Long-term Endogenous Androgen Priming in Bologna Criteria Poor Responder Patients - A Pilot Study
Condition: Poor Ovarian Response
Study type: Observational

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).
    

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.
    

Intervention name(s): Androgen priming
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): low dose hCG and aromatase inhibitor priming
Intervention MeSH terms: Androgens; Aromatase Inhibitors
Observational model: Case-Only
Time perspective: Prospective
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)
      
Biospecimen description: 
      Blood samples Follicular fluid Granulosa cells