High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes.

PURPOSE: There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO). METHODS: We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2 ng/mL or 3-day area under the curve > 4.5 ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes. RESULTS: Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol ≥ 4000 pg/mL had a greater likelihood of GBO compared to cycles < 1000 pg/mL (aRR = 1.32, 95% CI 1.13-1.54). Pairwise comparisons of estradiol between < 1000 pg/mL versus 1000-1999 pg/mL and 1000-1999 pg/mL versus 2000-2999 pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73-0.95; aRR 0.91, 95% CI 0.85-0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000-2999 pg/mL versus 3000-3999 pg/mL, aRR 1.04, 95% CI 0.97-1.11; 3000-3999 pg/mL versus ≥ 4000 pg/mL, aRR 0.96, 95% CI 0.9-1.04). CONCLUSION: In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000-2999 pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered.

Live birth associated with peak serum estradiol levels in letrozole intrauterine insemination cycles.

OBJECTIVE: To identify whether the serum estradiol (E2) level on the day of human chorionic gonadotropin (hCG) trigger or luteinizing hormone (LH) surge (hCG-LH) was associated with the live birth rate (LBR) during ovulation induction (OI) or controlled ovarian hyperstimulation with letrozole followed by intrauterine insemination (IUI). DESIGN: Retrospective cohort study. SETTING: Large, multicenter private practice. PATIENT(S): A total of 2,368 OI-IUI cycles in patients treated with letrozole followed by IUI were evaluated from January 1, 2014, to July 31, 2019. INTERVENTION(S): Ovulation induction with letrozole, followed by autologous IUI. MAIN OUTCOME MEASURE(S): The primary outcome measure was the LBR as a function of the serum E2 level at the time of hCG administration or LH surge, adjusting for age, body mass index, the largest follicle diameter, and the number of follicles ≥14 mm in diameter. The clinical pregnancy rate as a function of the E2 level, pregnancy rate as a function of the lead follicle diameter, and pregnancy loss rates were the secondary outcome variables. RESULT(S): A total of 2,368 cycles met the inclusion criteria. Outcomes were evaluated at the 25th (E2 level, 110 pg/mL), 50th (157 pg/mL), 75th (225 pg/mL), and 90th (319 pg/mL) percentiles. The LBRs ranged from 9.4% to 11.1% in the lower E2 cohorts and from 12.5% to 13.5% in the higher E2 cohorts. The LBR was significantly greater in the cohort of women with higher E2 levels in all percentile comparisons except for the 90th percentile. The mean periovulatory follicle diameter of ≥20 or <20 mm was not independently associated with the LBR or clinical pregnancy rate, despite a significantly higher mean E2 level in the larger follicle group. CONCLUSION(S): In letrozole OI cycles followed by IUI, lower LBRs and clinical pregnancy rates were found in women with lower E2 levels than in those with higher E2 levels at the 25th, 50th, and 75th percentile E2 level quartiles. Where possible, delaying hCG trigger until the E2 level increases after aromatase inhibition and approaches the physiologic periovulatory level may improve the pregnancy rates with letrozole followed by IUI.

Use of low dose vaginal misoprostol in office hysteroscopy: a pre-post interventional study.

A pre-post interventional study of patients undergoing office hysteroscopy alone and in combination with endometrial biopsy was performed during October 2015-March 2018 to evaluate the effect of low dose vaginal misoprostol on patient's pain. Pain scores were assessed using the visual analog scale at the completion of the procedure. There were 646 patients included in the study. Of these, 462 had office hysteroscopy alone; 206 (44.6%) received 50 mcg of vaginal misoprostol the night prior to the procedure and the remaining 256 (55.4%) patients had no cervical ripening. The reported pain score following hysteroscopy was significantly lower among patients who received misoprostol [4(0-10) vs. 5(0-10); p=.001]. Most patients (78.2%) did not report any misoprostol related side effects. Of the 184 patients who underwent a combination of office hysteroscopy and endometrial biopsy, 97 (52.7%) received pre-procedure vaginal misoprostol while 87 (47.3%) did not. Post procedure pain was independent of pre-treatment with vaginal misoprostol (6.3 ± 2.7 vs. 6.6 ± 2.7; p = .54).Impact statementWhat is already known on this subject? Office hysteroscopy and endometrial biopsy is increasingly performed for evaluation of various gynaecologic conditions, however, patients' perceived pain at the time of procedure may lead to incomplete procedures. Various doses of misoprostol have been tested to reduce patients' pain, however none lower than 200 mcg vaginally, and at these doses, side effects are reported.What the results of this study add? To date, there is a scarcity of published data on the use of low dose misoprostol (50 mcg) in gynaecologic procedures. Our study found that the use of low dose vaginal misoprostol prior to office hysteroscopy is associated with lower reported pain and tenaculum utilisation during the procedure. However, vaginal misoprostol prior to successive office hysteroscopy and endometrial biopsy failed to decrease the reported pain, and the overall pain score was higher than hysteroscopy alone.What the implications are of these findings for clinical practice and/or further research? The use of low dose vaginal misoprostol (50 mcg) the evening prior to office hysteroscopy is associated with lower reported pain and tenaculum utilisation and is not associated with significant side effects. Therefore, 50 mcg of misoprostol could be used in clinical practice as a method to reduce patients' reported pain during office hysteroscopy.

Does supraphysiologic estradiol level during IVF have any effect on oocyte/embryo quality? A sibling embryo cohort analysis of fresh and subsequent frozen embryo transfer.

BACKGROUND: The aim of this paper was to determine the effect of supraphysiologic serum estradiol (E2) level on oocyte and embryo development during IVF cycles. METHODS: This is a retrospective data analysis of all autologous IVF cycles where fresh embryo transfer was performed followed by subsequent frozen embryo transfer (FET) using cryopreserved sibling embryos. Primary outcome was live birth rate (LBR). Secondary outcomes were oocyte and embryo characteristics. RESULTS: Patients with high E2 (defined as serum peak E2>50th percentile [3727 pg/mL]) recorded prior to HCG trigger had significantly higher number of matured oocytes, zygotes exhibiting two pronuclei, cleavage stage embryos, blastocysts, and vitrified embryos. Following FET, LBR was higher among patients with high than normal E2 (55% vs. 37%, odds ratio [OR] 2.02; 95% confidence interval [CI] 1.05-3.88, P=0.03). Paired analysis revealed that the likelihood of achieving live birth was higher with FET compared to fresh transfer both among high E2 (54.7% vs. 26.7%; OR 3.3; 95% CI: 1.67-6.58, P<0.001) and normal E2 (37.3% vs. 18.7%; OR 2.6; 95% CI 1.23-5.47, P=0.01) patients. CONCLUSIONS: Supraphysiologic serum E2 level prior to HCG trigger does not appear to have negative impact on oocyte and embryo quality.

Comparison of patients' reported pain following office hysteroscopy with and without endometrial biopsy: a prospective study.

BACKGROUND: When performing office based gynecologic procedures, one must provide patients with appropriate counseling on anticipated pain prior to the procedure. The goal of this study was to investigate whether there is any difference in patients' pain perception when office hysteroscopy (OH) is performed alone compared with when it is performed with endometrial biopsy (EMB) for various gynecologic indications. METHODS: A prospective study was performed of patients undergoing office hysteroscopy alone or in combination with endometrial biopsy between October 2015 and February 2017. Procedures were performed using standard gynecologic techniques. Patients described their post procedural pain using the visual analogue scale from 0-10 and data was compared between groups using SPSS version 24. RESULTS: Group 1 had OH alone (N.=243) and group 2 had OH combined with EMB (N.=80). Patients who underwent both procedures had significantly higher reported median (range) pain scores than those undergoing OH alone (7 [0-10]. vs. 5 [0-10], P=0.004). The patients in-group 2 were significantly older than those in group 1 (42.6±7.6 vs. 36.6±6.5, P<0.0001). The patients in group 2 had higher gravidity (2 vs. 1, P=0.04), were more likely to have a tenaculum used during the procedure (36.3% vs. 21.4%, P=0.01) and were more likely to be diagnosed with uterine fibroids (73% vs. 31%, P<0.0001). After controlling for patients age, gravidity, tenaculum use and diagnosis of fibroids using a multivariable regression model, patients undergoing OH with EMB had a 0.51-unit pain score greater than those that had OH alone; however, this difference was not statistically significant (95% CI: -0.32, 1.33 P=0.23). CONCLUSIONS: Patients undergoing both OH and EMB appear to report similar pain scores as those undergoing OH alone after controlling for confounding variables. The presence of fibroids was found to contribute to higher reported pain in the patients having OH in combination with EMB.

Electromechanical morcellators' black-box warning: tribulations, expectations and solutions.

Laparoscopic minimally invasive gynecologic surgery (MIGS) for benign conditions results in decreased morbidity, and faster recovery, compared with laparotomy. Tissue fragmentation by electromechanical morcellation permits the removal of large specimens through small laparoscopic incisions. Since the US Food and Drug Administration (FDA) published its safety warning about the risk of power morcellators spreading cancer during fibroid surgery in 2014, power morcellation has become rare. MIGS for fibroids and other large tissue specimens has declined. Current alternatives to preserve MIGS for large specimens include intact specimen retrieval through periumbilical mini-laparotomy incisions, vaginal removal, or in-bag manual morcellation, have limitations. Innovative intracorporeal containment tissue extraction system (ICTES) prototypes capable of enclosing, manipulating, morcellating, and removing tissue, while avoiding intraperitoneal leakage and maintaining pneumoperitoneum, are being evaluated. There is ample opportunity to optimize efficacy of ICTES by scientific study in clinical trials.

Optimal Order of Successive Office Hysteroscopy and Endometrial Biopsy for the Evaluation of Abnormal Uterine Bleeding: A Randomized Controlled Trial.

OBJECTIVE: To estimate the optimal order of office hysteroscopy and endometrial biopsy when performed successively for evaluation of abnormal uterine bleeding. METHODS: Patients undergoing successive office hysteroscopy and endometrial biopsy were included in a single-blind, prospective, randomized trial. The primary outcome was to evaluate the effect of order of procedures on patients' pain score. Prespecified secondary outcomes include procedure duration, hysteroscopic visualization of the uterine cavity, endometrial sample adequacy, and number of attempts at biopsy. Pain scores were assessed using a visual analog scale from 0 to 10 and endometrial sample adequacy was determined from the histopathology report. Hysteroscopy images were recorded. Sample size of 34 per group (n=68) was determined to be adequate to detect a difference of 20% in visual analog scale score between hysteroscopy first (group A) and biopsy first (group B) at α of 0.05 and 80% power. RESULTS: Between October 2015 and January 2017, 78 women were randomized to group A (n=40) and group B (n=38). There was no difference in global pain perception [7 (0-10) vs 7 (0-10); P=.57, 95% CI 5.8-7.1]. Procedure duration [3 (1-9) vs 3 (2-10), P=.32, 95% CI 3.3-4.1] and endometrial sample adequacy (78.9% vs 75.7%, P=.74) were similar in both groups. Group A patients had better endometrial visualization (P<.001) than group B based on the hysteroscopic images: excellent (50% vs 7.9%), good (20% vs 34.2%), and fair (22.5% vs 44.7%); group B participants required fewer endometrial biopsy attempts at obtaining adequate tissue sample (two vs one; P<.001, 1.6-1.9). CONCLUSION: Patients having successive office hysteroscopy and endometrial biopsy for evaluation of abnormal uterine bleeding, the global pain perception, and time required are independent of the order in which procedures are performed. Performing hysteroscopy first ensures better image, whereas biopsy first yields adequate tissue sample with fewer attempts. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02472184.

Laparoscopic Hemi-hysterectomy and Trachelectomy in a Case of Herlyn-Werner-Wunderlich Syndrome.

BACKGROUND: Herlyn-Werner-Wunderlich Syndrome (HWWS) is a rare Müllerian anomaly characterized by uterus didelphys coexisting with an obstructed hemivagina and ipsilateral renal agenesis. CASE: A 13-year-old female presented one-year after menarche with severe dysmenorrhea and a right-sided pelvic mass. Imaging identified a right uterus with hematometra, hematocolpos, absent right kidney, normal left kidney, ureter, left uterus, and vagina compressed to the left by right hematocolpos. We performed laparoscopic hemi-hysterectomy of the non-communicating hemi-uterus, and laparoscopic trachelectomy. CONCLUSION: Laparoscopic hemi-hysterectomy and trachelecotmy is a minimally invasive surgical option for patients with Herlyn-Werner-Wunderlich Syndrome.

Elevated human chorionic gonadotropin and hyperandrogenemia in a woman with Müllerian agenesis.

BACKGROUND: Müllerian agenesis is a congenital malformation characterized by absence of the uterus, cervix, and upper vagina. A positive home pregnancy test in a woman with Müllerian agenesis mandated evaluation for malignancy. CASE: A woman with Müllerian agenesis presented with elevated levels of human chorionic gonadotropin (hCG), testosterone, and dehydroepiandrosterone sulfate. Pelvic magnetic resonance imaging (MRI), abdominal and pelvic computed tomography scan, chest computed tomography scan, brain MRI, and body positron emission tomography scan did not identify a malignancy. Human chorionic gonadotropin characterization revealed 74% hyperglycosylated and 1.6% free ß-hCG, suggesting a trophoblast-containing tumor. Interventional ovarian venous sampling and repeat pelvic MRI suggested a right adnexal source. After laparoscopic removal of a stage 1C right ovarian dysgerminoma, hCG and testosterone returned to normal. CONCLUSION: A dysgerminoma coincident with Müllerian agenesis expressed hCG before detection by MRI. Human chorionic gonadotropin molecular characterization, ovarian vein sampling, and repeat pelvic MRI led to successful treatment.

Infertility evaluation and treatment among women in the United States.

OBJECTIVE: To examine the characteristics of women seeking infertility evaluation and treatment. DESIGN: Cross-sectional survey based on in-person interviews, followed by two-step hurdle analysis. SETTING: Not applicable. PATIENT(S): 4,558 married or cohabitating women ages 25 to 44 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Likelihood of seeking a preliminary infertility evaluation and of seeking infertility treatment once evaluated, and the treatment type provided. RESULT(S): Of 623 women (13.7%) who reported seeking an infertility evaluation, 328 reported undergoing subsequent infertility treatment. Age at marriage, marital status, education, health insurance status, race/ethnicity, and religion were associated with the likelihood of seeking infertility evaluation. For example, the predicted probability that a non-white woman who married at age 25 will seek evaluation was 12%. This probability increased to 34% for white women with a graduate degree who had married at age 30. Among women who were evaluated, income, employment status, and ethnicity correlated strongly with the likelihood of seeking infertility treatment. Infertility drug therapy was the most frequent treatment used, and reproductive surgery and in vitro fertilization (IVF) were used the least often. CONCLUSION(S): The use of infertility services is not random. Understanding the sociodemographic factors correlated with use may assist new couples with family planning. Roughly 50% of the women evaluated for infertility progressed to treatment, and only a small proportion were treated with more advanced assisted reproductive technologies such as in vitro fertilization. Future research aimed at improving access to effective health-care treatments within the boundaries of affordability is warranted.

Fertility and reproductive considerations in premenopausal patients with breast cancer.

BACKGROUND: Approximately 10% of all new breast cancer diagnoses occur in young women. Although lacking medical comorbidities, these patients often have unique issues with regard to their reproductive health that merit special consideration. As breast cancer outcomes continue to improve, quality of life for patients and their families after breast cancer treatment has come to the forefront of cancer research, particularly in the growing field of oncofertility. METHODS: This article reviews the literature on the singular situations and controversies faced by premenopausal breast cancer patients. RESULTS: Data on amenorrhea and the effects of modern chemotherapeutic agents on amenorrhea are limited, although the role of tamoxifen in amenorrhea is more clearly defined as increasing the rate of amenorrhea across several studies. At the forefront of studies on fertility and premenopausal breast cancer patients are investigations on fertility preservation via ovarian protection and on assisted reproductive technologies. The use of gonadotropin-releasing hormone analogs for ovarian protection remains controversial and continues to be investigated. CONCLUSIONS: Early integration of assessment and counseling regarding fertility preservation is part of the multidisciplinary approach in the care of the premenopausal breast cancer patient and is key to optimizing both cancer treatment and fertility plans for the future. Because of the many ongoing biological, practical, and ethical controversies surrounding oncofertility, eligible patients should be strongly encouraged to participate in clinical trials and studies to further increase our knowledge in this growing field.

Endometrial polyps in reproductive-age fertile and infertile women.

Endometrial polyps are a frequent finding in infertile patients. Little is known about the true prevalence of polyps in infertile patients. It is unproved whether polyps are causative of infertility, or whether surgical polypectomy by hysteroscopy improves the likelihood of successful conception. This article reviews endometrial polyps in reproductive-age fertile and infertile women.