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

AIM: 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. MATERIALS AND METHODS: 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: 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). TRIAL ID: ACTRN12622000917730. DISCUSSION: 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. CONCLUSION: 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.

Ethical issues raised by uterus transplantation: A report from the People's Republic of China.

The recent advances in assisted reproductive technology, such as hormonal stimulation, IVF, and intracytoplasmic sperm injection (ICSI), have made it possible to circumvent many causes of male and female factor infertility. However, uterine infertility is still considered an ''unconditionally infertile'' condition. Owing to the continued advances in organ transplantation, microvascular anastomosis techniques, and immunosuppressive medicine, the transplantation of organs is no longer restricted to the ones necessary for continued life. Quality-of-life enhancing types of transplantation, such as uterine transplantation, in recent years, have also entered the clinical arena. This undoubtedly brings new hope to such women, but also creates ethical challenges. Selection of the donor, the impact on the recipient and offspring, as well as challenges to moral and social norms are issues that cannot be ignored. In the present review, the ethical issues of transplantation of the uterus will be discussed in light of recent progress in the procedure.

Effect of autologous bone marrow stem cells-scaffold transplantation on the ongoing pregnancy rate in intrauterine adhesion women: a randomized, controlled trial.

Intrauterine adhesion is a major cause of female reproductive disorders. Although we and others uncontrolled pilot studies showed that treatment with autologous bone marrow stem cells made a few patients with severe intrauterine adhesion obtain live birth, no large sample randomized controlled studies on this therapeutic strategy in such patients have been reported so far. To verify if the therapy of autologous bone marrow stem cells-scaffold is superior to traditional treatment in moderate to severe intrauterine adhesion patients in increasing their ongoing pregnancy rate, we conducted this randomized controlled clinical trial. Totally 195 participants with moderate to severe intrauterine adhesion were screened and 152 of them were randomly assigned in a 1:1 ratio to either group with autologous bone marrow stem cells-scaffold plus Foley balloon catheter or group with only Foley balloon catheter (control group) from February 2016 to January 2020. The per-protocol analysis included 140 participants: 72 in bone marrow stem cells-scaffold group and 68 in control group. The ongoing pregnancy occurred in 45/72 (62.5%) participants in the bone marrow stem cells-scaffold group which was significantly higher than that in the control group (28/68, 41.2%) (RR=1.52, 95%CI 1.08-2.12, P=0.012). The situation was similar in live birth rate (bone marrow stem cells-scaffold group 56.9% (41/72) vs. control group 38.2% (26/68), RR=1.49, 95%CI 1.04-2.14, P=0.027). Compared with control group, participants in bone marrow stem cells-scaffold group showed more menstrual blood volume in the 3rd and 6th cycles and maximal endometrial thickness in the 6th cycle after hysteroscopic adhesiolysis. The incidence of mild placenta accrete was increased in bone marrow stem cells-scaffold group and no severe adverse effects were observed. In conclusion, transplantation of bone marrow stem cells-scaffold into uterine cavities of the participants with moderate to severe intrauterine adhesion increased their ongoing pregnancy and live birth rates, and this therapy was relatively safe.

Estimation of the prevalence of uterine infertility and its different causes in France according to data from a literature review.

INTRODUCTION: Uterine infertility (UI) is defined as the complete absence of a uterus (absolute uterine infertility or AUI) or the presence of a non functional uterus (non-absolute uterine infertility or NAUI). The exact prevalence of uterine infertility is currently unknown. Our aim was to assess the number of French women concerned by Uterine Infertility according to a recent literature review. MATERIALS AND METHODS: We have previously conducted a systematic review of the literature on UI and its various causes in the world. Based on these study and demographic data of 2022 from INSEE (Institut National de la Statistique et des Études Économiques), we attempted to estimate the number of women under 40 years of age in France affected by potential UI using direct standardization. RESULTS AND DISCUSSION: Based on the estimation from INSEE data, approximately 2066 women of childbearing age would have MRKH syndrome in France, 380 the Androgen Insensitivity Syndrome and 3700 had an haemostasis hysterectomy in France. We did not find data on the prevalence of hysterectomies before the age of 40 in France. For the following pathologies: uterine malformations, radiation uterus, synechiae, myomas and adenomyosis there was a huge amount of missing data, which does not allow us to estimate the number of potentially infertile patients. CONCLUSION: Prevalence of UI is poorly known. UI probably concerns several thousand patients in France. The creation of a UI registry would make enable to assess the number of patients potentially eligible for adoption, uterus transplantation or even surrogacy.

Current Status of Tissue Regenerative Engineering for the Treatment of Uterine Infertility.

With the recent developments in tissue engineering, scientists have attempted to establish seed cells from different sources, create cell sheets through various technologies, implant them on scaffolds with various spatial structures, or load scaffolds with cytokines. These research results are very optimistic, bringing hope to the treatment of patients with uterine infertility. In this article, we reviewed articles related to the treatment of uterine infertility from the aspects of experimental treatment strategy, seed cells, scaffold application, and repair criteria so as to provide a basis for future research.

Platelet-rich fibrin improves repair and regeneration of damaged endometrium in rats.

Purpose: Intrauterine adhesion (IUA) is the most common cause of uterine infertility. This study aims to evaluate whether platelet-rich fibrin (PRF) treatment can stimulate damaged endometrium regeneration in rats. Methods: First, hematoxylin and eosin (HE) staining, scanning and transmission electron microscopy, and ELISAs were used to evaluate the microstructure of PRF. Then, mechanical damage was used to establish an IUA rat model. A total of 40 SD female rats were randomized to three groups: PRF transplantation group, IUA group, and sham group. Rats were sacrificed at 3, 7, and 14 days and uteruses were obtained for further analysis. Finally, functional and histological recovery of the damaged endometrium was analyzed by pregnancy test, HE staining, Masson's staining, and immunohistochemistry. Results: PRF has two distinct zones, platelets and fibrin zone. Long and narrow fibrin fibers interconnected with each other and formed a three-dimensional, flexible, and elastic structure; platelet aggregates were trapped in fibrin fibers, and each platelet is associated with several fibrin fibers. PRF exudates promoted endometrial stromal cell proliferation and migration in vitro. PRF transplantation was beneficial for maintaining uterine structure, promoting endometrial luminal epithelium and endometrial gland regeneration, and decreasing fibrotic areas in vivo. Conclusion: Intrauterine administration of PRF was demonstrated to be effective in preventing IUA and stimulating damaged endometrium regeneration in rats. This study not only provided a promising method for its potential in endometrial regeneration in women who suffer from uterine infertility but also may prevent IUA after intrauterine surgery in clinical cases.

Gender-affirming hysterectomy in the United States: A comparative outcomes analysis and potential implications for uterine transplantation.

PURPOSE: Hysterectomy is a gynecological procedure sometimes performed as part of the gender-affirming process for transgender and gender-expansive patients assigned female at birth. Our goal was to compare surgical outcomes between patients undergoing gender-affirming hysterectomy and patients undergoing hysterectomy for benign menstrual disorders. We then explored the implications of gender-affirming hysterectomy for uterine transplantation. METHODS: We performed a retrospective cohort study using data from the American College of Surgeons National Surgical Quality Improvement Program database from 2009 through 2018. We identified patients undergoing hysterectomy in the United States based on Current Procedural Terminology code. We used the International Classification of Diseases 9 or 10 codes to identify patients with benign menstrual disorders (non-gender-affirming group) and gender dysphoria (gender-affirming group). We compared patient characteristics and surgical complications. RESULTS: Of the 40,742 patients that met inclusion criteria, 526 (1.3%) patients were individuals with gender dysphoria. Compared to patients who underwent hysterectomy for benign menstrual disorders, gender-affirming patients were younger, were healthier, had a lower prevalence of diabetes, and were more likely to undergo surgery in the outpatient setting, with shorter time to discharge. Complication rates were similar between groups. Logistic regression controlling for the American Society of Anesthesiology classification determined the difference of return to the operating room was not statistically significant (OR 1.082; 95% CI, 0.56-2.10; p = 0.816). CONCLUSION: Gender-affirming hysterectomy has a safety profile similar to hysterectomy performed for benign menstrual disorders. Researchers should further explore the possibility of uterus donation among these patients as they may be suitable candidates.

Procurement of Uterus in a Deceased Donor Multi-Organ Donation National Program in France: A Scarce Resource for Uterus Transplantation?

Uterus transplantation is a new possibility for women suffering from absolute uterine infertility to become pregnant and have children. In the case of a deceased donor, a list of exclusion criteria is defined to ensure the high quality of the uterus graft. This study evaluates the number of potentially available uterus grafts based on the pre-defined exclusion criteria in a national deceased donor multi-organ donation program in France. We analyzed the data reported in the CRISTAL database regarding all women aged 18 to 60 on whom organ procurement was performed between 2014 and 2019. Potential deceased women donors were classified into three categories: very ideal donor, ideal donor, and expanded criteria donor. Between 2014 and 2019, 4544 women underwent organ procurement. Using the very ideal donor, ideal donor, and expanded criteria donor classification, we found that, respectively, only 124, 264, and 936 donors were potentially eligible for UTx. This represents 2.8 per million people (PMP) very ideal donors, 3.8 PMP ideal donors, 8.6 PMP expanded criteria donors (ECDs). The restricted number of grafts requires a complementary strategy of living and deceased donors to meet the demand of all women with AUI.

Single bilateral ovarian venous return in uterine transplant: Validation in an orthotopic auto-transplant model in the Yucatan minipig.

BACKGROUND: Uterine transplant (UT) represents an opportunity to treat absolute uterine infertility. However, the use of uterine veins for venous return, in addition to ovarian veins, significantly increases the risk of ureteral wounds in the living donor and UT time for the recipient. Our aim was to demonstrate that dual ovarian venous return is sufficient for graft viability and survival. METHODS: Uterine orthotopic auto-transplant was performed under general anaesthesia in six Yucatan minipig sows. The uterus graft was implanted with termino-lateral anastomoses between the ovarian and external iliac veins, and between the uterine and external iliac arteries, respectively. RESULTS: The macroscopic physical aspect of the graft was adequate in 83 % of the sows (5/6) 30 min after reperfusion with a surgical time of 439±54 min (mean anastomosis time: 153±49 min). Two sows died the day after surgery. In the four remaining sows, two uteri were necrotic and two were adequately vascularized on Day 7. CONCLUSIONS: the learning curve was relatively fast, the sole use of bilateral ovarian venous return is possible and might reduce post-surgery morbidity in human living donors as well as UT time for the recipient.

Collagen-binding basic fibroblast growth factor improves functional remodeling of scarred endometrium in uterine infertile women: a pilot study.

Intrauterine adhesion (IUA) is a common cause of uterine infertility and one of the most severe clinical features is endometrial fibrosis namely endometrial scarring for which there are few cures currently. Blocked angiogenesis is the main pathological change in the scarred endometrium. The fibroblast growth factor 2 (bFGF), a member of FGF family, is usually applied to promote healing of refractory ulcer and contributes to angiogenesis of tissues. In this study, the sustained-release system of bFGF 100 µg was administrated around scarred endometrium guiding by ultrasound every 4 weeks in 18 patients (2-4 times). Results showed that after treatment, the menstrual blood volume, endometrial thickness and the scarred endometrial area were improved. Histological study showed blood vessel density increased obviously. Three patients (3/18) achieved pregnancy over 20 gestational weeks. Therefore, administrating the bFGF surrounding scarred endometrium may provide a new therapeutic approach for the patients with endometrial fibrosis.

Endometrial regeneration using cell sheet transplantation techniques in rats facilitates successful fertilization and pregnancy.

OBJECTIVE: To regenerate functional endometrium tissue using "cell sheet" techniques as a regenerative medicine approach to address endometrial disorders causing female factor infertility. DESIGN: In vivo experimental study. SETTING: Preclinical surgical and biomedical research laboratories. ANIMAL(S): Green fluorescent protein (GFP) transgenic rats [SD-Tg (CAG-EGFP) rats] and nude rats (F344/NJcl-rnu/rnu). INTERVENTION(S): GFP-positive rat uterine-derived cells as cell sheets were transplanted into resected rat uterine endometrial sites. Transplanted cell sheet areas were then analyzed using macroscopic observations and histological analysis including immunohistochemistry. Subsequently, crossbreeding was performed to establish fertility and confirm pregnancy in the rat-regenerated uterus. MAIN OUTCOME MEASURE(S): Morphologic and biochemical markers of regenerated endometrium and establishment of pregnancy in otherwise sterile animals. RESULT(S): After cell sheet transplantation, regenerated endometrium was confirmed as GFP-positive tissue engraftment both visually and under histological analysis. After crossbreeding, GFP-positive tissue areas and living fetuses were observed in the transplantation group. CONCLUSION(S): Cell sheet transplantation can regenerate endometrial tissue with histological structure and physiological function supporting pregnancy similar to normal endometrial tissue. Translation of this endometrial cell sheet transplantation method to human patients with endometrial disorders could yield a novel therapy for uterine infertility.

Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: a phase I clinical trial.

BACKGROUND: Intrauterine adhesions (IUA) are the most common cause of uterine infertility and are caused by endometrium fibrotic regeneration following severe damage to the endometrium. Although current stem cell treatment options using different types of autologous stem cells have exhibited some beneficial outcomes in IUA patients, the reported drawbacks include variable therapeutic efficacies, invasiveness and treatment unavailability. Therefore, the development of new therapeutic stem cell treatments is critical to improving clinical outcomes. METHODS: Twenty-six patients who suffered from infertility caused by recurrent IUA were enrolled in this prospective, non-controlled, phase I clinical trial with a 30-month follow-up. During the procedure, 1 × 107 umbilical cord-derived mesenchymal stromal cells (UC-MSCs), loaded onto a collagen scaffold, were transplanted into the uterine cavity following an adhesion separation procedure. Medical history, physical examination, endometrial thickness, intrauterine adhesion score and the biological molecules related to endometrial proliferation and differentiation were assessed both before and 3 months after cell therapy. RESULTS: No treatment-related serious adverse events were found. Three months after the operation, the average maximum endometrial thickness in patients increased, and the intrauterine adhesion score decreased compared to those before the treatment. A histological study showed the upregulation of ERα (estrogen receptor α), vimentin, Ki67 and vWF (von Willebrand factor) expression levels and the downregulation of ΔNP63 expression level, which indicates an improvement in endometrial proliferation, differentiation and neovascularization following treatment. DNA short tandem repeat (STR) analysis showed that the regenerated endometrium contained patient DNA only. By the end of the 30-month follow-up period, ten of the 26 patients had become pregnant, and eight of them had delivered live babies with no obvious birth defects and without placental complications, one patient in the third trimester of pregnancy, and one had a spontaneous abortion at 7 weeks. CONCLUSIONS: Transplanting clinical-grade UC-MSCs loaded onto a degradable collagen scaffold into the uterine cavity of patients with recurrent IUA following adhesiolysis surgery is a safety and effective therapeutic method. TRIAL REGISTRATION: Clinicaltrials.gov . NCT02313415 , Registered December 6, 2014.

[Uterine transplantation: is there a real demand?]. / Transplantation utérine : une demande réelle ?

OBJECTIVES: To study the demand there is for uterus transplantation (UTx). PATIENTS AND METHODS: Recent media coverage of developments in UTx prompted associations of patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome and of women suffering from UI to contact us. We sent them anonymous questionnaires devised to sound out their attitude towards UTx and towards adoption and gestational surrogacy (GS). A clinical psychologist also carried out a qualitative discourse analysis. RESULTS: Sixty patients answered the questionnaire. Thirty-eight patients were married or living with a male partner. Seven patients had had a hysterectomy. Fifty-one patients had uterine agenesis. Of the 60 patients, 19 and 21, respectively, had ruled out the option of adoption or GS, and 11 would not envisage either possibility. Thirty-five patients were willing to take part in a clinical study into UTx despite the uncertainty of the outcome and the potential risks involved. Of these 35 volunteers, 23 were in a heterosexual relationship and aged ≤35 years. DISCUSSION AND CONCLUSION: For women with UI the condition is all the more distressing because there is no medical solution for it. UTx could hold out hope for some of these patients despite the complexity of the procedure and the attendant risks. Because of the feelings of vulnerability engendered by UI, any UTx programme should provide full information to patients and ensure they are carefully screened and selected.

Risks for donors in uterus transplantation.

Uterus transplantation (UTx) is an alternative to gestational surrogacy and adoption for patients with absolute uterine infertility. Studies have been conducted in animals, and UTx is now within the reach of clinical application in humans. Procedures in humans have been published, but many medical, ethical, and social problems and risks of UTx require discussion prior to widespread clinical application, from the perspectives of donors, recipients, families, and newborns. In this article, we summarize the burdens and risks of UTx, with a focus on donors who provide the uterus.