Anti-Müllerian Hormone (AMH) regulates BRCA1 and BRCA2 gene expression after ovarian cortex transplantation.

OBJECTIVE: To test whether recombinant anti-Müllerian hormone (rAMH) could exert an inhibitory function on BRCA1/2 expression in human ovarian cortex. METHODS: Pilot study on ovariectomized nude mice xenotransplanted with human vitrified/warmed ovarian cortex and treated with rAMH via infusion pump. Twelve nude mice were ovariectomized and Alzet pumps delivering 1.23 mcg rAMH/day to reach a serum concentration of 17.5 ng/mL, or placebo (controls), were inserted intraabdominally. Previously vitrified/warmed 2x2 mm ovarian cortex fragments were transplanted on day 7 and then harvested on day 14 after pump placement. PCR analyses determined mRNA levels for BRCA1 and BRCA2 in the human ovarian cortex. RESULTS: In mice treated with rAMH, BRCA1 expression was significantly lower (0.196 fg/µg RNA, IQR 0.158, 0.236) than in controls (0.544 fg/µg RNA, IQR 0.458, 0.554; p = .030), while BRCA2 expression remained similar in rAMH mice (5.355 fg/µg RNA, IQR 4.479, 6.230) and in controls (4.011 fg/µg RNA, IQR 3.650, 4.182; p = .327). CONCLUSION: Administration of rAMH in the peri-transplant period caused downregulation of BRCA1, but not of BRCA2 expression, in human ovarian cortex. These results help our understanding of DNA repair mechanism in the ovarian cortex and identify AMH's possible protective effect on ovarian reserve in BRCA1 mutation carriers.

Pilot study establishing a nomogram of yolk sac growth during the first trimester of pregnancy.

AIM: The yolk sac (YS) has been reported as a reliable predictor of adverse pregnancy outcomes, however, it has always been evaluated cross-sectionally with a single ultrasound per patient. We sought to validate the use of YS dimensions in serial ultrasounds throughout the first 10 weeks of singleton and multiple gestations. METHODS: This was a prospective cohort study where YS diameters were serially obtained with 2D ultrasound in singleton and multiple gestations from 5 to 11 weeks. Nonparametric test were used for comparisons with P < 0.05 indicating significance. RESULTS: One hundred ninety-three patients were included, 42 twins (3 monochorionic and 39 dichorionic), 2 triplets (monochorionic twins plus a singleton) and 148 singleton pregnancies (238 total fetuses). There was no difference in YS dimensions in singleton versus multiple pregnancies. Starting at 5 weeks' gestation, the YS increased 0.4 mm (95% CI 0.3-0.5 mm) per week until 10 weeks' gestation. Forty-five fetuses were lost in the first trimester. The risk of pregnancy loss was higher with a large YS until 8 weeks (P ≤ 0.001), while after 8 weeks it was higher with a small YS (P < 0.005). CONCLUSION: We established a nomogram of YS development during the first 10 weeks of pregnancy. The YS reliably detected pregnancies that ended in loss as early as 6 weeks' gestation. The YS was either smaller or larger than in ongoing pregnancies. While all pregnancies with large YS were lost within 10 weeks, those with smaller YS were lost beyond the first 10 weeks.

Prevalence of pathogenic variants and digenic disease in patients diagnosed with normosmic hypogonadotropic hypogonadism/Kallmann Syndrome.

BACKGROUND: Hypogonadotropic hypogonadism (HH) is due to impaired gonadotropin releasing hormone (GnRH) action resulting in absent puberty and infertility. At least 44 genes have been identified to possess genetic variants in 40-50% of nHH/KS, and 2-20% have presumed digenic disease, but not all variants have been characterized in vitro. HYPOTHESIS: The prevalence of pathogenic (P)/likely pathogenic (LP) variants in monogenic and digenic nHH/KS is lower than reported. DESIGN: Cross-sectional study. SETTING: University Research Laboratory. SUBJECTS: 158 patients with nHH/KS. METHODS: Exome sequencing (ES) was performed and variants were filtered for 44 known genes using Varsome and confirmed by Sanger Sequencing. MAIN OUTCOME MEASURES: P/LP variants in nHH/KS genes. RESULTS: ES resulted in >370,000 variants, from which variants in 44 genes were filtered. Thirty-one confirmed P/LP variants in 10 genes (ANOS1, CHD7, DUSP6, FGFR1, HS6ST1, KISS1, PROKR2, SEMA3A, SEMA3E, TACR3), sufficient to cause disease, were identified in 30/158 (19%) patients. Only 2/158 (1.2%) patients had digenic variant combinations: a male with hemizygous ANOS1 and heterozygous TACR3 variants and a male with heterozygous SEMA3A and SEMA3E variants. Two patients (1.2%) had compound heterozygous GNRHR (autosomal recessive) variants-one P and one variant of uncertain significance (VUS). Five patients (3.2%) had heterozygous P/LP variants in either GNRHR or TACR3 (both autosomal recessive), but no second variant. CONCLUSION: Our prevalence of P/LP variants in nHH/KS was 19%, and digenicity was observed in 1.2%. These findings are less than those previously reported, and probably represent a more accurate estimation since VUS are not included.

Perplexing findings during laparoscopic evaluation for tubal factor infertility resulting from a gastric leak after bariatric surgery: A case report.

Tubal factor is the primary type of female infertility, accounting for 25-35% of cases. Common causes include inflammation due to pelvic inflammatory disease, septic abortion, tubal surgery, and surgical adhesions. Bariatric surgery is becoming increasingly popular as rates of obesity rise, with over 256,000 surgeries performed in 2019. Half of these procedures were performed on women of reproductive age. This is the first reported case of a patient with tubal factor infertility as a result of a gastric leak from a remote sleeve gastrectomy that led to extensive abdominal and pelvic adhesions.

Crisis Management of Hysteroscopic Surgical Complications in the Office Setting.

IMPORTANCE: As health care providers are increasingly motivated to perform office procedures, there is marginal training and attention related to crisis management (CM). OBJECTIVE: We review the CM in office gynecology and illustrate the value of applying the STOP (stop, think, observe, plan) mental framework to acute management of office hysteroscopy complications. EVIDENCE ACQUISITION: We performed a literature review on crisis management in gynecology. RESULTS: Concepts of team leadership, simulation training, awareness of human error, and panic control are implemented in CM. CONCLUSIONS: Health care providers need to be cognizant of the importance of CM for optimizing patient safety and quality improvement and consider its application on office-based procedures. RELEVANCE: Crisis management has become increasingly relevant in the outpatient setting, seeking to better equip physicians with the skills to manage adverse outcomes while performing office-based procedures.

A comparison of four systems for uterine septum diagnosis and indication for surgical correction.

INTRODUCTION: Existing guidelines do not settle on a specific length to indicate surgical incision of subseptations because of differences in the four published diagnostic methods: AFS-10 mm classification, 1988/2003, ESHRE-ESGE classification, 2013, ASRM criteria, 2016- and 5.9-mm length cut-off, 2017. With this review and data analysis we sought to identify the classification method with the most accurate association with early pregnancy loss, as to identify a subseptation length cut-off to indicate surgical correction. EVIDENCE ACQUISITION: We performed an exhaustive literature search of PubMed (MEDLINE), Embase, and Cochrane Library databases until April 20, 2020 (limited to articles published in English) of the terms "uterine septum," "arcuate uterus," "subseptation," "Müllerian anomalies," from 1980-2020. After identifying all the available classifications for uterine subseptations, we performed a secondary data analysis of our departmental database on uterine subseptations and compared the identified classification criteria. Measurement of the subseptation's length was obtained on 2-D and 3-D ultrasound in accordance with the different methods. The incidence of uterine subseptations according to each method's specifications was compared among the groups and the association with pregnancy loss was evaluated. EVIDENCE SYNTHESIS: The database comprised 125 women with uterine subseptations and all four diagnostic systems identified septate uteri within it. The 5.9-mm cut-off diagnosed 89 septate, and 36 normal uteri and was the most inclusive while the ASRM cut-off was the most restrictive one, diagnosing 92/125 as arcuate uteri, only 8/125 as septate, and 25 in the gray zone. The AFS-10 mm criteria diagnosed 92/125 as arcuate, and 33 (26.4%) as septate uteri. Subseptations were inconsistently diagnosed by the ESHRE-ESGE classification, as some subseptations longer than 10 mm would be classified as normal uteri. Five/24 women had had one previous early loss and 19/24 had recurrent pregnancy loss. The 5.9-mm system was the most sensitive, while the ASRM was the least sensitive in predicting pregnancy loss (71.2% vs. 9.5% of septate uteri). CONCLUSIONS: The proposed 5.9-mm cut-off was the most sensitive in diagnosing a septate uterus and in predicting an associated early pregnancy loss. Conversely, the AFS-10 mm and the ASRM were the most restrictive, potentially missing treatment for hazardous subseptations. This update highlights the major weaknesses in the current diagnosis of uterine subseptations and indication for surgical treatment. Standardization of clinical practice is essential for reproductive clinicians and efforts should be made to prevent even one further early pregnancy loss to uterine subseptations.

Reproductive and oncologic outcomes after fertility-sparing surgery for early stage cervical cancer: a systematic review.

This review sought to evaluate the current literature on reproductive and oncologic outcomes after fertility-sparing surgery for early stage cervical cancer (stage IA1-IB1) including cold-knife conization/simple trachelectomy, vaginal radical trachelectomy, abdominal radical trachelectomy, and laparoscopic radical trachelectomy with or without robotic assistance. A systematic review using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist to evaluate the current literature on fertility-sparing surgery for early stage cervical cancer and its subsequent clinical pregnancy rate, reproductive outcomes, and cancer recurrence was performed. Sixty-five studies were included encompassing 3,044 patients who underwent fertility-sparing surgery, including 1,047 pregnancies with reported reproductive outcomes. The mean clinical pregnancy rate of patients trying to conceive was 55.4%, with the highest clinical pregnancy rate after vaginal radical trachelectomy (67.5%). The mean live-birth rate was 67.9% in our study. Twenty percent of pregnancies after fertility-sparing surgery required assisted reproductive technology. The mean cancer recurrence rate was 3.2%, and the cancer death rate was 0.6% after a median follow-up period of 39.7 months with no statistically significant difference across surgical approaches. Fertility-sparing surgery is a reasonable alternative to traditional radical hysterectomy for early-stage cervical cancer in women desiring fertility preservation. Vaginal radical trachelectomy had the highest clinical pregnancy rate, and minimally invasive approaches to fertility-sparing surgery had equivalent oncologic outcomes compared with an abdominal approach. The results of our study allow for appropriate patient counseling preoperatively and highlight the importance of a multidisciplinary approach to achieve the best outcomes for each patient.

Operative Gynecological Laparoscopy Under Conscious Sedation.

BACKGROUND AND OBJECTIVES: Operative laparoscopy is generally performed under general anesthesia. Local anesthesia and conscious sedation may be useful in select short procedures. In the present study, we evaluated safety and efficacy of operative laparoscopy under conscious sedation. METHODS: Retrospective observational study evaluating patients undergoing gynecologic laparoscopy. Laparoscopy under conscious sedation was performed for each patient with umbilical direct insertion of a 12-mm port, followed by 2 ancillary ports at 1 cm medially to the anterior superior iliac spine. Conversion to conventional laparoscopy or laparotomy was recorded. Conscious sedation was obtained using Remifentanil and Propofol, administered by an infusion system based on pharmacokinetic and pharmacodynamic models. Local anesthesia was administered at port insertion sites and for paracervical block. Pain intensity was evaluated with the Visual Analog Scale (VAS). Adverse events and drug concentrations throughout the procedure were retrieved. RESULTS: Our study population included 166 patients. They underwent laparoscopic unilateral versus bilateral salpingo-oophorectomy, ovarian cystectomy, bilateral salpingo-oophorectomy and omentectomy for a borderline ovarian tumor, myomectomy; or underwent surgery for unexplained infertility evaluation, pelvic pain, staging of ovarian cancer. Mean duration of pneumoperitoneum was 22.3 ± 7.2 min. Rate of conversion to laparoscopy under general anesthesia was 17/166 (10.2%) and there were only 3 cases of patients with low tolerability to the procedure. No severe adverse events occurred. Hospital discharge occurred in all unconverted cases after 6 to 18 h. CONCLUSIONS: Operative laparoscopy under conscious sedation and local anesthesia appears to be a feasible technique in gynecologic surgery with no adverse patient outcomes.

Nerve-Sparing Modified Radical Hysterectomy for Severe Endometriosis and Complex Pelvic Pathology.

Background Laparoscopic nerve-sparing modified radical hysterectomy with or without robotic assistance is known for its benefits as a definitive treatment for severe endometriosis. Undiagnosed endometriosis is common in patients with symptomatic fibroids or chronic pelvic pain. There are minimal studies that outline the safety and feasibility of nerve-sparing modified radical hysterectomy for other complex pelvic pathology in addition to endometriosis. Objectives The aim of this study is to evaluate the incidence of hospital readmission, intraoperative and postoperative complications, and long-term pain relief after laparoscopic nerve-sparing modified radical hysterectomy for severe endometriosis and complex benign pelvic pathology. Study design We performed a retrospective observational study of patients who underwent laparoscopic nerve-sparing modified radical hysterectomy with and without robotic-assistance with a high-volume minimally invasive endoscopic surgeon between November 2017 and December 2019. Results A total of 112 patients met the inclusion criteria. There were no cases of vaginal cuff dehiscence, venous thromboembolism, genitourinary system injury, gastrointestinal tract injury, vessel injury, nerve injury, sepsis, or death. Three patients required postoperative hospital admission for the management of umbilical cellulitis, acute blood loss anemia, and possible Addison's crisis. Other postoperative complications included allergic reaction to adhesives (1.8%) and urinary retention (0.9%). All patients reported significant pain relief at the time of their postoperative visits. Three patients reported return of pain symptoms within the first seven months after surgery, with one requiring an additional surgery for persistent pain. Conclusions Laparoscopic nerve-sparing modified radical hysterectomy with or without robotic assistance is a safe and feasible alternative that provides long-term symptom relief in patients undergoing hysterectomy for a variety of indications.

Early pregnancy ultrasound measurements and prediction of first trimester pregnancy loss: A logistic model.

Our objective was to prospectively validate the use of gestational sac (GS), yolk sac (YS) diameter, crown-rump length (CRL), and embryonal heart rate (HR) dimensions to identify early pregnancy loss. This was a prospective cohort study of first trimester pregnancies. GS and YS diameter, CRL, and HR measurements were serially obtained in singleton and twin pregnancies from 6 through 10 weeks' gestation. Non-parametric tests and logistic regression models were used for comparisons of distributions and testing of associations. A total of 252 patients were included, of which 199 were singleton pregnancies, 51 were twins, and 2 were triplets (304 total fetuses). Fifty-two patients had 61 losses. We built nomograms with the changes of the parameters evaluated in ongoing, as well as in pregnancy loss. In the pregnancies which failed, all the parameters showed significant changes, with different temporal onsets: GS and YS were the first to become abnormal, deviating from normality as early as 6 weeks' gestation (OR 0.01, 95% CI 0.0-0.09, and OR 3.36, 95% CI 1.53-7.34, respectively), followed by changes in HR, and CRL, which became evident at 7 and 8 weeks (OR 0.96, 95% CI 0.92-1.0, and OR 0.59, 95% CI 0.48-0.73, respectively). Our observations showed that, after 5 complete weeks' gestation, a small GS and a large YS reliably predicted pregnancy loss. The YS reliably identified the occurrence of a miscarriage at least 7 days prior its occurrence. CRL and HR became abnormal at a later time in pregnancy and closer to the event. These findings have important implications for patient counseling and care planning, as well as a potential bearing on cost effectiveness within early pregnancy care.

BCL-6 Overexpression as a Predictor for Endometriosis in Patients Undergoing In Vitro Fertilization.

OBJECTIVE: To evaluate the positive predictive value (PPV) of endometrial BCL-6 overexpression as a noninvasive screening test endometriosis in patients undergoing in vitro fertilization (IVF). METHODS: Retrospective cohort study at a university-affiliated private practice. Inclusion criteria were reproductive age females currently undergoing IVF with a diagnosis of unexplained infertility or unexplained recurrent pregnancy loss. Those with endometrial BCL-6 overexpression underwent laparoscopic surgery with an indication for treatment of suspected endometriosis. The primary outcome was the PPV of endometrial BCL-6 testing to surgically diagnose endometriosis. Statistical analysis was performed using SPSS v.25.0. RESULTS: Seventy-five patients met inclusion criteria for our study. The PPV of BCL-6 testing for endometriosis was 96%. Of those patients without endometriosis, 100% had other inflammatory pelvic pathologies, which were diagnosed and treated at the time of laparoscopy. CONCLUSIONS: Endometrial BCL-6 overexpression has a high PPV for diagnosing endometriosis and can help identify a patient population that may require surgical treatment before embryo transfer.

Diagnosis of Placental Position by Early First-Trimester Ultrasound: A Pilot Study.

OBJECTIVE: Conventional wisdom is that placental location cannot be identified before 8 weeks' gestation when the placenta first becomes hyperechogenic on ultrasound. We sought to evaluate whether placental location could be reliably diagnosed between 5 and 6 weeks' gestation. MATERIALS AND METHODS: This was a retrospective analysis of prospectively acquired data. Early placental location was diagnosed by evaluation of the embryonal and yolk sac position inside the gestational sac on transvaginal ultrasound. Placental position was described as anterior, posterior, fundal, or lateral. Early and mid-pregnancy placental locations were compared and coded as being the same, having migrated to an adjacent surface, or being on an opposite surface. RESULTS: A total of 111 patients met study criteria, providing 141 placental locations, comprising 85 singleton and reduced pregnancies and 28 dichorionic twin pregnancies. The most common placental location was anterior in both singleton and twin/triplet pregnancies. Placental location at the mid-pregnancy ultrasound was consistent with early pregnancy location in 100% of cases, with 79.5% (112/141) being on the same surface and 20.5% (29/141) having expanded onto an adjacent surface. Placental location was not associated with pregnancy outcome, although our study may have been underpowered to detect a significant difference. CONCLUSIONS: Placental location diagnosed at 5 to 6 weeks' gestation is consistent with the location on mid-pregnancy ultrasound. Excluding the presence of an ectopic, cornual, or cesarean section scar and uterine subseptation pregnancy in early first trimester would allow a more effective tailoring of pregnancy follow-up.