Associations between follicular fluid trace elements and ovarian response during in vitro fertilization.

INTRODUCTION: Exposure to trace elements has been associated with ovarian response in experimental studies. We conducted a hypothesis-generating study of associations between ovarian follicular fluid (FF) trace elements and measures of ovarian response among women using in vitro fertilization (IVF). METHODS: We collected ovarian FF specimens from 56 women. We determined concentrations (µg/L) of 11 trace elements using inductively coupled plasma-tandem mass spectrometry. We estimated associations between women's FF trace elements per interquartile range difference, and measures of ovarian response using linear (peak estradiol (E2), baseline anti-mullerian hormone (AMH), and follicle stimulating hormone (FSH)) and negative binomial (baseline antral follicle count (AFC) and oocyte count) regression, adjusting for confounding factors. We used principal component analysis (PCA) to estimate the associations of the FF trace elements mixture. We also explored FF oxidative stress enzymes as causal mediators of the associations. RESULTS: Higher FF cobalt was associated with greater peak E2 (mean difference = 351.48 pg/mL; 95%CI: 21.76, 724.71) and AFC (rate ratio = 1.14; 95%CI: 1.01, 1.28), and higher FF copper was associated with greater peak E2 (mean difference = 335.66 pg/mL; 95%CI: 81.77, 753.08) and oocyte count (rate ratio = 1.19; 95%CI: 1.02, 1.43). Higher FF mercury was also associated with greater peak E2 (mean difference = 410.70 pg/mL; 95%CI: 61.90, 883.39). Higher FF lead was associated with lesser AFC (rate ratio = 0.85; 95%CI: 0.73, 0.98). Using PCA, the mixture of Sr, Hg, and As was associated with higher peak estradiol, AFC, and oocyte count. FF glutathione peroxidase, paraoxonase, and arylesterase activities were inconsistent mediators of the associations, but the effect estimates were imprecise. CONCLUSION: Our results suggest that essential and non-essential trace elements in FF were associated with ovarian response during IVF.

Decision regret, and other mental health outcomes, following fertility preservation in the transgender individual compared to the cisgender woman.

PURPOSE: This study aimed to (1) determine differences in depression, anxiety, body image, quality-of-life (QOL), and decision regret scale (DRS) scores in transgender individuals undergoing fertility preservation (FP) compared to those who decline and (2) determine if DRS score following FP varies between transgender individuals and cisgender women. METHODS: Sixteen transgender birth-assigned (BA) females and 13 BA males, undergoing FP consultation at an academic center between January 2016 and November 2019, were compared to each other and cisgender cohorts with pre-existing data: 201 women undergoing elective oocyte cryopreservation (EOC) between 2012 and 2016 and 44 women with cancer undergoing FP between 1993 and 2007. Outcomes included demographics; validated scales for depression, anxiety, body image, QOL (see below) in the trans cohort; DRS score in all three cohorts. RESULTS: Of 29 transgender individuals participating, 10 BA females (62%) and 12 BA males (92%) underwent FP. Beck Depression Inventory II, Hospital Anxiety and Depression Scale, Body Image Scale for Transsexuals, Satisfaction with Life Scale, Short Form Health Survey-36, and DRS scores were not significantly different between trans individuals who underwent FP and those who declined. On univariate modeling, regret was significantly lower in transpeople undergoing FP compared to those who did not (OR 0.118, p = 0.03). BA female and BA male transpatients undergoing FP reported DRS median scores 5 (mean 9) and 7.5 (mean 15), respectively, both were not significantly different from cisgender women (p = 0.97, p = 0.25) nor from each other (p = 0.43). CONCLUSIONS: Depression, anxiety, body image, and QOL, in a group of individuals presenting for FP consultation, appear similar between transpeople undergoing FP and not, while regret is significantly lower in those choosing FP. FP is an option for transgender individuals without significant differences in regret compared to cisgender women.

Hormone concentrations of dominant follicles in the TALES randomized controlled trial comparing letrozole with tamoxifen.

BACKGROUND: In this secondary analysis of the TAmoxifen or Letrozole in Estrogen Sensitive tumors (TALES) trial, we aimed to investigate if concurrent administration of letrozole vs. tamoxifen vs. no added treatment affects hormonal composition and size of stimulated ovarian follicles. METHODS: TALES is a randomized controlled trial of IVF stimulation for estrogen receptor (ER)-positive breast cancer patients stimulated with gonadotropins and administered concurrent tamoxifen 20 mg or letrozole 5 mg. We analyzed estradiol (E2), testosterone (T), progesterone (P4), follicle stimulating hormone (FSH), luteinizing hormone (LH), and anti-Mullerian hormone (AMH). We used ANOVA/Kruskal-Wallis, logistic, and linear regression models to examine differences in follicular hormone levels, size, and mature oocyte yield between trial arm. RESULTS: We included data from total 246 follicles (94 letrozole, 82 tamoxifen, and 70 control) from 123 unique participants. E2 was lower (letrozole 187.4, tamoxifen 1026.0, control 821.5 ng/mL, p < 0.01) and T was higher (letrozole 2489, tamoxifen 571, and control 504 ng/mL, p < 0.03) in the letrozole group compared to tamoxifen and control groups, while other hormone levels and follicle size were similar across groups. There were no significant differences in hormone concentrations within the follicle between tamoxifen and control arms. On multivariate logistic regression, there was no significant association of mature oocyte yield by follicle size, hormone levels, or trial arm. CONCLUSIONS: Concurrent administration of letrozole with gonadotropins affects follicular E2 and T concentrations compared to tamoxifen/control. Tamoxifen was not associated with any differences in hormone concentrations within the follicle. Mature oocyte yield was similar across groups.

Breast cancer grade and stage do not affect fertility preservation outcomes.

PURPOSE: To investigate if breast cancer stage and grade affect fertility preservation outcomes. METHODS: We performed a retrospective cohort study that included premenopausal women with breast cancer undergoing fertility preservation diagnosed between January 2011 and January 2019. The primary outcome measure was the number of mature oocytes (MII) per antral follicle count (AFC). Secondary outcome measures included total oocytes retrieved, total mature oocytes retrieved, and greater than 10 mature oocytes preserved. Univariate and multivariate models were used to assess the association of low vs. high stage (low stage I-II and high stage III-IV) and grade I vs. grade II/III with each outcome, with adjustment for confounders. RESULTS: A total of 267 premenopausal breast cancer patients undergoing fertility preservation were included in our study, with the majority presenting with low stage (N = 215, 80.5%), grade II/III (N = 235, 88.1%) disease. Baseline AFC, total gonadotropin dose, days of stimulation, and follicles [Formula: see text] 13 mm on the day of trigger did not differ by stage or grade. After adjusting for age, BMI, and baseline AFC, we found that the mean MII per AFC did not differ by stage (1.0 vs. 1.1, P = 0.3) or grade (1.0 vs. 1.0, P = 0.92). Similarly, total oocytes retrieved, total MII retrieved, and percentage of patients who were able to preserve greater than 10 MII did not differ by breast cancer stage or grade (all P > 0.2). CONCLUSION: Breast cancer grade and stage do not impact ovarian stimulation or fertility preservation outcome.

Müllerian Duct Anomalies: Role in Fertility and Pregnancy.

Müllerian duct anomalies (MDAs) have important implications for the reproductive health of female patients. In patients with both infertility and recurrent pregnancy loss, the incidence of MDAs is as high as 25%. Congenital uterine anomalies are often only part of a complex set of congenital anomalies involving the cervix, vagina, and urinary tract. Multiple classification systems for MDAs exist, each with different criteria that vary most for the diagnosis of septate uterus. Recognizing the features that guide clinical management is essential for interpretation. Identification of an MDA should prompt evaluation for associated urinary tract anomalies. In patients with infertility who seek to use assisted reproductive technologies such as intrauterine insemination, recognition of MDAs may have an affect on reproductive success, particularly in patients who have an incomplete and clinically occult septum that divides the cervix. Two-dimensional US is the first-line modality for evaluating the uterus and adnexa. Three-dimensional (3D) US or MRI may help to visualize the external uterine fundal contour and internal indentation of the endometrial cavity, which are two morphologic characteristics that are keys to the diagnosis of congenital uterine anomalies. Hysterosalpingo contrast-enhanced US may be performed in conjunction with 3D US to evaluate uterine morphologic characteristics, the endometrial cavity, and tubal patency in a single examination. MRI helps to characterize rudimentary uteri in patients with müllerian hypoplasia and allows assessment for ectopic ureters, abnormally positioned ovaries, or associated deep infiltrative endometriosis. Online supplemental material is available for this article. ©RSNA, 2021.

Variability of essential and non-essential trace elements in the follicular fluid of women undergoing in vitro fertilization (IVF).

Both essential and non-essential elements have been associated with female reproductive function in epidemiologic investigations, including among IVF populations. To date, most investigators have used blood or urine to assess biomarkers of exposure, with few employing ovarian follicular fluid (FF). FF may offer a more direct "snapshot" of the oocyte microenvironment than blood or urine, however previous studies report follicle-to-follicle variability in FF constituents that may contribute to exposure misclassification. Our objectives were to investigate sources of trace element variability, to estimate FF biomarker reliability among women undergoing IVF (n = 34), and to determine the minimum number of follicles required to estimate subject-specific mean concentrations. We measured As, Hg, Cd, Pb, Cu, Mn, Se, and Zn in FF samples using inductively coupled plasma tandem mass spectrometry. Inter-subject (between-women) variability contributed most of the variability in FF element concentrations, with ovarian, follicular, and analytical as smaller sources of variability. The proportion of variability attributable to sources between-follicles differed by age, body mass index (BMI), race, and cigarette smoking for Cu, Se, and Zn, by BMI and cigarette smoking for As, by primary infertility diagnosis for Hg, Cu, Se, and Zn, and by ovarian stimulation protocol for Mn and Se. Four to five individual follicles were sufficient to estimate subject-specific mean Cu, Se, and Zn concentrations, while >14 were necessary for As, Hg, Cd, Pb, and Mn. Overall, our results suggest that FF is a suitable source of biomarkers of As and Hg exposure in ovarian follicles. Although limited in size, our study offers the most comprehensive exploration of biological variation in FF trace elements to date and may provide guidance for future studies of ovarian trace element exposures.

Is Preimplantation Genetic Testing Associated with Increased Risk of Abnormal Placentation After Frozen Embryo Transfer?

OBJECTIVE: This study aimed to assess the association of preimplantation genetic testing (PGT) with abnormal placentation among a cohort of pregnancies conceived after frozen embryo transfer (FET). STUDY DESIGN: This is a retrospective cohort study of women who conceived via FET at the University of California, San Francisco from 2012 to 2016 with resultant delivery at the same institution. The primary outcome was abnormal placentation, including placenta accreta, retained placenta, abruption, placenta previa, vasa previa, marginal or velamentous cord insertion, circumvallate placenta, circummarginate placenta, placenta membranacea, bipartite placenta, and placenta succenturiata. Diagnosis was confirmed by reviewing imaging, delivery, and pathology reports. Our secondary outcome was hypertensive disease of pregnancy. RESULTS: A total of 311 pregnancies were included in analysis; 158 (50.8%) underwent PGT. Baseline demographic characteristics were similar between groups except for age at conception and infertility diagnosis. Women with PGT were more likely to undergo single embryo transfer (82.3 vs. 64.1%, p < 0.001). There were no statistically significant differences in the rate of the primary outcome (26.6 vs. 27.4%, p = 0.86) or hypertensive disorders of pregnancy (33.5 vs. 33.3%, p = 0.97), which remained true after multivariate analysis was performed. CONCLUSION: Among pregnancies conceived after FET, PGT is not associated with a statistically significant increased risk of abnormal placentation or hypertensive disorders of pregnancy. KEY POINTS: · In pregnancies conceived by FET, PGT is not associated with increased risk of abnormal placentation.. · In pregnancies conceived by FET, PGT is not associated with increased risk of hypertensive disorders.. · Differences in outcomes of PGT pregnancies may be related to FET rather than trophectoderm biopsy..

Conception after chemotherapy: post-chemotherapy method of conception and pregnancy outcomes in breast cancer patients.

PURPOSE: As the paradigm shifts towards improving cancer survivorship, an important concern for reproductive-aged women diagnosed with cancer is how their disease and its treatment will affect their future fertility. We sought to characterize pregnancy attempts and outcomes in breast cancer patients following chemotherapy. METHODS: We conducted a prospective cohort study of women diagnosed with breast cancer seen between 2010 and 2019. A questionnaire was administered following cancer treatment with questions regarding oncologic and reproductive history and attempts and method of conception. RESULTS: Of 181 participants, 46 (25.4%) attempted to conceive following chemotherapy. Thirty-five patients (76.1%) had return of ovarian function. Of those, 34 patients (mean age 32.8 years) first attempted to conceive by intercourse, and 22 (64.7%) became pregnant, resulting in 17 live births. Of the remaining 12 who did not successfully conceive through intercourse, eight went on to try other methods, resulting in five additional pregnancies and one live birth. Twelve patients (mean age 34.6 years) proceeded directly to ART; of those, eight (66.7%) became pregnant, resulting in six live births. CONCLUSION: In breast cancer patients with return of ovarian function after chemotherapy, half were able to conceive by intercourse alone. In order to maximize reproductive potential in patients who have return of ovarian function, providers should offer natural conception as a reasonable option prior to the use of cryopreserved tissue. For those who did not attempt to conceive on their own, the use of pre-treatment cryopreserved eggs or embryos had a high likelihood of success.

Concomitant tamoxifen or letrozole for optimal oocyte yield during fertility preservation for breast cancer: the TAmoxifen or Letrozole in Estrogen Sensitive tumors (TALES) randomized clinical trial.

PURPOSE: To determine whether concomitant tamoxifen 20 mg with gonadotropins (tamoxifen-gonadotropin) versus letrozole 5 mg with gonadotropins (letrozole-gonadotropin) affects mature oocyte yield. METHODS: Open-label, single-institution, randomized trial. Inclusion criteria included the following: females, ages 18-44 years old, with new diagnosis of non-metastatic breast cancer, who were undergoing fertility preservation with either oocyte or embryo cryopreservation. Those with estrogen-receptor-positive (ER+) breast cancer were randomized to tamoxifen-gonadotropin or letrozole-gonadotropin. Another group with estrogen-receptor-negative (ER-) breast cancer was recruited, as a prospectively collected comparison arm who took neither letrozole nor tamoxifen (gonadotropin only). The primary outcome was the number of mature oocytes obtained from the cycle. The randomized groups were powered to detect a difference of three or more mature oocytes. RESULTS: Forty-five patients were randomized to tamoxifen-gonadotropin and fifty-one to letrozole-gonadotropin. Thirty-eight patients completed gonadotropin only. Age, antral follicle count, and body mass index were similar between the randomized groups. Our primary outcome of mature oocyte yield was similar between the tamoxifen-gonadotropin and letrozole-gonadotropin groups (12±8.6 vs. 11.6±7.5, p=0.81, 95%CI of difference =-2.9 to 3.7). In a pre-specified secondary comparison, mature oocyte yield was also similar with tamoxifen-gonadotropin or letrozole-gonadotropin versus gonadotropin only (12±8.6 vs. 11.6±7.5 vs. 12.4±7.2). There were no serious adverse events in any of the groups. CONCLUSIONS: Tamoxifen-gonadotropin and letrozole-gonadotropin produced a similar number of mature oocytes. Women who received either tamoxifen-gonadotropin or letrozole-gonadotropin had a similar number of oocytes to the gonadotropin-only group. TRIAL REGISTRATION: NCT03011684 (retrospectively registered 1/5/2017, after 9% enrolled).

Seafood consumption is associated with higher follicular fluid arsenic (As) and mercury (Hg) concentrations in women undergoing in vitro fertilization (IVF).

Human exposure to non-essential toxic metals such as cadmium (Cd), mercury (Hg), and lead (Pb), and metalloids such as arsenic (As) commonly occurs through diet. Toxic trace element exposures have been reported in association with fertility and fecundity in epidemiologic studies even at low to moderate levels. While most previous studies employed blood and urine biomarkers of exposure, few have assessed toxic trace elements in ovarian follicular fluid (FF), which surrounds the developing oocyte and hence may better reflect concentrations potentially affecting reproductive outcomes. Our objective was to identify dietary predictors of FF toxic trace elements in n = 56 women (mean age: 38.3 years) undergoing in vitro fertilization (IVF) at the University of California at San Francisco. We determined As, Hg, Cd, and Pb in 197 FF specimens, collected on the day of oocyte retrieval, using inductively coupled plasma tandem mass spectrometry. A comprehensive food frequency questionnaire was used to assess the weekly and annual dietary "patterns" of participants. Consumption of specific seafood items and turkey were correlated with individual FF toxic trace elements. We also found that each unit higher seafood consumption in the past week dominated by mollusks, shrimp, and bass was associated with 60% higher FF As (95% confidence interval (CI): 25%, 105%) and FF Hg (95%CI: 7%, 136%) concentrations. Higher annual seafood consumption dominated by urchin, crab, and trout was associated with 16% higher FF As (95%CI: -2%, 38%) and 31% higher FF Hg (95%CI: 7%, 60%) concentrations per unit intake. No associations were noted between diet and Cd and Pb levels in FF. Overall, our results suggest that higher seafood consumption contributes to elevated levels of As and Hg in FF. These findings are consistent with previous IVF studies that assessed toxic trace element exposures in blood and urine. To our knowledge, this is the first study to report that diet might be a source of As, Hg, Cd, and Pb in FF.

Ultra-trace element analysis of human follicular fluid by ICP-MS/MS: pre-analytical challenges, contamination control, and matrix effects.

Follicular fluid (FF), which is the fluid that envelops the developing oocyte (egg cell) in the ovary, can be analyzed to assess trace element content as well as to determine potential exposure to toxic elements in women seeking in vitro fertilization (IVF) treatment. Such measurements may be useful in establishing associations with potential adverse effects on oocyte viability and subsequent pregnancy outcomes. The principal goal of this study was to leverage the next generation of inorganic mass spectrometry based on ICP-MS/MS to address the numerous analytical challenges of (ultra-)trace element analysis of human FF specimens. Ultra-trace element measurements are defined by the Clinical Laboratory Standards Institute as fluid concentrations below 10 µg L-1 or tissue mass fractions below 1 µg g-1. Stringent pre-analytical procedures were developed to minimize exogenous contamination during FF specimen collection and storage in a prospective study of 56 women seeking IVF treatment. ICP-MS/MS instrumental parameters were carefully optimized, and the method validated for 11 biologically important elements that included 4 at trace levels (Cu, Se, Sr, and Zn) and 7 at ultra-trace levels (As, Cd, Co, Mo, Mn, Hg, and Pb). Method limits of detection (LODs) for ultra-trace elements varied from 5.6 ng L-1 for Cd to 0.11 µg L-1 for Mo. A total of 197 human FF specimens were analyzed using the proposed ICP-MS/MS method with 84% of specimens detectable for Pb and 100% detectable for Co, Cu, Mn, Mo, Sr, and Zn. The method based on ICP-MS/MS was compared to a previous method developed for FF using SF-ICP-MS.

Ovarian stimulation for fertility preservation or family building in a cohort of transgender men.

PURPOSE: The purpose of this study was to compare ovarian stimulation and pregnancy outcomes between transgender men (1) with and without a history of testosterone use (HRT) and (2) to cisgender women. METHODS: Retrospective chart review between January 1st 2015 and March 1st, 2019 of transgender men and cisgender women seeking ovarian stimulation (OS) matched by BMI and age. Outcomes were compared using Fisher's exact or Wilcoxon's rank sum tests. RESULTS: Thirteen transgender men presented for OS, 7 who used HRT. When comparing transgender men with and without a history of HRT, there were no differences in the baseline follicle count, cycle length, or FSH and hmG used (p = 0.193, 0.306, 0.200, and 0.197, respectively). Transgender men who used HRT had lower peak estradiol and oocytes retrieved compared to transgender men with no HRT use; peak estradiol levels of 1175 pg/mL IQR [559.5-2684]) vs 2713.5 pg/mL IQR [2335-3105]; oocytes retrieved 12 IQR [4-26]) vs. 25.5 [18-28] (p = 0.046. and 0.038, respectively). There were no differences in the estradiol level per oocyte, meiosis II oocyte yield, or maturity rate (MII/oocytes) between the two groups (p = 1.000, 0.148, and 0.147, respectively). Peak estradiol levels were lower among transgender men compared to cisgender women (p = 0.016), but the remaining cycle characteristics were similar between the two groups. Three successful pregnancies were conceived using the oocytes of transgender men who used HRT. CONCLUSION: HRT use may not negatively impact ovarian stimulation outcomes. Clinical pregnancies are possible from the oocytes of transgender men with a history of HRT.

Back-to-back random-start ovarian stimulation prior to chemotherapy to maximize oocyte yield.

PURPOSE: To evaluate the feasibility of utilizing back-to-back random-start ovarian stimulation to increase oocyte yield for fertility preservation prior to cancer treatment. METHODS: A case series of 15 patients who underwent back-to-back random-start stimulation cycles prior to chemotherapy. RESULTS: Of the 15 back-to-back random-start stimulation cases, 13 had breast cancer and 2 had other cancers. The average age was 38 years (range 30-43) and average AFC was 8 (range 3-14). Fourteen of the 15 women (93%) who underwent two ovarian stimulation cycles completed both of them. The average time to complete back-to-back random-start ovarian stimulation was 33 days (range 13-43 days). The average time between the first cycle completion and the second cycle start in our back-to-back random-start stimulations was 9 days (range 0-14 days). Two of the women underwent back-to-back random-start ovarian stimulation prior to starting neoadjuvant chemotherapy for breast cancer. Eleven of our 15 women at least doubled their oocyte or embryo yield relative to their first cycle. Only 1 of the 15 second cycles was canceled. The mature oocyte rate, fertilization rate, and embryo yield were similar among the first and second cycles. CONCLUSIONS: Back-to-back random-start ovarian stimulation may be an effective way to maximize fertility preservation, even in time-limited settings.

Random start ovarian stimulation for fertility preservation appears unlikely to delay initiation of neoadjuvant chemotherapy for breast cancer.

STUDY QUESTION: Is random start ovarian stimulation associated with delays in initiation of neoadjuvant chemotherapy for breast cancer? SUMMARY ANSWER: Among women who complete fertility preservation (FP) consultation, random start ovarian stimulation is unlikely to delay time to initiation of neoadjuvant chemotherapy start. WHAT IS KNOWN ALREADY: Neoadjuvant chemotherapy is now a widely accepted treatment modality for operable breast cancer and random start ovarian stimulation is an increasingly-utilized modality for FP. While conventional ovarian stimulation does not appear to delay starting adjuvant chemotherapy, the relationship between random start ovarian stimulation and neoadjuvant chemotherapy start is not well-understood. STUDY DESIGN, SIZE, DURATION: Cross-sectional study of all women seen between from January 2011 to April 2017 for FP consultation prior to starting neoadjuvant chemotherapy for breast cancer. PARTICIPANTS/MATERIALS, SETTING, METHODS: A chart-review was performed. Study inclusion criteria were female sex; age 18-45; non-metastatic breast cancer diagnosis; underwent FP consultation; underwent neoadjuvant chemotherapy. Referrals for FP evaluation came from a regional referral base of oncology clinics. Various time-points related to cancer diagnosis, FP or chemotherapy were obtained from medical record review. We compared time-points between those who underwent ovarian stimulation for FP versus those who did not using T-tests and linear modeling. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 89 women who had FP consultation prior to neoadjuvant chemotherapy were identified. Sixty-seven percent underwent ovarian stimulation prior to cancer treatment and 33% did not. Women who underwent ovarian stimulation were similar in parity and clinical cancer stage to those who did not. Overall, the average time from cancer diagnosis to chemotherapy start was similar between the group that did undergo ovarian stimulation and those who did not (38.1 ± 11.3 versus 39.4 ± 18.5 days, P = 0.672). Those that underwent ovarian stimulation were referred 9.4 ± 6.8 days after diagnosis versus 17.9 ± 15.3 days for those who did not undergo ovarian stimulation (P < 0.001). LIMITATIONS REASONS FOR CAUTION: Retrospective study with potential for selection bias among those who underwent ovarian stimulation versus those who did not. Reasons for caution include the possibility of unmeasured differences among those who did and did not undergo ovarian stimulation, including: patients' and providers' perceptions of the urgency to start chemotherapy, ongoing oncology work-up and treatment planning, FP decision-making, and the pursuit of second and third opinions. The difference in time from referral to FP consultation may have also influenced patients' decisions about whether to undergo ovarian stimulation. WIDER IMPLICATIONS OF THE FINDINGS: In this study, FP with random start ovarian stimulation was not associated with a delay cancer treatment in the neoadjuvant setting, so long as there was a prompt FP referral. Patients undergoing neoadjuvant chemotherapy should be informed of these findings to avoid unnecessary anxiety due to concern for delays. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by departmental research funding within the University of California, San Francisco Department of Obstetrics, Gynecology and Reproductive Sciences. There are no conflicts of interest to declare.

Follicular flushing and in vitro fertilization outcomes in the poorest responders: a randomized controlled trial.

STUDY QUESTION: Does follicular flushing during oocyte retrieval improve the number of oocytes retrieved in the poorest responders? SUMMARY ANSWER: Follicular flushing in the poorest responders does not increase the number of oocytes retrieved and may result in lower implantation and clinical pregnancy rates. WHAT IS KNOWN ALREADY: Although previous studies have shown no beneficial effect of follicular flushing in normal responders, no study has demonstrated a detrimental effect and many IVF centers continue to perform this technique in poor responders. Data on follicular flushing in this patient group are limited, with no randomized trial to date assessing its utility in the poorest responders. STUDY DESIGN, SIZE, DURATION: This randomized controlled trial compared the effects of follicular flushing and direct aspiration on IVF outcomes in the poorest responders, defined as having four or fewer follicles ≥12 mm on the day of hCG administration. Fifty patients were randomized during the 12-month enrollment period. PARTICIPANTS/MATERIALS, SETTING, METHODS: The patients were treated at an academic fertility center at Weill Cornell Medical College, New York. MAIN RESULTS AND THE ROLE OF CHANCE: Fifty women were randomized to follicular flushing (n = 25) or direct aspiration (n = 25). One patient in the direct aspiration group was canceled prior to oocyte retrieval for premature ovulation and was included in the intent-to-treat analysis. There was no difference in the number of oocytes retrieved with a median (IQR) of 4 (2-6) in the aspiration group versus 3 (2-5) in the flushing group (95% CI: -0.78, 1.98; P = 0.41). Patients who underwent follicular flushing had significantly fewer embryos transferred {1.7 [standard deviation (SD) 0.6] versus 2.5 (SD 1.2), P = 0.03}, a lower implantation rate (5.3 versus 34.2%, P = 0.006) and a lower clinical pregnancy rate (4 versus 36%, P = 0.01). The difference in pregnancy rates remained significant after adjusting for embryos transferred. LIMITATIONS, REASONS FOR CAUTION: Findings, including results for secondary outcome measures, may not be generalizable to natural IVF cycles as these were excluded from the study. WIDER IMPLICATIONS OF THE FINDINGS: This is the first randomized trial to evaluate the utility of follicular flushing in the poorest responders, and the first to demonstrate a potentially detrimental effect of flushing on IVF outcomes. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: NCT 01558141.

Evidence of Spermatogenesis in the Presence of Hypothalamic Suppression and Low Testosterone in an Adolescent Transgender Female: A Case Report.

Objective: To report a novel case of semen cryopreservation after testicular sperm extraction in an adolescent transgender female without cessation of gonadotropin-releasing hormone (GnRH) agonist therapy and feminizing hormone therapy. Methods: This is a case report of a 16-year-old transgender female using leuprolide acetate for 4 years and estradiol for 3 years requesting semen cryopreservation at the time of gender-affirming orchiectomy. She desired to proceed without cessation of gender affirming hormone therapy. The patient's consent was obtained for written publication. Results: The patient underwent testicular sperm extraction followed by orchiectomy. The sample was processed and cryopreserved in a 1:1 Test Yolk Buffer. Multiple early and late spermatids were identified as well as spermatagonium in the TESE specimen. Conclusions: Advanced spermatogenesis may occur in the presence of a GnRH agonist. Cessation of GnRH agonist therapy may not be essential for semen cryopreservation in adolescent transgender females.

Inflammatory Activity After Diverse Fertility Treatments: A Multicenter Analysis in the Modern Multiple Sclerosis Treatment Era.

BACKGROUND AND OBJECTIVES: Patients with multiple sclerosis (MS) may seek fertility treatment (FT)-including in vitro fertilization (IVF). Variable relapse risk after IVF has been reported in small historical cohorts, with more recent studies suggesting no change in annualized relapse rate (ARR). The objective of this study was to evaluate ARR 12 months pre-FT and 3 months post-FT in a multicenter cohort and identify factors associated with an increased risk of relapse. METHODS: Patients with clinically isolated syndrome (CIS) or MS aged 18-45 years with at least 1 FT from January 1, 2010, to October 14, 2021, were retrospectively identified at 4 large academic MS centers. The exposed period of 3 months after FT was compared with the unexposed period of 12 months before FT. FTs included controlled ovarian stimulation followed by fresh embryo transfer (COS-ET), COS alone, embryo transfer (ET) alone, and oral ovulation induction (OI). The Wilcoxon signed rank test and mixed Poisson regression models with random effects were used to compare ARR pre-FT vs post-FT, with the incidence rate ratio (IRR) and 95% CI reported. RESULTS: One hundred twenty-four FT cycles among 65 patients with MS (n = 56) or CIS (n = 9) were included: 61 COS-ET, 19 COS alone, 30 ET alone, and 14 OI. The mean age at FT was 36.5 ± 3.8 years, and the mean disease duration was 8.2 ± 5.0 years. Across 80 cycles with COS, only 5 relapses occurred among 4 unique patients within 3 months of treatment. The mean ARR after COS and before was not different (0.26 vs 0.25, p = 0.37), and the IRR was 0.95 (95% CI: 0.52-1.76, p = 0.88). No cycles with therapeutic disease-modifying therapies (DMTs) during COS had 3 months relapse (ARR 0 post-COS vs 0.18 pre-COS, p = 0.02, n = 34). Relapse rates did not vary by COS protocol. Among COS-ET cycles that achieved pregnancy (n = 43), ARR decreased from 0.26 to 0.09 (p = 0.04) within the first trimester of pregnancy. There were no relapses 3 months after ET alone and 1 relapse after OI. DISCUSSION: In this modern multicenter cohort of patients with MS undergoing diverse FTs, which included 43% on DMTs, we did not observe an elevated relapse risk after FT.

Fertility preservation in transgender men without discontinuation of testosterone.

Objective: To report two cases of fertility preservation in two transgender men without an extended period of higher dose testosterone cessation. Design: Chart abstraction was completed for two cases of oocyte preservation in transgender men without stopping testosterone gender-affirming therapy before controlled ovarian stimulation (COS). Setting: A university-affiliated fertility clinic in San Francisco, California. Patients: Two 27-year-old transgender men on higher dose testosterone undergoing oocyte cryopreservation. Interventions: Not applicable. Main Outcome Measures: Both patients had been on 6 and 20 months of testosterone therapy, respectively, and continued throughout COS. A random start antagonist plus letrozole protocol was used for the patient in case 1, with a leuprolide acetate trigger. A luteal start antagonist protocol was applied to the patient in case 2 with a leuprolide acetate trigger. Results: In case 1, a total of 35 oocytes were retrieved, with a total of 23 metaphase II (MII) oocytes cryopreserved. An additional 7 MII oocytes were obtained after in vitro maturation for a total of 30 MII oocytes that were vitrified. In case 2, 14 oocytes were retrieved, and 9 mature oocytes (MII) were vitrified. Conclusions: Transgender men have historically been advised to discontinue testosterone before COS, a process that may be distressing for many individuals. This is the first published case report demonstrating the proof of concept of COS without cessation of high-dose testosterone therapy in two transgender men. Future studies with larger sample sizes should be performed to confirm these findings.

Public attitudes in the United States toward insurance coverage for in vitro fertilization and the provision of infertility services to lower income patients.

Objective: To assess attitudes and factors that influence public opinion in the general US population toward insurance coverage and provision of infertility care to lower income patients. Design: Cross-sectional survey. Setting: Online. Patients: A nationally representative sample of US residents. Interventions: Questionnaire with multiple choice and open response questions. Main Outcome Measures: Public attitudes toward in vitro fertilization and infertility care coverage for lower income patients. Results: A total of 1,027 (90.2%) participants completed the survey, among whom 620 (60.4%) had private insurance, 275 (26.8%) had Medicare/Medicaid, and 56 (5.5%) were uninsured. The majority (916, 89.2%) did not consider infertility a disease. Over half of the respondents (568, 55.3%) supported private insurance coverage of infertility services, including for in vitro fertilization. Most respondents, 735 (71.6%) believed that the prevalence and psychosocial impact of infertility were equal among the lower and higher income people. The majority of respondents with an opinion (512, 67.6%) believed that doctors should provide infertility treatments regardless of the income level of the patients. Of supporters, 40.1% believed in the right to have a family regardless of income, and 38.2% believed that doctors had a social responsibility to provide infertility services. After adjusting for covariates, age <45 years, noncollege graduates, desiring more children, believing that infertility was a disease, and residence in the Northeast region remained significant predictors for support of private insurance coverage. Conclusions: Public perception of infertility as a disease is one of the strongest predictors of support for insurance coverage for infertility services, underscoring the need for enhanced advocacy and education in the general public.