19 August 2019: 

UK media recently reported that a Birmingham-based company called ProFaM (Protecting Fertility and Menopause) were offering a “new” procedure for women: cryopreservation of autologous ovarian tissue to delay menopause through later reimplantation. The company, co-founded by Arri Coomarasamy, Christiani Amorim, Yousri Afifi and Simon Fishel, four world-renowned experts in reproductive medicine, are proposing to perform laparoscopy in premenopausal women, within 40 years of age, to collect sections of ovarian tissue. The ovarian tissue is frozen at -150C and preserved in an authorised bank until women reach the menopause, when it is then thawed and transplanted back into the body, where it will replace the function of the original ovaries.

This is not a new procedure. It was developed for cancer patients undergoing potentially gonadotoxic treatments and was first described by Kutluk Oktay and collegues in 2000 in a patient who had undergone bilateral salpingo-oophorectomy by age 29 and for whom wedges of ovarian tissue had been cryopreserved. Ovarian tissue was later reimplanted in an attempt to cure persistent menopausal symptoms [1]. In 2004, another pioneering group lead by Jacques Donnez achieved a livebirth after successful orthotopic transplantation of cryopreserved ovarian tissue in a woman with stage IV Hodgkin's lymphoma [2]. Other groups worldwide, like that lead by Xiangyan Ruan, have gone on to successfully perform the procedure on patients with the specific short-term goal of achieving a pregnancy [3, 4]. The procedure is specifically indicated for fertility preservation in child and adolescent patients and patients who cannot delay cancer treatment to pursue other methods of fertility preservation such as oocyte or embryo cryopreservation[5,6].

ProFaM’s objective, in the case of naturally menopausal women, is hormonal preservation. The idea behind this procedure is to prevent, by reimplanting functioning ovarian tissue, debilitating conditions which occur more frequently in women after the menopause, such as cardiovascular disease and osteoporosis. Moreover, the procedure would potentially delay bothersome symptoms of the menopause to an age when a woman is not struggling with family and career issues. Nine cases of UK women, age range 22-36, were reported to have undergone the protocol thus far.

The British Menopause Society (BMS) recently published online a consensus statement regarding this issue [7] and recommends that “this procedure should be initially assessed in controlled clinical research trials to evaluate its safety and feasibility before it could be considered as a potential option in clinical practice”. Specific concerns of the BMS (7) are:

• the lack of long-term reporting on the safety and efficacy of this technique
• the ethics behind performing surgery on healthy women, with the potential risks associated to the laparoscopic procedure and general anesthesia
• the potential impact of removing ovarian tissue on future fertility
• the potential risk of ovarian cancer associated with re-implanting ovarian tissue
• the potential risk of breast cancer with delayed menopause.

Moreover, ovarian function after reimplantation is completely dependent on the follicular density at the time of ovarian-tissue cryopreservation [8] and by consequence, the duration and function of the ovarian tissue may be variable. The ProFaM group claim a delay of the menopause for up to 20 years, but do not provide long-term follow up to support this conclusion [7].

The International Menopause Society (IMS) is in agreement with and supports the BMS consensus. When asked her view on the issue, Xiangyan Ruan, Board member of the IMS and expert in the procedure in China, stated that “enough ovarian tissue (for example more than 20 slices) would need to be collected and cryopreserved in order to ensure hormonal preservation for that many years. In my experience 4 cortex slices, lasting 3-5 years, would need to be reimplanted at least 4-6 times to delay the menopause by 20 years. Personally, I think the main aim of this technique should be that of preventing iatrogenic premature ovarian insufficiency”. All patients considering this procedure should be thoroughly counseled on the considerable physical, emotional, financial and time investment involved.

References

1. Oktay K, Karlikaya G. Ovarian function after transplantation of frozen, banked autologous ovarian tissue. N Engl J Med. 2000 Jun 22;342(25):1919.
   https://www.ncbi.nlm.nih.gov/pubmed/10877641
2. Donnez J, Dolmans MM, Demylle D, Jadoul P, Pirard C, Squifflet J, Martinez-Madrid B, van Langendonckt A.Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004; 3649443:1405‐1410.
   https://www.ncbi.nlm.nih.gov/pubmed/15488215
3. Ruan X, Du J, Korell M, Kong W, Lu D, Jin F, Li Y, Dai Y, Yin C, Yan S, Gu M, Mueck AO. Case report of the first successful cryopreserved ovarian tissue retransplantation in China. Climacteric. 2018 Dec;21(6):613-616.
   https://www.ncbi.nlm.nih.gov/pubmed/30378441
4. Li Y, Ruan X, Liebenthron J, Montag M, Zhou Q, Kong W, Du J, Jin F, Li S, Cheng J, Wang H, Mueck AO. Ovarian tissue cryopreservation for patients with premature ovary insufficiency caused by cancer treatment: optimal protocol. Climacteric. 2019 Aug;22(4):383-389
   https://www.ncbi.nlm.nih.gov/pubmed/30676094
5. Oktay K, Harvey BE, Partridge AH, Quinn GP, Reinecke J, Taylor HS, Wallace WH, Wang ET, Loren AW.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
6. Donnez J, Dolmans MM. Fertility preservation in women. N Engl J Med. 2018 Jan 25;378(4):400-401.
   https://www.ncbi.nlm.nih.gov/pubmed/29365297
7. New medical procedure could delay menopause by twenty years – BMS response
   https://thebms.org.uk/2019/08/new-medical-procedure-could-delay-menopause-by-twenty-years-bms-response/
8. Donnez J, Dolmans MM, Diaz C, Pellicer A. Ovarian cortex transplantation: time to move on from experimental studies to open clinical application. Fertil Steril 2015;104:1097-1098.
   https://www.ncbi.nlm.nih.gov/pubmed/26342246