Human UTx Research Articles

A study protocol for live and deceased donor uterus transplantation as a treatment for women with uterine factor infertility.

Uterus transplantation (UTx) is an emerging treatment option for women with uterine factor infertility (UFI) or the absence of a functional uterus. This is the study protocol for the first human UTx clinical trial in Australia. This protocol outlines the approved training program used to plan, diagnose, screen, and treat patients who may be eligible for UTx using living and deceased donors. This multi-site clinical research study includes three tertiary hospital sites within New South Wales (NSW), Australia - Prince of Wales, Royal Hospital for Women and Westmead Hospitals. Our UTx protocol is based on that used by our collaborative partner, the inaugural UTx team in Gothenburg, Sweden. The Swedish UTx team provides ongoing preceptorship for the Australian UTx team. Ethics approval for six UTx procedures using living or deceased donors (Western Sydney Local Health District Human Research Ethics Committee: 2019/ETH138038) was granted in 2020. Results from surgeries and live births will be published. Data will be prospectively entered into the registry of the International Society of Uterus Transplantation (ISUTx), a sub-section of The Transplantation Society (TTS). ACTRN12622000917730. A multidisciplinary research team has been formed between three tertiary hospitals in Sydney - The Royal Hospital for Women, Prince of Wales and Westmead Hospitals; and with the Swedish UTx, University of Gothenburg. The Swedish team pioneered animal and human UTx studies since 1998, including publishing the first live birth after UTx. (1) This Australian trial commenced in January 2023. Uterus transplantation gives women with UFI the opportunity to be gestational and genetic mothers. It is a complex procedure for both the donor and recipient, with medical and surgical risks. An extensive multidisciplinary approach is required to optimise patient safety and graft outcomes. This protocol outlines our Australian UTx team strategy for screening, recruitment, surgical approach, and clinical management of UTx recipients and donors.

Differences between living and deceased donation in human uterus transplantation: A narrative review.

The decision to use a living or deceased donor to perform uterus transplantation (UTx) is an evaluation of benefit and harm and is based on the medical team's choices. The current study determines the differences between living and deceased donation in human UTx according to determinant factors in choosing the donor type. For this review study, the PubMed database was searched without time, language, and location limitations up to May 2022. From 113 identified articles, 45 papers were included in the study for review. According to the results, in comparison to living donation, the biggest advantage of deceased donation is the lack of surgical and or psychological risks for the donor. In contrast, a comprehensive pre-transplantation medical assessment is less possible in deceased donation, and preplanned surgery cannot be realized. According to published peer-reviewed clinical trials on UTx, the graft failure rates in living and deceased donor UTx are 21% and 36%, respectively. Supposing all recipients who did not have graft failure underwent embryo transfer, live birth rates in living and deceased donor UTx procedures are almost 63% and 71%, respectively. Currently, considering the occurrence of live births from both donations, particularly from nulliparous deceased donor, increased demand for UTx in the near future, shortage of uterus grafts, and lack of sufficient data for a comprehensive comparison between the 2 types of donation, the use of both donations still seems necessary and rational.

Assisted Reproduction and Live Births in Uterus Transplantation—The Swedish View

Objective: Uterus transplantation (UTx) has evolved as the first true infertility treatment for absolute uterine factor infertility (AUFI), caused by a lack (congenital or surgical) of the uterus or presence of a non-functional uterus. Ever since the proof-of-concept of UTx as an infertility treatment, by the first live birth in 2014, the field has evolved with a number of ongoing clinical trials in several countries. Results are now gradually building up to estimate the efficacy of the procedure in terms of outcome of assisted reproduction, including live births. An update of these results will be presented along with our own experience. Mechanism: PubMed search for research articles with human UTx procedures. Findings in Brief: We could identify 62 UTx cases with data from research articles in peer-reviewed journals. Out of these, 51 were live donor procedures and 11 were deceased donor UTx. Surgical success was 78% in live donor UTx and 64% in deceased donor UTx. Limited data indicate a pregnancy and live birth rate per embryo transfer (ET), somewhat lower that in the general IVF population. The 24 published live births were premature (<37 gestational weeks) in 83%, with a high frequency (37%) of respiratory distress syndrome. Gestational hypertension/preeclampsia was seen in 17% and gestational diabetes in 12% of pregnancies. Post-natal health of children was fine. Conclusions: Uterus transplantation has entered the scene as the first available treatment for women with absolute uterine factor infertility. The procedure is still in an experimental phase and through ongoing clinical trials, with modifications of procedures, this type of combined infertility treatment and major transplantation surgery will improve regarding outcomes, such as surgical success, rate of pregnancy/live birth per ET, rate of term pregnancy, and rate of live births with only a minor rate of neonatal and postnatal complications.

Involving Animal Models in Uterine Transplantation.

BackgroundAbsolute uterine factor infertility affects 0. 2% women of childbearing age around the world. Uterine transplantation (UTx) is a promising solution for many of them since the first birth from UTx was described by the Swedish team in 2014. The success of Utx in humans has become possible after a systematic and meticulous approach involving years of research on animal models. To date, more than 80 UTx procedures have been performed worldwide and 30 children were born.Material and MethodThis review summarizes the research preparation conducted in animals before beginning UTx in humans. It focuses on the advantages and limits of each animal model, their place in surgical training, and current contribution in research to improve UTx successes in humans. The different steps in the process of UTx have been analyzed, such as imaging, surgery, ischemia-reperfusion effects, rejection markers, immunosuppressive treatment, and pregnancy.ConclusionAnimal models have played an essential role in the implementation of UTx, which is a highly complex procedure. While respecting the 3R requirements (replacement, refinement, and reduction), the surgical training using large animal models, such as notably ewes remain irreplaceable for teams wishing to initiate a UTx program. Furthermore, animal models are still mandatory in current research to improve the success rates of UTx in humans as well as to reduce the morbidity associated with this experimental infertility treatment.

AZFa candidate gene UTY and its X homologue UTX are expressed in human germ cells.

SummaryThe Ubiquitous Transcribed Y (UTY a.k.a. KDM6C) AZFa candidate gene on the human Y chromosome and its paralog on the X chromosome, UTX (a.k.a. KDM6A), encode a histone lysine demethylase removing chromatin H3K27 methylation marks at genes transcriptional start sites for activation. Both proteins harbour the conserved Jumonji C (JmjC) domain, functional in chromatin metabolism, and an extended N-terminal tetratricopeptide repeat (TPR) block involved in specific protein interactions. Specific antisera for human UTY and UTX proteins were developed to distinguish the expression of both proteins in human germ cells by immunohistochemical experiments on appropriate tissue sections. In the male germ line, UTY was expressed in the fraction of A spermatogonia located at the basal membrane, probably including spermatogonia stem cells. UTX expression was more spread in all spermatogonia and in early spermatids. In female germ line, UTX expression was found in the primordial germ cells of the ovary. UTY was also expressed during fetal male germ cell development, whereas UTX expression was visible only at distinct gestation weeks. Based on these results and the conserved neighboured location of UTY and DDX3Y in Yq11 found in mammals of distinct lineages, we conclude that UTY, such as DDX3Y, is part of the Azoospermia factor a (AZFa) locus functioning in human spermatogonia to support the balance of their proliferation-differentiation rate before meiosis. Comparable UTY and DDX3Y expression was also found in gonadoblastoma and dysgerminoma cells found in germ cell nests of the dysgenetic gonads of individuals with disorders of sexual development and a Y chromosome in karyotype (DSD-XY). This confirms that AZFa overlaps with GBY, the Gonadoblastoma susceptibility Y locus, and includes the UTY gene.Lay summaryAZFa Y genes are involved in human male germ cells development and support gonadoblastoma (germ cell tumour precursor cells) in the aberrant germ cells of the gonads of females with genetic disorders of sexual development. The AZFa UTY gene on the male Y chromosome is equivalent to UTX on the female X chromosome. These genes are involved in removing gene regulators to enable activation of other genes (i.e. removal of histone methylation known as epigenetic modifications). We wanted to learn the function of UTY and UTX in developing sperm and eggs in human tissues and developed specific antibodies to detect both proteins made by these genes. Both UTY and UTX proteins were detected in adult and fetal sperm precursor cells (spermatogonia). UTX was detected in egg precursor cells (primordial germ cells). UTY was detected in gonadoblastoma and dysgerminoma tumour cells (germ cell tumours originating from genetic disorders of sexual development due to having a Y chromosome). Based on our study, we conclude that UTY is not only part of AZFa, but also of GBY the overlapping gonadoblastoma susceptibility Y region.

Experimental techniques for the development of a uterus transplantation model in cynomolgus macaques.

Uterus transplantation (UTx) is now a treatment for women with uterine factor infertility to have a child. However, UTx is still largely at the experimental stage, and many medical issues remain unsolved. Therefore, adequate studies in large animals including non-human primates are required for validation of these issues. UTx research, especially in non-human primates, can provide important information for its full establishment in humans due to the anatomical and physiological similarities between the two. We accumulated data from UTx studies using cynomolgus macaques since 2009 and established autologous and allogeneic UTx models which led to deliveries after performing the procedure. In this paper, we summarized key points to develop UTx models in cynomolgus macaques based on our experience. UTx models in non-human primates can surely contribute new and beneficial knowledge in this field and can be useful for the further development of UTx in humans.

Adapting surgical skills from robotic-assisted radical hysterectomy in cervical cancer to uterine transplantation: a look to an optimistic future!

Uterus transplantation (UTx) is the first treatment for absolute uterine factor infertility. The first birth after human UTx in Sweden occurred in 2014 and very favourable results of the Swedish trial performed with laparotomy raised great hope. Several teams are leading their own trial among the world, but UTx is still in its experimental phase. Surgical intervention needs to be optimized. The long surgical duration (> 10h), vascular dissection and risks of ureteral damages for live donors are major drawbacks. Minimal invasive surgery by means of robotic-assisted laparoscopy for live donors could become an improved option. Our collaborative Swedish-French team has initiated efforts to introduce minimal invasive surgery in one trial in Sweden and one in France. UTx is somewhat similar to a radical colpohysterectomy for arterial dissection. We describe a robotic-assisted radical colpohysterectomy and its transposition to uterus retrieval in a living donor. We report our experience on nine cases that were completed prior to our French UTx robot-assisted trial.

Clinical applications of uterus transplantation in China: Issues to take into consideration.

Uterus transplantation (UTx) is an emerging surgical treatment for patients with absolute uterine factor infertility. However, the initial low surgical success of human UTx from the teams worldwide has revealed the difficulty of the surgery and called for preparatory team training in large animals. Also, the team who carried out the human UTx without previous systematic research in large animals or deceased donors encountered transplant failures, which was controversial and even deprived them of further trials. Various UTx studies in large animals, including dogs, pigs, sheep and macaques have been performed in China from different teams, compared to other countries around the world. However, among over 70 UTx that have been carried out worldwide, only three were carried out in China, with one live baby achieved. In this paper, we explore the possible challenges for human UTx in China. We conclude that it is critical to learn the lessons from the international team and adopt the international ethic views regarding UTx on humans. Also, it would be positive for the Chinese groups to establishing an academic society for UTx with regular meetings, which will raise public awareness of UTx, and guide the proper development of human UTx in China.

Long-Term Outcome and Rejection After Allogeneic Uterus Transplantation in Cynomolgus Macaques.

Uterus transplantation (UTx) is an option for women with uterine factor infertility to have a child, but is still in the experimental stage. Therefore, allogeneic animal models of UTx are required for resolution of clinical issues. In this study, long-term outcomes were evaluated in four recipients (cases 1–4) after allogeneic UTx in cynomolgus macaques. Immunosuppression with antithymocyte globulin induction and a triple maintenance regimen was used. Postoperative ultrasonography and biopsy of the transplanted uterus and immunoserological examinations were performed. All four recipients survived for >3 months after surgery, but continuous menstruation did not resume, although temporary menstruation occurred (cases 1 and 2). All animals were euthanized due to irreversible rejection and no uterine blood flow (cases 1, 2 and 4) and post-transplant lymphoproliferative disorder (case 3). Donor-specific antibodies against MHC class I and II were detected in cases 1, 2 and 4, but not in case 3. Peripheral lymphocyte counts tended to elevate for CD3+, CD20+ and NK cells in conjunction with uterine rejection, and all animals had elevated stimulation indexes of mixed lymphocyte reaction after surgery. Establishment of allogeneic UTx in cynomolgus macaque requires further exploration of immunosuppression, but the clinicopathological features of uterine rejection are useful for development of human UTx.

Current Progress in Uterus Transplantation Research in Asia.

Uterus transplantation (UTx) is now a possible approach for women with absolute uterine factor infertility to deliver a child, following the first successful delivery by Brännström et al. in Sweden in September 2014. This remarkable achievement attracted major attention worldwide and caused many countries to prepare for UTx, including countries in Asia. To date, three groups have performed UTx in humans in Asia, and many others are aiming for the clinical application of UTx with accumulation of basic experimental data. Therefore, it is likely that UTx will expand rapidly in Asia in the near future, although this will depend on ethical, social and religious views in each country. With this background, herein we summarize the current progress of UTx in East, Southeast and South Asia, with the purpose of increasing understanding of the current status of basic and clinical UTx research in each country and sharing progress and knowledge to ensure future development of UTx research in Asia.

The auto-transplantation of uterus in swine: surgical techniques and long-term graft survival

Objective: Uterus transplantation (UTx) provides a available treatment for women with absolute uterus-related infertility. The aim of this study was to develop surgical techniques for UTx and to observe the long-term graft survival in the swines. Materials and Methods: Ten female swines received uterus auto-transplantation surgery after general anesthesia. The operative time, ischemic time, and vascular injury in each swine were recorded. The bicornual uterus with vaginal canal and main vessel were removed, bake-table preparation was performed with cooled at 4°C, and perfused with heparin saline with continuous flushing. The uterus was placed in original pelvic position. The uterus arteries and veins were end-side anastomosed with external iliac arteries and veins in the host swines. Results: One case was randomly selected as the preliminary experiment. The remaining nine cases showed that the uterine arteries and veins were anastomosed successfully and only eight cases attained long-term survival. The host in another case died four days after surgery from suspicious embolism postoperation. The blood flow of uterus arteries was observed by Doppler ultrasonography at four days after the operation and no congestion was found. The second-look laparotomy at six months after surgical was subsequently performed and the uterus showed a normal morphology and size. However, the pregnancy was unsuccessful due to the shorter observation time, and the severe adhesion and tubal obstruction after surgery may have affected pregnancy of those swines. Conclusion: These preliminary experiences suggest that the uterine auto-transplantation using the end-side vascular anastomosed method is feasible. The accumulation of basic data and experiences from swine experiments can provide important guidance for establishment of UTx in humans.

Basic research on uterus transplantation in nonhuman primates in Japan.

Uterus transplantation (UTx) is now a potential option for women with uterine factor infertility to have a child. However, UTx is still in an experimental stage and basic animal studies including in nonhuman primates are needed for accumulation of data that will provide important information for establishment of UTx in humans. Herein, we summarized our experiences using cynomolgus macaques, with the goal of promoting further development of UTx studies in nonhuman primates. Our basic studies using cynomolgus macaques were summarized, including the results of other teams in nonhuman primates. Our team in Japan launched UTx research in 2009 using cynomolgus macaques and has accumulated a large archive of results in the UTx research field, including examination of uterine blood flow, surgical procedures of autologous and allogeneic UTx, organ perfusion methods in deceased donor models, immunological response and rejection and ischemia/reperfusion injury. We achieved the first delivery after autologous UTx in primates and the first periodic recovery of menstruation after allogeneic UTx in nonhuman primate models. Results from animal studies, including those in nonhuman primates, provide the basis for clinical application of UTx. Therefore, our accumulated data since 2009 and our basic experience in cynomolgus macaque are meaningful for future UTx trials in Japan. In addition, more validation in nonhuman primate models is needed for resolution of medical issues and further development of UTx in humans, despite clinical application of UTx in several countries.

UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling.

SummaryNeural stem cell (NSC) proliferation and differentiation in the developing brain is a complex process precisely regulated by intrinsic and extrinsic signals. Although epigenetic modification has been reportedly involved in the regulation of the cerebral cortex, whether UTX, an H3K27me3 demethylase, regulates the development of cerebral cortex during the embryonic period is unclear. In this study, we demonstrate that Utx deficiency by knockdown and conditional knockout increases NSC proliferation and decreases terminal mitosis and neuronal differentiation. Furthermore, we find that impairment of cortical development caused by lack of Utx is less significant in males than in females. In addition, UTX demethylates H3K27me3 at the Pten promoter and promotes Pten expression. P-AKT and P-mTOR levels are increased in the Utx conditional knockout cortices. Finally, Utx or Pten overexpression can rescue the impairment of brain development caused by Utx loss. These findings may provide important clues toward deciphering brain diseases.

Uterus Transplantation: Current State and Future Perspectives

Absolute uterine factor infertility (AUFI) has traditionally been regarded as untreatable. Gestational surrogacy (GS) is not permitted in most countries and societies in the world due to ethical, religious or legal reasons. The interest in uterus transplantation (UTx) as a treatment for AUFI started in the 1960s and, after some disappointing results, raised again in the new century, when our and other groups obtained live off-spring after UTx in the mouse, and here we review extensively the results of animal research. In September 2014, the first baby was born after human UTx and this proof-of-concept of UTx as an infertility treatment has been followed by several more births. All cases described in the literature are also reviewed. The overall evidence suggests that the clinical introduction of UTx as the first available treatment for AUFI has been successful. However, UTx will stay at experimental stage for several years whilst optimizing the procedure and ensuring its safety from a medical and psychological perspective.

Uterine transplantation is not a good use of limited resources: AGAINST: It is a highly effective infertility treatment.

Infertility is, according to the World Health Organization, ‘a disease of the reproductive system’ and ‘generates disability and access to health care falls under the Convention on the Rights of Persons with Disability’. After the medical breakthroughs of in vitro fertilisation and intracytoplasmic sperm injection, absolute uterine factor infertility (AUFI) remained the only untreatable, major infertility subgroup. In the UK there are >12 000 women with AUFI (Sieunarine et al. Int Surg 2005;90:249–56). Gestational surrogacy has until now been a way for women with AUFI to acquire genetic motherhood. The procedure is prohibited in most countries because of legal, religious or ethical concerns. The first livebirth after uterus transplantation (UTx) in 2014 [Brännström et al. 2015;385(9968):607–16] has been followed by four births (our unpublished observations). Naturally, these healthy livebirths have led to a substantial increase in the quality-of-life of these couples. In the UTx trial (Brännström et al. Fertil Steril 2014;101:1228–36; Johannesson et al. Fertil Steril 2015;103:199–204) there is a high (87%) clinical pregnancy rate, indicating that it is a highly effective infertility treatment. Importantly, UTx will stay at the clinical experimental stage for several years, as will ovarian autotransplantation. Hence, all new attempts of human UTx should be performed within clinical trials to acquire all possible data. All the active UTx groups worldwide met in January 2016 to form an international society. Three important goals of this society will be: to form a compulsory registry with data from all new cases, to establish mandatory requirements that would apply for teams performing human UTx, and to perform yearly audits at centres that are conducting UTx. These regulations and the registry will be beneficial for the efficiency and safety of the procedure. Hence, the UTx-related assisted reproductive technologies and surgical procedures will be optimised. It is not until we have data from several studies and the registry that the health authorities in each country can decide whether this procedure should be a clinical infertility treatment. The cost of the procedure will differ between countries, just as the price for a live-donor renal transplantation differs by a factor of at least four. In some countries the public health insurance will most probably pay for UTx whereas others will consider that the procedure should be paid for by the patient, just like cosmetic surgery. The introduction of new medical treatments may raise important ethical conflicts that often have conflicting effects, for example the principle of human dignity that states that ‘all people are equal in dignity regardless of their personal characteristics’ and the principle of need and solidarity, which states that ‘resources should be committed to the person more in need’. In conclusion, patients with AUFI should in the future be offered UTx as an alternative treatment to surrogacy. Surrogacy after in vitro fertilisation has been practised for more than 20 years. However, the possible effects on offspring and families after gestational surrogacy are not clear (Söderström-Anttila et al. Hum Reprod Update 2015). The cost of a UTx procedure is markedly less than of other types of transplantations, because the expensive immunosuppression is for only a few years. Moreover, UTx will not only increase the quality of life of the infertile couple but also create new life. None declared. Completed disclosure of interests form available to view online as supporting information.■ Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

One uterus bridging three generations: first live birth after mother-to-daughter uterus transplantation

To determine whether a uterus from the mother of a woman with absolute uterine factor infertility can be transplanted to daughter and carry a pregnancy with delivery of a healthy child. Part of an observational study. University teaching hospital. Twenty eight-year-old woman with uterine agenesis, her male partner, and her 50-year-old mother. Invitro fertilization with embryo cryopreservation before live donor uterus transplantation (UTx). Induction immunosuppression. Embryo transfer 12months after UTx, pregnancy controls, delivery, and hysterectomy. Results of IVF-ET, parameters of pregnancy/birth, and surgical data of transplantation/cesarean section/hysterectomy. Two IVF cycles before UTx resulted in 10 cryopreserved embryos. Donor surgery included hysterectomy with vascular pedicles of uterine vessels and proximal vessels up to and including parts of internal iliacs. Recipient surgery was by bilateral vascular connections to external iliacs, vaginal-vaginal anastomosis, and uterine fixation. Pregnancy occurred at the first single ET, and the pregnancy proceeded uneventfully until gestational week 34, when the patient developed cholestasis with intense pruritus. Cesarean section was performed at 34+6, with delivery of a healthy boy (weight 2,335g). Hysterectomy was performed 3.5months after delivery. The weight of the healthy child at 12months was 9.3kg. Grandmother (uterus donor) and mother are in good health 3years after UTx. This is the first report of a live birth after mother-to-daughter UTx, and it also represents the second birth ever after human UTx. NCT01844362.

Human uterus transplantation in focus.

Uterus transplantation (UTx) is introduced as the first treatment for absolute uterine factor infertility (AUFI), affecting 1:500 fertile aged women. This review presents potential patients, research and human UTx cases. Published articles and our research experience. The first UTx live births in 2014 established UTx as a possible treatment for AUFI. This was proceeded by 15 years of systematic research. Is a deceased donor UTx as effective as the proven successful live donor UTx?. Human UTx trials will accumulate data on risks, effectiveness and long-term consequences for donors, recipients and children. These should also include aspects of quality of life, psychological well-being and cognitive/neuropsychiatric development of children. All new activities in human UTx within the coming years should be conducted as prospective observational studies, and data should also be collected within an international registry.

Uterus transplantation.

The recent first live birth after human uterus transplantation (UTx) is a proof-of-concept of UTx as a factual treatment for women with absolute uterine factor infertility. This review summarizes the 15-year-long translational UTx research project, from the beginning in rodents until the first human UTx live birth in 2014. It also gives detailed information about the 11 human UTx cases performed so far. The first live birth after UTx in any species was demonstrated already in 2003, in the syngeneic mouse model. Subsequent studies, in rats, large domestic species, and in nonhuman primates optimized the UTx procedure in regards to surgery, immunosuppression, rejection diagnosis, and pregnancy. Worldwide, only 11 human UTx attempts have been performed. The first two single cases were unsuccessful and performed with no research preparations. The following nine transplantations were completed within a clinical UTx trial in 2013. So far, four healthy babies have been born from this cohort and additional patients are pregnant. Uterus transplantation, still at its early experimental stage, has the potential to become the first true treatment for the around 1.5 million women worldwide that are infertile because of absence of the uterus or presence of a nonfunctional uterus.

The Swedish uterus transplantation project: the story behind the Swedish uterus transplantation project.

The Swedish uterus transplantation project: the story behind the Swedish uterus transplantation project.

Role of UTX in retinoic acid receptor-mediated gene regulation in leukemia.

Human UTX, a member of the Jumonji C family of proteins, associates with mixed-lineage leukemia 3/4 complexes. Stimulation with retinoic acid leads to the recruitment of UTX-containing complexes to HOX genes, which results in demethylation of histone H3 lysine 27 and concomitant methylation of histone H3 lysine 4. Here, we show that UTX interacts with the retinoic acid receptor α (RARα) and that this interaction is essential for proper differentiation of leukemic U937 cells in response to retinoic acid. UTX occupies the promoters of several RAR target genes and regulates their transcriptional output by modulating ASH2L complex recruitment. Overexpression of UTX in promyelocytic NB4 cells results in enhanced cellular differentiation upon retinoic acid treatment. Our results show that UTX is important for RAR-mediated transcription and provide insight into the critical role of cross talk between histone H3 lysine 4 methylation and histone H3 lysine 27 demethylation during cellular differentiation.