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Background and objectivesPatients 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.MethodsPatients 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.ResultsOne 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.DiscussionIn 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.

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 patients 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.

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

PurposeTo investigate if breast cancer stage and grade affect fertility preservation outcomes.MethodsWe 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.ResultsA 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).ConclusionBreast cancer grade and stage do not impact ovarian stimulation or fertility preservation outcome.

ObjectiveTo 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.DesignCross-sectional survey.SettingOnline.PatientsA nationally representative sample of US residents.InterventionsQuestionnaire with multiple choice and open response questions.Main outcome measuresPublic attitudes toward in vitro fertilization and infertility care coverage for lower income patients.ResultsA 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

PurposeTo determine whether concomitant tamoxifen 20 mg with gonadotropins (tamoxifen-gonadotropin) versus letrozole 5 mg with gonadotropins (letrozole-gonadotropin) affects mature oocyte yield.MethodsOpen-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.ResultsForty-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.ConclusionsTamoxifen-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 registrationNCT03011684 (retrospectively registered 1/5/2017, after 9% enrolled).

PurposeAs 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.MethodsWe 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.ResultsOf 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.ConclusionIn 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.

Study questionAre follicular fluid (FF), arsenic (As), mercury (Hg), cadmium (Cd) and lead (Pb) concentrations associated with IVF outcomes among women undergoing IVF?Summary answerThere was a non-linear association between higher FF Hg concentration and a lower likelihood of biochemical pregnancy and live birth. Higher FF Pb concentration was also associated with a lower probability of live birth.What is known alreadyPrevious research suggests that toxic elements may affect fertility among couples conceiving with and without assistance. However, the results have been inconsistent, possibly related in part to exposure misclassification. Very few studies have used ovarian FF to measure toxic elements, as it requires an invasive collection procedure, yet it may offer a more accurate estimate of a biologically effective dose than blood or urine.Study design size durationThis is a prospective study of 56 women undergoing IVF, from October 2015 to June 2017. FF was collected for analysis on the day of oocyte retrieval.Participants/materials setting methodsAs, Cd, Hg and Pb were determined in 197 FF specimens, using inductively coupled plasma tandem mass spectrometry. FF glutathione peroxidase, glutathione reductase, total glutathione-S-transferase, superoxide dismutase, arylesterase and paraoxonase (PON1p) activities were measured using kinetic enzyme assays.Main results and the role of chanceNon-linear associations were detected, in which the probabilities of biochemical pregnancy (P = 0.05) and live birth (P = 0.05) were lower in association with FF Hg greater than ∼0.51 µg/l Hg, adjusted for age, race, cigarette smoking and recent seafood consumption. Higher FF Pb was also associated with a lower likelihood of live birth (relative risk (RR) = 0.68, 95% CI: 0.46, 1.00; P = 0.05). We also found a suggestive, although imprecise, antagonizing mediating effect of PON1p activity on the association between FF Pb and live birth (-28.3%; 95% CI: -358%, 270%).Limitations reasons for cautionThe results should be interpreted judiciously given the limited sample size and difficulty accounting for correlated data in generalized additive models and mediation analyses. Additionally, women undergoing IVF are highly selected with respect to age and socioeconomic status, and so the generalizability of the results may be limited.Wider implications of the findingsOverall, the results suggest that FF Hg was associated with a lower likelihood of biochemical pregnancy and live birth, with a potential threshold effect, and that higher FF Pb was associated with a lower probability of live birth. These results may help to guide clinical recommendations for limiting the exposure of patients to Hg and Pb and ultimately improve IVF success rates.Study funding/competing interestsThis work was funded in part by the National Institute of Environmental Health Sciences (NIEHS), grant number 1R56ES023886-01, to the University at Albany (M.S.B.), and in part by the National Institute of Environmental Health Sciences (NIEHS), grant number 1U2CES026542-01, to the Wadsworth Center (P.J.P.). The authors declare no competing interests.Trial registration numberN/A.

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.

Phthalates are reproductive toxicants in experimental animal studies and exposure has been associated with infertility in human populations, although the results have been inconsistent. To help to address the data gap, we conducted a hypothesis-generating investigation of associations between urinary phthalate metabolites and reproductive outcomes among women (n = 56) and their male partners (n = 43) undergoing in vitro fertilization (IVF). Urine was collected from participants on the day of oocyte retrieval. Samples were analyzed for a series of phthalates, MEP, MBP, MPP, MHxP, MEHP, MEHHP, MECPP, MiNP, MiDP, MCHP, and MBzP, using liquid chromatography-tandem mass spectrometry. We employed Poisson regression with robust variance estimation to estimate associations between urinary phthalate levels and biochemical pregnancy and live birth, adjusted for partner's concentration and confounding factors. Doublings in women's MBP (relative risk (RR) = 0.32, 95 % CI: 0.13, 0.78), and men's MEHP (RR = 0.28, 95 % CI: 0.09, 0.83), were associated with a lower likelihood for pregnancy. Doublings in women's (RR = 0.08, 95 % CI: 0.01, 0.67) and men's (RR = 0.13, 95 % CI: 0.02, 0.92) MHxP were associated with a lower likelihood of live birth. Our results suggest that phthalate exposure may impact IVF outcomes, and underscore the importance of including male partners when investigating the impact of phthalate exposure on IVF. These results also suggest that clinical recommendations should include male partners for limiting phthalate exposure. Still, a larger and more comprehensive investigation is necessary to more definitively assess the risks.

PurposeThe 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.MethodsRetrospective 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.ResultsThirteen 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.ConclusionHRT use may not negatively impact ovarian stimulation outcomes. Clinical pregnancies are possible from the oocytes of transgender men with a history of HRT.

PurposeTo evaluate the feasibility of utilizing back-to-back random-start ovarian stimulation to increase oocyte yield for fertility preservation prior to cancer treatment.MethodsA case series of 15 patients who underwent back-to-back random-start stimulation cycles prior to chemotherapy.ResultsOf 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.ConclusionsBack-to-back random-start ovarian stimulation may be an effective way to maximize fertility preservation, even in time-limited settings.

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.

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. [ABSTRACT FROM AUTHOR]