Uterine transplantation: the move from the animal model into the human setting – surgical, reproductive and clinical aspects

Women with absolute uterine factor infertility (AUFI) are considered as being ‘unconditionally infertile’. Uterine transplantation (UTx) may be a possible treatment option in the future for such women. This thesis describes a number of key areas of research that are important in order to move closer to a successful and crucially, safe transplant in the human setting. Nine allogeneic transplants were carried out in a rabbit model to investigate anatomical and surgical aspects necessary for a successful UTx. An attempt to characterise and quantify the immunological mechanisms involved in allogeneic UTx (rejection patterns) was made. Out of the nine recipients, one was a long-term survivor. Embryo transfer was performed in this one doe with the aim of establishing pregnancy. Performing UTx in a large-animal model is necessary as the pelvis resembles a woman’s reproductive system more closely. In addition, the anastomotic technique is similar. Five sheep autotransplants were performed to further define surgical techniques. The anastomotic model was internal to external iliac vessel. Out of the five transplants, three sheep demonstrated adequate perfusion in the immediate post-operative period. Furthermore, the suitability of two different imaging modalities, pulse oximetry and multispectral imaging, for assessing uterine perfusion and extent of ischaemia were been studied in both the rabbit and sheep models. Biophotonics was also applied in the form of Endoscopic Laser Speckle Contrast Analysis to characterize blood flow in the two models. Both Multispectral Imaging and Endoscopic Laser Speckle Contrast Analysis have never been assessed before in a gynecological context. In order to transfer the concept of UTx to the human, we carried out a retrospective study of abdominal radical trachelectomy (ART) as a potential replacement for radical hysterectomy in patients with early stage cervical cancer desiring a fertility-sparing procedure. ART forms the foundation of the original work into aspects of UTx. This original body of research revolved around the potential blood supply to a uterus. Furthermore, an attempt has been made to analyse the motivations, aims and feelings of patients diagnosed with AUFI towards UTx. Forty patients were interviewed. The final study involved the evaluation of the perceptions of health care professionals towards UTx, with 528 participants surveyed.Open Acces

Use of Cyclosporine in Uterine Transplantation

Uterine transplantation has been proposed as a possible solution to absolute uterine factor infertility untreatable by any other option. Since the first human attempt in 2000, various teams have tried to clarify which immunosuppressant would be most suitable for protecting the allogeneic uterine graft while posing a minimal risk to the fetus. Cyclosporine A (CsA) is an immunosuppressant widely used by transplant recipients. It is currently being tested as a potential immunosuppressant to be used during UTn. Its effect on the mother and fetus and its influence upon the graft during pregnancy have been of major concern. We review the role of CsA in UTn and its effect on pregnant transplant recipients and their offspring

Translation to success of surgical innovation

Contemporary thoracic and cardiovascular surgery uses extensive equipment and devices to enable its performance. As the specialties develop and new frontiers are crossed, the technology needs to advance in a parallel fashion. Strokes of genius or problem-solving brain-storming may generate great ideas, but the metamorphosis of an idea into a physical functioning tool requires a lot more than just a thinking process. A modern surgical device is the end-point of a sophisticated, complicated and potentially treacherous route, which incorporates new skills and knowledge acquisition. Processes including technology transfer, commercialisation, corporate and product development, intellectual property and regulatory routes all play pivotal roles in this voyage. Many good ideas may fall by the wayside for a multitude of reasons as they may not be marketable or may be badly marketed. In this article, we attempt to illuminate the components required in the process of surgical innovation, which we believe must remain in the remit of the modern-day thoracic and cardiovascular surgeo

Gynecological cancers: an alternative approach to healing

Grief and hope are two conflicting emotions that a patient recently diagnosed with cancer has to master. The real challenge for gynecologic oncologists is how to reach out. Conventional wisdom states that offering patients focus and belief when combating cancer in their lives allows them to embrace hope with greater confidence, which minimizes their grief. Three pictorial models are presented: ‘4-cusp approach’ model used at the initial consultation; ‘tapestry of bereavement or landscape of grief’ model at the postsurgery consultation; and ‘Venn-diagram’ model at any time during patient management. We have applied these models in our practice and believe that they can act as a fulcrum for the patient, the family and healthcare team around which therapy should be centered., Grief and hope are two emotions that a patient faces if diagnosed with cancer. The real challenge for the doctor is how to reach out and help the patient through this process. A doctor's role may be to offer focus and belief to the patient which may allow her to embrace hope with greater confidence. This will hopefully lessen the grief. We present three models which we believe can play a crucial part: ‘4-cusp approach’ used at the initial consultation; ‘tapestry of bereavement or landscape of grief model’ at the postsurgery consultation; and ‘Venn-diagram model’ at any time during care

How to manage the left subclavian artery during endovascular stenting of the thoracic aorta

We performed a systematic review of the literature to establish whether revascularisation of the left subclavian territory is necessary when this artery is covered by a stent. We retrieved data from 99 studies incorporating 4906 patients. Incidences of left-arm ischaemia (0.0% vs 9.2%, p=0.002) and stroke (4.7% vs 7.2%, p≪0.001) were significantly less following revascularisation, although mortality (10.5% vs 3.4%, p=0.032) and endoleak incidence (25.8% vs 12.6%, p=0.008) were increased. No significant differences in spinal-cord ischaemia were seen. Revascularisation may reduce downstream ischaemic complications but can cause significant risk. Indications must be carefully considered on an individual patient basi

Reproductive outcomes from ten years of elective oocyte cryopreservation

Research question: To assess the relationship between the number of oocytes retrieved during elective oocyte cryopreservation (EOC) cycles with various clinical, biochemical, and radiological markers, including age, body mass index (BMI), baseline anti-Müllerian hormone (AMH), antral follicle count (AFC), Oestradiol level (E2) and total number of follicles ≥ 12 mm on the day of trigger. To also report the reproductive outcomes from women who underwent EOC. Methods: A retrospective cohort of 373 women embarking on EOC and autologous oocyte thaw cycles between 2008 and 2018 from a single London clinic in the United Kingdom. Results: 483 stimulation cycles were undertaken amongst 373 women. The median (range) age at cryopreservation was 38 (26–47) years old. The median numbers of oocytes retrieved per cycle was 8 (0–37) and the median total oocytes cryopreserved per woman was 8 (0–45). BMI, E2 level and number of follicles ≥ 12 mm at trigger were all significant predictors of oocyte yield. Multivariate analysis confirmed there was no significant relationship between AFC or AMH, whilst on univariate analysis statistical significance was proven. Thirty six women returned to use their cryopreserved oocytes, of which there were 41 autologous oocyte thaw cycles undertaken. There were 12 successful livebirths achieved by 11 women. The overall livebirth rate was 26.8% per cycle. No livebirths were achieved in women who underwent EOC ≥ 40 years old, and 82% of all livebirths were achieved in women who had done so between 36 and 39 years old. Conclusion: Clinical, biochemical and radiological markers can predict oocyte yield in EOC cycles. Reproductive outcomes are more favourable when cryopreservation is performed before the age of 36, with lower success rates of livebirth observed in women aged 40 years and above

Multispectral imaging of organ viability during uterine transplantation surgery in rabbits and sheep

Uterine transplantation surgery (UTx) has been proposed as a treatment for permanent absolute uterine factor infertility (AUFI) in the case of the congenital absence or surgical removal of the uterus. Successful surgical attachment of the organ and its associated vasculature is essential for the organ’s reperfusion and long-term viability. Spectral imaging techniques have demonstrated the potential for the measurement of hemodynamics in medical applications. These involve the measurement of reflectance spectra by acquiring images of the tissue in different wavebands. Measures of tissue constituents at each pixel can then be extracted from these spectra through modeling of the light–tissue interaction. A multispectral imaging (MSI) laparoscope was used in sheep and rabbit UTx models to study short- and long-term changes in oxygen saturation following surgery. The whole organ was imaged in the donor and recipient animals in parallel with point measurements from a pulse oximeter. Imaging results confirmed the re-establishment of adequate perfusion in the transplanted organ after surgery. Cornual oxygenation trends measured with MSI are consistent with pulse oximeter readings, showing decreased StO2 immediately after anastomosis of the blood vessels. Long-term results show recovery of StO2 to preoperative levels

Age-related fertility decline: is there a role for elective ovarian tissue cryopreservation?

Age-related fertility decline (ARFD) is a prevalent concern amongst western cultures due to the increasing age of first-time motherhood. Elective oocyte and embryo cryopreservation remain the most established methods of fertility preservation, providing women the opportunity of reproductive autonomy to preserve their fertility and extend their childbearing years to prevent involuntary childlessness. Whilst ovarian cortex cryopreservation has been used to preserve reproductive potential in women for medical reasons, such as in pre- or peripubertal girls undergoing gonadotoxic chemotherapy, it has not yet been considered in the context of ARFD. As artificial reproductive technology (ART) and surgical methods of fertility preservation continue to evolve, it is a judicious time to review current evidence and consider alternative options for women wishing to delay their fertility. This article critically appraises elective oocyte cryopreservation as an option for women who use it to mitigate the risk of ARFD and introduces the prospect of elective ovarian cortex cryopreservation as an alternative

Endometrial autotransplantation in rabbits: Potential for fertility restoration in severe Asherman's syndrome

[EN] Objective: Uterine transplantation is now considered a feasible treatment for women with absolute uterine factor infertility and has been successfully performed for a woman with Asherman's syndrome (AS). The endometrium is a clinically and histologically distinct entity from the surrounding myometrium. Endometrial transplantation (ETx) may offer a less invasive option, with less immunogenic impact, to restore fertility in women with severe AS. The objective of this study was to assess the feasibility of ETx by evaluating surgical and reproductive outcomes following endometrial autotransplantation in a rabbit model. Study design: A longitudinal study assessing surgical, biochemical, radiological, reproductive and histological outcomes following endometrial autotransplantation in ten New Zealand white rabbits. Results: Ten procedures were performed, including 8 endometrial auto-transplants (ETx) and 2 endometrial resections (ER), to control against endometrial regeneration. Eight procedures were successful, whereas two rabbits from the ETx group died intra-operatively. Three rabbits were euthanised at 48, 72 and 96 h post-operatively to assess gross and histological appearances. Two rabbits, one from the ETx group and one from the ER group, died four weeks and eight weeks post-operatively. Three rabbits subsequently underwent two cycles of in-vitro fertilization. The first cycle resulted in an implantation rate of 57% in the un-operated uteri. In two rabbits who underwent ETx, an implantation rate of 28.6% was seen. In the second cycle, an implantation rate of 61.9 % (13 implantations) was observed in the control uteri. In the two ETx females, an implantation rate of 14.3 % was seen. No pregnancies were seen in either cycle in the animals who underwent ER. Despite successful implantations in both cycles in the ETx rabbits, no livebirths were achieved. Following death or euthanasia there was gross and microscopic evidence of viable endometrium following ETx, but not following ER. Conclusion: This study has revealed, for the first time, the feasibility of ETx with gross and microscopic evidence of viable endometrium, and the demonstration of clinical pregnancies. Whilst further studies are essential, and the achievement of successful livebirths fundamental, ETx may offer a potential fertility restoring opportunity for women with severe, treatment refractory cases of AS.The study was funded by registered charity Womb Transplant UK (1138559).Jones, BP.; Vali, S.; Saso, S.; Garcia-Dominguez, X.; Chan, M.; Thum, M.; Ghaem-Maghami, S.... (2020). Endometrial autotransplantation in rabbits: Potential for fertility restoration in severe Asherman's syndrome. European Journal of Obstetrics & Gynecology and Reproductive Biology. 248:14-23. https://doi.org/10.1016/j.ejogrb.2020.03.011S1423248Asherman, J. G. (1950). TRAUMATIC INTRA-UTERINE ADHESIONS. BJOG: An International Journal of Obstetrics and Gynaecology, 57(6), 892-896. doi:10.1111/j.1471-0528.1950.tb06053.xHooker, A. B., de Leeuw, R., van de Ven, P. M., Bakkum, E. A., Thurkow, A. L., Vogel, N. E. A., … Huirne, J. A. F. (2017). Prevalence of intrauterine adhesions after the application of hyaluronic acid gel after dilatation and curettage in women with at least one previous curettage: short-term outcomes of a multicenter, prospective randomized controlled trial. Fertility and Sterility, 107(5), 1223-1231.e3. doi:10.1016/j.fertnstert.2017.02.113Wallach, E. E., Schenker, J. G., & Margalioth, E. J. (1982). Intrauterine adhesions: an updated appraisal. Fertility and Sterility, 37(5), 593-610. doi:10.1016/s0015-0282(16)46268-0Westendorp, I. C., Ankum, W. M., Mol, B. W., & Vonk, J. (1998). Prevalence of Asherman’s syndrome after secondary removal of placental remnants or a repeat curettage for incomplete abortion. Human Reproduction, 13(12), 3347-3350. doi:10.1093/humrep/13.12.3347Wallach, E., & Czernobilsky, B. (1978). Endometritis and Infertility. Fertility and Sterility, 30(2), 119-130. doi:10.1016/s0015-0282(16)43448-5Baradwan, S., Baradwan, A., & Al-Jaroudi, D. (2018). The association between menstrual cycle pattern and hysteroscopic march classification with endometrial thickness among infertile women with Asherman syndrome. Medicine, 97(27), e11314. doi:10.1097/md.0000000000011314Hooker, A. B., Lemmers, M., Thurkow, A. L., Heymans, M. W., Opmeer, B. C., Brolmann, H. A. M., … Huirne, J. A. F. (2013). Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Human Reproduction Update, 20(2), 262-278. doi:10.1093/humupd/dmt045Yu, D., Wong, Y.-M., Cheong, Y., Xia, E., & Li, T.-C. (2008). Asherman syndrome—one century later. Fertility and Sterility, 89(4), 759-779. doi:10.1016/j.fertnstert.2008.02.096Yamamoto, N., Takeuchi, R., Izuchi, D., Yuge, N., Miyazaki, M., Yasunaga, M., … Inoue, Y. (2013). Hysteroscopic adhesiolysis for patients with Asherman’s syndrome: menstrual and fertility outcomes. Reproductive Medicine and Biology, 12(4), 159-166. doi:10.1007/s12522-013-0149-xThomson, A. J. M., Abbott, J. A., Kingston, A., Lenart, M., & Vancaillie, T. G. (2007). Fluoroscopically guided synechiolysis for patients with Asherman’s syndrome: menstrual and fertility outcomes. Fertility and Sterility, 87(2), 405-410. doi:10.1016/j.fertnstert.2006.06.035Deans, R., & Abbott, J. (2010). Review of Intrauterine Adhesions. Journal of Minimally Invasive Gynecology, 17(5), 555-569. doi:10.1016/j.jmig.2010.04.016Song, D., Liu, Y., Xiao, Y., Li, T.-C., Zhou, F., & Xia, E. (2014). A Matched Cohort Study Comparing the Outcome of Intrauterine Adhesiolysis for Asherman’s Syndrome After Uterine Artery Embolization or Surgical Trauma. Journal of Minimally Invasive Gynecology, 21(6), 1022-1028. doi:10.1016/j.jmig.2014.04.015Panchal, S., Patel, H., & Nagori, C. (2011). Endometrial regeneration using autologous adult stem cells followed by conception by in vitro fertilization in a patient of severe Asherman′s syndrome. Journal of Human Reproductive Sciences, 4(1), 43. doi:10.4103/0974-1208.82360Singh, N., Mohanty, S., Seth, T., Shankar, M., Dharmendra, S., & Bhaskaran, S. (2014). Autologous stem cell transplantation in refractory Asherman′s syndrome: A novel cell based therapy. Journal of Human Reproductive Sciences, 7(2), 93. doi:10.4103/0974-1208.138864Tan, J., Li, P., Wang, Q., Li, Y., Li, X., Zhao, D., … Kong, L. (2016). Autologous menstrual blood-derived stromal cells transplantation for severe Asherman’s syndrome. Human Reproduction, 31(12), 2723-2729. doi:10.1093/humrep/dew235Santamaria, X., Cabanillas, S., Cervelló, I., Arbona, C., Raga, F., Ferro, J., … Simón, C. (2016). Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman’s syndrome and endometrial atrophy: a pilot cohort study. Human Reproduction, 31(5), 1087-1096. doi:10.1093/humrep/dew042Puntambekar, S., Telang, M., Kulkarni, P., Puntambekar, S., Jadhav, S., Panse, M., … Phadke, U. (2018). Laparoscopic-Assisted Uterus Retrieval From Live Organ Donors for Uterine Transplant: Our Experience of Two Patients. Journal of Minimally Invasive Gynecology, 25(4), 622-631. doi:10.1016/j.jmig.2018.01.009Saso, S., Haddad, J., Ellis, P., Lindsay, I., Sebire, N., McIndoe, A., … Smith, J. (2011). Placental site trophoblastic tumours and the concept of fertility preservation. BJOG: An International Journal of Obstetrics & Gynaecology, 119(3), 369-374. doi:10.1111/j.1471-0528.2011.03230.xViudes‐de‐Castro, M. P., Marco‐Jiménez, F., Más Pellicer, A., García‐Domínguez, X., Talaván, A. M., & Vicente, J. S. (2019). A single injection of corifollitropin alfa supplemented with human chorionic gonadotropin increases follicular recruitment and transferable embryos in the rabbit. Reproduction in Domestic Animals, 54(4), 696-701. doi:10.1111/rda.13411Garcia-Dominguez, X., Marco-Jimenez, F., Viudes-de-Castro, M. P., & Vicente, J. S. (2019). Minimally Invasive Embryo Transfer and Embryo Vitrification at the Optimal Embryo Stage in Rabbit Model. Journal of Visualized Experiments, (147). doi:10.3791/58055Esteves, P. J., Abrantes, J., Baldauf, H.-M., BenMohamed, L., Chen, Y., Christensen, N., … Mage, R. (2018). The wide utility of rabbits as models of human diseases. Experimental & Molecular Medicine, 50(5), 1-10. doi:10.1038/s12276-018-0094-1Graur, D., Duret, L., & Gouy, M. (1996). Phylogenetic position of the order Lagomorpha (rabbits, hares and allies). Nature, 379(6563), 333-335. doi:10.1038/379333a0Saso, S., Petts, G., David, A. L., Thum, M.-Y., Chatterjee, J., Vicente, J. S., … Smith, J. R. (2015). Achieving an early pregnancy following allogeneic uterine transplantation in a rabbit model. European Journal of Obstetrics & Gynecology and Reproductive Biology, 185, 164-169. doi:10.1016/j.ejogrb.2014.12.017Saso, S., Petts, G., Chatterjee, J., Thum, M.-Y., David, A. L., Corless, D., … Smith, J. R. (2014). Uterine allotransplantation in a rabbit model using aorto-caval anastomosis: a long-term viability study. European Journal of Obstetrics & Gynecology and Reproductive Biology, 182, 185-193. doi:10.1016/j.ejogrb.2014.09.029Ozsoy, M., Gonul, Y., Bal, A., Ozkececi, Z. T., Celep, R. B., Adali, F., … Tosun, M. (2015). Effect of IL-18 binding protein on hepatic ischemia-reperfusion injury induced by infrarenal aortic occlusion. Annals of Surgical Treatment and Research, 88(2), 92. doi:10.4174/astr.2015.88.2.92Hare, A., & Olah, K. (2005). Pregnancy following endometrial ablation: a review article. Journal of Obstetrics and Gynaecology, 25(2), 108-114. doi:10.1080/01443610500040745Johannesson, L., Enskog, A., Molne, J., Diaz-Garcia, C., Hanafy, A., Dahm-Kahler, P., … Brannstrom, M. (2012). Preclinical report on allogeneic uterus transplantation in non-human primates. Human Reproduction, 28(1), 189-198. doi:10.1093/humrep/des381Brännström, M., Johannesson, L., Dahm-Kähler, P., Enskog, A., Mölne, J., Kvarnström, N., … Olausson, M. (2014). First clinical uterus transplantation trial: a six-month report. Fertility and Sterility, 101(5), 1228-1236. doi:10.1016/j.fertnstert.2014.02.02

Options for acquiring motherhood in absolute uterine factor infertility:adoption, surrogacy and uterine transplantation

Key content Following the diagnosis of absolute uterine factor infertility (AUFI), women may experience considerable psychological harm as a result of a loss of reproductive function and the realisation of permanent and irreversible infertility. Adoption enables women with AUFI, and their partners, to experience social and legal parenthood, also often providing benefits for the adopted child. Surrogacy offers the opportunity to have genetically related offspring. Outcomes are generally positive in both surrogates and the children born as a result. Uterine transplantation is the only option to restore reproductive anatomy and functionality. While associated with considerable risk, it allows the experience of gestation and the achievement of biological, social and legal parenthood. Learning objectives To gain an understanding of the routes to parenthood available for women with AUFI experiencing involuntary childlessness, such as adoption, surrogacy and, most recently, uterine transplantation To consider a suggested management plan to facilitate counselling in women with AUFI who experience involuntary childlessness. Ethical issues In the UK, whilst the number of children requiring adoption continues to increase, the number being adopted from care is decreasing. Some cultures may hold ethical or religious beliefs that surrogacy is unacceptable, and its legal position in many jurisdictions is problematic. Restrictive selection criteria and high costs may limit future availability of uterine transplantatio