Clinical trial NCT03447184: Long-term Endogenous Androgen Priming in Bologna Criteria Poor Responder Patients - A Pilot Study
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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Poor Ovarian Response
Lead sponsor: Mỹ Đức Hospital
Sponsor class: OTHER
First posted: 2018-02-27
Enrollment: 30
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 41
Standard ages: ADULT
Accepts healthy volunteers: no
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)

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).

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.

Eligibility 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.

Primary outcomes:
measure: Serum concentrations of AMH
timeFrame: 8 weeks after starting androgen priming
Secondary outcomes:
measure: Number of antral follicles
timeFrame: 8 weeks after starting androgen priming
measure: Serum concentrations of testosterone
timeFrame: Up to 2 weeks after starting FSH stimulation
measure: Serum concentrations of hCG
timeFrame: Up to 2 weeks after starting FSH stimulation
measure: Serum concentrations of progesterone
timeFrame: Up to 2 weeks after starting FSH stimulation
measure: Number of antral follicles
timeFrame: Up to 2 weeks after starting FSH stimulation
measure: Number of pre-ovulatory follicles
timeFrame: Up to 2 weeks after starting FSH stimulation
Other outcomes:
measure: Follicular fluid concentration of estradiol
timeFrame: Up to one hour after ovum pick-up
measure: Follicular fluid concentration of androstenedione
timeFrame: Up to one hour after ovum pick-up
measure: Follicular fluid concentration of testosterone
timeFrame: Up to one hour after ovum pick-up
measure: Follicular fluid concentration of progesterone
timeFrame: Up to one hour after ovum pick-up
measure: Follicular fluid concentration of inhibin B
timeFrame: Up to one hour after ovum pick-up
measure: Cumulus and mural Luteinising hormone receptor (LHR) gene expression
timeFrame: Up to one hour after ovum pick-up
measure: Cumulus and mural 3β-hydroxy-steroid-dehydrogenase (3ßHSD) gene expression
timeFrame: Up to one hour after ovum pick-up
measure: Cumulus and mural inhibin-Ba (INHB-A) receptor gene expression
timeFrame: Up to one hour after ovum pick-up
measure: Cumulus and mural androgen receptor gene expression
timeFrame: Up to one hour after ovum pick-up
measure: Cumulus and mural FSH receptor gene expression
timeFrame: Up to one hour after ovum pick-up
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: Lan N Vuong
Study officials:
affiliation: Mỹ Đức Hospital
name: Tuong M Ho, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.