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Transplantation of Frozen Thawed Ovarian Tissue –

State of the Art

Schmidt KT, Ernst E, Greve T, Andersen CY

J. Reproduktionsmed. Endokrinol 2013; 10 (Sonderheft

1), 55-58

Transplantation of Frozen Thawed Ovarian Tissue

J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 55

Transplantation of Frozen Thawed Ovarian Tissue –State of the Art

K. T. Schmidt1, E. Ernst2, T. Greve3, C. Y. Andersen3

Received: June 6, 2012; accepted: September 11, 2012From the 1The Fertility Clinic, University Hospital of Copenhagen, Rigshospitalet, Copenhagen; the 2Department of Gynaecology and Obstetrics, University Hospital of Aarhusand the 3Laboratory of Reproductive Biology, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, DenmarkCorrespondence: Kirsten Tryde Schmidt, The Fertility Clinic section 4071, University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark;e-mail: kirsten.tryde.schmidt@rh.regionh.dk

Introduction

The 5-year survival rate after many can-cers has improved significantly over thepast decades, especially regarding child-hood cancers and cancers in the youngadults [1]. As a consequence, one in 593adults will be a survivor of a childhoodcancer [2] and this can be attributed tothe more aggressive chemotherapy regi-mens and the targeted radiotherapytreatment that are used today. A paradoxexists, however, between the wanted de-struction of the malignant cells and theunwanted side effects that may arise dueto destruction of benign cells. Foryounger women in their fertile years amost unwanted and serious side effect tocancer treatment is the loss of ovarianfunction that occurs if all the ovarian fol-licles are destroyed. This is a known sideeffect to both chemotherapy, especiallyif the protocol includes an alkylatingagent, and to abdominal radiationtherapy [3, 4]. For many young womenwho have not yet attempted to conceivebefore they are diagnosed with cancer,this risk of infertility is very serious andalarming and for this reason, several op-tions of fertility preservation have beendeveloped and are offered to more andmore young women before the initiationof their cancer treatment. Cryopreserva-tion of ovarian tissue is one method offertility preservation, which has beendeveloped and refined primarily over thelast decade [5]. An entire ovary, a semi-ovary or ovarian cortical biopsies are

collected and cryopreserved for lateruse. If the woman as a consequence ofher treatment experiences prematureovarian insufficiency (POI) she can re-quest the frozen ovarian tissue thawedand transplanted. This has been per-formed on many cancer survivors world-wide and the majority of these have re-gained their ovarian function after trans-plantation [6, 7] and so far a total of 18children have been born as a result fromtransplantation [8–20].

Effect of Chemo- and Ra-

diation Therapy on the

Ovary

Different chemotherapeutic agents exertdifferent mechanisms of action on thecells and on the follicles in the ovary.The alkylating agents act on both restingand dividing cells and the quiescent,meiotically inactive oocytes in the pri-mordial follicles are more susceptibleto the damaging effects of alkylatingagents than other chemotherapeuticagents. This has been found in a study byMeirow, who compared the risk of POIin young cancer patients according towhich drugs they received. Administra-tion of alkylating agents had an OR of4.0 for POI, which was a significantlyhigher risk than when platinum agents(OR = 1.8), plant alkaloids (OR = 1.2),or antimetabolites (OR < 1) were used[21]. Oocytes are very susceptible to thedamage caused by radiotherapy [4] andthe majority of patients receiving a dose

> 20 Gy will become sterile as a conse-quence [22]. Treatment with bone mar-row transplantation (BMT), which is of-ten used in leukaemia patients or pa-tients with non-malignant haematologi-cal conditions such as Thallasaemia oraplastic anemia, causes loss of ovarianfunction in most patients [23] as a conse-quence of the pre-conditioning protocolsconsisting of high-dose chemotherapyand total body irradiation.

Cryopreservation of Ova-

rian Tissue

By laparoscopy, ovarian tissue can beexcised on a short notice, usually with-out any significant delay of a potentiallygonadotoxic treatment. Cryopreserva-tion of ovarian tissue involves removalof an entire ovary or parts of an ovaryprior to treatment. The ovarian cortex,which harbours the primordial follicles,is isolated in a thickness of approxi-mately 1 mm. After appropriate equili-bration in a cryoprotectant medium thetissue is frozen and stored in liquid nitro-gen and can potentially be kept frozenfor many years [24]. When the womanhas been cured she can have some of thepieces of tissue thawed and transplanted,if she has become menopausal as a con-sequence of her treatment. Some of theprimordial follicles within the pieces ofcortical tissue will survive the freezingand transplantation procedure and havethe capacity to be reactivated and start togrow and thus re-establish a cyclic endo-

Worldwide, an increasing number of cancer patients have some of their ovarian tissue cryopreserved for fertility preservation purposes prior to treatmentof a malignant disease. The purpose of this review is to summarize the results from ovarian tissue transplantation and the different techniques that can beapplied when autotransplanting the tissue. To date, a total of 18 babies have been born as a result of cryopreserved/thawed autotransplanted ovariancortical tissue and an even larger number of premenopausal women have regained their ovarian function and menstrual cyclicity as a result of autotrans-plantation. Orthotopic or heterotopic sites can be chosen for the cortical grafts, but so far all babies born have been from orthotopical graft sites. Follow-up studies after transplantation have shown encouraging results regarding the longevity of the grafts with up to 8 years of graft viability. Reassuringly, nocases of introduction of the original disease have so far been reported in cancer survivors grafted with frozen/thawed ovarian tissue. J Reproduktions-med Endokrinol 2013; 10 (Special Issue 1): 55–8.

Key words: cancer, cortex, cryopreservation, fertility preservation, ovary

For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH.

56 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1)

Transplantation of Frozen Thawed Ovarian Tissue

crine milieu needed for a normal men-strual cycle and conception.

Orthotopic Transplantation

Orthotopic transplantation means trans-planting tissue into its normal place inthe body, which, in the case of ovariantissue, means grafting it into the remain-ing ovary or at the site of the removedovary. So far, all the children that havebeen born as a result of ovarian tissuetransplantation originate from ortho-topically grafted tissue. Table 1 gives anoverview of the 18 children that have sofar been born following autotransplanta-tion of cryopreserved/thawed ovariantissue. The first report came fromDonnez’ group in Belgium in 2004 [8].They transplanted strips and small cubesof cryopreserved/thawed ovarian corti-cal tissue to a small peritoneal window,which was created by laparoscopy 7 daysearlier, beneath the right ovarian hilus.This was repeated after 4 months. After10 months the patient conceived sponta-neously and later gave birth to a healthybaby girl. Later, other groups followedreporting successful pregnancies in can-cer patients after orthotopically trans-planted tissue into the remaining ovariesas either cortical strips or fragments [9–12, 14–16] or tiny ovarian fragments im-

mersed in oocyte wash buffer [9], al-though in the latter method ovarian func-tion never resumed. Other orthotopicgrafts sites have been introduced such asthe broad ligament or a peritoneal pocketclose to the broad ligament [18, 19] or aperitoneal pocket between the iliac ves-sels [13]. In theory, when grafting to anorthotopic site, the patient should beable to conceive naturally and so far, themajority of the babies born followingthis procedure have resulted from spon-taneous conceptions. But some womenwill need in vitro fertilization, IVF, inorder to become pregnant, either be-cause they already had a history of sub-fertility before their cancer diagnosis orfor other reasons such as a partner with alow sperm count.

Heterotopic Transplanta-

tion

So far, no children have been born fol-lowing transplantation to a heterotopictransplantation site. In our group, wehave had 2 biochemical pregnanciesarising from oocytes aspirated from agraft site in the anterior abdominal wall,but unfortunately these pregnanciesnever developed further [7]. But the factthat IVF led to the aspiration of maturemetaphase II oocytes that were fertilized

and able to implant, although onlybriefly, means that oocytes derivingfrom cryopreserved/thawed ovarian tis-sue are able to undergo a normal matura-tion process and there is no reason to be-lieve that the pregnancies reported aftertransplantation have not arised from thegrafted tissue. Oktay and co-workersused a heterotopic graft site for their firstautotransplantation. Two women withcervical cancer and recurrent benignovarian cysts, respectively, had some oftheir ovarian tissue transplanted sub-cutaneously to the forearm [25]. After 10weeks and 6 months, respectively, a fol-licle appeared at the graft site and levelsof FSH normalized. Percutaneous oo-cyte aspirations yielded a mature oocyte.The same author later transplantedcryopreserved/thawed ovarian tissue be-low the skin of the abdomen but severalIVF attempts only yielded three meta-phase II oocytes from a total of 20 fol-licles [26]. Kim transplanted ovarian tis-sue into the space between the rectussheath and the rectus muscle in five can-cer survivors, who all regained their ova-rian function between 12–20 weeks aftertransplantation [27]. We have trans-planted fragments of cortical tissue intoa peritoneal pocket corresponding to theabdominal wall between the umbilicusand the pubic bone. After IVF this graft

Table 1. 18 Live Births after Transplantation of Frozen-Thawed Ovarian Tissue

Age at Cryo- Disease Gestation Sex Weight Referencepreservation (Weeks) (kg)(Years)

25 Hodgkin’s Lymphoma 39 F 3.720 Donnez, 2004 [8]

17 Neuroectodermic Tumor 38 M 2.830 Donnez, 2011 [17]

28 Non Hodgkin’s Lymphoma 38 F 3.000 Meirow, 2005 [9]

24 Hodgkin’s Lymphoma 41 F 3.130 Demeestere, 2007 [10]39 F 2.870 Demeestere, 2010 [16]

27 Ewing Sarcoma 39 F 3.204 Andersen, 2008 [11]39 F 3.828 Ernst, 2010 [15]41 M 4.015 Andersen, 2012 [37]

25 Hodgkin’s Lymphoma 37 M 2.600 Andersen, 2008 [11]

20 Hodgkin’s Lymphoma 38 M 3.089 Silber, 2008 [12]

27 Microscopic polyangiitis 37 F 2.030 Donnez, 2011 [17]

36 Breast Cancer 33 M 1.650 Sánchez-Serrano, 2010 [14]33 M 1.830

20 Sickle Cell Anemia 38 F 3.700 Roux, 2010 [13]

19 Thalassemia 39 M 3.026 Revel, 2011 [18]

n. s. Hodgkin’s Lymphoma n. s. n. s. n. s. Silber, 2012 [20]

n. s. Premature Ovarian Failure n. s. n. s. n. s. Silber, 2012 [20]

25 Hodgkin’s Lymphoma 38 M 3.360 Dittrich, 2012 [19]

n. s.: not stated, M: male, F: female

Transplantation of Frozen Thawed Ovarian Tissue

J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 57

site has yielded mature oocytes and inspontaneous cycles the site has revealedpre-ovulatory follicles as well [7].

Transport of Ovarian Tissue

Prior to Cryopreservation

There is no doubt that cryopreservingovarian tissue is a specialist task thatshould ideally be centralised to only afew centres with a sufficient number ofcases to maintain skills and a high exper-tise. This facilitates quality control,proper equipment and personnel thatmaintain a proper expertise and can ful-fil all the clinical, legal and scientificstandards that are required for appropri-ate conduction of the procedure. How-ever, this still allows other centres to of-fer the initial counselling and the collec-tion of the tissue. We have previouslyshown that ovarian tissue remains viableafter transport of up to five hours cooledon ice prior to freezing [28] and shownin another case that the tissue remainedviable after a 20 hour period on ice priorto freezing [24]. In fact, all of the 4 chil-dren so far born in Denmark originatefrom tissue that has been transported forup to 5 hours before cryopreservation.Recently, Dittrich and co-workers re-ported of a live birth after ovarian tissueautotransplantation, where the tissue hadoriginally been transported overnightand had been kept cool for more than 20hours before it was cryopreserved [19].This should encourage centres that donot offer ovarian tissue cryopreservationto enter collaboration with a centre withthe required expertise and still offer thisprocedure to their patients, as the tissuedoes not need to be cryopreserved assoon as it has been collected.

Risk of Reintroduction of

the Original Disease after

Transplantation

In cancer patients it cannot be excludedthat the tissue harvested before cancertreatment may harbour malignant cells. Ifthe ovarian tissue is infiltrated with ma-lignant cells there may be a risk of intro-ducing a sufficient number of malignantcells to cause a relapse. For certain cancertypes this risk is higher than for others.Ovarian tissue from leukaemia patients,for instance, has a high risk of harbouringleukaemic cells [29, 30] and so far no pa-tients cured of leukaemia have been of-fered ovarian tissue transplantation due tothe risk of relapse. Other cancers have amuch lower risk of malignant cell con-tamination in the ovaries, especially if theovary is cryopreserved in patients withlocal disease only. It has been estimatedthat worldwide approximately 45 patientswith a previous cancer diagnosis have hadovarian tissue transplantation and so farthere have been no reports of relapse dueto the grafted tissue. This is reassuring,but further studies on the safety are war-ranted. So far studies on breast cancerpatients and lymphoma patients haveshown a very low risk of malignant cellinfiltration in the cortical tissue fromthese patients [31–34].

Our Experience

In Denmark, a total of 22 patients haveso far received transplantation of frozen/thawed tissue a total of 31 times. Thus,9 patients have received one additionaltransplant, either to augment the folliclepool and thus their chances of becomingpregnant or because the function of the

first grafted tissue was exhausted and thepatient had become menopausal again.Figure 1 shows spontaneous folliculardevelopment corresponding to the firstgraft site during a second autotransplan-tation just above the first graft in a peri-toneal pocket above the internal iliac ar-tery. All 22 patients resumed endog-enous hormone production and follicu-lar development after transplantation.Levels of follicle stimulating hormone(FSH) that were high before transplanta-tion decreased gradually and after ap-proximately 20 to 25 weeks a preovula-tory follicle appeared on ultrasonogra-phy and the patient resumed menses.Figure 2 shows the mean concentrationof FSH (IU/l) ± SEM following trans-plantation. Apart from a 13-year-oldgirl, who had her tissue transplanted inorder to induce a natural puberty andthree other adult cancer survivors whowanted their tissue transplanted to alle-viate menopausal symptoms, all of ourpatients initially requested transplanta-tion because of a pregnancy wish. So far,6 women have experienced a total of9 pregnancies after transplantation lead-ing to 2 biochemical pregnancies, 2 firsttrimester spontaneous abortions, oneinduced abortion [35] and the delivery of4 healthy babies. One patient, who wasdiagnosed with Ewing’s sarcoma in 2004,has had 3 babies after transplantation ofsome of her cryopreserved/thawed tissuein 2005. Her first pregnancy was the re-sult of IVF but the other 2 children werespontaneously conceived [11, 36]. Theother patient to deliver a child had beentreated with BMT for Hodgkin’s diseaseand conceived after several attempts ofIVF and a second transplantation anddelivered a healthy boy [11].

Figure 1. Spontaneous follicular development from the first graft site in a peritonealpocket at the pelvic wall above the internal iliac artery.

Figure 2. Mean concentration of FSH (IU/L) ± SEM following transplantation of fro-zen/thawed ovarian tissue to 15 Danish women.

58 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1)

Transplantation of Frozen Thawed Ovarian Tissue

The duration of the transplants in ourseries has varied. In general, the age ofthe patient at the time of cryopreserva-tion is a determining factor on the lon-gevity of the graft; i.e. the younger thepatient at the time of cryopreservationthe longer the graft will last. Other deter-mining factors are the amount of tissuethat is transplanted and whether or notthe patient has received any chemo-therapy prior to collection of the tissue.Most patients in our series have experi-enced at least 2–4 years of activity withthe tissue still functional. One patienthad her first transplant in 2004 and a sec-ond transplant in 2008 while the firstgraft was still functioning and still hasfunctional tissue 8 years after the firsttransplant. Additionally, most of the pa-tients in our series still have tissue in thefreezer for 1 or 2 more transplants aftertheir first grafts stop functioning.

Fertility After Cryopreser-

vation of an Ovary and

Cancer Treatment

We have recently conducted a question-naire study looking at the ovarian func-tion and fertility after treatment of a ma-lignant disease in women with one ovarydue to cryopreservation of the other. For-tunately, not all women experienced POIafter their potentially gonadotoxic treat-ment. In fact, we found that only 21% of143 responders stated that they had be-come menopausal after treatment. In theremaining women with an intact ovarianfunction those with a pregnancy wishsucceeded in becoming pregnant andgiving birth to healthy children in themajority of the cases [37].

Conclusion

Although still considered experimental,cryopreservation of ovarian tissue hasproved to be a viable way of restoringovarian function after cancer treatmentand with 20 babies born worldwide, theresults are promising. For many womenfacing a potential gonadotoxic treatmentand a risk of POI, cryopreservation ofovarian tissue offers a hope of keepingher fertility in the future and her ownendogenous hormone production andfor many cancer patients this is a reliefduring an otherwise difficult period oftheir lives. It is very likely that in the fu-ture, fertility preservation will be an in-tegrated part of the cancer treatment ad-

ministered to young cancer patients thusimproving their quality of life and reduc-ing one of the potential side effects ofcancer treatment: infertility.

Conflict of Interest

No potential conflict of interest to thisarticle was reported.

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