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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Poor Ovarian Response

Intervention / Treatment
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* Drug: Androgen priming


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 41 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Androgen priming<br>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<br>* 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<br>* Other names: low dose hCG and aromatase inhibitor priming;|

What is the study measuring?
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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 |