Window of Opportunity: Rate of Referral to Infertility Providers among Reproductive-Age Women with Newly Diagnosed Gynecologic Cancers.

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.

Resolving the chromatin impact of mosaic variants with targeted Fiber-seq.

Accurately quantifying the functional consequences of non-coding mosaic variants requires the pairing of DNA sequence with both accessible and closed chromatin architectures along individual DNA molecules-a pairing that cannot be achieved using traditional fragmentation-based chromatin assays. We demonstrate that targeted single-molecule chromatin fiber sequencing (Fiber-seq) achieves this, permitting single-molecule, long-read genomic and epigenomic profiling across targeted >100 kilobase loci with ~10-fold enrichment over untargeted sequencing. Targeted Fiber-seq reveals that pathogenic expansions of the DMPK CTG repeat that underlie Myotonic Dystrophy 1 are characterized by somatic instability and disruption of multiple nearby regulatory elements, both of which are repeat length-dependent. Furthermore, we reveal that therapeutic adenine base editing of the segmentally duplicated γ-globin (HBG1/HBG2) promoters in primary human hematopoietic cells induced towards an erythroblast lineage increases the accessibility of the HBG1 promoter as well as neighboring regulatory elements. Overall, we find that these non-protein coding mosaic variants can have complex impacts on chromatin architectures, including extending beyond the regulatory element harboring the variant.

STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179.

Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants' thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary-thyroid feedback regulation.

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).

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).

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.

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.

Attention to novelty interferes with toddlers' emerging memory decision-making.

Memory decision-making in 26- to 32-month-olds was investigated using visual-paired comparison paradigms, requiring toddlers to select familiar stimuli (Active condition) or view familiar and novel stimuli (Passive condition). In Experiment 1 (N = 108, 54.6% female, 62% White; replication N = 98), toddlers with higher accuracy in the Active condition showed reduced novelty preference in that condition, but not in the Passive condition (d = -.11). In Experiment 2 (N = 78; 52.6% female; 70.5% White), a brief 5% increase in target size boosted gaze transitions across conditions (d = .50) and accuracy in the Active condition (d = .53). Overall, evidence suggests that better attentional distribution can support decision-making. Research was conducted between 2014 and 2020 in Northern California.

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.

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.