Uterus transplantation: a rescue technique to save the viability and functionality of the graft after intra-operative outflow thrombosis.

Objective: To study a surgical approach to venous vascular thrombosis after uterus transplantation (UTx). Uterus transplantation is the only treatment for uterine factor infertility when conventional therapies are not possible. One of the major limitations of UTx is the high incidence of vascular thrombosis, which in most series reaches approximately 20%. Design: A case report. Setting: Hospital. Patients: We report here a technique used in a 30-year-old woman with congenital absence of the uterus who developed intraoperative thrombosis after a UTx from a brain-dead donor. Intervention: The UTx was performed by revascularizing the graft through bilateral donor internal iliac vessels (artery and vein) anastomosed end-to-side to the external iliac vessels of the recipient. The superior uterine veins were not anastomosed and were left unreconstructed. An end-to-end graft to the recipient's vaginal anastomosis was performed. After uterus reperfusion, congestion of the organ was noted, and bilateral venous thrombosis of the internal iliac veins of the graft was found. A "Y-shaped" venous jump graft was used to restore venous outflow of the left superior uterine vein and the internal iliac vein of the graft after thrombectomy. Main Outcome Measures: Viability and functionality of the uterus graft after intraoperative bilateral venous thrombosis. Results: The postoperative course was uneventful, and this UTx resulted in the delivery of a healthy infant. Conclusion: To our knowledge, this is the first successful rescue technique used to restore venous outflow and save the viability and functionality of a transplanted uterus. We demonstrated that a transplanted uterus from a deceased donor with a monolateral outflow could succeed in pregnancy and the delivery of a healthy infant.

Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer.

BACKGROUND: Platinum resistance is the primary cause of poor survival in ovarian cancer (OC) patients. Targeted therapies and biomarkers of chemoresistance are critical for the treatment of OC patients. Our previous studies identified cell surface CD55, a member of the complement regulatory proteins, drives chemoresistance and maintenance of cancer stem cells (CSCs). CSCs are implicated in tumor recurrence and metastasis in multiple cancers. METHODS: Protein localization assays including immunofluorescence and subcellular fractionation were used to identify CD55 at the cell surface and nucleus of cancer cells. Protein half-life determinations were used to compare cell surface and nuclear CD55 stability. CD55 deletion mutants were generated and introduced into cancer cells to identify the nuclear trafficking code, cisplatin sensitivity, and stem cell frequency that were assayed using in vitro and in vivo models. Detection of CD55 binding proteins was analyzed by immunoprecipitation followed by mass spectrometry. Target pathways activated by CD55 were identified by RNA sequencing. RESULTS: CD55 localizes to the nucleus of a subset of OC specimens, ascites from chemoresistant patients, and enriched in chemoresistant OC cells. We determined that nuclear CD55 is glycosylated and derived from the cell surface pool of CD55. Nuclear localization is driven by a trafficking code containing the serine/threonine (S/T) domain of CD55. Nuclear CD55 is necessary for cisplatin resistance, stemness, and cell proliferation in OC cells. CD55 S/T domain is necessary for nuclear entry and inducing chemoresistance to cisplatin in both in vitro and in vivo models. Deletion of the CD55 S/T domain is sufficient to sensitize chemoresistant OC cells to cisplatin. In the nucleus, CD55 binds and attenuates the epigenetic regulator and tumor suppressor ZMYND8 with a parallel increase in H3K27 trimethylation and members of the Polycomb Repressive Complex 2. CONCLUSIONS: For the first time, we show CD55 localizes to the nucleus in OC and promotes CSC and chemoresistance. Our studies identify a therapeutic mechanism for treating platinum resistant ovarian cancer by blocking CD55 nuclear entry.

In vitro fertilization practice in patients with absolute uterine factor undergoing uterus transplant in the United States.

OBJECTIVE: To report detailed, pooled multicenter experiences and outcomes after in vitro fertilization (IVF) treatment among patients undergoing uterus transplantation (UTx) in the US. DESIGN: Cohort study. SETTING: Hospital. PATIENTS: Patients undergoing UTxsfrom the three longest-running UTx clinical trials in the US. INTERVENTION: In vitro fertilization treatment among patients undergoing UTx.. MAIN OUTCOME MEASURES: Reproductive outcomes pretransplant and posttransplant ovarian stimulation. RESULTS: Thirty-one uterus transplant recipients were included in this cohort (mean [±SD] age at transplant was 31 ± 4.7 years). Before transplant, recipients completed a mean of two oocyte retrievals (range 1-4), banking a mean of eight untested embryos (range 3-24) or six euploid embryos (range 2-10). Posttransplant retrieval cycles were required in 19% (n = 6/31) of recipients, for a total of 16 cycles (range 2-4 cycles per recipient). All posttransplant retrievals were performed vaginally without complications. Preimplantation genetic testing was used by 74% (n = 23/31) of subjects. Seventy-two autologous single embryo transfers (ETs) occurred in 23 patients who completed at least one ET. Two ETs followed a fresh IVF treatment cycle, and the remainder (n = 70) were frozen ETs. Endometrial preparation was more commonly performed with programmed protocols (n = 61) (exogenous administration of estrogen and progesterone) compared with natural cycle protocols (n = 9). The overall live birth rate (LBR) for this cohort was 35% (n = 25/72) per ET. Among those patients (n = 21) who had an ET leading to a live birth, a mean of 2.2 ETs were performed. The overall LBR after the first ET was 57% (n = 13/23) and rose to 74% (n = 17/23) after a second ET. There was no difference in rate of preeclampsia, live birth, neonatal birth, or placental weights among programmed vs. natural cycle frozen ETs. There were no differences in the LBR between living or deceased donor uteri (37% vs. 32%). CONCLUSIONS: Posttransplant ovarian stimulation was required in 26% (n = 6/23) of recipients undergoing at least one ET, despite high rates of preimplantation genetic testing and pretransplant embryo cryopreservation. Posttransplant retrievals were performed transvaginally, without complications. Future reporting of IVF treatment experiences will be essential to optimizing reproductive outcomes after a uterus transplant. CLINICAL TRIAL REGISTRATION NUMBERS: NCT02656550 (Baylor University Medical Center); NCT03307356 (University of Pennsylvania); and NCT02573415 (Cleveland Clinic).

Classification and treatment of vaginal strictures at the donor-recipient anastomosis after uterus transplant.

OBJECTIVE: To describe the incidence and management of vaginal stricture after uterus transplantation (UTx) in the US, to propose a grading system to classify stricture severity, and to identify risk factors for stricture formation. DESIGN: Prospective cohort study. SETTING: University Hospital. PATIENTS: Recipients undergoing UTx from 2016-2023 at Baylor University Medical Center in Dallas, Cleveland Clinic, the University of Pennsylvania, and the University of Alabama at Birmingham were monitored postoperatively with regular pelvic examinations. Stricture was defined as vaginal narrowing of <3 cm in patients with graft survival of at least 7 days. INTERVENTION: Demographic and surgery characteristics. MAIN OUTCOME MEASURES: Stricture development and severity (grade 1 for diameter 2-<3 cm, grade 2 for 1-<2 cm, or grade 3 for <1 cm). RESULTS: Of the 45 UTx from 2016-2023 (16 deceased donors and 29 living donors), 3 were excluded from the analysis because of graft loss within 7 days. Of the 42 remaining recipients, 39 (92.9%) had Mayer-Rokitansky-Küster-Hauser syndrome and 3 (7.1%) had a prior hysterectomy. Twenty-eight (66.7%) UTx recipients developed postoperative vaginal strictures with a median time to stricture of 33 days (interquartile range 19-53 days). Most strictures were of moderate severity, with 4 (14.3%) strictures categorized as grade 1, 19 (67.9%) as grade 2, and 5 (17.9%) as grade 3. History of Mayer-Rokitansky-Küster-Hauser syndrome and preoperative recipient vaginal length were significant risk factors for stricture, after adjustment for donor and recipient age and body mass index, anastomosis technique, total ischemia time, center, and year. Patients with longer preoperative vaginal length had a lower risk of stricture (hazard ratio 0.45, 0.29-0.70). The severity grading of the stricture was associated with the effectiveness of a nonoperative treatment approach (grade 1 vs. grade 3). No patients with grade 3 strictures improved with self-dilation alone; all required surgical repair and/or dilation under anesthesia. Conversely, for grade 1 or 2 strictures, self-dilation alone was successful in 47.8% (11/23), and no grade 1 strictures required surgical repair. CONCLUSIONS: Vaginal stricture is a common postoperative complication after UTx, affecting >65% of recipients. Short preoperative vaginal length and history of müllerian agenesis in the recipient are significant risk factors. Vaginal self-dilation was effective for some mild to moderate strictures, although dilation under anesthesia or surgical repair was required in most cases. CLINICAL TRIAL REGISTRATION NUMBERS: Dallas UtErus Transplant Study (DUETS) at Baylor University Medical Center (NCT02656550), Uterine transplantation for the treatment of uterine factor infertility at the Cleveland Clinic (NCT02573415), The University of Pennsylvania Uterus Transplant for Uterine Factor Infertility Trial (UNTIL) (NCT03307356).

Pelvic Floor Dysfunction Among Persons With Marfan and Loeys-Dietz Syndrome.

IMPORTANCE: Connective tissue disorders are proposed in the literature to be predisposing risk factors for pelvic floor disorders. Prior data characterizing the prevalence of and symptom burden related to pelvic floor disorders are limited for individuals with Marfan syndrome and are nonexistent for those with Loeys-Dietz syndrome. OBJECTIVE: The objective of this study was to determine the prevalence and severity of symptoms related to pelvic floor disorders among individuals with Marfan syndrome and Loeys-Dietz syndrome using the Pelvic Floor Distress Inventory-20 (PFDI-20). STUDY DESIGN: In this cross-sectional study, a survey including the PFDI-20 was administered to biologically female individuals older than 18 years with a confirmed diagnosis of Marfan syndrome or Loeys-Dietz Syndrome. Respondents were solicited through the websites, email lists, and social media forums of The Marfan Foundation and The Loeys-Dietz syndrome Foundation. RESULTS: A total of 286 respondents were included in the final analysis, 213 with Marfan syndrome and 73 with Loeys-Dietz syndrome. The median PFDI-20 score of the cohort was 43.8. Individuals with Loeys-Dietz syndrome had higher PFDI-20 scores and were more likely to have established risk factors for pelvic floor disorders that correlated with their PFDI-20 scores compared with those with Marfan syndrome. CONCLUSIONS: Respondents with Marfan syndrome and Loeys-Dietz syndrome experience a high burden of symptoms related to pelvic floor disorders. Despite the similar pathophysiology and clinical manifestations of these disorders, there were differences in PFDI-20 responses that may suggest that these diseases differ in the ways they affect the pelvic floor.

Impact of Mandated Insurance Coverage of Assisted Reproductive Technology on Clinic Website Transparency.

Objective: The purpose of this study was to determine whether website transparency of service costs, accepted insurance plans, and financing options differs between reproductive endocrinology and infertility clinics located in states that do and do not mandate insurance coverage of assisted reproductive technology (ART). Methods: Six hundred forty-six clinics were identified using the Society for Assisted Reproductive Technology online locator. Clinics were excluded for missing website links, duplicate entries, broken websites, or permanent closure. Mandated coverage by state was gathered on resolve.org Chi-squared testing and logistic regression were performed. Results: Of the 311 clinic websites analyzed, 28.6% were in states that mandate ART coverage and 71.4% were not. Clinics in states that have mandated coverage were more likely to list specific prices on their websites. These clinics were 2.13 times more likely to list specific costs (odds ratio [OR]; 95% confidence interval [CI]: 1.19-3.81, p = 0.01). There was also a significant difference between the percent of clinics in mandated coverage states and nonmandated states that listed accepted insurance plans. These clinics were 2.44 times more likely to report accepted insurance plans (OR; 95% CI: [1.47-4.05], p = 0.005). There was no significant difference in the mention of financial assistance between the groups. Clinics in states with mandated coverage were more likely to mention discount programs, but there was no significant difference for other types of financial assistance. Conclusion: Clinics located in states that mandate insurance coverage of ART are more likely to list specific costs, accepted insurance plans, and the availability of discount programs on their website. Patients living in states without mandated coverage are more likely to need to finance their own treatment, yet these patients are less likely to have nearby clinics that provide financial transparency on their websites.

Treatment of endometriomas: Surgical approaches and the impact on ovarian reserve, recurrence, and spontaneous pregnancy.

Endometriomas may contribute to infertility and are associated with diminished ovarian reserve. Surgical management can damage the ovarian cortex and further diminish ovarian reserve. Surgical therapy of endometriomas can be achieved via cystectomy, ablation (electrosurgical, laser, or plasma energy), sclerotherapy, or oophorectomy. Each approach has varying effects on ovarian reserve, spontaneous pregnancy rates, and recurrence rates: Cystectomy is associated with a low recurrence rate but higher risk of diminished ovarian reserve; Ablation (with laser or plasma energy) appears to have minimal effect on ovarian reserve while also having low recurrence rates; Sclerotherapy is mixed in terms of effect on ovarian reserve as well as recurrence rates. Fertility preservation counseling is recommended for patients considering surgical management. The surgical approach selected should be tailored to each individual patient with respect to their fertility and therapeutic goals.

Awareness and Interest in Uterus Transplantation over Time: Analysis of Those Seeking Surgical Correction for Uterine-Factor Infertility in the US.

This study describes the characteristics of women who contacted an active program performing uterus transplantation (UTx) in the US, expressing interest in becoming a uterus transplant recipient or a living donor. Basic demographic and self-reported clinical information was collected from women who contacted any of the three US UTx programs from 2015 to July 2022. The three centers received 5194 inquiries about becoming a UTx recipient during the study timeframe. Among those reporting a cause of infertility, almost all of the reports (4066/4331, 94%) were absence of a uterus, either congenitally (794/4066, 20%) or secondary to hysterectomy (3272/4066, 80%). The mean age was 34 years, and 49% (2545/5194) had at least one child at the time of application. The two centers using living donors received 2217 inquiries about becoming living donors. The mean age was 34 years, and 60% (1330/2217) had given birth to ≥1 child. While most of the UTx clinical trial evidence has focused on young women with congenital absence of the uterus, these results show interest from a much broader patient population in terms of age, cause of infertility, and parity. These results raise questions about whether and to what extent the indications and eligibility criteria for UTx should be expanded as the procedure transitions from the experimental phase to being offered as a clinical treatment.

Fertility Preservation in Women with Endometriosis.

Several mechanisms have been implicated in the pathogenesis of endometriosis-related infertility. For patients considering surgery, the risk of iatrogenic injury is among the most important factors in the context of fertility preservation, along with age and individual reproductive goals. In the case of endometrioma excision, evidence overwhelmingly demonstrates the negative impact of surgery on ovarian reserve, with significant reductions in antimullerian hormone (up to 30% in unilateral versus up to 44% in bilateral endometriomas). The surgical endometriosis patient should be thoroughly counseled regarding fertility preservation and discussion should include tissue, embryo, and oocyte cryopreservation options. For the latter, data support cryopreservation of 10-15 oocytes in women ≤35 years and over 20 for those >35 years for a realistic chance to achieve one or more live births. When performing surgical interventions for endometriosis, reproductive surgeons should employ fertility-conserving surgical methods to reduce the likelihood of postoperative iatrogenic diminished ovarian reserve.

Perforation During Gynecological Procedures.

This article in the Women's Health series discusses uterine perforation occurring during gynecological procedures, including prevention, identification of risk factors, recognition, management, and long-term outcomes.

Uncommon Surgical Emergencies in the Adult Gynecologic Patient: Two Cases of Missed Diagnosis of Outflow Tract Obstruction from Congenital Uterine Anomalies.

Gynecologic emergencies may result from congenital uterine anomalies (CUAs) with outflow tract obstruction. Not limited to the "classic" presentation of an adolescent amenorrheic pain patient, such anomalies should be part of the differential diagnosis for adult female patients presenting with severe pelvic pain. Obstructed rudimentary noncommunicating cavitary horns may result in severe chronic or acute pain and necessitate urgent surgical management. While two-dimensional (2D) ultrasound is often the initial diagnostic tool, three-dimensional (3D) ultrasound and MRI can accurately delineate CUAs for definitive diagnosis. When excision of a rudimentary horn is required, a laparoscopic approach is preferable. This case series focuses on two adult patients with severe pelvic pain due to unicornuate uteruses with obstructed noncommunicating cavitated rudimentary horns. Both cases involve a delayed diagnosis, the inability to make the diagnosis at standard surgical observation, and the resultant need for urgent surgical management.

Uterus Transplantation: Revisiting the Question of Deceased Donors versus Living Donors for Organ Procurement.

Uterus transplantation is a surgical treatment for women with congenital or acquired uterine factor infertility. While uterus transplantation is a life-enhancing transplant that is commonly categorized as a vascular composite allograft (e.g., face or hand), it is similar to many solid organ transplants (e.g., kidney) in that both living donors (LDs) and deceased donors (DDs) can be utilized for organ procurement. While many endpoints appear to be similar for LD and DD transplants (including graft survival, time to menses, livebirth rates), there are key medical, technical, ethical, and logistical differences between these modalities. Primary considerations in favor of a LD model include thorough screening of donors, enhanced logistics, and greater donor availability. The primary consideration in favor of a DD model is the lack of physical or psychological harm to a living donor. Other important factors, that may not clearly favor one approach over the other, are important to include in discussions of LD vs. DD models. We favor a stepwise approach to uterus transplantation, one in which programs first begin with DD procurement before attempting LD procurement to maximize successful organ recovery and to minimize potential harms to a living donor.

The First 5 Years of Uterus Transplant in the US: A Report From the United States Uterus Transplant Consortium.

Importance: Uterus transplant is a viable surgical treatment for women affected by absolute uterine-factor infertility, which affects 1 in 500 women. Objective: To review transplant and birth outcomes of uterus transplant recipients in the US since the first case in 2016. Design, Setting, and Participants: In this cohort study, 5 years of uterus transplant outcome data were collected from the 3 centers performing uterus transplants in the US: Baylor University Medical Center, Dallas, Texas; Cleveland Clinic, Cleveland, Ohio; and University of Pennsylvania, Philadelphia. A total of 33 women with absolute uterine-factor infertility who underwent uterus transplant between February 2016 and September 2021 were included. Main Outcomes and Measures: Graft survival, live birth, and neonatal outcome. Results: Of the 33 included uterus transplant recipients, 2 (6%) were Asian, 1 (3%) was Black, 1 (3%) was South Asian, and 29 (88%) were White; the mean (SD) age was 31 (4.7) years; and the mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 24 (3.6). Most uterus transplant recipients (31 of 33 [94%]) had a congenitally absent uterus (Mayer-Rokitansky-Küster-Hauser syndrome), and 21 of 33 (64%) received organs from living donors. Mean (range) follow-up was 36 (1-67) months. There was no donor or recipient mortality. One-year graft survival was 74% (23 of 31 recipients). Through October 2021, 19 of 33 recipients (58%) had delivered 21 live-born children. Among recipients with a viable graft at 1 year, the proportion with a live-born child was 83% (19 of 23). The median (range) gestational age at birth of neonates was 36 weeks 6 days (30 weeks, 1 day to 38 weeks), and the median (range) birth weight was 2860 (1310-3940) g (median [range], 58th [6th-98th] percentile). No congenital malformations were detected. Conclusions and Relevance: Uterus transplant is a surgical therapy that enables women with uterine-factor infertility to successfully gestate and deliver children. Aggregate data from US centers demonstrate safety for the recipient, living donor, and child. These data may be used to counsel women with uterine-factor infertility on treatment options.