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Can Dormant Perimenopausal Ovarian Follicles Become FSH Responsive?

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ClinicalTrials.gov Identifier: NCT01201226
Recruitment Status : Unknown
Verified September 2010 by The Baruch Padeh Medical Center, Poriya.
Recruitment status was:  Not yet recruiting
First Posted : September 14, 2010
Last Update Posted : September 14, 2010
Information provided by:
The Baruch Padeh Medical Center, Poriya

Brief Summary:
The purpose of this study to obtain ovarian cortical fragments from perimenopausal patients, who undergo pelvic organ surgery and test whether treatment with PTEN inhibitor and PI3K activating peptide would induce these fragments to produce FSH responsive follicles in the nude mouse model.

Condition or disease Intervention/treatment
Low Ovarian Reserve Poor Responders to Gonadotropihins Treatment Other: Removal of half an ovary

Detailed Description:

Introduction Women stop menstruating at the mean age of 51, yet pregnancies become much less prevalent beyond 40, with pregnancy at 43 being a relative rarity. Current common perception attributes the regression of fertility to depletion of the primordial follicles' pool (Burger et al. 2008). The decline in fertility may result not necessarily from a sharp depletion of the primordial follicle pool (Hansen et al. 2008) but may be due to failure of adequate transition from primordial to antral, gonadotropin-responsive follicles. It is not infrequent to encounter a fertility patient at her late thirties or early forties, who would not respond to the most extreme doses of exogenous FSH, but will nevertheless continue to menstruate until the age of 50. The usual practice is to refer these patients to oocyte donation programs.

Recently, Li et al. (2010) demonstrated that incubation of neonatal mouse ovarian fragments with an inhibitor of the Phosphatase with TENsin homology deleted in chromosome 10 (PTEN) phosphatase and a PI3K activating peptide, increased nuclear exclusion of Foxo3 and propelled large numbers of dormant primordial follicles into becoming FSH-responsive antral follicles. Furthermore, in the nude mice model (mice lacking immune system) they showed that transplanted human ovarian fragments containing mainly primordial follicles from surgical specimens, treated by the same incubation, also underwent activation of dormant follicles to derive preovulatory follicles containing mature oocytes.

Based on all the above we hypothesize, that ovaries of women at their perimenopausal years could be propelled to become FSH-responsive, using incubation with PTEN inhibitor and PI3K activating peptide to activate dormant primordial follicles.

If found feasible, this technique could provide hope of achieving fertility to patients who would otherwise be referred to receive oocyte donation.

Aim of the proposed study To obtain ovarian cortical fragments from perimenopausal patients, who undergo gynecological surgery, and test whether treatment with PTEN phosphatase and PI3K activating peptide would induce these fragments to produce FSH responsive follicles in the nude mouse model.

Study subjects and specimen harvest Up to ten women, older than 45 years, who are scheduled to gynecological operation, will be asked to provide half of an ovary for the study. The tissue will then be cut to multiple fragments, suitable for cryopreservation.

Laboratory methods Cryopreservation of ovarian fragments will use a vitrification protocol similar to earlier report for oocyte cryo-storage (Yoon et al. 2003). Because the cryo-preservation reagents can easily penetrate primordial follicles as compared with the large oocytes, we anticipate efficient preservation of these follicles. In young patients, one 1 mm cortical cubes contains ~50 primordial follicles.

Three tissue samples from each patient will be transferred to the Hsueh laboratory in Stanford (attached letter), and will be thawed for in vitro activation followed by xeno-transplantation using the same protocol as that described by Li et al. from that laboratory. (Li et al. 2010). The in vitro incubation will be in bpV(pic) (Calbiochem), a PTEN inhibitor, which allows the activation of dormant follicles. and a cell-permeable phospho-peptide (740Y-P) (Tocris) capable of binding to the SH2 domain of the p85 regulatory subunit of PI3K to stimulate enzyme activity. Activated PI3K converts phosphatidylinositol (4, 5)-bisphosphate (PIP2) to phosphatidylinositol (3-5)-trisphosphate (PIP3), whereas the PTEN inhibitor prevents the conversion of PIP3 back to PIP2. Accumulated PIP3, in turn, could stimulate the phosphorylation of Akt and increase the nuclear exclusion of the transcriptional factor Foxo3.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Can Dormant Ovarian Follicles From Perimenopausal Women Become Gonadotropin Responsive by Incubation With PTEN Inhibitor and PI3K Activating Peptide?
Study Start Date : November 2010
Estimated Primary Completion Date : November 2011
Estimated Study Completion Date : November 2011

Arm Intervention/treatment
No Intervention: Patients
Perimenopausal women, who will undergo oelvic organ surgery, and will allow harvest of about half an oary for the study purpose
Other: Removal of half an ovary
Removal of half an ovary

Primary Outcome Measures :
  1. Ability of primordial follicles to respond to FSH after incubation [ Time Frame: Two weeks ]
    Human ovarian fragments will be incubated with PTEN inhibitor and PI3K activating peptide and will then be transplanted to nude mice. Subsequently mice will recieve FSH, and follicular response will be monitored.

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Ages Eligible for Study:   45 Years to 51 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Women older than 45 years, undergoing pelvic organ surgery

Exclusion Criteria:

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01201226

Contact: Izhar Ben-Shlomo, MD 972-52-6124781 ibenshlomo@poria.health.gov.il
Contact: Moshe Ben-Smi, MD mbenami@poria.health.gov.il

Department of Obstetrics and Gynecology, Baruch Padeh Medical Center, Poria Not yet recruiting
Tiberias, Israel, 15208
Principal Investigator: Izhar Ben-Shlomo, MD         
Sponsors and Collaborators
The Baruch Padeh Medical Center, Poriya
Study Chair: Izhar Ben-Shlomo, MD Dept. Ob/Gyn, Baruch Padeh Medical Center, Poria, Israel