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).

Prefoldin-5 Expression Is Elevated in Eutopic and Ectopic Endometriotic Epithelium and Modulates Endometriotic Epithelial Cell Proliferation and Migration In Vitro.

Endometriosis is a common disease among women of reproductive age in which endometrial tissue grows in ectopic localizations, primarily within the pelvic cavity. These ectopic "lesions" grow as well as migrate and invade underlying tissues. Despite the prevalence of the disease, an understanding of factors that contribute to these cellular attributes remains poorly understood. Prefoldin-5 (PFDN5) has been associated with both aberrant cell proliferation and migration, but a potential role in endometriosis is unknown. As such, the purpose of this study was to examine PFDN5 expression in endometriotic tissue. PFDN5 mRNA and protein were examined in ectopic (lesion) and eutopic endometrial tissue from women with endometriosis and in eutopic endometrium from those without endometriosis using qRT-PCR and immunohistochemistry, respectively, while function of PFDN5 in vitro was evaluated using cell count and migration assays. PFDN5 mRNA and protein were expressed in eutopic and ectopic endometrial tissue, predominantly in the glandular epithelium, but not in endometrium from control subjects. Expression of both mRNA and protein was variable among endometriotic eutopic and ectopic endometrial tissue but showed an overall net increase. Knockdown of PFDN5 by siRNA transfection of endometriotic epithelial 12Z cells was associated with reduced cell proliferation/survival and migration. PFDN5 is expressed in eutopic and ectopic glandular epithelium and may play a role in proliferation and migration of these cells contributing to disease pathophysiology.

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.

Endometriosis with colonic and rectal involvement: surgical approach and outcomes in 142 patients.

PURPOSE: Endometriosis involving the colon and/or rectum (CRE) is operatively managed using various methods. We aimed to determine if a more limited excision is associated with 30-day complications, symptom improvement, and/or recurrence. METHODS: This is a retrospective review of consecutive cases of patients who underwent surgical management of CRE between 2010 and 2018. Primary outcomes were the associations between risk factors and symptom improvement, 30-day complications, and time to recurrence. Multivariable logistic regression assessed the independent risk factors. RESULTS: Of 2681 endometriosis cases, 142 [5.3% of total, mean age 35.4 (31.0; 39.0) years, 73.9% stage IV] underwent CRE excision (superficial partial = 66.9%, segmental = 27.5%, full thickness = 1.41%). Minor complications (14.8%) were associated with blood loss [150 (112; 288) vs. 100 (50.0; 200) mls, p = 0.046], Sigmoid involvement [45.5% vs. 12.2%, HR 5.89 (1.4; 22.5), p = 0.01], stoma formation [52.6% vs. 8.9%, HR 10.9 (3.65; 34.1), p < 0.001], and segmental resection [38.5% vs. 5.8%, HR 9.75 (3.54; 30.4), p < 0.001]. Superficial, partial-thickness resections were associated with decreased risk [(4.2% vs. 36.2%), HR 0.08 (0.02; 0.24), p < 0.001]. Factors associated with major complications (8.5%) were blood loss [250 (100; 400) vs. 100 (50.0; 200) mls, p = 0.03], open surgery [31.6% vs. 4.9%, HR 8.74 (2.36; 32.9), p = 0.001], stoma formation [42% vs. 3.3%, HR 20.3 (5.41; 90.0), p < 0.001], and segmental colectomy [28.2% vs. 0.9%, HR 34.6 (6.25; 876), p < 0.001]. Partial-thickness resection was associated with decreased risk ([.05% vs. 23.4%, HR 8.74 (2.36; 32.9), p < 0.001]. 19.1% experienced recurrence. Open surgery [5.2% vs. 21.3%, HR 0.14 (0.02; 1.05), p = 0.027] and superficial partial thickness excision [23.4% vs. 10.6%, HR 2.86 (1.08; 7.59), p = 0.027] were associated. Segmental resection was associated with decreased recurrence risk [7.6% vs. 23.5%, HR 0.27 (0.08; 0.91), p = 0.024]. CONCLUSION: Limiting resection to partial-thickness or full-thickness disc excision compared to bowel resection may improve complications but increase recurrence risk.

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.

Bilateral Cornual Resection for Uterine-sparing Removal of Tubal Sterilization Devices.

STUDY OBJECTIVE: To describe a uterine-sparing minimally invasive surgical technique for laparoscopic resection of tubal occlusion devices using bilateral cornuectomy. DESIGN: This video reviews the background of the tubal occlusion device known as Essure and the indications and methods for surgical removal with a stepwise demonstration of a minimally invasive technique with narrated video footage. SETTING: The most cited reason for patients' desire for removal of the Essure device is pelvic pain. Both hysteroscopic and laparoscopic methods have been used for removal of these devices. Laparoscopy is indicated if it has been >3 months since insertion, if a coil is noted to be malpositioned, or if the patient desires continued permanent sterilization. Techniques for removal include salpingostomy, salpingectomy, and cornuectomy. Removal of the entire device is essential, given that any remaining coil or polyethylene terephthalate fibers may continue to cause symptoms. The coils of the device can easily be fractured; therefore, in our practice we perform a bilateral cornuectomy when uterine retention is desired Supplemental Videos 1 and 2, because fracture rates are higher with salpingectomy than cornuectomy. We demonstrate the steps of this method and highlight the critical aspects for surgeons to consider during the procedure. INTERVENTIONS: Laparoscopic bilateral cornuectomy approach to a uterine-sparing excision of Essure tubal occlusion devices to reduce the risk of coil retention and fracture: 1) Injection of dilute vasopressin at the uterine cornua for vasoconstriction and hemostasis 2) Circumferential dissection of the uterine cornua using monopolar energy 3) Confirmation of endometrial cavity entry using methylene blue 4) Excision of fallopian tube along mesosalpinx to include the fimbriated end 5) Closure of the myometrial layers using a unidirectional barbed suture in a running fashion CONCLUSION: In patients who desire uterine preservation, we recommend a minimally invasive technique of bilateral cornual resection for removal of tubal sterilization devices to avoid device fracture and inadvertent retention of coils.

The Impact of Fertility Goals on Long-term Quality of Life in Reproductive-aged Women Who Underwent Myomectomy versus Hysterectomy for Uterine Fibroids.

STUDY OBJECTIVE: The objective of this study is to compare quality of life (QOL) for myomectomy with hysterectomy 1 to 5 years after surgical management for fibroids. This study evaluated the difference in QOL in a population of women of reproductive age, including those who desire fertility. DESIGN: A retrospective cohort study. INTERVENTIONS: Not applicable. SETTING: A large academic hospital. PATIENTS: A total of 142 women who underwent hysterectomy or myomectomy in 2015 to 2020. Included patients were women aged 18 years or older who underwent surgical intervention owing to uterine fibroids. MEASUREMENTS AND MAIN RESULTS: The 36-Item Short Form Health Survey (SF-36) provides a total score as a single measure of health-related QOL. The Uterine Fibroid Symptom Quality of Life Questionnaire for Hysterectomy and Myomectomy (UFS-QOL) is a patient-reported outcome measure of fibroid symptoms and health-related QOL after hysterectomy and myomectomy. There was no significant difference in SF-36 QOL scores in women after myomectomy who desired fertility compared with those who did not desire fertility, except in the social functioning domain (p = .025). UFS-QOL scores in women after myomectomy who desired fertility were not significantly different compared with women after myomectomy who did not desire fertility (p = .37). There were no significant differences between women who underwent myomectomy and hysterectomy in overall QOL scores on the SF-36 (p = .13) and UFS-QOL scores (p = .16). CONCLUSION: Myomectomy is not associated with significant differences in measures of general health and QOL compared with hysterectomy, making it a viable fibroid management option for women who desire fertility. Our study highlights the importance of discussing fertility goals and QOL when counseling patients for surgical fibroid 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.

Immunosuppression in uterus transplantation: from transplant to delivery.

INTRODUCTION: Uterus transplantation introduces unique challenges regarding immunosuppression, including the effects of immunosuppressive drugs on the fetus and graft rejection during pregnancy. Although immunosuppressive regimens are based on protocols used after solid organ transplantation, in recipients of uterus grafts, the physician must consider therapy modifications based on the phase of the transplant, from the intra-operative period through to delivery. AREAS COVERED: This review discusses the current immunosuppressive rationale in uterus transplantation, focusing on the therapy in each phase of the transplant. The authors present an overview of the already approved immunosuppressive medications for solid organ transplantation, their application in uterus transplant prior to pregnancy, during pregnancy and as rejection treatment. EXPERT OPINION: Most medications used for uterus transplant are adopted from solid organ transplantation experience, especially kidney transplantation, and rejection is treated in standard fashion. Research is needed to clarify the drugs' effects on fetal and neonatal well-being and to develop new medications to achieve better tolerance. Early markers of uterus graft rejection need to be identified, and prior rejection episodes should no longer be a cause to remove the graft during delivery in a recipient who wants a further pregnancy.

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 Relationship and Expression of miR-451a, miR-25-3p and PTEN in Early Peritoneal Endometriotic Lesions and Their Modulation In Vitro.

BACKGROUND: miR-451a can function as a tumor suppresser and has been shown to be elevated in both endometriotic lesion tissue and serum from women with endometriosis. To further explore the role of miR-451a in the pathophysiology of endometriosis, specifically, further evaluating its association with the tumor suppressor, phosphatase and tensin homolog (PTEN), we examined their expression in individual endometriotic lesion tissue to gain insight into their relationship and further explore if miR-451a regulates PTEN expression. METHODS: A total of 55 red, peritoneal endometriotic lesions and matched eutopic endometrial specimens were obtained from 46 patients with endometriosis. miR-451a, miR-25-3p and PTEN mRNA levels were assessed by qRT-PCR and reported for each matched eutopic and ectopic sample. To evaluate miR-451a and miR-25-3p expression of miR-25-3p and PTEN, respectively, 12Z cells (endometriotic epithelial cell line) were transfected and miR-25-3p expression was assessed by qRT-PCR, while PTEN protein expression was assessed by Western blotting. RESULTS: PTEN and miR-25-3p expression exhibited an inverse relationship, as did miR-25-3p and miR-451a in individual lesions. Over-expression of miR-451a in 12Z cells resulted in down-regulation of miR-25-3p, while up-regulation of miR-25-3p resulted in down-regulation of PTEN protein expression. CONCLUSIONS: By assessing individual endometriotic lesion expression, we discovered an inverse relationship between miR-451a, miR-25-3p and PTEN, while in vitro cell transfection studies suggest that miR-451a may regulate PTEN expression via modulating miR-25-3p.

Salpingo-oophorectomy or surveillance for ovarian endometrioma in asymptomatic premenopausal women: a cost-effectiveness analysis.

BACKGROUND: The lifetime risk of ovarian cancer is 1.9% among women with endometriosis compared with 1.3% among the general population. When an asymptomatic endometrioma is incidentally discovered on imaging, gynecologists must weigh the procedural complications and the potential for subsequent surgical menopause against future ovarian pathology or cancer. OBJECTIVE: We aimed to determine if performing unilateral salpingo-oophorectomy is a more cost-effective strategy for the prevention of death than surveillance for asymptomatic endometriomas. STUDY DESIGN: We created a cost-effectiveness model using TreeAge Pro (TreeAge Software Inc; Williamstown, MA) with a lifetime horizon. Our hypothetical cohort included premenopausal patients with 2 ovaries who did not desire fertility. Those diagnosed with asymptomatic endometrioma underwent either unilateral salpingo-oophorectomy or surveillance (ultrasound 6-12 weeks after diagnosis, then annually). Our primary effectiveness outcome was mortality, including death from ovarian cancer or surgery and all-cause mortality related to surgical menopause (± hormone replacement therapy) if the contralateral ovary is removed. We modeled the probabilities of surgical complications, occult malignancy, development of contralateral adnexal pathology, surgical menopause, use of hormone replacement therapy, and development of ovarian cancer. The costs included surgical procedures, complications, ultrasound surveillance, hormone therapy, and treatment of ovarian cancer, with information gathered from Medicare reimbursement data and published literature. Cost-effectiveness was determined using the incremental cost-effectiveness ratio of Δ costs / Δ deaths with a willingness-to-pay threshold of $11.6 million as the value of a statistical life. Multiple 1-way sensitivity analyses were performed to evaluate model robustness. RESULTS: Our model demonstrated that unilateral salpingo-oophorectomy is associated with improved outcomes compared with surveillance, with fewer deaths (0.28% vs 1.50%) and fewer cases of ovarian cancer (0.42% vs 2.96%). However, it costs more than sonographic surveillance at $6403.43 vs $5381.39 per case of incidental endometrioma. The incremental cost-effectiveness ratio showed that unilateral salpingo-oophorectomy costs $83,773.77 per death prevented and $40,237.80 per case of ovarian cancer prevented. As both values were well below the willingness-to-pay threshold, unilateral salpingo-oophorectomy is cost-effective and is the preferred strategy. If unilateral salpingo-oophorectomy were chosen over surveillance for premenopausal patients with incidental endometriomas, 1 diagnosis of ovarian cancer would be prevented in every 40 patients and 1 death averted in every 82 patients. We performed 1-way sensitivity analyses for all input variables and determined that there were no reasonable inputs that would alter our conclusions. CONCLUSION: Unilateral salpingo-oophorectomy is cost-effective and is the preferred strategy compared with surveillance for the management of incidental endometrioma in a premenopausal patient not desiring fertility. It incurs fewer deaths and fewer cases of ovarian cancer with costs below the national willingness-to-pay thresholds.

The impact of endometriosis on embryo morphokinetics: embryos from endometriosis patients exhibit delayed cell cycle milestones and decreased blastulation rates.

PURPOSE: To compare morphokinetic parameters in embryos obtained from women with and without endometriosis. METHODS: We evaluated a total of 3471 embryos resulting from 434 oocyte retrievals performed at a single academic center. One thousand seventy-eight embryos were obtained from women affected by endometriosis and 2393 came from unaffected controls. All embryos were cultured in a time-lapse incubator chamber for up to 6 days. IVF cycle outcomes and morphokinetic parameters collected prospectively were retrospectively reviewed. RESULTS: Morphokinetic data suggest that embryo development is impaired in embryos obtained from women with endometriosis (EE). EE were slower to achieve the 2-8 cell stages compared to control embryos (CE) (p < 0.001); additionally, time to compaction was delayed compared to CE (p = 0.015). The timing of late developmental events, including morulation and blastulation was also delayed in the endometriosis cohort (p < 0.001). In addition to demonstrating delayed cell cycle milestones, EE were less likely than controls to progress to morula, blastocyst, and expanded blastocyst stages (p < 0.001). Furthermore, a smaller proportion of embryos in the endometriosis group fell into optimal kinetic ranges for cc2 (p = 0.003), t5 (p = 0.019), tSB (p < 0.001), and tEB (p = 0.007). There were no significant differences in clinical pregnancy or live birth rates between groups. CONCLUSION: Embryos from endometriosis patients demonstrate impairments in both early and late developmental events, and progress to the morula, blastocyst, and expanded blastocyst stages at lower rates than control embryos. Despite these differences, IVF outcomes are similar for patients with and without endometriosis.

Perioperative outcomes in a nationwide sample of patients undergoing surgical treatment of ovarian endometriomas.

OBJECTIVE: To evaluate the perioperative outcomes of premenopausal women undergoing cystectomy or oophorectomy for ovarian endometriomas (OMAs) and other benign neoplasms. DESIGN: Retrospective cohort study. SETTING: Clinical database containing information from 580 US hospitals. PATIENT(S): Women 18 to 50 years old who underwent ovarian cystectomy or oophorectomy for benign indications between 2010 and 2020. INTERVENTION(S): We compared procedure route, length of hospital stay, and complication rates by surgical indication (OMA vs. other benign neoplasms) and surgical procedure (cystectomy vs. oophorectomy). MAIN OUTCOME MEASURE(S): Thirty-day perioperative adverse events following adnexal surgery, including conversion to laparotomy, blood transfusion, ileus, urinary tract injury, bowel injury, readmission, and death. RESULT(S): We identified 120,208 ovarian cystectomies (28,182 OMAs and 92,026 other indications) and 53,476 oophorectomies (8,622 OMAs and 44,854 other indications). During cystectomy, patients with OMAs more commonly experienced conversion to laparotomy (5.1% vs. 3.1%) and readmission (8.5% vs. 7.1%). For oophorectomies, patients with OMAs less frequently had minimally invasive surgery (55.8% vs. 64.8%) or outpatient procedures (33.8% vs. 41.8%). Urinary tract and bowel injuries were rare. Multivariable logistic regression demonstrated that the presence of OMA predicted composite complications during cystectomy (adjusted odds ratio [aOR] 1.23, 95% confidence interval [CI] 1.18-1.28) but not during oophorectomy (aOR 1.05, 95% CI 0.99-1.12). Patients with OMAs had 1.37 times the odds of a composite complication during oophorectomy than during cystectomy (95% CI 1.28-1.47). CONCLUSION(S): Patients undergoing ovarian cystectomy for OMAs had higher rates of perioperative adverse events than patients undergoing ovarian cystectomy for other benign neoplasms. Laparotomies were performed more often during oophorectomies for OMAs than for other benign indications.