25 March 2019: 

Summary

Ovarian cryopreservation and retransplantation for fertility protection is well established in Europe, but not in China or other Asian countries. Four recent publications [1-4] stress that this technique is no longer experimental and should be regarded as a valid ART treatment option especially for some cancer types. However, this technique is not only performed to restore fertility but also to restore ovarian function after surgery, radiotherapy and chemotherapy. China's first official "International Center of Fertility Protection Specialized in Ovarian Tissue Cryopreservation and Transplantation" was established in 2012 within the Beijing Obstetrics and Gynecology Hospital, Capital Medical University, with the help of European experts. In 2016 the first retransplantation of cryopreserved ovarian tissue was performed, and has recently been published as a "case report" [5]. The cryopreservation and transplantation was performed to preserve ovarian function in a patient with squamous cell cervical carcinoma I b1 after surgery. The 35-year-old nulliparous patient came in June 2015 for consultation. During cervical cancer surgery half of her left ovary was removed and transferred to the cryobank. Ovarian cortical strips were frozen using a standardized slow-freezing process and stored in liquid nitrogen. Following 19 cycles of radiotherapy and 3 cycles of chemotherapy, between August 2015 and October 2015, severe menopausal symptoms appeared (estradiol (E2) about 30 pg/ml, FSH > 100 IU/l); these were treated with E2 patches 50µg/day until August 2016 (E2 about 90 pg/ml, FSH about 50 IU/l). After oncologists confirmed a disease-free condition, the cryopreserved-thawed ovarian tissue retransplantation was performed in September 2016. Thawing of the cortical strips was performed using a standardized protocol and four ovarian tissue fragments were transplantated into a peritoneal pocket in the area of the right peritoneal ovarian fossa. Restoration of ovarian endocrine function was shown in the third month after transplantation, accompanied by a significant reduction in Kupperman score from 37 before transplantation to 5 in the first month after transplantation. The score subsequently remained low and stable.

Commentary

Cryopreserved-thawed ovarian tissue is mainly transplanted orthotopically (i.e. into the peritoneum, into or onto the ovary) [6]. However, in some cases retransplantation is also performed in heterotopic sites, and one pregnancy has been reported worldwide [7]. In our case, the tissue fragments were retransplanted into a peritoneal pocket lateral to the right ovary where the blood supply was proved to be rich. The same approach has been used in most cases of retransplantation in 16 European centres, and has resulted in high success rates and may be an alternative to transplantation into the ovary [8]. The first signs of ovarian activity usually occur after 3 months based on the time of follicular growth, and most patients recuperate ovulatory cycles within 4-9 months after retransplantation [8]. This case may be  very "normal" for other countries, especially in Europe, where ovarian tissue preservation was introduced years ago but, for China, this first report of successful retransplantation represents a milestone in the field of fertility preservation, although until now no live birth has been reported. Worldwide this technique has lead to more than 130 live births were reported until June 2017, and restoration of ovarian activity in over 95% of cases [2]. No frozen-thawed ovarian tissue retransplantation has been previously reported in China, and, to our knowledge, the center in the Beijing OB/GYN Hospital is still the only one to have performed this technique, although other large hospitals in China have been showing a growing interest in establishing a cryobank and performing ovarian preservation and retransplantation. This large interest finds its expression in the "First Chinese Guideline of Ovarian Tissue Cryopreservation and Transplantation" [9]. With regards to the medical content, the consensus is very similar to Western guidelines but with a focus on practical issues joining gynecologists, embryologists, oncologists, pediatricians, breast oncologists, hematologists and experts in Traditional Chinese Medicine (TCM). The guideline includes: selection criteria, evaluation and indications, standard operating procedures of ovarian tissue removal, transportation, preparation, freezing and thawing, approaches to ovarian tissue transplantation and follow-up, practical recommendations for ovarian tissue cryopreservation and transplantation including recommendations of the diseases for which this method could be applied, and treatment of menopausal symptoms during the time between cryopreservation and retransplantation. In our center, currently, the ovarian tissue of more than 200 patients has been cryopreserved and six other patients have undergone successful retransplantation. To understand the importance of China's first center the special situation of fertility protection in China must be considered. Until 2016 China (with some exceptions in the countryside) was officially ruled under the "One-Child-Policy", without much support to the introduction of new techniques in the field of fertility protection.

In general, a long time and much paper-work were needed in China to introduce new techniques in medicine considered as "experimental" for clinical use. Indeed, the idea of this first new project in China began in December 2011, after I had learned about it during a scholarship program in 2010 in Germany and experts from Germany (already cooperating with the Beijing OB/GYN Hospital in other projects) had proposed this technique to leaders of China's foreign government. It took three years to establish the cryobank, and permission from the government was only given with the precondition that, for the clinical part, a network all over China would be implemented. Ovarian tissue sampling surgery and transplantation surgery can now be performed in standardized clinical centers around the country, but cryopreservation and preservation needs to be centralized – this was recently the consensus published in the first Chinese guideline [9]. 

Because cryopreservation and thawing are decisive steps, the quality control of the laboratory part is most important for performing retransplantations successfully [10]. Cryopreservation should be performed in a specialized center with the appropriate expertise and with efficient collaboration between the laboratory and clinic. Thus according to the model, for example, of the German network for fertility protection techniques "Fertiprotekt" [6] with centers in Germany, Austria and Switzerland, a similar network is currently under construction in China. Currently, there is only one centralized cryobank, but certainly more will follow to cover the huge country of China. Within this network, doctors must be informed that ovarian tissue cryopreservation not only can preserve fertility but can also restore endocrine function for patients with severe and recurrent endometriosis or with high risk of premature ovarian insufficiency, and is suitable for patients with tumors and non-malignant diseases. Good candidiates are pre-pubertal patients, patients whose chemoradiation treatment cannot be delayed, and patients with malignancies like breast cancer, sarcoma, pelvic tumors (including borderline ovarian tumors), hematological diseases (leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma), and also non-malignant diseases requiring radiotherapy, chemotherapy or stem cell transplantion (aplastic anemia; thalassemia; systemic lupus erythematosus, etc). The main current problem is that patients have no knowledge about this new method of fertility preservation and do not get adequate information from their doctors before undergoing surgery, followed by chemotherapy and radiotherapy. Additionally, most doctors in China do not know how to proceed in practice even if they have some knowledge about protection of ovarian function and fertility by cryopreservation. Therefore, there is an urgent need to introduce this technology now in China as well.

Xiangyan Ruan

Director of the Department of Endocrinology for Gynecology, Director of the Menopause Clinic, and Director of the Fertility Protection Centre, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, China

References 

1. Oktay K, Harvey BE, Partridge AH, et al. Fertility Preservation in Patients with Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2018; 36: 1994-2001
   https://www.ncbi.nlm.nih.gov/pubmed/29620997
2. Donnez J, Dolmans MM. Fertility Preservation in Women. N Engl J Med 2018; 378: 400-01
   https://www.ncbi.nlm.nih.gov/pubmed/29365297
3. Christianson MS, Lindheim SR. Pediatric ovarian tissue cryopreservation: time to lift the experimental label? Fertil Steril 2018;109 : 805-06
   https://www.ncbi.nlm.nih.gov/pubmed/29691062
4. Forman EJ. Ovarian tissue cryopreservation: still experimental? Fertil Steril 2018; 109: 443-44
   https://www.ncbi.nlm.nih.gov/pubmed/29566858
5. Ruan X, Juan Du J, Korell M et al. Case report of the first successful cryopreserved ovarian tissue retransplantation in China. Climacteric 2018; 21: 613-616
   https://www.ncbi.nlm.nih.gov/pubmed/30378441
6. von Wolff M, Germeyer A, Liebenthron J et al. Practical recommendations for fertility preservation in women by the FertiPROTEKT network. Part II: fertility preservation techniques. Arch Gynecol Obstet 2018; 297 :257-67
   https://www.ncbi.nlm.nih.gov/pubmed/29181578
7. Stern CJ, Gook D, Hale LG et al. First reported clinical pregnancy following heterotopic grafting of cryopreserved ovarian tissue in a woman after a bilateral oophorectomy. Hum Reprod 2013; 28:2996-9
   https://www.ncbi.nlm.nih.gov/pubmed/24014608
8. Van der Ven H, Liebenthron J, Beckmann M et al. 95 orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates. Hum Reprod 2016; 31:2031-41
   https://www.ncbi.nlm.nih.gov/pubmed/27378768
9. Ruan X. Chinese Society of Gynecological Endocrinology affiliated to the International Society of Gynecological Endocrinology Guideline for Ovarian Tissue Cryopreservation and Transplantation. Gynecol Endocrinol 2018; 34: 1005-1010
   https://www.ncbi.nlm.nih.gov/pubmed/30129788
10. Li Y, Ruan X, Liebenthron et al. Ovarian tissue cryopreservation for patients with premature ovary insufficiency caused by cancer treatment: optimal protocol. Climacteric 2019 Jan 24:1-7
    https://www.ncbi.nlm.nih.gov/pubmed/30676094