Optimizing care for MRKH patients: From malformation screening to uterus transplantation eligibility.

INTRODUCTION: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome with utero-vaginal aplasia is the most severe form of the Müllerian duct anomalies and can be associated with extra-genital abnormalities such as renal or skeletal anomalies, hearing loss, or cardiac defects. The past two decades have witnessed significant advances both in understanding the etiologies of MRKH and in the development of fertility treatments such as uterine transplantation. The present work aimed to determine the rate of women with MRKH syndrome who underwent optimal initial management (after comprehensive malformation assessment) and to establish the rate of patients eligible for uterine transplantation (i.e., those with a vaginal length ≥7 cm without reconstruction using a bowel segment, and an anti-Müllerian hormone level >1.5 ng/mL before 35 years). MATERIAL AND METHODS: Cohort study of 85 women with MRKH syndrome consulting in our tertiary center. RESULTS: 62.4% of women with MRKH syndrome had an exhaustive malformative evaluation according to the French guidelines (Protocole National de Diagnostic et de Soin [PNDS]), of which 76.5% had associated malformations (MRKH type II). Pedigree, when available, showed a family history of infertility or a urogenital tract spectrum anomaly in 60% of cases. Concerning the uterine transplantation selection criteria, when evaluated, 22.6% of women had an anti-Müllerian hormone level <1.5 ng/mL and 36% a vaginal length <7 cm. On the 21 women with complete evaluation of both primary and secondary outcomes, 14 of them would be eligible for a uterine transplantation program at the time of consultation according to the main inclusion criteria of uterine transplantation program. CONCLUSIONS: Women with MRKH syndrome are often inadequately explored for associated malformations. Early assessment and monitoring of the ovarian reserve is key for fertility preservation, especially in the era of uterine transplantation.

Could IVF replace reproductive surgery? No, reproductive surgery is still very much alive.

Could IVF replace reproductive surgery? The answer is no. Reproductive surgery still has a place, at least in some indications that will be explored in this contribution. While IVF can offer infertile couples the chance to have a healthy baby, it should be acknowledged that reproductive surgery can heal or harm the organs where reproduction takes place. This paper reviews different diseases and conditions with an impact on fertility, which may benefit from the technological innovations of recent decades, novel applications and the skill of reproductive surgeons. Reproductive surgery is certainly not dead. It lives on with the promise of restoring the functional anatomy to enhance the chances of pregnancy. It is our responsibility to train young residents adequately in this field to provide the right treatment at the right time.

Fertility treatment, valuable life projects and social norms: In defence of defending (reproductive) preferences.

Fertility treatment enables involuntary childless people to have genetically related children, something that, for many, is a valuable life project. In this paper, I respond to two sets of objections that have been raised against expanding state-funded fertility treatment provision for existing treatments, such as in vitro fertilisation (IVF), and against funding new treatments, such as uterine transplantation (UTx). Following McTernan, I refer to the first set of objections as the 'one good among many' objection. It purports that it is unjustifiable for the state to prioritise the funding of the life project of becoming a parent through fertility treatment provision over the funding of other life projects that people might have. Following Lotz, I refer to the second set of objections as the 'norm-legitimation' objection. It maintains that the provision of costly forms of fertility treatment, such as UTx, would legitimise problematic social norms concerning genetic relatedness, reproduction and parenting, and that states should not engage in such a legitimation. In response to these objections, I defend the view that (reproductive) preferences ought to be taken more seriously when discussing fertility treatment provision and parental projects, and that not doing so can be costly, especially for women. The approach defended in this paper seeks to avoid disregarding and policing preferences and to reconcile their fulfilment with political projects aimed at improving the material and social conditions of sub-fertile people: people who, for social or biological reasons (or an intersection of the two), are unable to reproduce unassisted.

Summary of the ISFP congress, Brussels, 10-12 November, 2022.

The 7th International Congress of the ISFP was held in Brussels in November 2022. Hundreds of attendees from all over the world had the rare opportunity to hear the most distinguished leaders discuss and debate the latest advances in the field. Participants were also able to attend workshops under the guidance of skilled practitioners. Numerous topics were considered, including a recap on fertility preservation approaches in cancer and benign pathologies and a section on male factor infertility. Other aspects covered were in vitro maturation and poor responders, the impact of chemotherapy on the ovary, and future perspectives. Participants had the chance to listen to a symposium on fertility preservation techniques, and finally, a keynote lecture on fertility preservation in gynecological cancers brought this prominent and highly influential event to a close.

Perspectives on uterine transplantation.

Uterine transplantation is a groundbreaking solution for absolute uterine factor infertility (AUFI), offering hope for motherhood. Advances in transplant surgeries and immunosuppressants have enabled thousands of women to safely become mothers. Approximately 1.5 million women globally suffer from AUFI and thus Uterine transplantation is a significant breakthrough in this arena. So far, 23 babies have been born from transplanted wombs. Uterine transplantation redefines possibilities for motherhood, empowering women's reproductive rights. Ethical considerations persist, but it marks significant progress in reproductive medicine and transplantation science. Further research is needed to evaluate risks and benefits for the future.

A synopsis of the 2021 International Society of Fertility Preservation bi-annual meeting.

On November 19, 2021, the first virtual meeting of the International Society for Fertility Preservation (ISFP) took place. Eight experts in the field of reproductive medicine presented important updates on their research in the field of fertility preservation and reproductive surgery for absolute uterine factor infertility. Presentations included talks on ovarian stem cell therapy for premature ovarian insufficiency, practical aspects of oocyte vitrification, ovarian stimulation for patients with breast cancer, in vitro maturation of oocytes at the time of ovarian tissue harvesting, male fertility preservation, and uterine transplantation. These presentations are summarized below and can be viewed in their entirety at www.isfp-fertility.org.

Relationship between uterine veins, ureter, and hypogastric nerve for uterine transplantation: An anatomic study.

Uterine transplantation is on the rise worldwide. In contrast to its arterial anatomy, venous drainage of the uterus is poorly defined in the literature. Our aim was to provide a standardized description of uterine veins through a multimodal approach to establish anatomical landmarks for the uterine transplantation surgeon. Data were obtained from: (1) an anatomical study of eight fresh female cadavers (16 hemipelves) studied separately by an extra fascial dissection from the iliac bifurcation to the uterine pedicle, with analysis of the urinary tract and nerve structures and (2) a virtual anatomical study from the Anatomage® Table comprising a high-fidelity virtual reconstruction of two deceased female subjects by imaging and anatomical methods. An inconstant duality of uterine veins was identified: a deep uterine vein of larger caliber and a superficial uterine vein observed in 25% of cases. A close relationship of the ureter passing posterior to the superficial uterine vein and anterior to the deep uterine vein was evident in the parametrium. The inferior hypogastric plexus was identified in all cases immediately behind the deep uterine vein. The data obtained from the fresh female cadavers were validated by the Anatomage® Table. We describe the close relationship of the uterine veins with the ureter and the inferior hypogastric plexus. This knowledge represents a surgical landmark to support the success of uterine transplantation by respecting both the graft and the safety of the living donor by limiting the risk of injuries during uterus procurement.

Anaesthetic considerations for fertility-sparing surgery and uterine transplantation.

A number of benign and malignant gynaecological conditions can cause infertility. Advancements in assisted reproductive technologies have facilitated the rapidly evolving subspecialty of fertility preservation. Regardless of clinical indication, women now have the reproductive autonomy to make fully informed decisions regarding their future fertility. In particular, there has been an increasing interest and demand among patients and healthcare professionals for fertility-sparing surgery. Gynaecologists find themselves continually adapting surgical techniques and introducing novel procedures to facilitate this rapidly emerging field and anaesthetists need to manage the consequent physiological demands intra-operatively. Not only is it important to understand the surgical procedures now undertaken, but also the intra-operative management in an ever evolving field. This article reviews the methods of fertility-sparing surgery and also describes important anaesthetic challenges including peri-operative care for women undergoing complex fertility-sparing surgeries such as uterus transplantation.

The Activation of Cannabinoid Type-2 Receptor with JWH-133 Protects Uterine Ischemia/Reperfusion-Induced Damage.

INTRODUCTION: Uterus transplantation is a complex surgical procedure. Uterine ischemia/reperfusion (IR) damage occurring in this process may cause loss of function in the uterus. Cell damage must be prevented for a healthy uterine function and successful transplantation. Cannabinoids, with their increasing clinical use, are substances with strong anti-inflammatory and antioxidative effects and have a role in immune system regulation. However, their efficacy in uterine IR damage is still unknown. This study provides information on the potential applications cannabinoids agonist JWH-133 in uterine IR damage and, hence, in the transplant process. METHODS: Rats were divided into 4 groups (n = 8), performed uterine IR, and treated 2 groups with JWH-133. After anesthesia, ischemia was applied for 1 h to the uterus while reperfusion was applied for 3 h. After the experiment, malondialdehyde (MDA) levels and phosphorylated nuclear factor-kappa B (p-NF-κB) expression were examined in the tissue samples. Also, cell damage was evaluated by histopathological imaging and TUNEL staining. RESULTS: In the uterine IR group, NF-κB expression and MDA levels were detected at high levels. Histopathological examinations and TUNEL staining revealed extensive cell damage. On the other hand, in groups treated with JWH-133, dose-dependent NF-κB expression and MDA levels decreased (p < 0.05). Depending on the dose, the rate of surviving cells increased in TUNEL staining results. CONCLUSION: The results showed that JWH-133 was effective in reducing uterine IR damage. Cannabinoids may be a new alternative that may be used in the transplantation process in the future.

Uterine Transplantation with Robot-assisted Uterus Retrieval from Living Donor: First Case in Brazil.

OBJECTIVE: To present the first robot-assisted uterus retrieval from a living donor for uterine transplantation in Brazil. DESIGN: Stepwise demonstration of the technique with narrated video footage. SETTING: A uterine transplantation was performed in a 33-year-old patient with Mayer-Rokitansky-Küster-Hauser syndrome. The donor was a 50-year-old woman who underwent a robotic-assisted uterus retrieval. The procedure was held at Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil. INTERVENTIONS: After approval from the national and local institutional review board, the protocol was submitted to ClinicalTrials.gov (NCT04249791), and the first case was performed. The screening of the patients was done. The uterus was retrieved through a Pfannenstiel incision to avoid complications to the uterine vessels. Uterus was transplanted in the recipient by end-to-end anastomosis of the internal iliac arteries and end-to-side anastomosis of the external iliac vein with a gonadal vein from the infundibulopelvic ligament. Surgical intraoperative parameters were measured. The docking time was 4 minutes. Robotic donor surgery took 400 minutes, bench surgery took 62 minutes, and laparotomic recipient surgery was completed in 240 minutes. There were no intraoperative complications. The donor patient was discharged from the hospital in 48 hours and the recipient patient in 5 days. CONCLUSION: To the best of our knowledge, this is the first case in Brazil of uterine transplantation with a living donor. Traditionally, patients who undergo uterine transplantation by minimally invasive surgery are managed by laparoscopy. This video demonstrates a feasible robotic approach to uterine transplantation with superior imaging affording a 3-dimensional vision and stabilization of instruments allowing wrist-like movements.

Ectogenesis and gender-based oppression: Resisting the ideal of assimilation.

In a recent article in this journal, Kathryn MacKay advances a defence of ectogenesis that is grounded in this technology's potential to end-or at least mitigate the effects of-gender-based oppression. MacKay raises important issues concerning the socialization of women as 'mothers', and the harms that this socialization causes. She also considers ectogenesis as an ethically preferable alternative to gestational surrogacy and uterine transplantation, one that is less harmful to women and less subject to being co-opted to further oppressive ends. In this article, I challenge some of the assumptions that underlie MacKay's case in favour of ectogenesis by questioning whether the relationship between women's capacity to gestate and birth children and gender-based oppression is as strong as MacKay makes it out to be. I subsequently argue that-even if MacKay's reading of this relationship is accurate-ectogenesis is not a desirable means to end gender-based oppression. It embodies a strategy that could be used to pursue liberating projects that follow what Iris Marion Young defines as 'the ideal of assimilation', but that must be resisted. I then concur with MacKay's contention that ectogenesis is better than gestational surrogacy and uterine transplantation. My argument is that many of the problematic issues that MacKay herself sees as features of these practices will not disappear with ectogenesis. Finally, I conclude that MacKay's narrow focus on women's biology and ectogenesis as a solution to gender-based oppression results in the overlooking of broader systemic issues that contribute to the upholding of oppressive norms.

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.

Assisted reproductive methods - current status and perspectives.

OBJECTIVE: Evaluation of the development of assisted reproduction methods and their success from the time of their origin to the present. DESIGN: Review article. SETTING: Department of Obstetrics and Gynaecology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague. METHODS: Literature search using the Web of Science, Google Scholar and PubMed databases with keywords (assisted reproduction, in vitro fertilization, infertility, ICSI, ovarian hyperstimulation syndrome, OHSS, uterine transplantation) and analysis of articles published in impact and reviewed journals. RESULTS: At present children born using assisted reproduction methods are not considered as a miracle of modern medicine, but as a  more difficult way of human reproduction. Reproductive medicine helps to fulfill the desires of infertile couples for their own child and thus improve the quality of their life. Since its introduction into clinical practice it has made extraordinary progress. Robert Edwards and Patrick Steptoe, thanks to systematic scientific research and clinical work, contributed to the birth of the first „test tube“ baby in 1978. Edwards received the 2010 Nobel Prize in Physiology and Medicine for his discoveries in the field of assisted reproduction. The first child of assisted reproduction in the Czech Republic was born in 1982 in Brno. In 1986, the worlds first cryoembryotransfer was performed. 1990 was the beginning of preimplantation genetic examination. In 1992, the first pregnancy was achieved using intracytoplasmic sperm injection. The work of specialists in reproductive medicine results in more than 8 million births worldwide. CONCLUSION: Despite the fact that around 4000 children are born in the Czech Republic each year using assisted reproduction methods, its methods are rejected by part of the society. Assisted reproduction brings a number of controversies, but the spread of information smog around it should not suppress a  rational view of the professional and general public. Indications for assisted reproduction vary, often are on the male side, but the age of the infertile woman is the most important determinant of the success of the process. The question is whether the continuous improvement of medical technologies and scientific discoveries threatens to inadequate manipulation of human gametes or embryos. The society should monitor these controversial aspects through its legislative and control mechanisms and ensure that these methods are not misused for other than strictly medical purposes.

Uterine transplantation.

Successful human uterine transplantation followed by subsequent pregnancy and live birth in a woman for whom this would otherwise have been impossible is a laudable goal. Research programs have been developed in several countries aimed at achieving this goal. The pioneering Swedish program has reported live births in six women, two of whom had a second pregnancy and birth. Five other live births have been reported from other countries. Most transplants were from a live donor, although recently a live birth has been reported following transplant from a deceased donor. The surgical procedure on a live donor is highly invasive, complex, hazardous, and long and may decrease her quality of life. The use of a deceased donor would partly simplify this issue and is being explored in several centers. Also explored are technical modifications to simplify the procedure and shorten the operating times. The American Society for Reproductive Medicine (ASRM) reminds us of the full array of options available to patients: 'including gestational carriers (surrogacy), adoption and child-free living'. The ASRM also recommends 55 years as the upper age limit for transfer of donor oocytes and embryos in healthy women. Would it not be more practical and less onerous for the prospective live donor to carry the pregnancy instead? Uterine transplantation remains an experimental procedure that requires the study and resolution of ethical, technical, financial, and social issues, all very important.

Provider Perceptions, Opinions, and Insights Into Uterine Transplantation in Canada.

OBJECTIVE: This study sought to evaluate perceptions and insights regarding uterine transplantation among members of a women's health care national specialty organization in Canada. METHODS: The investigators obtained permission and used an electronic survey developed by Bortoletto et al. to conduct a cross-sectional study of members of the SOGC between April and May 2018. Participants were requested to answer a total of 29 questions grouped into four different categories: personal opinions and attitudes, medical opinions, ethical opinions, and demographics. The investigators compared answers with a published survey of members of the American Society for Reproductive Medicine (ASRM) and the American Association of Gynecologic Laparoscopists (AAGL). RESULTS: Of a total 247 responses, 230 were complete, for a completion rate of 93%. Respondents were primarily female, White, obstetrician-gynaecologists within 15 years of starting practice. Statements viewed favourably by most of respondents (strongly agree or agree) included "Women should be allowed to donate or receive a transplanted uterus" (53.5%), "Uterine transplantation should be considered a potential treatment option for infertile women with severe uterine factor infertility" (42.4%), and "Uterine transplantation is ethical" (39.9%). Statements that were viewed unfavourably by the majority of respondents (strongly disagree or disagree) included "Uterine transplantation carries an acceptable risk for recipients" (43.7%) and "Uterine transplantation for severe uterine factor infertility should be covered by health insurance" (59.1%). When compared with members of the ASRM and AAGL, the degree of agreement was similar, except with regards to "Uterine transplantation carries an acceptable risk for donors" (50.0% vs. 65.3% ASRM/67.8% AAGL; P < 0.001), and "In countries or states where gestational surrogacy is illegal, uterine transplantation is a more permissible ethical option" (42.0% vs. 65.0% ASRM/51.4% AAGL; P < 0.001). CONCLUSION: Most respondents either felt that uterine transplantation was ethical or were neutral to the subject. However, only a small minority would currently recommend the procedure to their patients. As advances in uterine transplants are made, future studies should re-evaluate providers' perceptions towards this procedure before it is introduced into clinical practice.

Changes in the metabolic composition of storage solution with prolonged cold ischemia of the uterus.

INTRODUCTION: The development of uterine transplantation (UTx) from deceased donors requires knowledge of the tolerance of the uterus to prolonged cold ischemia (CI). This can be evaluated through the use of biological parameters to assess degradation of the organ between its procurement and transplantation. The objective of this study was to analyze changes in the metabolic composition of the storage solution in cases of prolonged CI in uteri from ewes. METHODS: Eighteen uterine auto-transplantations were performed in ewes. CI time was 1 h (T1) or 24 h (T24). Samples of Celsior® were taken when the explanted uterus was flushed (T0) and at the end of CI. A dual approach to metabolic analyses was followed: targeted biochemical analyses targeting several predefined metabolites and non-targeted metabolomics analyses based on nuclear magnetic resonance (NMR). RESULTS: Metabolic analyses were performed on 16 explanted uteri. Metabolomic profiles differed significantly between T1 and T24 (p = 0.003). Hypoxia-associated degradation of the organ was demonstrated by the significantly higher lactate levels at T24 than at T1 (p < 0.05), accompanied by cell lysis, and significantly higher levels of creatine kinase activity in T24 than in T1 uteri (p < 0.05). Oxidative stress increased over time, with a significantly higher oxidized glutathione/glutathione ratio for T24 than for T1 uteri (p < 0.05). CONCLUSION: The metabolic results indicate a significant degradation of the uterus during 24 h of CI. Metabolic analysis of the storage solution could be used as a non-invasive tool for evaluating uterine degradation during CI before transplantation.

A Survey of Public Opinion in the United States Regarding Uterine Transplantation.

STUDY OBJECTIVE: To evaluate the opinions and attitudes of the general public regarding uterine transplantation (UTx) in the United States. DESIGN: A cross-sectional study (Canadian Task Force classification II-2). SETTING: A Web-based survey. PATIENTS: A nationally representative sample of adult US residents by age and sex. INTERVENTIONS: A Web-based questionnaire administered in November 2016. MEASUREMENTS AND MAIN RESULTS: Respondents who supported UTx were compared with those who were opposed using log binomial regression to calculate relative risk ratios and 95% confidence intervals. Of the 1444 respondents recruited, 1337 (93%) completed the survey. Ninety respondents (6%) disagreed with the use of in vitro fertilization for any indication and were excluded. Of the remaining 1247 respondents, 977 (78%) supported and 48 (4%) opposed allowing women to undergo UTx. Respondents with higher yearly incomes and education level were more likely to agree that "taking the uterus from one person and putting it into another person is ethical." Respondents who answered that UTx is safe for the donor, recipient, and baby were more likely to believe that UTx is an acceptable, ethical alternative to a gestational carrier. Forty-five percent of respondents believed that UTx should be covered by insurance, whereas 24% did not. CONCLUSION: The majority of respondents in a sample of US residents support UTx, find it ethical, and believe that it is an acceptable alternative to a gestational carrier although support varies. These findings suggest that the US public is in favor of uterine transplantation as a treatment for uterine factor infertility.

Uterine Transplantation: A Survey of Perceptions and Attitudes of American Reproductive Endocrinologists and Gynecologic Surgeons.

OBJECTIVE: To determine whether reproductive endocrinologists and minimally invasive surgeons support uterine transplantation as a treatment option for absolute uterine factor infertility (AUFI). DESIGN: A cross-sectional study (Canadian Task Force classification II-2). SETTING: A Web-based survey. PATIENTS: Physician members of the American Society of Reproductive Medicine (ASRM) and the American Association of Gynecologic Laparoscopists (AAGL). INTERVENTIONS: A Web-based questionnaire administered between January and February 2017. MEASUREMENTS AND MAIN RESULTS: Support for (strongly agree or agree) or opposition to (strongly disagree or disagree) various aspects of uterine transplantation were described using descriptive statistics and analyzed using chi-square tests. A total of 414 physicians (ASRM: 49.5%, AAGL: 50.5%) responded to the Web-based survey; 43.7% were female, 52.4% were between the ages of 45 and 65 years, and 73.4% were white. Nearly fifty-six percent supported women being allowed to donate or receive a transplanted uterus. Fifty-four percent strongly agreed or agreed that uterine transplantation carried an acceptable risk for donors, 28.0% for the recipient and 21.0% for the infant. Forty-two percent agreed that uterine transplantation should be considered a therapeutic option for women with AUFI, whereas 19.6% felt it should be covered by insurance. Nearly 45% of respondents felt uterine transplantation to be ethical. The most common ethical concerns regarding uterine transplantation were related to medical or surgical complications to the recipient (48.8%). CONCLUSION: Just under half of the reproductive endocrinologists and minimally invasive surgeons surveyed find uterine transplantation to be an ethical option for patients with AUFI. Important concerns remain regarding the risk to donors, recipients, and resulting infants, all contributing to only a minority currently recommending it as a therapeutic option.

Uterine Transplantation: Surgical Innovation in the Treatment of Uterine Factor Infertility.

Uterine factor infertility (UFI) is a condition that affects thousands of women and is estimated to have a prevalence as high as one in five hundred reproductive-aged women. A wide range of circumstances can lead to UFI and include women with congenital absence of a uterus (Mayer Rokitansky Kuster Hauser or MRKH syndrome), women who have undergone iatrogenic removal of the uterus, or women who have uteri that are in situ but have been damaged by infection or surgical instrumentation. There have been 17 published reports of human uterine transplantation in the world. This article will summarize the history of human uterine transplantation and discuss our current understanding of the medical, surgical, and ethical considerations surrounding this innovative procedure.

Pushing the boundaries: Uterine transplantation and the limits of reproductive autonomy.

Over the course of recent years, various scientific advances in the realm of reproduction have changed the reproductive landscape, enhancing women's procreative rights and the choices available to them. Uterus transplants (UTx) are the latest of such medical innovations aimed at restoring fertility in women suffering from absolute uterine factor infertility, providing them with the possibility not only of conceiving a genetically related child but also of gestating their own pregnancies. This paper critically examines the primacy of reproductive liberty in the context of uterus transplantation. It questions whether and to what extent we should respect the reproductive autonomy of a woman who chooses UTx, given the significant risks that attach to the procedure and existing concerns that UTx may perpetuate potentially troubling gendered norms surrounding pregnancy and the role of women's bodies in reproduction, which may place undue reproductive pressures on women.