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

NCT02322060 | Completed DMC

• 1 other identifier: RMCZZU-IVA
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

In Vitro Activation; Dormant Follicle; Primary Ovarian Insufficiency; Ovarian Resistance Syndrome

Keywords

IVA, ovary tissue grafting, POI, ORS

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Follicle growth

  1 year

Study Arms (2)

Primary ovarian insufficiency

Primary ovarian insufficiency (POI; also known as premature ovarian failure/dysfunction/insufficiency or premature menopause) is characterised by amenorrhoea, sex hormone (oestrogen, progesterone and testosterone) deficiency and elevated gonadotrophins levels in a woman aged more than two standard deviations below the mean age of menopause estimated for her reference population. POI is defined as a disorder in ovarian function in any woman before the age of 40 years, irrespective of the cause. In our study, we mainly recruit POI patients who also desire to have a baby of their own.

Procedure: Ovariotomy; Procedure: Activate dormant follicles; Procedure: Ovary tissue transplantation; Procedure: Ovarian superficial cut

Ovarian resistance syndrome

We currently also include patients diagnosed with Ovarian resistance syndrome, which means that follicles exist, but do not response to FSH.

Procedure: Ovariotomy; Procedure: Activate dormant follicles; Procedure: Ovary tissue transplantation; Procedure: Ovarian superficial cut

Interventions

Ovariotomy PROCEDURE

Remove one ovary (maybe both ovaries depending on the condition) by laparoscopic surgery or by laparotomy in some cases.

Ovarian resistance syndrome; Primary ovarian insufficiency

Activate dormant follicles PROCEDURE

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.

Ovarian resistance syndrome; Primary ovarian insufficiency

Ovary tissue transplantation PROCEDURE

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 resistance syndrome; Primary ovarian insufficiency

Ovarian superficial cut PROCEDURE

Superficial cut of the ovarian cortex by laparoscopy or laparotomy

Ovarian resistance syndrome; Primary ovarian insufficiency

Eligibility Criteria

• Age: 18 Years - 39 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Women diagnosed with POI/ORS who also want to get pregnant by IVF/ICSI-ET with their own oocyte.

You may qualify if:

• Married women (18-39) diagnosed with POI/ORS
• With both ovaries present
• With normal uterine cavity
• Healthy and can stand surgery

Sponsors & Collaborators

• The First Affiliated Hospital of Zhengzhou University: lead
• Stanford University: collaborator
• St. Marianna University School of Medicine: collaborator

Study Sites (1)

Reproductive Medical Center, First Affiliated Hospital of Zhengzhou University

Zhengzhou, Henan, 450052, China

Location

Related Publications (4)

• Zhai J, Yao G, Dong F, Bu Z, Cheng Y, Sato Y, Hu L, Zhang Y, Wang J, Dai S, Li J, Sun J, Hsueh AJ, Kawamura K, Sun Y. In Vitro Activation of Follicles and Fresh Tissue Auto-transplantation in Primary Ovarian Insufficiency Patients. J Clin Endocrinol Metab. 2016 Nov;101(11):4405-4412. doi: 10.1210/jc.2016-1589. Epub 2016 Aug 29.

  PMID: 27571179 BACKGROUND

• 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. doi: 10.1093/humupd/dml032. Epub 2006 Jul 18.

  PMID: 16849817 BACKGROUND

• 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.

  PMID: 20479243 BACKGROUND

• 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.

  PMID: 24082083 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Serum, ovary tissue

MeSH Terms

Conditions

Primary Ovarian Insufficiency; Acidemia, isovaleric; Osteoarthritis

Condition Hierarchy (Ancestors)

Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases

Study Officials

• Yingpu Sun, MD,PhD

  The First Affiliated Hospital of Zhengzhou University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Target Duration: 2 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Reproductive Medical Center

Study Record Dates

• First Submitted: December 17, 2014
• First Posted: December 22, 2014
• Study Start: September 1, 2014
• Primary Completion: October 1, 2021
• Study Completion: October 1, 2021
• Last Updated: March 5, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)