Follicle Activation by Inhibition of the Hippo Pathway

Auto-transplantation of Fragmented Ovarian Cortical Tissue in Infertile Patients With Premature Ovarian Oocyte Depletion - a Study to Promote Follicular Activation and Subsequent Fertility

The aim of this project is to activate recruitment and growth of resting primordial follicles in the ovaries of women with diminished ovarian reserve, in attempt to increase the chance to become pregnant, either naturally or after assisted reproduction.

For this study investigators will carefully select 20 women with low AMH and imminent POI. They will be randomized to have cortical ovarian biopsies taken from either the left or right ovary. The biopsies will be fragmented in 1x1 mm2 pieces and immediately auto-transplanted in a peritoneal pocket under the right ovary. The contralateral untouched ovary will act as the control, making each woman their own control. Follow up: each week in 2,5 months the women will be assessed by transvaginal ultrasound and hormonal status. After 2,5-6 months the women will receive a FSH stimulation cycle (rFSH 300 IU or Corifollitropin) followed by standard IVF/ICSI, Hypothesis: the ovaries contain a pool of resting primordial follicles. By fragmentation of cortical ovarian tissue, manipulation of the local environment in the tissue will inhibit the Hippo Pathway and hereby active recruitment and growth of primordial follicles.

IVA, Hippo Pathway, Follicle activation, Low Responder, POI, Poor Ovarian Reserve, Poor Ovarian Response, Salvador/Warts/Hippo pathway

Biopsies will be taken from either right or left side. The cortical tissue will be isolated and fragmented in 1x1 mm2 pieces, followed by auto-transplantation to a peritoneal pocket.

Number of follicles > 12 mm in response to controlled ovarian stimulation with corifollitropin from the biopsied ovary versus the contralateral untreated ovary

Frequency of ovulations occurring at the "biopsy side" versus the contralateral side in the subsequent 4- 6 months

Changes (increase - decrease) in serum AMH over time, using the highly sensitive new AMH Assay (Elecsys Assay; Roche), which has been implemented as a routine analysis at The Department of Clinical Biochemistry Rigshospitalet in June 1st 2015

Inclusion Criteria: Infertility with indication for IVF/ICSI Imminent POI, still cycling Age 25 - 39 years Two ovaries Serum AMH measurements < 5 pmol/l (two independent measurements) Antral follicle count (AFC) (sum of both ovaries < 5) Exclusion Criteria: Ovarian pathology (endometriosis, cysts) Known chromosomal abnormality Known autoimmune disease (except TPO-antibodies) Patients who have contraindication for laparoscopy

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