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Uterus Transplantation: Potential Patients, Fertility in Animal Models and Ethics Díaz-García C, Brännström M J

Uterus Transplantation: Potential Patients, Fertility in Animal Models and Ethics Díaz-García C, Brännström M J

Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive and –

Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie

Uterus Transplantation: Potential Patients, Fertility in Animal Models and Ethics Díaz-García C, Brännström M J. Reproduktionsmed. Endokrinol 2013; 10 (Sonderheft 1), 72-81

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Wir freuen uns auf Sie! Transplantation Uterus Transplantation: Potential Patients, Fertility in Animal Models and Ethics C. Díaz-García1, 2, M. Brännström1, 3

Uterus transplantation (UTx) has been suggested as an alternative to to achieve genetic motherhood. Extensive experimental research must be done before any kind of transplantation moves to the clinical field in order to guarantee its safety and effectiveness. Since the final aim of this kind of transplantation is to accomplish motherhood, the success of UTx should be evaluated not only in terms of organ/patient survival but also in terms of functionality, which means that full-term with healthy offspring should be considered as the measure of success. In this review we summarize the experimental studies accomplished during the last decade, using fertility as the main outcome, which we consider as the base for further development of UTx towards a clinical setting. Characteristics of potential patients and ethical concerns are also discussed. J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1): 72–81. Key words: uterus, transplantation, , , ethics

 Introduction essential aspect of the quality-of-life [5] that may benefit from UTx and also to of a woman and her partner. Uterine in- cover the animal-based UTx research During the last 2–3 decades the clinical fertile patients can today attain genetic that has tested the fertility potential of a fields of transplantation and re- parenthood by use of gestational surro- transplanted uterus (Tab. 1). Addition- productive medicine have been the birth- gacy, which is permitted in some coun- ally, the central ethical aspects of UTx places of several clinical innovations, tries although most societies disapprove will be discussed. which have had profound positive con- of its use because of ethical, religious or sequences for large patient groups. Sev- legal reasons [6].  Uterine Infertility eral of the novel treatments have as well affected the society at large and resulted The research field of UTx has advanced Several groups of patients can be classi- in active media debate, in particular considerably during the last decade, re- fied as infertile due to absence of the from the ethics perspective. search with activities and interest aug- uterus or presence of a type of uterine mented by the human UTx case, which dysfunction that cannot be corrected by In , the introduc- was performed in Saudi Arabia in 2000 surgery or hormonal/pharmacological tion of gonadotropin stimulation, in [7]. The human UTx effort was partly treatment. This uterine infertility can vitro fertilisation, intracytoplasmic successful since the surgery, involving a either be acquired or occur as a conse- sperm injection and oocyte donation living donor and a 26-year old recipient, quence of a congenital malformation have led to that most types of female and went uneventful. The uterus did not and include causes with no uterus present male infertility now can be effectively reject but had to be removed 3 months and those with a malfunctioning uterus treated. The groups of infertile women after transplantation due to uterine pro- (Fig. 1). The prevalence of uterine infer- that today, in spite of the developments lapse with thrombotic vessels. tility among patients of childbearing age in reproductive medicine, are untreat- is not exactly known but it is likely to be able are those that are irreversibly infer- The large amount of UTx research dur- significant, with a recent estimation of as tile due to uterine cause. ing recent years have used several ani- many as 12,000–15,000 uterine infertile mal models to study issues such as tech- patients in the United Kingdom [9]. This During the last decade, the discipline of niques for retrieval and transplantation estimation would indicate the presence transplantation surgery has introduced surgery, uterine tolerance to - of more than 150,000 uterine infertile several organs/tissues for transplanta- reperfusion, rejection mechanisms and patients in Europe, although obviously tion, which of would enhance the qual- tests of immunosuppressants to prevent only a portion of these would have the ity-of-life of a patient rather than being rejection [8]. The ultimate goal of UTx firm desire to carry a pregnancy through necessary for a continued life. Examples research is to develop techniques that UTx. of these novel types of procedures are can enable long-term survival of a uter- transplantations of the hand [1], the ab- ine with the potential to success- Numerically, the largest group of women dominal wall [2], the larynx [3], and the fully implant an embryo and to carry a with uterine infertility is that of women face [4]. Uterus transplantation (UTx) pregnancy to term. that have undergone dur- may provide a chance for uterine infer- ing fertile age. Each year in the United tile patients to experience pregnancy and The purpose of this review is to summa- States, around 600,000 women are hys- to give birth, which naturally is a very rize the groups of uterine infertile patient terectomized and a substantial propor-

Received: July 11, 2012; accepted after revision: October 8, 2012 From the 1Department of and Gynecology, Sahlgrenska Academy, University of Gothenburg, , and the 2Department of Obstetrics and Gynecology, La Fe University Hospital, University of Valencia, Spain Correspondence: Mats Brännström MD, PhD, Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, SE-41345 Sweden; e-mail: [email protected]

72 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Uterus Transplantation

nal trachelectomy [18] should be per- Table 1. Results of the experimental models analyzing fertility after uterus trans- plantation. formed. Larger tumours have to be sur- gically removed by a radical hysterec- Degree of histo- Study Animal Position of Mode of Pregnancy tomy. In an analysis of cervical cancer compatibility model the graft conception rate (per surgery) patients who had undergone radical hys- terectomy at a major cancer centre in the Syn Racho 2002 [59] Mouse Heterotopic Embryo-transfer * United States, during a time-era before Racho 2003 [60] Mouse Heterotopic Embryo-transfer 100% introduction of the trachelectomy proce- Racho 2003 [62] Mouse Heterotopic Embryo-transfer 47.4% dure, it was found that more than 40% Wranning 2011 [63] Rat Orthotopic Natural mating 40.7% were of fertile age at the time of diagno- Auto Enskog 2010 [71] Baboon Orthotopic Natural mating 0% sis [15]. Out of these patients, about half Wranning 2010 [67] Sheep Orthotopic Natural mating 21.4% of them would today still be, recom- mended radical hysterectomy because of Allo Díaz-García 2010 [73] Rat Orthotopic Natural mating 62.5% a tumour size greater than 2 cm, in spite Ramírez 2011 [74] Sheep Orthotopic Embryo-transfer 25% of the availability of trachelectomy sur- * Only one animal underwent embryo-transfer as part of the graft evaluation protocol gery. These patients could in the future be candidates for UTx. Even if adjuvant radiotherapy over the pelvis or chemo- , which both may be toxic to the , are given after cervical cancer surgery, future fertility for these patients would be possible by gonadotropin stimulation followed by oocyte cryo- preservation [19] or IVF and embryo cryopreservation prior to these adjuvant cancer . More than 99% of cer- vical cancers are caused by an infection with an oncogenic strain of human papillomavirus [20] and it has to be en- Figure 1. Uterine infertile patients that may become treated by uterus transplantation. © M. Brännström sured that the virus is cleared from the epithelia of the upper , before tion of these are performed in plasia [14]. Still, cervical cancer affects transplantation. Clearance of cervical patients below 40 years of age [10]. In an a large proportion of relatively young HPV infection usually occurs within 2 IVF program, including surrogate gesta- women, also in developed countries, years after primary infection although tion as a second step, around half of the with around > 30% being of fertile age at HPV persistence is seen in around 15% enrolled women with uterine infertility diagnosis [13, 15]. Since the average age of oncogenic HPV types [21]. had previously been hysterectomized of first-time motherhood is rising in the [11], which give an indication of the western world, a large portion of cervi- Endometrial cancer of stage 1 and local- relatively great size of this population cal cancer patients of fertile age will be ized uterine sarcoma are rare in fertile- among uterine infertile patients. The nulliparous. Many of these young pa- aged women, only around 2.5% of the grounds to perform a hysterectomy at tients with cervical cancer have an early cases occur during this life period [12]. fertile age are numerous as described stage disease, with the tumour limited to The surgical treatment of these malig- below in some cases, a hysterectomy; to the and in some cases also involv- nancies normally includes oophorec- remove a non-functional uterus, could ing the upper parts of the vagina. The tomy but sparing of the ovaries or cryo- also be an initial step in the UTx proce- 5-year survival rate for these women is preservation of oocytes/embryos could dure. above 75% [16]. In patients with early be considered, so that UTx would be stage cervical cancer with stromal inva- useful at a later stage. Gynaecologic Cancer and Uter- sion of less than 3 mm, a cervical cone is ine Infertility the treatment of choice in women of fer- Non-Gynecologic Malignan- In women of fertile age, the and tile age. Larger tumours and those with cies and Uterine Infertility the cervix are by far the most common greater invasion (stage Ib-IIa) should be Treatments of non-gynecological malig- primary sites of a gynecologic malig- treated with a surgical procedure that is nancies may result in uterine infertility. nancy although primary malignant more radical than conisation and also in- Cancer during childhood or early adult tumours of the uterus do also occur in cluding pelvic lymphnode dissection. life affects around 1 in every 400 female women below the age of 40 years [12]. The ovaries are generally spared since and the long-term survival of these can- Cervical cancer is universally the most the risk of ovarian metastasis is very low. cer victims is today above 70% [22]. Ra- common gynecological malignancy Concerning squamous cell carcinoma of diotherapy, given either as total body ir- [13], but with relatively low incidence in the cervix with a size < 2 cm and with radiation in preparation for bone marrow several developed countries after the in- invasion depth < 10 mm, a local radical transplantation, abdominal irradiation troduction of effective screening pro- fertility preserving procedure such as (mostly for Wilm’s tumor, rhabdomyo- grams to detect high grade cervical dys- vaginal trachelectomy [17] or abdomi- sarcoma, Ewing’s sarcoma) or total lym-

J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 73 Uterus Transplantation phoid irradiation causes considerable symptomatic myoma belong to the around 6.7% in the general female popu- (around 60%) reduction in uterine vol- group of myoma-related uterine infertile lation, 7.3% among infertile patients and ume [23] and this shrinkage is irrevers- patients that could be treated by UTx. 16.7% in women with recurrent miscar- ible [24, 25]. Even though a small num- riage have been approximated [45]. As ber of women with radiation-shrunken Intrauterine Adhesions and further pointed out in the paragraphs be- uteri will achieve pregnancies there will Uterine Infertility low, a majority of the total group of these be a considerable risk for miscarriage Intrauterine adhesions (IUA), with a patients are fertile. Nevertheless, a con- and mid-trimester pregnancy loss [26]. prevalence of around 1.5% among fer- siderable portion of the patients will re- Radiation is gonadotoxic and doses of tile-aged females [38], is another cause main infertile, in spite of corrective sur- 5–20 Gy administered to a field that in- of absolute uterine infertility. Endo- gery. cludes the ovaries impairs gonadal func- metritis, especially that caused by geni- tion in most women [27]. Thus, post- tal tuberculosis, is the most common The most prevalent type of structural pubertal females given radiation over the cause of severe IUA [39]. Other origins congenital uterine anomaly among in- pelvis will become menopausal within a of adhesions inside the are fertile women is the septate uterus [45], short time after radiation in > 90% [28] surgical curettage at legal or which is the result of incomplete resorp- and pretreatement cryopreservation of post partum [40]. In general, these adhe- tion of the central parts of the two fused oocytes, embryos or ovarian cortex sions results in infertility in around 50% Müllerian ducts. The septate uterus would be a prerequisite for UTx in these of women and in the event of early preg- makes up around 1/3 of all uterine mal- women. In the situation of a radiation- nancy the miscarriage rate is around formations [46]. Spontaneous abortion damaged uterus in a prospective UTx- 40% [41]. The treatment of choice for occurs in about 80% of pregnancies in patient, the organ could be replaced in a intrauterine adhesions is hysteroscopic untreated septate uteri [47] but hystero- combined procedure of hysterectomy adhesiolysis which shows effectiveness scopic resection is an effective treatment and transplantation. At such hysterec- to cure infertility in mild, moderate and and substantially decreases the miscar- tomy of a radiation-injured uterus, the severe IUA of around 90%, 70% and riage rate [47]. Even so, a small propor- long proximal ends of the uterine arter- 30%, respectively [42]. From these data tion of patients with surgically treated ies and veins could be spared to facilitate it can be estimated that around 1/3 of the uterine septate will still remain infertile the transplantation surgery. A concern in patients with in this category are un- [48]. this type of patient is however the surgi- reservedly uterine infertile and these cal difficulties related to scarring, adhe- women may in the future be treated by a The second most common type of uter- sions and impaired healing induced by combined hysterectomy-UTx proce- ine malformation is the bicornuate radiation [29]. dure. uterus, where disturbed fusion of the two Müllerian ducts results in two fully de- Myoma and Uterine Factor Emergency Peripartum Hyster- veloped uterine horns with a smaller Infertility ectomy and Uterine Infertility common cavity. The bicornuate uterus The prevalence of uterine myoma in- Emergency peripartum hysterectomy is represents around 1/4 of all uterine mal- creases with age [30] with a frequency of performed to save the life of the mother formations [46]. The rate of spontaneous around 8% in a random sample of Scan- in situations of severe bleeding due to abortion among women with bicornuate dinavian women between 33 and 40 uterine rupture/atony, invasive malpla- uteri is around 35% [49]. Surgery de- years [31]. In the United States, a com- centation or uncontrolled bleeding at creases the rate of [50], but parable prevalence was seen in Cauca- . The incidence of hys- a substantial number of women with sian women but with a 2-fold higher terectomy in conjunction with birth is bicornuate uteri will not be able to carry prevalence in Afro-American woman around 5 in 10,000 deliveries and will a pregnancy to the second or third tri- [32]. Myoma and the related symptoms most likely increase in the future due to mester and there is also an increased risk is a common cause of hysterectomy dur- the escalating number of women having of uterine rupture during the 3rd trimes- ing the premenopausal period and in the caesarean section [43]. ter. United States approximately 1% of all women between 30 and 34 years and Congenital Uterine Malforma- The less common unicornuate and around 2.5% of those between 35 and 39 tions and Uterine Infertility uterus didelphys comprise around 20% have been hysterectomized due to myo- Congenital uterine malformations, of uterine malformations [46]. Disturbed ma [33]. In addition, myoma [34, 35] is a which occur because of disturbances development of one of the Müllerian factor behind infertility, although the during foetal life in the formation, devel- ducts will result in the unicornuate myoma-related infertility can be surgi- opment or fusion of the Müllerian uterus, with or without a contralateral cally treated to some extent [36]. Con- (paramesonephric) ducts, represent a rudimentary uterine horn. A total failure cerning surgical myomectomy of large/ large group of uterine infertility, but of fusion of the Müllerian ducts results multiple intramural myoma, a prospec- these malformations may also increase in uterus didelphys, i. e. two separate tive but non-randomized study showed the risk of premature birth and obstetric uterine horns without a common cavity. fertility in around 60% of the operated problems [44]. The potential to establish a pregnancy in patients [37]. The patients that remain these two types of malformed uteri is de- infertile despite myomectomy and the The factual prevalence of uterine mal- creased and in case of pregnancy around large numbers that have undergone formations in the general population 30% will end in miscarriage and the total hysterectomy [10, 33] because of large is uncertain, although prevalences of live birth rate is only around 50% [46].

74 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) Uterus Transplantation

Surgery does not seem to improve the dysplasia), is found in around 30% [58]. syngenic transplantation is that of being pregnancy potential of the unicornuate/ Women with the typical MRKH syn- from the same inbred strain of a species. dideplhys uterus [51]. Thus, a consider- drome would be suitable patients for Therefore, the donor and recipient will able proportion of these patients are UTx in the future. Provided a neovagina then to a large extent be genetically iden- unable to carry a pregnancy into the of sufficient length exists, it could easily tical. In the human situation this would 3rd trimester. be surgically connected to the cervix of a be similar to transplantation between transplanted uterus. Caesarean section identical twins. The most extensive type of Müllerian would be the preferred mode of delivery anomaly is uterine agenesis, which on at a future pregnancy since it is unclear Concerning small experimental animals the other hand is fairly uncommon and whether a neovagina would have the ca- as the rodents, several inbred strains ex- representing only around 3% of all pacity for dilatation at labour. ist and can be used to avoid rejection in a Müllerian anomalies [46] or one in every transplantation situation. The mouse has 1:4500 females [52]. Typically these  Fertility in Experimental the advantages of ample availability of women have a rudimentary solid bipartite UTx Models gene-modified mouse strains and the ac- uterus in combination with absence of cessibility of recombinant proteins and the vagina above the hymenal ring. The A large number of studies on experimen- monoclonal antibodies in this species. syndrome is generally named the Mayer- tal UTx have been published during the The weight of these mice (20–25 g) is Rokitansky-Küster-Hauser (MRKH) syn- last decade, but most of these studies only about 10–15% of the weight of the drome or only the Rokitansky syndrome. have not involved fertility tests, which is rats used in UTx research (see below). It is usually diagnosed around the age of a very important issue in UTx develop- 14–16, because of primary amenorrhea ment. The reason for the scarcity of pub- Thus, our primary rodent model, which [53]. Girls with the MRKH syndrome lications of fertility outcome after UTx, was thoroughly explored concerning develop into phenotypically normal fe- is that the development of each experi- UTx and fertility, was the mouse model. male adults, with the exception of that mental model have been cumbersome, In the initial study F1 hybrids of females the there is no vagina above the hymenal with the need to initially give special at- of the inbred strains C57BL/6 and CBA/ ring. In general, a neovagina is surgi- tention to the complicated surgery of ca were used [59]. It was decided to use a cally created in young adulthood by use UTx [8]. model of heterotopic UTx, where the na- of either split-thickness skin grafts, peri- tive uterus was kept in situ as an internal toneal lining, sigmoid colon or dilatation In general, one basic problem in evaluat- control (Fig. 2). The donor surgery (45 from the vulvar indentation [54]. ing results, including fertility outcome, min duration) involved isolation of one of experimental transplantation is to uterine horn together with the common Women with the MRKH syndrome have separate the potentially harmful effects uterus cavity on a vascular pedicle con- a normal female karyotype and the spo- of ischemia-reperfusion and surgical taining all vessels and including the aorta radic occurrence of the syndrome may trauma from the degenerative process of and the vena cava. All branching vessels be because of a highly variable expres- rejection. Auto-transplantation experi- on this pedicle were ligated or coagulated sivity of a single mutant gene [55] or epi- ments and syngenic transplantation have with bipolar diathermy and the uterus was genetic changes during fetal life. Famil- commonly been used in initial animal- lifted out of the body after it had been ial aggregates of MRKH-cases have also based developments of transplantation freed from its attachments to the bladder, been reported [56]. The outcome of of new types of organs. ureters and the broad ligament. The trans- gestational surrogate pregnancies with plantation was end-to-side to vena cava MRKH patients as the genetic mothers The knowledge from auto/syngenic and aorta of the recipient, with advanced [57] does not demonstrate any increased transplantations, concerning surgical microsurgical skills needed since the lu- malformation risk in the offspring. Fifty techniques and other related issues have mina of the aorta and vena cava were only eight MRKH women underwent IVF then been used in the more complicated about 0.7 mm and 1.5 mm, respectively. stimulation with placement of embryos allogenic transplantation situation. Notably with the cervix of the hetero- in surrogate mothers. These attempts topically transplanted uterus kept intra- resulted in 34 live births (17 female) and The research concerning fertility after abdominally to avoid ascending infec- no genital malformation was seen UTx has also followed this pathway, as tions through the cervix of the graft. In among these. outlined below. this paper [59] the fertility potential of this first model of syngenic UTx was Three distinct subtypes of the MRKH Syngenic Experimental UTx tested only in one of the transplanted syndrome exist. The typical subtype, and Fertility mice. At about two weeks after UTx, which goes without extrauterine malfor- Experimental syngenic transplantation blastocysts were retrieved from a natu- mations, is present in around 50% of models can be used to isolate the effects rally mated mouse. The blastocysts were MRKH-patients. The atypical subtype of of surgery, ischemic effect and the new transferred to the uterine graft of the the MRKH syndrome, with associated anatomical placement of a transplanted transplanted mouse, which had been malformations in the renal system, is organ from effects of rejection and im- made pseudopregnant by mating with a present in around 20% and the severe munosuppressive agents, which add to vasectomised male. Since the complete form of the MRKH syndrome, named the complexity of experimental allo- uterine graft was positioned intra-ab- MURCS (Müllerian duct aplasia, Renal genic transplantation. The relationship dominally, the embryo transfer was per- aplasia, and Cervicothoracic Somite between the donor and the recipient in formed via a midline laparotomy and a

J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 75 Uterus Transplantation

Figure 2. Schematic drawing of uterus transplantation in the mouse. Figure 3. Schematic drawing of syngenic/allogenic uterus transplantation in the rat. © M. Brännström © M. Brännström thin cannula, which was inserted through stoma to drain any uterine and cervical placenta. There was no difference in the , provided a canal for fluid (Fig. 2). In this larger series of weight or length of animals as well as of transfer of the embryos to the lumen of animals, with the identical combination the placental weights between the the uterine cavity of the uterine graft but of inbred female mouse as described groups. In the second series of the ex- also to the native uterus. Out of the 6 above, the modified transplantation periment in the same paper the pregnan- transferrred blastocysts, 3 were placed in- model was used [60]. The pregnancy cies were allowed to go to full term and side the native uterus and 3 inside the rate in 12 transplanted animals carrying pups were delivered either spontane- graft with pregnancy evaluated 10 days both native and grafted uteri were com- ously but caesarean section delivery was after embryo transfer. The results were pared with 13 animals undergoing sham attempted from the grafted uterus, since that of 3 foetuses of normal size seen in surgery. The mice with transplanted uteri poor dilatation of the birth canal would the native uterus and one foetus in the received embryos during the interval be anticipated in the transplanted uterus transplanted uterus, which in addition ex- from 1-3 weeks after transplantation, with its cervix passing through the col- hibited an absorbed pregnancy. The paper with blastocysts (3–6 to each uterus) lagen-rich skin of the mouse. In some [59], although limited concerning tests of placed inside the uterine cavity by the cases spontaneous deliveries occurred fertility, represents the first important well-established transmyometrial ap- from the heterotopically transplanted proof-of-principle study in relation to the proach [61]. The experiments were di- uterus and that was typically seen 6–12 fertility potential after UTx. However, it vided into two series, where the first hours after spontaneous vaginal deliv- should be emphasized that the experi- evaluated fertility at day 18 of preg- ery. This delay in spontaneous labour ments were performed in a syngenic in- nancy, a time which is about 2–3 days from the grafted uterus is most likely due vestigational situation. before anticipated parturition. The preg- to mechanical factors, with slow cervical nancy rate was similar in the native and dilation at the point of passage through In the follow-up paper, also involving the grafted uterus of the transplanted the skin but other mechanisms related to the syngenic mouse UTx model the animals as compared to control animals poor innervation of the uterine graft or transplantation procedure was modified with pregnancy rates of 75% in the na- the higher abdominal position of the or- so that the cervix of the heterotopically tive uterus of transplanted animals, 66% gan cannot be ruled out. The growth tra- placed uterine graft (Fig. 2) was attached in the grafted uterus of the transplanted jectory of these offspring was followed to a cutaneous stoma [60], instead of be- animals and 66% in control animals. Im- for 8 postnatal weeks and growth was ing positioned intra-abdominally as in portantly, the median numbers of foet- found to be normal, as compared to ani- the initial method [59]. The reason for uses in the pregnant animals were simi- mals from native uteri and from control this modification was that the grafted lar in the groups with 4, 4 and 3 in native, animals. In order to rule out that the na- uteri of the initial study [59] often pre- grafted and control uterus, respectively. tive uterus would exhibit a positive ef- sented with accumulated intraluminal Taken together, the results of this paper fect on the grafted uterus, some animals mucus, which may have been caused by [60] points towards that the fertility po- underwent UTx with the native uterus poor drainage of uterine/cervical fluid tential and physiological environment to removed [60]. These experiments also through the intraabdominal cervix. support a pregnancy is similar in a trans- demonstrated pregnancies in the trans- planted uterus as in a normal situation. planted uteri, indicating that these preg- Thus, the surgery was adapted so that The paper [60] also examined the weight nancies were not dependent on influ- cervix would be attached to a cutaneous of the foetuses at day 18 and that of the ences from the native, intact uterus. The

76 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) Uterus Transplantation fertility of both male and female off- turbed, which was an important compo- the surgical procedure of transplanta- spring from the grafted uterus was nor- nent to allow for natural conception to tion, the tolerance of a graft to ischemia mal and the second generation offspring occur. The pregnancy potential of this and perfusion injury as well as effects of from these mice, with their foetal devel- syngenic model of a uterine graft, with the altered vascular supply of the graft. opment inside a transplanted uterus, one uterine horn excised, was compared The auto-UTx models that have been were also of normal birth weight. Taken to sham operated rats. In the series of 19 used in research are the sheep [65–67], together, this is the first study [60] ever animals of both transplanted and sham- the pig [68], the rhesus macaque [69], to demonstrate live births from a truly operated animals, pregnancy rate was the cynomolgus macaque [70] and the transplanted uterus. It is of importance similar (11 rats in the UTx group versus baboon [71]. However, fertility has only since it clearly shows that a denervated 12 in the sham). The median numbers of been evaluated in the sheep, the rhesus uterus with altered vascular connections pups were 3 in the UTx group and 3.5 in macaque and the baboon UTx models. and also devoid of proper lymphatic the sham group. However, the major dif- drainage as well as in an non-physiologi- ference, possibly of biological signifi- The sheep auto-UTx model, also in- cal position may act normally in a situa- cance, between the sham group and the cluded a uterine graft with one of the tion of embryo implantation and preg- UTx group was that the UTx group had uterine horn excised, in analogy with the nancy. lower rate of successful deliveries. An rodent syngeneic models [65]. The rea- explanation to this may be a protracted son for this surgical technique was to In a follow-up study, identical transplan- labour in the transplanted uterus, caused only use a vascular pedicle on one side, tation and embryo transfer techniques, by denervation. This assumption was and thereby simplify both the retrieval as discussed above, were used but the based on a previous paper showing that surgery and the vascular anastomosis transplanted uterus was tested for toler- the sensory innervation of the uterus is surgery. In view of the fact that there is a ance to cold ischemic injury by being necessary for a normal delivery in the rat close physiological interplay between kept ex vivo for 24 h or 48 h in Univer- [64]. The growth trajectory of the live the uterus and ovary in regulation of lu- sity of Wisconsin (UW) solution in be- births from the sham and the UTx groups teolysis [72] possibly involving counter- tween retrieval and transplantation was similar, although the number of live current mechanisms it was decided to [62].Uteri that had been subjected to births in the UTx group was too low to use a graft consisting of the common cold ischemia for 48 h became necrotic draw any firm conclusions. This paper uterine cavity with one uterine horn and after transplantation. However, those [63] represents the first UTx model of the ipsilateral oviduct and ovary (Fig. 4). with 24 h in UW showed normal mor- any species that has demonstrated live This would also allow for minimal surgi- phology 2 weeks after UTx and in these birth after natural mating. cal trauma to the oviduct, which would six animals fertility was by embryo be of importance to permit for natural transfer (3–6 embryos in each graft) and The results of these syngenic rodent conception. The vascular pedicle includ- pregnancies were seen in 5 out of six UTx models, as discussed above, are im- ing the ovarian artery, the uterine artery transplanted uteri with the growth trajec- portant as the first demonstrations of the and the ovarian uterine vein was dis- tory of pups during an 8 weeks follow- principle of fertility potential in a trans- sected. The ovarian artery of the sheep is up period being normal. planted uterus. An advantage of the ro- only about 1 mm wide and a direct anas- dent models is the existence of a vast tomosis with good vessel patency, of this The fertility after UTx has also been knowledge of rodent reproductive physi- tiny vessel would require great micro- tested in the other commonly used ro- ology and also the possibilities to in the surgical skills. Thus, to simplify the pro- dent model, the rat. The advantage of the future to use gene modified models, with cedure a patch (diameter of about 7 mm) rat, as compared to the mouse, is the also possibilities to compare a native from the aorta including the origin of the larger (> 4 times) body size, which prob- uterus with a gene-modified trans- uterine artery was included. The dura- ably is one reason why this species is a planted uterus or vice versa, within the tion of surgery for the procurement was popular animal model in transplantation same animal. However, being rodent about 4 h. Vascular anastomosis of the research in general. In our syngeneic rat models, the experimental situation is anterior portion of the internal iliac ar- UTx model the uterus was orthotopically certainly different from a human situa- tery, the utero-ovarian vein and the aor- transplanted between inbred rats of tion concerning surgery and also preg- tic patch with the ovarian artery were Lewis strain [63]. The transplantation nancy length as well as placentation. accomplished on the external iliac ves- procedure involved retrieval of the right sels (Fig. 4). uterine horn together with the caudal Autologous Experimental UTx common uterine component, the cervix and Fertility Initial animals were used to establish and 2–3 mm of the upper vagina. The Autologous transplantation is a method- that the vaginal anastomosis was healed vascular tree of the graft included the ology that has been used traditionally in after 2 months and that cyclicity was re- uterine vessels, internal iliac vessels and developments within solid organ trans- established, which also was seen at this around 4 mm of the common iliacs. The plantation in large animal models. In time-point. Five animals were subjected recipient underwent hysterectomy but these experiments, the organ will be sur- to natural mating some months after the tip (3 mm) of the native right uterine gically removed from the animal and transplantation. They were compared to horn was spared, to be anastomosed to kept in ex vivo for some time before it is 5 control animals, not undergoing any the cranial part of the grafted uterusi transplanted back either to an orthotopic surgery at all. All control animals mated (Fig. 3). In this way the uterotubal junc- site or to a heterotopic site. The autolo- and became pregnant with normal off- tion and the oviduct was left undis- gous transplantation situation will test spring. Four of the auto-UTx sheep

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Figure 4. Schematic drawing of autologous uterus Figure 5. Schematic drawing of autologous transplantation in the baboon. © M. Brännström transplantation in the sheep. © M. Brännström showed mating and pregnancies to full beit several breeding attempts. It was [73] and this should be regarded as a term were seen in 3 out of 5 animals. speculated that postoperative adhesions major breakthrough in the research field One of these pregnant ewes, showed prevented fertilization. of UTx. The surgical technique used in contractions compatible with initiation this study was essentially the same as for of labour but they disappeared after 24 h. Our group has also explored a primate the syngenic rat model (Fig. 3). The A caesarean section was made and a model (baboon) for autologous UTx uterus donor, of Dark Agouti (RT1av1) 360º-rotated uterus containing a twin [71]. In an initial study a surgical model strain, was operated by a midline laparo- pregnancy was found. The site of the tor- to transplant the uterus together with the tomy to surgically isolate the uterus, sion was the lower segment and both ovaries was developed [71]. The model with the right uterine horn excised. The lambs were dead. Uterine torsion at was later modified, which enhanced the vascular pedicle of the graft comprised labour is a well-known complication in success rate in terms of restored men- all vessels from the uterine vessels up to sheep, but it may well be that inadequate struation from 20% [71] to 60% (our un- and including the common iliacs. The fixation of the transplanted uterus con- published data). The modification in- graft was flushed ex vivo and preserved tributed to the torsion. cluded arterial vascular anastomosis cold in preservation solution. The uterus end-to-end in the internal iliac artery recipient, of Lewis (RT1l) strain, was In this study [67] the crown-rump lengths (Fig. 5) instead of end-to-side to the ex- prepared for UTx by hysterectomy and and the placental weights did not differ ternal iliac artery and also more exten- dissections of the common iliac artery between the groups. In conclusion, this sive flushing of the organ ex vivo. More and vein on the right side, to be used as fairly small animal study represents the than 50 occasions of timed mating oc- vascular anastomosis sites. Transplanta- first report of fertility after transplantation curred after UTx but no with pregnancy tion of the uterine graft was accom- in any large animal species. resulting. However, post mortem exami- plished by end-to-side anastomosis (10– nation showed tubal occlusion in all ani- 0 sutures) of the common iliac vessels of Studies on fertility after UTx, was actu- mals and this tubal blockage may well be the graft to the common iliac vessels of ally performed four decades ago when due to inflammatory changes secondary the recipient. The vaginal rim of the graft uterus and the oviducts were trans- to transplantation associated ischemic was anastomosed end-to-end to the na- planted in the rhesus macaque by use of damage. tive vaginal vault and the top of the uter- the omentum as a site for spontaneous ine graft was anastomosed end-to-end to neovascularisation [69]. The subtotal Allogenic Experimental UTx a tiny remaining distal portion of the hysterectomy specimen was attached to and Fertility native uterus containing the utero-tubal the cervical stump of the recipient and The allogenic UTx situation is naturally junction, which was preserved to enable the omentum was wrapped around and more complex than syngenic and autolo- mating with natural conception. The im- sutured to the uterus and oviduct in four gous UTx, since the effects of rejection munosuppressant given to prevent uter- monkeys as an auto-transplantation pro- and immunosuppressants are also added ine graft rejection was at a cedure. The auto-UTx uteri remained of as extra factors that may affect the fertil- dose of 0.5 mg·kg–1·day–1. In addition normal size and with signs of satisfac- ity potential of a transplanted uterus. to the transplanted group (UTx-Tac) 2 tory revascularization, since menstrua- control groups were included in this tion was resumed. However, no preg- In 2010, our group described for the first study: (1.) rats undergoing just sham sur- nancy occurred in any of these uteri al- time pregnancy after allogeneic UTx gery (hemihysterectomy; Sham) and

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(2.) rats undergoing sham surgery and tions between Sudanese and Ethiopian duction, which was the case for heart the same immunosuppressive protocol breeds with animals serving both as do- transplantation [78] and liver transplan- as the transplanted group (Sham-Tac) nors and recipients during simultaneous tation [79]. In modern times, this is ex- [73]. After introduction of the experi- surgeries [74]. All the animals were emplified by the extensive research in mental animals to males of proven-fertil- treated orally with cyclosporine A and rodent models on facial transplants [80] ity, cesarean sections were performed intramuscularly with prednisone, start- that preceded the first full facial trans- on pregnancy day 17. The number of ing two days before plant in the human that took place in the foetuses and implantation sites were of the uterus [74]. In this study pred- United States in 2009. In the UTx field, counted. Pregnancy rates were slightly nisone treatment was discontinued after several research groups have used ro- (but insignificantly possibly due to the 2 weeks post-transplantation and satis- dents, large domestic animals and non- small sample size [n = 19]) decreased in factory trough levels of cyclosporine human primates in their research to- the groups undergoing immunosuppres- were reached by day 5. Twelve animals wards clinical introduction of UTx [9, sion: 62.5% in the UTx-Tac-group, 60% underwent transplantation and four of 60, 67, 68, 71, 73, 81–84]. It is also im- in the Sham-Tac-group, as compared to them died during the immediate post- portant that teams planning to carry out 83% in the Sham-group [73]. This study operative period. Only 5 out of surviving human UTx belong to a strong and com- was only designed to prove that preg- 8 animals were considered suitable for prehensive institution, so that expertise nancy was possible after allogenic UTx undergoing embryo-transfer based on on all aspects before, during and after and to evaluate the possible impact on the viability of the graft and the presence the procedure is provided in a profes- implantation rate. This is a step-by-step of corpus luteum [74]. Three pregnan- sional way. The expertise needed for method we have used in studies on other cies were reported within these five ani- pre-transplantation work-up of both the aspects of experimental UTx. mals: one resulted in an ectopic preg- patient and a live donor would be at least nancy requiring removal of the uterus, a gynecologist, transplant surgeon, psy- Thus, we have continued with the re- one resulted in fetal demise at 105 days chologist, counsellor, reproductive search on fertility after allogenic UTx in of gestation and the remaining one re- medicine specialist, the rat model, to add the next important sulted in delivery of a fully developed specialist, radiologist and a specialist in step which is offspring health and devel- lamb at 138 days via cesarean section. maternal-fetal medicine. The gynaecolo- opment. In the follow up experiments in The lamb died 5 hours after delivery. A gist would evaluate the prospects for 2011 we used Lewis (RT1l) rats as do- criticism of this study on supposedly al- UTx in the recipient, where consider- nors and PVG (RT1c) rats as recipients logenic sheep is that the use of sheep ations would have to be taken in regards (our unpublished observations). Similar bred in farms may diminish the func- previous surgery, vaginal length and groups as in the previous study [73] were tional allogenicity of the transplantation position of the vaginal vault in relation used but the difference was that the preg- [76]. to the bladder. In MRKH patients with nancies were followed until term (day only previous self dilation to obtain a 22). The pregnancy rates were similar to  Uterus Transplantation vagina of sufficient length, the vagina those previously described (50% in the and Ethics may have to be lengthened before UTx UTx-Tac-group, 80% in the Sham-Tac by any type of neovagina surgery [85]. group and 70% in the Sham) and the We think it is essential that UTx is dis- The gynaecologist would be most suit- birth weights of the pups were similar in cussed from an ethical perspective, in able to explain the surgery and risks in- the groups (our unpublished observa- parallel with the animal UTx research. volved with uterus retrieval from the do- tions). These pups are currently being The ethics around UTx will naturally be nor. However, the transplant surgeon followed-up and different physiological influenced by the active bioethical de- should also have these discussions inde- and behavioral aspects are analyzed. bates surrounding both the field of trans- pendently with the potential donor. The plantation surgery and that of reproduc- best medical knowledge about the trans- There also exists some experience of tive medicine and in particular assisted plantation procedure, postoperative im- allogenic UTx in a larger animal. In reproduction [77]. munosuppression and follow up proto- 2011, another group reported two preg- cols is naturally among the transplanta- nancies and one birth after allogenic Clinical introduction of any novel major tion surgeon. A psychologist and a coun- UTx in the sheep [74]. In this experi- surgical procedure should occur only af- sellor should independently assess both ment the authors used a surgical model ter extensive experimental work in ani- the donor and the recipient well before previously described [75]. Via a small mal models to minimize the risk when the procedure, to assess that they are subumbilical incision the uterus and introduced as an experimental procedure properly informed about the risk of the proximal parts of the uterine vessels in the human. We are all aware of that procedure and the chances for a success were retrieved from one animal and several surgical procedures, also in gy- in the initial experimental situation of placed in another animal that underwent necology, are introduced by enthusiastic UTx. The recipient should be evaluated the same surgical treatment [75]. The doctors with a firm belief in the benefit by a specialist in reproductive medicine anastomoses were performed between of the new surgical intervention but with at an initial state of the pre-transplanta- the uterine arteries and veins bilaterally only minimal or none background data tion work up to ensure that the ovarian in an end-to-end fashion and the vaginal in animal models to support this. In function of the patient is normal and that vault of the graft was anastomosed to the transplantation surgery, there is a long the ovarian reserve is reasonable so that vaginal rim of the recipient. The experi- tradition to optimize and test techniques the couple would have a reasonable ment involved allogeneic transplanta- in animal models before clinical intro- chance to conceive at IVF. We would

J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 79 Uterus Transplantation recommend the patient to undergo IVF initial stages of UTx, a multiorgan donor cies and offspring after allogenic UTx treatment before UTx, to ensure fertility that have consented to in animal models, as has been done in within the couple but also to obtain and may not have considered the uterus as an the rat (see above). cryopreserve enough embryos that later organ that would be donated, besides the can be used at single embryo transfer, classical organ such as the heart, lung  Conflict of Interest which should occur at earliest 12 months and kidneys. Concerning a live donor, after UTx. The internal medicine spe- suitable donors would be a mother, sister No potential conflict of interest to this cialist would be an independent doctor, or aunt. The surgical risks of the donor article was reported. well suited to evaluate the medical risks would probably be similar to that of an for the donor and the recipient in a UTx ordinary abdominal hysterectomy [87], References: situation. A radiologist with a special in- taking into account that the risks related 1. Dubernard JM, Owen E, Herzberg G, Martin X, Guigal V, Dawahra M, et al. [The first transplantation of a hand in hu- terest in magnetic resonance and angiog- to the more extensive dissection of uter- mans. Early results]. Chirurgie 1999; 124: 358–65. raphy would be essential for preopera- ine vessels at hysterectomy for UTx 2. Levi DM, Tzakis AG, Kato T, Madariaga J, Mittal NK, Nery tive evaluation of the uterus and pelvic would be compensated by that this hys- J, et al. Transplantation of the abdominal wall. Lancet 2003; vascular system of the donor as well as terectomy would be carried out expert 361: 2173–6. 3. Strome M, Stein J, Esclamado R, Hicks D, Lorenz RR, Braun the pelvic vascular system of the recipi- gynae- surgeons. W, et al. Laryngeal transplantation and 40-month follow-up. ent. In a human UTx situation, preg- NEJM 2001; 344: 1676–9. nancy by embryo transfer should be at- The transplant patient, receiving the 4. Devauchelle B, Badet L, Lengele B, Morelon E, Testelin S, Michallet M, et al. First human face allograft: early report. tempted a year of post-transplantation uterine graft and her partner should be Lancet 2006; 368: 203–9. stabilization of the organ, since immu- extensively informed about other alter- 5. Aarts JW, van Empel IW, Boivin J, Nelen WL, Kremer JA, Verhaak CM. Relationship between quality of life and distress nosuppressive doses usually can be low- natives to motherhood than UTx and that in infertility: a validation study of the Dutch FertiQoL. Hum ered after this initial period. Any preg- this procedure would at its initial stage Reprod 2011; 26: 1112–8. nancy after UTx should in the initial be fully experimental. The surgical risks 6. Catsanos R, Rogers W, Lotz M. The ethics of uterus trans- plantation. Bioethics 2011. stage be considered a high risk preg- would probably be similar to that of kid- 7. Fageeh W, Raffa H, Jabbad H, Marzouki A. Transplantation nancy and be taken care of by a specialist ney transplantation, since the site for of the human uterus. Int J Gynaecol Obstet 2002; 76: 245–51. in high risk obstetrics/maternal-fetal blood vessel anastomosis would be simi- 8. Brannstrom M, Wranning CA, Altchek A. Experimental medicine and this doctor should have lar [71]. A somewhat longer surgical uterus transplantation. Hum Reprod Update 2010; 16: 329–45. 9. Sieunarine K, Zakaria FB, Boyle DC, Corless DJ, Noakes DE, long-standing experience of pregnancies time at UTx than at renal transplantation Lindsay I, et al. Possibilities for fertility restoration: a new of other organ transplanted women. would be anticipated because of the surgical technique. Int Surg 2005; 90: 249–56. smaller diameters of the vessels of the 10. Farquhar CM, Steiner CA. Hysterectomy rates in the United States 1990–1997. Obstet Gynecol 2002; 99: 229–34. An institutional stability would also be graft and that bilateral vascular anasto- 11. Goldfarb JM, Austin C, Peskin B, Lisbona H, Desai N, de important in a situation of human UTx. mosis would be performed. The patient Mola JR. Fifteen years experience with an in-vitro fertilization Thus, the procedure should only be car- should also be informed about the risks surrogate gestational pregnancy programme. Hum Reprod 2000; 15: 1075–8. ried out in a large hospital with long of immunosuppressive medication in re- 12. Creasman WT, Odicino F, Maisonneuve P, Quinn MA, standing and extensive programs in or- lation to nephrotoxicity [88], viral infec- Beller U, Benedet JL, et al. 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