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Objective: To examine publication trends pertaining to fertility-sparing management in patients of reproductive age with gynecological malignancies. Methods: Ovid MEDLINE was used to aggregate all publications on gynecological cancers and fertility between 1946 and 2022. Original research, reviews, case series/reports, and editorials were included. Publication information was extracted from Ovid MEDLINE. Individual authors' subspecialty credentials were individually reviewed and confirmed. Descriptive statistics were generated. Results: The initial query generated 2,057 publications. Of these, 1,057 (51.4%) publications met search criteria, with the first study being published in 1991 and with 16.6% published in the last 2 years. Only 34 (5.5%) studies were published with collaboration between reproductive endocrinology and infertility (REI) and gynecological oncology physicians in the United States. Gynecological oncologists comprised most senior authors (50.9%), followed by REI specialists (18.6%). Topics of the publications centered on fertility-sparing surgical management (43.1%), medical management of gynecological malignancies (11.3%), and oocyte/ovarian tissue preservation (6.0%). Most publications focused on ovarian malignancies (349, 33.3%), followed by cervical cancer (299, 28.5%), and uterine/endometrial cancer (258, 24.6%). While the number of publications regarding fertility-sparing management has increased over the last 30 years, the majority are retrospective studies and case reports/series. In the last 10 years, only five studies were randomized controlled trials. Conclusions: There is an urgent need for more prospective research in oncofertility. While fertility care in the setting of gynecological cancer is a collaborative effort between the specialties of gynecological oncology and REI, this partnership is not reflected in the authorship of current literature.

Purpose: To determine whether patients with Marfan syndrome are at an increased risk for reproductive disorders., Methods: This retrospective cohort study was conducted using the US collaborative network on the TriNetX research network of health care organizations. We included female patients aged 18-44 and identified a cohort of 4347 patients with Marfan syndrome (ICD-10 Q87.4). Our control cohort consisted of 16,424,990 patients without a diagnosis of Marfan syndrome or Ehlers-Danlos syndrome (ICD-10 Q79.6). The primary outcomes included gynecologic diagnoses such as dysmenorrhea and endometriosis, and our secondary outcomes included urogynecologic, fertility, and obstetric outcomes, all identified by ICD-10 codes. We conducted a relative risk analysis with a p-value of <0.05 considered significant., Results: Patients with Marfan syndrome were at an increased risk for pelvic and perineal pain, dysmenorrhea, abnormal uterine bleeding, endometriosis (all p <0.0001), dyspareunia (p =0.0009), leiomyoma (p =0.0076), polyp of female genital tract (p =0.016), urinary incontinence (p <0.0001), female genital prolapse (p =0.0006), fertility testing (p =0.0075), cesarean delivery (p =0.0003), gestational hypertension (p =0.0012), and pre-eclampsia (p =0.0024) compared to the control group following an adjusted, matched comparison., Conclusions: Patients with Marfan syndrome have an increased risk of numerous reproductive disorders and obstetric complications compared to patients without this diagnosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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)., Competing Interests: Declaration of Interests J.R.W. has nothing to disclose. L.J. has nothing to disclose. T.F. has nothing to disclose. M.P. has nothing to disclose. G.T. has nothing to disclose. E.G.R. has nothing to disclose. K.E.O has nothing to disclose., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: C.A.F. received authorship royalties from UpToDate and Elsevier. All other authors have declared they have no conflicts of interest., (Copyright © 2024 American Urogynecologic Society. All rights reserved.)

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)., Competing Interests: Declaration of Interests L.Z. has nothing to disclose. L.A.H. has nothing to disclose.P.M.P. G.T. has nothing to disclose. S.A. has nothing to disclose. J.R.W. has nothing to disclose. M.R. has nothing to disclose. C.A.F. has nothing to disclose. K.O. has nothing to disclose. E.G.R. has nothing to disclose., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background/Objective: Fertility preservation is an important part of oncologic care for newly diagnosed gynecologic cancers for reproductive-age women, as many treatment options negatively impact fertility. The goal of this study is to examine factors that influence access to fertility specialists for women with newly diagnosed gynecologic cancer. Methods: This institutional review board approved a retrospective cohort study investigating the impacting factors on the referral rate from gynecologic oncologists (GO) to reproductive endocrinologists and infertility (REI) specialists at a single academic institution between 2010-2022 for patients age 18-41 at diagnosis. Electronic medical records were used to identify demographics and referral patterns. Mixed logistic models were utilized to control cluster effects of the physicians. Results: Of 816 patients reviewed, 410 met the criteria for inclusion. The referral rate for newly diagnosed gynecologic malignancies was 14.6%. Younger patients were more likely to have an REI referral ( p < 0.001). The median time from first GO visit to treatment was 18.5 days, and there was no significant difference in those who had REI referrals ( p = 0.44). Only 45.6% of patients had fertility desire documented. A total of 42.7% had fertility-sparing treatment offered by a GO. REI referral did not significantly change the time to treatment ( p = 0.44). An REI referral was more likely to be placed if that patient had no living children, no past medical history, or if the referring GO was female (OR = 11.46, 6.69, and 3.8, respectively). Conclusions: Fertility preservation counseling is a critical part of comprehensive cancer care; yet, the referral to fertility services remains underutilized in patients with newly diagnosed gynecologic cancer. By demonstrating these biases in REI referral patterns, we can optimize provider education to enhance fertility care coordination.

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.

Competing Interests: Declaration of Interests A.Y. has nothing to disclose. E.H.F. has nothing to disclose. E.G.R. has nothing to disclose.

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., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.

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.

Background: Despite an estimated 10% prevalence of endometriosis among reproductive-age women, surgical population-based data are limited., Objective: We sought to investigate racial and ethnic disparities in surgical interventions and complications among patients undergoing endometriosis surgery across the United States., Study Design: We performed a retrospective cohort study of American College of Surgeons National Surgical Quality Improvement Program data from 2010 to 2018 identifying International Classification of Diseases, Ninth/Tenth Revision codes for endometriosis We compared procedures, surgical routes (laparoscopy vs laparotomy), and 30-day postoperative complications by race and ethnicity., Results: We identified 11,936 patients who underwent surgery for endometriosis (65% White, 8.2% Hispanic, 7.3% Black or African American, 6.2% Asian, 1.0% Native Hawaiian or Pacific Islander, 0.6% American Indian or Alaska Native, and 11.5% of unknown race). Perioperative complications occurred in 9.6% of cases. After adjusting for confounders, being Hispanic (adjusted odds ratio, 1.31; 95% confidence interval, 1.06-1.64), Black or African American (adjusted odds ratio, 1.71; confidence interval, 1.39-2.10), Native Hawaiian or Pacific Islander (adjusted odds ratio, 2.08; confidence interval, 1.28-3.37), or American Indian or Alaska Native (adjusted odds ratio, 2.34; confidence interval, 1.32-4.17) was associated with surgical complications. Hysterectomies among Hispanic (adjusted odds ratio, 1.68; confidence interval, 1.38-2.06), Black or African American (adjusted odds ratio, 1.77; confidence interval, 1.43-2.18), Asian (adjusted odds ratio, 1.87; confidence interval, 1.43-2.46), Native Hawaiian or Pacific Islander (adjusted odds ratio, 4.16; confidence interval, 2.14-8.10), and patients of unknown race or ethnicity (adjusted odds ratio, 2.07; confidence interval, 1.75-2.47) were more likely to be open. Being Hispanic (adjusted odds ratio, 1.64; confidence interval, 1.16-2.30) or Black or African American (adjusted odds ratio, 2.64; confidence interval, 1.95-3.58) was also associated with receipt of laparotomy for nonhysterectomy procedures. The likelihood of undergoing oophorectomy was increased for Hispanic and Black women (adjusted odds ratio, 2.57; confidence interval, 1.96-3.37 and adjusted odds ratio, 2.06; confidence interval, 1.51-2.80, respectively), especially at younger ages., Conclusion: Race and ethnicity were independently associated with surgical care for endometriosis, with elevated complication rates experienced by Hispanic, Black or African American, Native Hawaiian or Pacific Islander, and American Indian or Alaska Native patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Uterine transplantation is an emerging treatment for patients with uterine factor infertility (UFI). In order to determine patient candidacy for transplant, it is imperative to understand how to identify, counsel and treat uterine transplant recipients. In this article, we focus on patient populations with UFI, whether congenital or acquired, including Mayer-Rokitansky-Kuster-Hauser, complete androgen insensitivity syndrome, hysterectomy, and other causes of nonabsolute UFI. Complete preoperative screening of recipients should be required to assess the candidacy of each individual prior to undergoing this extensive treatment option., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Targeted cancer therapy is rapidly evolving the landscape of personalized health care. Novel approaches to selectively impeding tumour growth carry significant potential to improve survival outcomes, particularly for reproductive-aged patients harbouring treatment refractory disease. Current agents fall within two classes: immunotherapy and small molecule inhibitors. These are collectively divided into the following subclasses: monoclonal antibodies; immunomodulators; adoptive cell therapy; treatment vaccines; kinase inhibitors; proteasome inhibitors; metalloproteinase and heat shock protein inhibitors; and promoters of apoptosis. The short- and long-term effects of these treatments on the female reproductive system are not well understood. As a result, clinicians are rendered unable to appropriately counsel women on downstream effects to their fertility. Data-driven consensus recommendations are desperately needed. This review aims to characterize the effect of targeted cancer therapy on the female hypothalamic-pituitary-ovary axis, direct ovarian function and conception., (Published by Elsevier Ltd.)

Purpose: To provide a comprehensive review of uterus transplantation in 2021, including a discussion of pregnancy outcomes of all reported births to date, the donor and recipient selection process, the organ procurement and transplant surgeries, reported complications, postoperative monitoring, preimplantation preparation, and ethical considerations., Methods: Literature review and expert commentary., Results: Reports of thirty-one live births following uterus transplantation have been published from both living and deceased donors. The proper selection of donors and recipients is a labor-intensive process that requires advanced planning. A multidisciplinary team is critical. Reported complications in the recipient include thrombosis, infection, vaginal stricture, antenatal complications, and graft failure. Graft rejection is a common occurrence but rarely leads to graft removal. While most embryo transfers are successful, recurrent implantation failures in uterus transplant patients have been reported. Rates of preterm delivery are high but appear to be declining; more data, including long-term outcome data, is needed., Conclusions: Uterus transplantation is an emerging therapy for absolute uterine factor infertility, a condition previously without direct treatment options. It is paramount that reproductive health care providers are familiar with the uterus transplantation process as more patients seek and receive this treatment., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ovarian tissue cryopreservation (OTC) is an accepted method of fertility preservation. However, OTC is not standardized and many variations exist in the freezing strategy, tissue processing, and surgical approach. In this pilot study, we used a sheep model to compare slow freezing versus vitrification techniques, as well as the feasibility of processing ovarian tissue into a hyaluronan suspension of small ovarian units. Twelve ovaries were harvested from six female ewes. Paired tissues from each animal were assigned to different treatments and underwent freezing, thawing, autotransplantation, and second-look surgery, for a total of 18 surgical procedures and 3 measured time points. Treatments included whole tissue strips versus gel suspension and slow freezing versus vitrification. At each of the time points, tissue viability was measured by immunohistochemical analysis of CD31 and cleaved caspase-3 (CCASP3). CD31 and CCASP3 expression levels were equivalent between slow freezing and vitrification, and between whole ovarian tissue strips and gel suspension of fragmented ovarian tissue, at all time points. These preliminary data using a sheep model suggest that ovarian tissue is robust and likely to be minimally affected by aggressive fragmentation using a hyaluronan suspension. Furthermore, we provide evidence in support of vitrification as a viable option in OTC. Hyaluronan suspension of ovarian cortical fragments is novel and may represent a desirable method for reimplantation of frozen-thawed ovarian tissue in patients where occult malignant cells are a concern., (© 2021. Society for Reproductive Investigation.)

The parallel emergence of uterus transplantation (UTx) and other transplantation innovations including face and hand transplantation led to the categorization of the uterus as a vascular composite allograft (VCA). With >60 transplants and >20 births worldwide, UTx is transitioning rapidly from a research endeavor to an effective treatment option for women with uterine factor infertility. While it originally made sense to group the innovations under one umbrella, it is time to revisit the designation of UTx as a VCA. We describe how UTx needs unique policy, procedural codes, insurance contracts, and educational initiatives. We contend that separating UTx from VCAs may become necessary in the future to avoid hindering the growth and regulation of this field., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Uterus transplantation is a nascent but growing field. To support this growth, the United States Uterus Transplant Consortium proposes guidelines for nomenclature related to operative technique, vascular anatomy, and donor, recipient, and offspring outcomes. In terms of anatomy, the group recommends reporting donor arterial inflow and recipient anastomotic site delivering inflow to the graft and offers standardization of the names for the 4 veins originating from the uterus because of current inconsistency in this particular nomenclature. Seven progressive stages with milestones of success are defined for reporting on uterus transplantation outcomes: (1) technical, (2) menstruation, (3) embryo implantation, (4) pregnancy, (5) delivery, (6) graft removal, and (7) long-term follow-up. The 3 primary metrics for success are recipient survival (as reported for other organ transplant recipients), graft survival, and uterus transplant live birth rate (defined as live birth per transplanted recipient). A number of secondary outcomes should also be reported, most of which capture stage-specific milestones, as well as data on graft failure. Outcome metrics for living donors include patient survival, survival free of operative intervention, and data on complications and hospitalizations. Finally, we make specific recommendations on follow-up for offspring born from uterine grafts, which includes specialty surveillance as well as collection and reporting of routine pediatric outcomes. The goal of standardization in reporting is to create consistency and improve the quality of evidence available on the efficacy and value of the procedure., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: To evaluate the efficacy of two different in vitro fertilization culture media for blastocyst development, pregnancy, and live birth rate. Global (GB) medium (used without refreshment) and G-TL medium (designed specifically for culture in time-lapse incubators) were compared., Design: Prospective randomized study of sibling embryo culture in two culture media., Setting: In vitro fertilization clinic., Patient(s): Women undergoing fresh or frozen cycles using autologous or donor oocytes., Intervention(s): None., Main Outcome Measure(s): The primary endpoints were implantation, pregnancy, and live birth rate (LBR) after single blastocyst transfer. Secondary endpoints included embryo morphokinetics, development of good-quality blastocysts, and euploidy rate., Result(s): Kinetic data from 10,768 sibling pronucleate embryos cultured in the EmbryoScope were compared. GB embryos initiated compaction earlier and formed morula sooner than their G-TL counterparts. The mean timing for start of blastulation did not differ. The interval between start of blastulation and time of blastocyst formation was observed to be <12 hours for proportionately more GB compared with G-TL-cultured embryos. Despite a higher rate of observed dysmorphisms in GB embryos, the euploidy rate among biopsied blastocysts did not differ between media. A total of 820 single-embryo transfer cycles were performed. Implantation rates were similar between media, independent of whether the embryo transferred was fresh (GB 58.7% vs. G-TL 61.7%) or frozen (GB 64.1% vs. G-TL 60.5%). Live birth rates were also not different. With GB medium, the LBR for fresh and frozen transfers was 54.2% and 53.1%, respectively, as compared with 51.1% and 50%, respectively, with G-TL., Conclusion(s): Uninterrupted culture in a time-lapse incubator without medium refreshment was well supported by both media tested. Differences in morphokinetics did not necessarily dictate the superiority of one media over the other. Both pregnancy and LBR were not significantly influenced by choice of culture medium. The euploidy rate was also independent of culture medium., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare growth factor and cytokine profiles in the endometrial secretions of patients with and without endometriosis to determine whether a particular protein profile is predictive of the disease., Methods: Patients undergoing laparoscopic gynecologic surgery for benign indications were recruited for this prospective cohort study. Prior to surgery, endometrial fluid was aspirated and multiplex immunoassay was used to quantify 7 cytokines and growth factors. During surgery, each patient was staged according to the ASRM staging system for endometriosis. Cytokines and growth factors were evaluated using the Mann-Whitney and Kruskal-Wallis tests. Combinations of cytokines were evaluated using logistic regression analysis, and ROC curves were generated to evaluate the predictive capacity of the assay., Results: Endometrial secretions were analyzed from 60 patients. Nineteen had stage 3-4 endometriosis, 19 had stage 1-2 disease, and 22 had no endometriosis. There were no significant differences between controls and stage 1-2 endometriosis; however, levels of IL-1α and IL-6 were significantly increased in women with moderate-to-severe disease. A combination of IL-1α, IL-1β, and IL-6 in endometrial secretions predicts stage 3-4 endometriosis with an AUC of 0.78. A threshold value of 118 pg/mL yields a sensitivity of 75% and specificity of 70%., Conclusion: Aspiration of endometrial fluid is a safe and effective approach for evaluating the endometrial profile of women with endometriosis. Women with moderate-to-severe endometriosis demonstrate a distinct cytokine profile compared to controls. A combination of IL-1α, IL-1β, and IL-6 in the endometrial secretions is predictive of stage 3-4 endometriosis, but is not predictive of minimal-to-mild disease.

Endometriosis is a leading cause of pelvic pain and infertility. It is defined by the presence of endometrial tissue in extrauterine locations. The development of novel therapies and diagnostic tools for endometriosis has been limited due in part to challenges in studying the disease. Outside of primates, few mammals menstruate, and none develop spontaneous endometriosis. Rodent models are popular but require artificial induction of endometriosis, with many utilizing either immunocompromised mice or surgically induced disease. Recently, more attention has been given to models involving intraperitoneal injection. We present a murine model of endometriosis that integrates several features of existing endometriosis models into a novel, simplified system that relies on microscopic quantification in lieu of subjective grading. In this model, we perform hormonal stimulation of donor mice, intraperitoneal injection, systematic abdominal survey and tissue harvest, and histologic quantification that can be performed and verified at any time after necropsy. This model requires minimal resources and training; does not require expertise by lab technicians in murine survival surgery or in the identification of gross endometriotic lesions; can be used in immunocompromised, immunocompetent, and/or mutant mice; and reliably creates endometriotic lesions that are histologically consistent with human endometriotic disease.

Uterus transplantation is the only known potential treatment for absolute uterine factor infertility. It offers a unique setting for the investigation of immunologic adaptations of pregnancy in the context of the pharmacologic-induced tolerance of solid organ transplants, thus providing valuable insights into the early maternal-fetal interface. Until recently, all live births resulting from uterus transplantation involved living donors, with only 1 prior birth from a deceased donor. The Cleveland Clinic clinical trial of uterus transplantation opened in 2015. In 2017, a 35 year old woman with congenital absence of the uterus was matched to a 24 year old parous deceased brain-dead donor. Transplantation of the uterus was performed with vaginal anastomosis and vascular anastomoses bilaterally from internal iliac vessels of the donor to the external iliac vessels of the recipient. Induction and maintenance immunosuppression were achieved and subsequently modified in anticipation of pregnancy 6 months after transplant. Prior to planned embryo transfer, ectocervical biopsy revealed ulceration and a significant diffuse, plasma cell-rich mixed inflammatory cell infiltrate, with histology interpreted as grade 3 rejection suspicious for an antibody-mediated component. Aggressive immunosuppressive regimen targeting both cellular and humoral rejection was initiated. After 3 months of treatment, there was no histologic evidence of rejection, and after 3 months from complete clearance of rejection, an uneventful embryo transfer was performed and a pregnancy was established. At 21 weeks, central placenta previa with accreta was diagnosed. A healthy neonate was delivered by cesarean hysterectomy at 34 weeks' gestation. In summary, this paper highlights the first live birth in North America resulting from a deceased donor uterus transplant. This achievement underscores the capacity of the transplanted uterus to recover from a severe, prolonged rejection and yet produce a viable neonate. This is the first delivery from our ongoing clinical trial in uterus transplantation, including the first reported incidence of severe mixed cellular/humoral rejection as well as the first reported placenta accreta., (Copyright © 2020 Elsevier Inc. All rights reserved.)

While uterus transplantation was once considered only a theoretical possibility for patients with uterine factor infertility, researchers have now developed methods of transplantation that have led to successful pregnancies with multiple children born to date. Because of the unique and significant nature of this type of research, it has been undertaken with collaboration not only with scientists and physicians but also with bioethicists, who paved the initial path for research of uterus transplantation to take place. As the science of uterus transplantation continues to advance, so too must the public dialogue among obstetrician/gynecologists, transplant surgeons, bioethicists, and other key stakeholders in defining the continued direction of research in addition to planning for the clinical implementation of uterus transplantation as a therapeutic option. Given the rapid advances in this field, the time has come to revisit the fundamental questions raised at the inception of uterus transplantation and, looking forward, determine the future of this approach given emerging data on the procedure's impact on individuals, families, and society., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Endometriosis is estimated to affect 10% of reproductive-aged women. The gold standard for treatment is surgery; however, surgery carries a significant morbidity and cost burden. There is an ongoing need for safe, effective medical therapies for endometriosis patients, both in conjunction with and independent of surgical interventions. Most conventional therapies for endometriosis work by a similar mechanism, and efficacy is variable. In recent years, there has been increased interest in the development and testing of novel pharmacotherapies for endometriosis., Areas Covered: This review discusses both conventional and emerging treatments for endometriosis. The authors present the application of these drugs in different presentations of endometriosis across the lifespan and discuss how emerging therapies might fit into future medical management of endometriosis. Conventional therapies include nonsteroidal anti-inflammatory drugs, combined oral contraceptives, progestins, GnRH agonists/antagonists, and aromatase inhibitors. Emerging therapies are focused on disease-specific targets such as endothelial growth factor receptors., Expert Opinion: The field of endometriosis therapy is moving toward modifying the immune and inflammatory milieu surrounding endometrial implants. If these drugs show efficacy in clinical trials, combining them with current medical treatment is expected to result in a profound impact on symptom and disease burden for patients who suffer from endometriosis worldwide.

Breast cancer is the most prevalent malignancy and second leading cause of death in women worldwide, with hormone receptor-positive luminal breast cancers being the most widespread subtype. While these tumors are generally amenable to endocrine therapy, cellular heterogeneity and acquired ability of tumor cells to undergo cell state switching makes these populations difficult to be fully targeted and eradicated through conventional methods. We have leveraged a quality-by-design (QbD) approach that integrates biological responses with predictive mathematical modeling to identify key combinations of commercially available drugs to induce estrogen receptor expression for therapeutic targeting. This technology utilizes a high level of automation through a custom-built platform to reduce bias as well as design-of-experiments methodology to minimize the experimental iterations required. Utilizing this approach, we identified a combination of clinical compounds, each at concentrations well below their efficacious dose, able to induce the expression of estrogen receptor alpha (ESR1) in hormone-positive breast cancer cells. Induction of ESR1 in luminal cells leads to chemosensitization. These findings provide proof of concept for the utility of the QbD strategy and identify a unique drug cocktail able to sensitize breast cancer cells to tamoxifen.

Background: Despite procedural innovations and increasing numbers of uterus transplant attempts worldwide, the perspectives of uterus transplant (UTx) trial participants are lacking., Methods: We conducted a mixed-methods study with women with absolute uterine factor infertility (AUFI). Participants included women who had previously contacted the Cleveland Clinic regarding the Uterine Transplant Trial and met the initial eligibility criteria for participation. In-depth interviews were conducted in conjunction with FertiQoL, a validated and widely used tool to measure the impact of infertility on the quality of life of infertility patients., Results: All (n = 19) rated their overall health as good; some experienced grief and social isolation. AUFI is a life-framing experience that influences acceptance by family, partners, peers, and one's self. UTx is a means to gain control of reproductive autonomy. UTx allows family-building and the ability to play an active role in prenatal health and well-being. Establishing and maintaining a supportive relationship is a key issue of AUFI and when considering UTx. Risks of UTx are perceived relative to risks to self/child/family posed by adoption/surrogacy. Participants had no overall preference regarding living or deceased donor., Conclusions: The ways in which women with AUFI conceptualize this condition in their lives and choices around UTx and participating in a study of the procedure are multifaceted and textured. These perspectives are critical to understanding its ethical, legal, and social implications.

Purpose: To determine whether differences in birth outcomes among assisted reproductive technology (ART)-treated, subfertile, and fertile women exist in primiparous women with, singleton, vaginal deliveries., Methods: Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) data were linked to Massachusetts vital records and hospital discharges for deliveries between July 2004 and December 2010. Primiparous women with in-state vaginal deliveries, adequate prenatal care, and singleton birth at ≥ 20 weeks (n = 117,779) were classified as ART-treated (linked to ART data from SART CORS, n = 3138); subfertile (not ART-treated but with indicators of subfertility, n = 1507); or fertile (neither ART-treated nor subfertile, n = 113,134). Outcomes of prematurity (< 37 weeks), low birthweight (< 2500 g), perinatal death (death at ≥ 20 weeks to ≤ 7 days), and maternal prolonged length of hospital stay (LOS > 3 days) were compared using multivariable logistic regression., Results: Compared to fertile, higher odds were found for prematurity among ART-treated (adjusted odds ratio [AOR] 1.40, 95% confidence interval [CI] 1.25-1.50) and subfertile (AOR 1.25, 95% CI 1.03-1.50) women, low birthweight among ART-treated (AOR 1.41, 95% CI 1.23-1.62) and subfertile (AOR 1.40, 95% CI 1.15-1.71) women, perinatal death among subfertile (AOR 2.64, 95% CI 1.72-4.05), and prolonged LOS among ART-treated (AOR 1.33, 95% CI 1.19-1.48) women. Differences remained despite stratification by young age and absence of pregnancy/delivery complications., Conclusions: Greater odds of prematurity and low birthweight in ART-treated and subfertile, and perinatal death in subfertile deliveries are evident among singleton vaginal deliveries. The data suggest that even low-risk pregnancies to ART-treated and subfertile women be managed for adverse outcomes.

Objective: To quantify the effect of medical and obstetrical factors on the odds of cesarean delivery, comparing assisted reproductive technology (ART)-treated women and women with subfertility not treated with ART versus fertile women., Design: Retrospective cohort., Setting: Not applicable., Patient(s): Singleton deliveries to primiparous women; with the source of this data being the Massachusetts vital and hospital records linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System data (2004-2010)., Intervention(s): None., Main Outcome Measure(s): Mode of delivery., Result(s): The 173,130 deliveries included 5,768 ART-treated, 2,657 subfertile (1,627 non-ART medically assisted reproduction [MAR] and 1,030 unassisted infertile), and 164,705 fertile pregnancies and 117,743 vaginal and 55,387 cesarean deliveries. ART-treated women were older, more often white and non-Hispanic, and with more private insurance, previous uterine surgery, gestational diabetes, pregnancy hypertension, bleeding, and placental complications than fertile women. Overall rates of cesarean delivery were 45.7%, 43.3%, and 31.1% for ART-treated, subfertile, and fertile women and 41.7% and 45.9% for MAR and unassisted infertile deliveries. When adjusted for demographics, underlying medical factors, previous uterine surgery, and placental and delivery complications, adjusted odds ratios (ORs) compared with fertile women were 1.27 for ART-treated and 1.15 for subfertile women, with greater odds among unassisted infertile (OR 1.26) but not MAR (OR 1.09) women. The strongest confounders of odds of cesarean delivery were age and previous uterine surgery., Conclusion(s): ART and unassisted infertility were associated with greater odds of cesarean compared with fertile women. Underlying medical and obstetrical risks had strong confounding effects strongly attenuating the odds for cesarean delivery., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To demonstrate our technique of uterine procurement from a deceased donor., Design: This video uses live action footage from surgery and detailed illustrations to review the steps and techniques involved in deceased donor procurement surgery., Setting: Academic medical center., Patient(s): A deceased multiorgan donor., Intervention(s): Trial organ procurement of a viable uterus from a deceased donor., Main Outcome Measure(s): Procurement time and associated features of suitability of dissected specimen., Result(s): This video article describes the advantages of a deceased donor model over a live donor model, including eliminating the risk of surgical complications to a living donor, avoidance of ethical issues inherent in live donation, easier access to generous vascular pedicles for anastomosis, and faster procurement time. This video also outlines the key steps to a successful uterine procurement using illustrations and live action footage from a trial organ procurement., Conclusion(s): Uterine transplantation is an emerging surgical treatment for patients with absolute uterine factor infertility. Continued practice is essential in preparing for a deceased donor uterine procurement. The process continues to be refined and adapted as new information becomes available toward the goal of safe, efficient, ethical, and effective surgical treatment of absolute uterine factor infertility., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Endometriosis is a heterogeneous, recalcitrant disease that affects 10% of reproductive-age women. Resistance to conventional therapy critically raises the need for novel treatment options that target specific, dysregulated underlying molecular mechanisms. Dopamine receptor 2 (DRD2) has been shown to be associated with vascularity and fibrosis in endometriosis. Transcription factor KLF11 has been implicated in the pathogenesis of several human endocrine and reproductive tract diseases including endometriosis. KLF11 recruits epigenetic cofactors for regulation of target genes; dysregulation of critical target genes and associated signaling pathways results in diverse disease phenotypes. KLF11 regulates the expression of DRD2 in neurons. We investigated the regulation of DRD2 by KLF11 in the established eutopic and ectopic endometrial cell lines as well as in an animal model of endometriosis. KLF11 binding and activation of the DRD2 promoter was conserved across species. Promoter activation was reflected in correspondingly increased gene expression in an endometrial cell line and in primary endometriotic cells. In vivo, disease relevance was further evaluated in a surgically induced murine endometriotic model using Klf11-/- and wild-type mice. Consistent with loss of Klf11-mediated activation, lesions in Klf11-/- animals were associated with progressive fibrosis and decreased Drd2 expression. KLF11 binds specific epigenetic corepressors to repress several target genes. Activation of DRD2 by KLF11 could not be explained simply by loss of corepressor binding and is thus likely due to selective coactivator recruitment; identification of the precise pathway is the focus of ongoing investigation. Characterization of pharmacologically reversible epigenetic regulatory mechanisms has translational relevance in health and disease.

Abnormal uterine bleeding (AUB), a common health concern of women, is a heterogeneous clinical entity that is traditionally categorized into organic and nonorganic causes. Despite varied pharmacologic treatments, few offer sustained efficacy, as most are empiric, unfocused, and do not directly address underlying dysregulated molecular mechanisms. Characterization of such molecular derangements affords the opportunity to develop and use novel, more successful treatments for AUB. Given its implication in other organ systems, we hypothesized that bone morphogenetic protein (BMP) expression is altered in patients with AUB and hence comprehensively investigated dysregulation of BMP signaling pathways by systematically screening 489 samples from 365 patients for differences in the expression of BMP2, 4, 6, and 7 ligands, BMPR1A and B receptors, and downstream SMAD4, 6, and 7 proteins. Expression analysis was correlated clinically with data abstracted from medical records, including bleeding history, age at procedure, ethnicity, body mass index, hormone treatment, and histological diagnosis of fibroids, polyps, adenomyosis, hyperplasia, and cancer. Expression of BMP7 ligand was significantly increased in patients with AUB (H-score: 18.0 vs 26.7; P < .0001). Patients reporting heavy menstrual bleeding (menorrhagia) as their specific AUB pattern demonstrated significantly higher BMP7 expression. Significantly, no differences in the expression of any other BMP ligands, receptors, or SMAD proteins were observed in this large patient cohort. However, expression of BMPR1A, BMPR1B, and SMAD4 was significantly decreased in cancer compared to benign samples. Our study demonstrates that BMP7 is a promising target for future investigation and pharmacologic treatment of AUB.

Objective: A common concern of utilizing prenatal advanced genetic testing is that a result of uncertain clinical significance will increase patient anxiety. However, prenatal ultrasound may also yield findings of uncertain significance, such as 'soft markers' for fetal aneuploidy, or findings with variable prognosis, such as mild ventriculomegaly. In this study we compared risk perception following uncertain test results from each modality., Methods: A single survey with repeated measures design was administered to 133 pregnant women. It included 'intolerance of uncertainty' questions, two hypothetical scenarios involving prenatal ultrasound or advanced genetic testing, and response questions. The primary outcome was risk perception score., Results: Risk perception did not vary significantly between ultrasound and genetic scenarios (p = 0.17). The genetic scenario scored a higher accuracy (p = 0.04) but lower sense of empowerment (p = 0.01). Furthermore, patients were more likely to seek additional testing after an ultrasound than after genetic testing (p = 0.05). There were no differences in other secondary outcomes including perception of life-altering consequences and hypothetical worry, anxiety, confusion, or medical care decisions., Conclusions: Our data suggest that uncertain findings on prenatal genetic testing do not elicit a higher perception of risk or anxiety when compared to ultrasound findings of comparable uncertainty. © 2015 John Wiley & Sons, Ltd., (© 2015 John Wiley & Sons, Ltd.)

Cardiac malformations are commonly seen in individuals with terminal and interstitial deletions involving chromosome band 7p22. Although these malformations represent a significant cause of morbidity, the dosage-sensitive gene(s) that underlie these defects have yet to be identified. In this report, we describe a 16-month-old male with tetralogy of Fallot, bilateral second branchial arch remnants, and mild dysmorphic features. Array comparative genomic hybridization analysis revealed a less than 400 kb interstitial deletion on chromosome 7p22. The deletion was confirmed by real-time quantitative PCR and FISH analyses and was not detected in samples obtained from the child's parents. Molecular data from this de novo deletion, in combination with data from other isolated 7p deletions in the literature, can be used to define a less than 200 kb minimal deleted region for cardiac malformations on 7p22. This minimal deleted region spans all, or portions, of the coding regions of four known genes-MAD1L1, FTSJ2, NUDT1, and SNX8-and may include upstream regulatory elements of EIF3B. It is likely that one or more of these five genes, alone or in combination, plays an important, yet previously uncharacterized, role in cardiac development., (Copyright © 2011 Wiley-Liss, Inc.)

Osteosarcoma, the most common primary bone tumor, occurs most frequently in adolescents. Chromosomal aneuploidy is common in osteosarcoma cells, suggesting underlying chromosomal instability. Telomeres, located at chromosome ends, are essential for genomic stability; several studies have suggested that germline telomere length (TL) is associated with cancer risk. We hypothesized that TL and/or common genetic variation in telomere biology genes may be associated with risk of osteosarcoma. We investigated TL in peripheral blood DNA and 713 single nucleotide polymorphisms (SNPs) from 39 telomere biology genes in 98 osteosarcoma cases and 69 orthopedic controls. For the genotyping component, we added 1363 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer ScreeningTrial. Short TL was not associated with osteosarcoma risk overall (OR 1.39, P=0.67), although there was a statistically significant association in females (OR 4.35, 95% Cl 1.20-15.74, P=0.03). Genotype analyses identified seven SNPs in TERF1 significantly associated with osteosarcoma risk after Bonferroni correction by gene. These SNPs were highly linked and associated with a reduced risk of osteosarcoma (OR 0.48-0.53, P=0.0001-0.0006). We also investigated associations between TL and telomere gene SNPs in osteosarcoma cases and orthopedic controls. Several SNPs were associated with TL prior to Bonferroni correction; one SNP in NOLA2 and one in MEN1 were marginally non-significant after correction (P(adj)=0.057 and 0.066, respectively). This pilot-study suggests that females with short telomeres may be at increased risk of osteosarcoma, and that SNPs in TERF1 are inversely associated with osteosarcoma risk.

The specificity of binding of Watson-Crick base pairs by third strand nucleic acid residues via triple helix formation was investigated in a DNA pyrimidine triplex motif by thermal melting experiments. The host duplex was of the type A10-X-A10: T10-Y-T10, and the third strand T10-Z-T10, giving rise to 16 possible triplexes with Z:XY inserts, 4 duplexes with the Watson-Crick base pairs (XY) and 12 duplexes with mismatch pairs (XZ), all of whose stabilities were compared. Two Z:XY combinations confirm the primary binding of AT and GC target pairs in homopurine.homopyrimidine sequences by T and C residues, respectively. All other Z:XY combinations in the T:AT environment result in triplex destabilization. While some related observations have been reported, the present experiments differ importantly in that they were performed in a T:AT nearest neighbor environment and at physiological ionic strength and pH, all of which were previously untested. The conclusions now drawn also differ substantially from those in previous studies. Thus, by evaluating the depression in Tm due to base triplet mismatches strictly in terms of third strand residue affinity and specificity for the target base pair, it is shown that none of the triplet combinations that destabilize qualify for inclusion in the third strand binding code for the pyrimidine triplex motif. Hence, none of the mismatch triplets afford a general way of circumventing the requirement for homopurine.homopyrimidine targets when third strands are predominated by pyrimidines, as others have suggested. At the same time, the applicability of third strand binding is emphasized by the finding that triplexes are equally or much more sensitive to base triplet mismatches than are Watson-Crick duplexes to base pair mismatches.