In Vitro Activation of Dormant Follicles for Patients With Primary Ovarian Insufficiency

Primary Ovarian Insufficiency Clinical Trial

— IVADFPOI  

Official title:

Ovarian Tissue Cryopreservation and Auto-transplantation for in Vitro Activation of Dormant Follicles for Patients With Primary Ovarian Insufficiency

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02322060
• Other study ID #: RMCZZU-IVA
• Status: Recruiting
• Start date: September 2014
• Est. completion date: October 2021

Study information

• Verified date: December 2019
• Source: The First Affiliated Hospital of Zhengzhou University
• Contact: Yingpu Sun, MD,PhD.
• Phone: 86-13803841888
• Email: syp2008[@]vip.sina.com
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

In this study, the investigators used the newly developed technique i.e. in vitro activation of dormant follicles (IVA) to promote ovarian follicle growth much more efficiently than natural, in vivo process for women with Primary Ovarian Insufficiency (POI).Firstly, the investigators remove one ovary under laparoscopic surgery. Then, we dissect ovarian cortex from the ovarian medulla. The ovarian cortex is cut into small cubes and cultured with medium containing drugs to activate dormant follicles. After 2 days of culture, the ovarian cubes are transplanted mainly beneath the membrane of Fallopian tubes under laparoscopic surgery. The ovarian cortex could be cryopreserve for future re-transplantation and in some cases, for convenience to arrange second surgery. Once frozen, the ovary can be preserved semipermanently. After transplantation, patients receive ultrasound monitoring together with measurement of serum hormone levels for 10-12 months. If growing follicles are detected, follicle growth is stimulated by injection of hormones (gonadotropins). Using the same "ovum pick up" approach used in IVF (in vitro fertilization), we pick up oocytes from the follicles and fertilize them. Fertilized eggs are cultured and then cryopreserved for future embryo transfer.

Currently, we recurit patients diagnosed with POI, or Ovarian resistance syndrome (ORS). The procedure can also be: Only superficial cut of the ovarian cortex by laparoscopy or laparotomy, without taking ovary outside or cultured with medium.

Description:

I: Former IVA

1. Remove one ovary (maybe both ovaries depending on the condition) is performed by laparoscopic surgery. (Depending on the condition of patients, the investigators remove both ovaries to increase a chance to obtain residual follicles. Also, in some cases, the investigators need to perform laparotomy, i.e. open surgery, depending on the patient's condition).

2. Quickly dissect ovarian cortex from the ovarian medulla and cut into small stripes. Histological analyses are performed using small parts of the ovarian stripes to find residual follicles.

3. Optional: Cryopreserve the ovarian stripes by a vitrification method. Two days before the day of reimplantation, thaw the ovarian stripes.

4. The ovarian stripes are cut into small cubes (1 x1 mm2). The ovarian cubes are cultured with medium containing drugs to activate dormant follicles for 2 days before transplantation. After washing, the cubes are transplanted beneath the membrane of both Fallopian tubes and the remaining ovary under laparoscopic surgery.

5. Monitor follicle growth by ultrasound and serum hormone assays. Once follicles reach >16 mm in diameter, patients receive hCG, followed by egg retrieval in ~36 hours. Then the investigators will perform intracytoplasmic sperm injection (ICSI) using the husband's sperm. When embryos reached the four-cell stage, they were cryopreserved, waiting for frozen-thaw embryo transfer.

II Current procedure:

Only superficial cut of the ovarian cortex by laparoscopy or laparotomy, without taking ovary outside or cultured with medium.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: October 2021
• Est. primary completion date: October 1, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 39 Years

Eligibility

Inclusion Criteria:

• Married women (18-39) diagnosed with POI/ORS

• With both ovaries present

• With normal uterine cavity

• Healthy and can stand surgery

Exclusion Criteria:

• Any one that does not meet the inclusion criteria

Related Conditions & MeSH terms

• Dormant Follicle
• Gonadal Dysgenesis
• in Vitro Activation
• Menopause, Premature
• Ovarian Resistance Syndrome
• Primary Ovarian Insufficiency
• Turner Syndrome

Intervention

Procedure:
• Ovariotomy
Remove one ovary (maybe both ovaries depending on the condition) by laparoscopic surgery or by laparotomy in some cases.
• Activate dormant follicles
Cut ovary into small cubes, which are then cultured with medium containing BPV(pic), a PTEN inhibitor, and 740YP, an activator of phosphoinositol 3 kinase, to activate dormant follicles for 2 days before transplantation.
• Ovary tissue transplantation
After extensive washing to remove drugs, the ovary cubes are transplanted beneath the membrane of both Fallopian tubes and the remaining ovary under laparoscopic surgery.
• Ovarian superficial cut
Superficial cut of the ovarian cortex by laparoscopy or laparotomy

Locations

Country	Name	City	State
China	Reproductive Medical Center, First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan

Sponsors (3)

Lead Sponsor	Collaborator
The First Affiliated Hospital of Zhengzhou University	St. Marianna University School of Medicine, Stanford University

Country where clinical trial is conducted

China, 

References & Publications (3)

Donnez J, Martinez-Madrid B, Jadoul P, Van Langendonckt A, Demylle D, Dolmans MM. Ovarian tissue cryopreservation and transplantation: a review. Hum Reprod Update. 2006 Sep-Oct;12(5):519-35. Epub 2006 Jul 18. Review. — View 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. — View Citation

Li J, Kawamura K, Cheng Y, Liu S, Klein C, Liu S, Duan EK, Hsueh AJ. Activation of dormant ovarian follicles to generate mature eggs. Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10280-4. doi: 10.1073/pnas.1001198107. Epub 2010 May 17. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical pregnancy	Clinical pregnancy was confirmed by detection of one or more gestational sacs during transvaginal scan 4 weeks after embryo transfer.	1 year
Secondary	Follicle growth	Detection of estrogen level elevation and follicle diameter increases reflecting follicle growth.	1 year