Clinical trial NCT02792569: Follicle Activation by Inhibition of the Hippo Pathway
Official title: Auto-transplantation of Fragmented Ovarian Cortical Tissue in Infertile Patients With Premature Ovarian Oocyte Depletion - a Study to Promote Follicular Activation and Subsequent Fertility
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Infertility
Keywords: IVA
Hippo Pathway
Follicle activation
Low Responder
POI
Poor Ovarian Reserve
Poor Ovarian Response
Salvador/Warts/Hippo pathway
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2016-06-07
Enrollment: 20
Sex: FEMALE
Minimum age (years): 25
Maximum age (years): 39
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of follicles > 12 mm
timeFrame: Up to 6 month after the auto-transplantation
Secondary outcomes:
measure: Side of ovulation
timeFrame: Up to 6 months after auto-transplantation
Other outcomes:
measure: AFC count
timeFrame: Up to 10 month after auto-transplantation
measure: AMH changes
timeFrame: Up up to 10 month after auto-transplantation
measure: Pregnancy
timeFrame: Through study completion, an average of 1 year
Locations:
city: Copenhagen
country: Denmark
facility: The Fertility Clinic, Rigshospitalet, Copenhagen University Hospital
Study officials:
affiliation: Rigshospitalet, Denmark
name: Anders N Andersen, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S, Ho CH, Kawamura N, Tamura M, Hashimoto S, Sugishita Y, Morimoto Y, Hosoi Y, Yoshioka N, Ishizuka B, Hsueh AJ. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17474-9. doi: 10.1073/pnas.1312830110. Epub 2013 Sep 30.
citation: Hsueh AJ, Kawamura K, Cheng Y, Fauser BC. Intraovarian control of early folliculogenesis. Endocr Rev. 2015 Feb;36(1):1-24. doi: 10.1210/er.2014-1020. Epub 2014 Sep 9.
citation: Suzuki N, Yoshioka N, Takae S, Sugishita Y, Tamura M, Hashimoto S, Morimoto Y, Kawamura K. Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency. Hum Reprod. 2015 Mar;30(3):608-15. doi: 10.1093/humrep/deu353. Epub 2015 Jan 6.
citation: Lunding SA, Pors SE, Kristensen SG, Landersoe SK, Jeppesen JV, Flachs EM, Pinborg A, Macklon KT, Pedersen AT, Andersen CY, Andersen AN. Biopsying, fragmentation and autotransplantation of fresh ovarian cortical tissue in infertile women with diminished ovarian reserve. Hum Reprod. 2019 Oct 2;34(10):1924-1936. doi: 10.1093/humrep/dez152.