IVM for Patients With Low Ovarian Response. Does it Improve IVFoutcomes and Does it Improve the Following IVF Cycle?
Primary Purpose
Infertility Female
Status
Unknown status
Phase
Not Applicable
Locations
Israel
Study Type
Interventional
Intervention
In Vitro Maturation Procedure
Sponsored by
![Sheba Medical Center](https://trials-media.s3.amazonaws.com/orgs/sheba-medical-center.jpeg)
About this trial
This is an interventional treatment trial for Infertility Female focused on measuring IVM, HIPPO signaling
Eligibility Criteria
Inclusion Criteria:
Poor ovarian response IVF cycle
Exclusion Criteria:
Normal ovarian response
-
Sites / Locations
- Sheba Medical CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
IVF after IVM
Arm Description
If the patients will not concive during the IVM cycle . results of this following IVF cycle will be compared to the initial IVF preformance Intervention : In Vitro Maturation Procedure
Outcomes
Primary Outcome Measures
Number of oocytes
IVF cycle after IVM results will be compared to the IVF cycle with poor ovarian response
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02498210
Brief Title
IVM for Patients With Low Ovarian Response. Does it Improve IVFoutcomes and Does it Improve the Following IVF Cycle?
Official Title
IVM Treatment in Patients With Low Ovarian Response. Does it Improve IVF Outcome or May it Cause Activation of Ovarian Follicles and Increase the Chances of Success in the Following IVF Cycle?
Study Type
Interventional
2. Study Status
Record Verification Date
November 2019
Overall Recruitment Status
Unknown status
Study Start Date
October 2016 (Actual)
Primary Completion Date
July 2020 (Anticipated)
Study Completion Date
July 2020 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sheba Medical Center
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Poor ovarian response (POR) is one of the major therapeutic challenges in in vitro fertilization. Several therapeutic approaches for POR have been explored; yet, a single effective strategy has not yet been established. Recently, a live birth was reported after ovarian cortex fragmentation and in vitro disruption of the Hippo signaling pathway and activation of Akt signaling. During IVM procedure increased mechanical stimulation of the ovarian cortex takes place. , with the consequent disruption of the Hippo signaling pathway. Our aim is to investigate whether the mechanical manipulation and triggering of ovarian cortex caused by IVM can cause ovarian follicular activation and recruitment by the mechanisms mentioned above. Thus stimulation in the following regular IVF cycle will result in improved ovarian response and increased oocytes yield
Detailed Description
IVM treatment in patients with low ovarian response. Does it improve IVF outcome or may it cause activation of ovarian follicles and increase the chances of success in the following IVF cycle?
Scientific background:
Poor ovarian response (POR) is one of the major therapeutic challenges in in vitro fertilization. The prevalence of poor responders patients varies in the literature between 9 and 24%, however due to the increase in childbearing age it is expected to be one of the main infertility cause. Failure to respond adequately to standard protocols and to recruit adequate follicles results in decreased oocyte production, cycle cancellation and, overall, it is associated with a significantly diminished probability of pregnancy Several therapeutic approaches for POR have been explored; yet, a single effective strategy has not yet been established. Previously it was shown that mechanical manipulation on ovarian cortex such as ovarian wedge resection or ovarian "drilling" by diathermy or laser, induced follicle growth in polycystic ovarian syndrome (PCOS) patient.
Recently, a live birth was reported after ovarian cortex fragmentation and in vitro disruption of the Hippo signaling pathway and activation of Akt signaling. The treated ovarian fragments were grafted back to the patient and after follicle growth, retrieval of mature eggs, in vitro fertilization and embryo transfer; a healthy baby was delivered. The Hippo signaling pathway is essential to maintain optimal organ size and is conserved in all metazoan animals [6-8]. In this study it was shown that ovarian fragmentation increased actin polymerization and disrupted Hippo signaling by decreasing phosphorylated Yes-associated protein (pYAP) levels together with increased nuclear localization of YAP, leading to increased expression of CCN growth factors genes and BIRC apoptosis inhibitors. Secreted CCN2 and related factors promoted follicle growth
Genes involved in ovarian fragmentation, Hippo signaling, and follicle growth is important for ovarian physiology and pathophysiology. Ovarian fragmentation led to changes in intercellular tension and facilitated the conversion of G-actin to F-actin. Subsequent disruption of Hippo signaling decreased pYAP to total YAP ratios, leading to increased expression of downstream CCN growth factors and BIRC apoptosis inhibitors
In vitro maturation (IVM) has been practiced in a clinical setting for over a decade. It has been suggested as an alternative to conventional IVF for minimizing the risk of the ovarian hyperstimulation syndrome (OHSS) in patients with the PCOS. Recently, IVM has been proposed as the method for patients undergoing anticancer treatment, particularly for women who require rapid fertility preservation [9] or face the risk of estrogen-sensitive cancer recurrence involve. Although IVM has been applied to IVF poor responders with equivocal results, several researchers have shown benefits in IVM in women who have low ovarian response.
For the purpose of IVM, oocytes are retrieved from ovarian follicles as small as 4-5mm in diameter, under ultrasound guidance with a single-lumen thinner aspiration needle. The aspiration pressure is reduced compared to regular IVF. Therefore, multiple needle punctures are needed because lower aspiration pressures are used and bloody aspirates may block the thin needle lumen. Because immature oocytes are enclosed in tightly packed cumulus cells, curettage of the follicle wall is needed to dislodge the cumulus oocyte complex. All leads to the fact that during IVM procedure increased mechanical stimulation of the ovarian cortex takes place, with the consequent disruption of the Hippo signaling pathway.
Hypothesis and aims Our aim is to investigate whether the mechanical manipulation and triggering of ovarian cortex caused by IVM can cause ovarian follicular activation and recruitment by the mechanisms mentioned above. Thus stimulation in the following regular IVF cycle will result in improved ovarian response and increased oocytes yield.
Materials and Methods Patients Prospective cohort study on POR patients. Twenty five POR patients will be selected based on the bologna criteria and all patients will have at least one documented POR cycle.
IVM protocol POR patients will be treated in IVM cycle according to our IVF unit protocol, using FSH-priming . Briefly, a baseline evaluation that included a hormonal profile and an ultrasound scan was performed on day 3 of the menstrual cycle. On day 3, 150 IU/day recombinant FSH was added for 3 days. A second evaluation was performed on day 6 of the menstrual cycle. An injection of 10,000 IU hCG (Pregnyl; Organon, Oss, Holland) was administered subcutaneously when the endometrial thickness will be ≥6 mm and the leading follicle will be at least 12 mm. Oocyte retrieval will be performed under ultrasound guidance with a 19G single-lumen aspiration needle (Cook; Queensland, Australia) with a reduced aspiration pressure of 7.5 kPa. The follicular fluid will be collected in culture tubes containing follicle flush buffer (Cook) with 2 IU/ml heparin. Because of the difficulty in identifying compacted oocyte complexes, all aspirates were filtered to identify the additional oocytes.
In-Vitro Oocyte Maturation Germinal vesicles and M1 oocytes will be cultured in IVM medium (Sage; CT, USA) supplemented with 75 IU FSH and 75IU luteinizing hormone (LH; Ferring, Keil, Germany) and checked for maturity between 24-48 hours after culture. Mature oocytes were will be denuded of the granulosa cells and fertilized by intracytoplasmic sperm injection (ICSI). After ICSI, the oocytes will be transferred into IVF medium. Fertilization will be assessed 18 hours after ICSI by examining the oocytes for the appearance of two distinct pronuclei (2PN) and the extrusion of two polar bodies.
IVF protocol Following the IVM treatment, if the patient failed to conceive, she will be offered a conventional IVF treatment, using the same controlled ovarian hyperstimulation protocol, as in her previous IVF treatment (prior to the IVM cycle). Each patient will serve as her own control.
Outcome measurements Outcome measurements will include controlled ovarian hyperstimulation variables, number of retrieved oocytes, mature oocytes on the day of the aspiration, fertilization rate, embryos quality and number of embryos transferred.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infertility Female
Keywords
IVM, HIPPO signaling
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
25 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
IVF after IVM
Arm Type
Experimental
Arm Description
If the patients will not concive during the IVM cycle . results of this following IVF cycle will be compared to the initial IVF preformance
Intervention : In Vitro Maturation Procedure
Intervention Type
Other
Intervention Name(s)
In Vitro Maturation Procedure
Intervention Description
POR patients will be treated in IVM cycle. After baseline evaluation on day 3, 150 IU/day recombinant FSH or HMG will be added for 3 days. A second evaluation will be performed on day 6 of the menstrual cycle. An injection of 10,000 IU hCG (Pregnyl; Organon, Oss, Holland) or Ovitrelle 250mcg (Merck Serono ) will be administered subcutaneously when the endometrial thickness will be ≥6 mm and the leading follicle will be at least 12 mm. Oocyte retrieval will be performed under ultrasound guidance with a 19G single-lumen aspiration needle (Cook; Queensland, Australia). The follicular fluid will be collected in culture tubes containing follicle flush buffer (Cook) with 2 IU/ml heparin. All aspirates were filtered to identify additional oocytes
Primary Outcome Measure Information:
Title
Number of oocytes
Description
IVF cycle after IVM results will be compared to the IVF cycle with poor ovarian response
Time Frame
3 month
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Poor ovarian response IVF cycle
Exclusion Criteria:
Normal ovarian response
-
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ettie Maman, MD
Phone
972526666451
Email
ettiemaman@gmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Raoul Orvieto, MD
Phone
972-53-7678933
Email
Raoul.Orvieto@sheba.health.gov.il
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ettie Maman, MD
Organizational Affiliation
Sheba Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sheba Medical Center
City
Kiryat Ono
ZIP/Postal Code
5229910
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
ettie maman, MD
Phone
97235302882
Email
ettiemaman@gmail.com
12. IPD Sharing Statement
Citations:
PubMed Identifier
20840273
Citation
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Results Reference
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PubMed Identifier
17253503
Citation
Shanbhag S, Aucott L, Bhattacharya S, Hamilton MA, McTavish AR. Interventions for 'poor responders' to controlled ovarian hyperstimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004379. doi: 10.1002/14651858.CD004379.pub2.
Results Reference
background
PubMed Identifier
14380378
Citation
STEIN IF Sr. The management of bilateral polycystic ovaries. Fertil Steril. 1955 May-Jun;6(3):189-205. doi: 10.1016/s0015-0282(16)31980-x. No abstract available.
Results Reference
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PubMed Identifier
22696324
Citation
Farquhar C, Brown J, Marjoribanks J. Laparoscopic drilling by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev. 2012 Jun 13;(6):CD001122. doi: 10.1002/14651858.CD001122.pub4.
Results Reference
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PubMed Identifier
24082083
Citation
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PubMed Identifier
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PubMed Identifier
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Citation
Hergovich A. Mammalian Hippo signalling: a kinase network regulated by protein-protein interactions. Biochem Soc Trans. 2012 Feb;40(1):124-8. doi: 10.1042/BST20110619.
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Maman E, Meirow D, Brengauz M, Raanani H, Dor J, Hourvitz A. Luteal phase oocyte retrieval and in vitro maturation is an optional procedure for urgent fertility preservation. Fertil Steril. 2011 Jan;95(1):64-7. doi: 10.1016/j.fertnstert.2010.06.064. Epub 2010 Aug 5.
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Citation
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IVM for Patients With Low Ovarian Response. Does it Improve IVFoutcomes and Does it Improve the Following IVF Cycle?
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