinising hormone receptor (LHR) gene expression [ Time Frame: Up to one hour after ovum pick-up ]
    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.

  7. Cumulus and mural 3β-hydroxy-steroid-dehydrogenase (3ßHSD) gene expression [ Time Frame: Up to one hour after ovum pick-up ]
    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.

  8. Cumulus and mural inhibin-Ba (INHB-A) receptor gene expression [ Time Frame: Up to one hour after ovum pick-up ]
    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.

  9. Cumulus and mural androgen receptor gene expression [ Time Frame: Up to one hour after ovum pick-up ]
    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.

  10. Cumulus and mural FSH receptor gene expression [ Time Frame: Up to one hour after ovum pick-up ]
    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.


Biospecimen Retention:   Samples With DNA
Blood samples Follicular fluid Granulosa cells


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 41 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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)
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03447184


Locations
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Vietnam
Lan N Vuong
Ho Chi Minh City, Vietnam
Sponsors and Collaborators
Mỹ Đức Hospital
Investigators
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Principal Investigator: Tuong M Ho, MD Mỹ Đức Hospital

Publications:
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Responsible Party: Mỹ Đức Hospital
ClinicalTrials.gov Identifier: NCT03447184     History of Changes
Other Study ID Numbers: CS/BVMD/18/01
First Posted: February 27, 2018    Key Record Dates
Last Update Posted: July 4, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Androgens
Ascorbic Acid
Methyltestosterone
Estrogens, Conjugated (USP)
Aromatase Inhibitors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Vitamins
Micronutrients
Nutrients
Growth Substances
Estrogens
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anabolic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Estrogen Antagonists
Hormone Antagonists