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Previous studies have shown decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. We investigated infertility and time to pregnancy in female childhood cancer survivors, and analysed treatment characteristics associated with infertility and subsequent pregnancy. The Childhood Cancer Survivor Study (CCSS) is a cohort study including 5 year cancer survivors from 26 Canadian and US institutions who were younger than 21 years at the time of diagnosis between Jan 1, 1970, and Dec 31, 1986, and a sibling control group. We included women aged 18–39 years who had ever been sexually active. We gathered demographic, medical, and reproductive data via a baseline questionnaire, and quantified exposure to alkylating agents and radiation therapy. Self-reported infertility, medical treatment for infertility, time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analysed. 3531 survivors and 1366 female sibling controls who enrolled between Nov 3, 1992, and April 4, 2004, were included. Compared with their siblings, survivors had an increased risk (relative risk [RR] 1·48 [95% CI 1·23–1·78]; p<0·0001) of clinical infertility (ie, >1 year of attempts at conception without success), which was most pronounced at early reproductive ages (RR 2·92 [95% CI 1·18–7·20], p=0·020, in participants ≤24 years; 1·61 [1·05–2·48], p=0·029, in those aged 25–29 years; and 1·37 [1·11–1·69], p=0·0035, in those aged 30–40 years). Despite being equally likely to seek treatment for infertility, survivors were less likely than were their siblings to be prescribed drugs for treatment of infertility (0·57 [95% CI 0·46–0·70], p<0·0001). Increasing doses of uterine radiation and alkylating agent chemotherapy were strongly associated with infertility. Although survivors had an increased time to pregnancy compared with their siblings (p=0·032), 292 (64%) of 455 participants with self-reported clinical infertility achieved a pregnancy. A more comprehensive understanding of infertility after cancer is crucial for counselling and decision making about future conception attempts and fertility preservation. National Cancer Institute, American Lebanese Syrian Associated Charities, Swim Across America.

Aims/hypothesis Disorders of the reproductive system, including hypogonadism and reduced fertility, are an under-recognized complication of diabetes. Based on experimental data in mice, hyperglycemia and obesity may modify epigenetic marks in sperm and impact health and development of offspring, but data are more limited in humans. Thus, we sought to study the impact of type 2 diabetes and glycemic control on sperm quality and DNA methylation. Methods In this prospective cohort study, we recruited 40 men with BMI greater than 25 kg/m 2 including 18 with type 2 diabetes, 6 with prediabetes, and 16 normoglycemic controls. Assessments were repeated after 3 months in 9 men with type 2 diabetes and 7 controls. We analyzed reproductive hormones, sperm concentration and motility, and sperm DNA methylation (MethylationEPIC BeadChip). Results Men with type 2 diabetes had higher levels of follicle-stimulating hormone (FSH), but similar testosterone levels and sperm quality as controls. Sperm DNA methylation was stable with repeat sampling at 3 months in men with and without type 2 diabetes. We identified differential methylation at 655 of 745,804 CpG sites in men with type 2 diabetes versus controls (FDR < 0.05). Of these, 96.5% showed higher methylation in type 2 diabetes, with a mean difference in DNA methylation (beta value, β) of 0.16 ± 0.004 (16 ± 0.4%). Ontology analysis of differentially methylated loci revealed annotation to genes regulating synaptic signaling, actin, cAMP-dependent pathways, and G protein-coupled receptor pathways. 24% of probes differentially regulated in men with type 2 diabetes versus control overlapped with probes associated with HbA1c, suggesting additional factors beyond glycemic control contributed to diabetes-associated differences in DNA methylation. Conclusions/interpretation Men with type 2 diabetes showed higher DNA methylation levels in sperm relative to normoglycemic controls with similar BMI. Whether these differences are reversible with glucose-lowering treatment or may contribute to post-fertilization transcriptional regulation warrants further investigation. Trial registration NCT03860558

PurposeTo determine the expected out-of-pocket costs of IVF with preimplantation genetic testing for aneuploidy (PGT-A) to attain a 50%, 75%, or 90% likelihood of a euploid blastocyst based on individual age and AMH, and develop a personalized counseling tool.MethodsA cost analysis was performed and a counseling tool was developed using retrospective data from IVF cycles intended for PGT or blastocyst freeze-all between January 1, 2014 and August 31, 2017 (n = 330) and aggregate statistics on euploidy rates of > 149,000 embryos from CooperGenomics. Poisson regression was used to determine the number of biopsiable blastocysts obtained per cycle, based on age and AMH. The expected costs of attaining a 50%, 75%, and 90% likelihood of a euploid blastocyst were determined via 10,000 Monte Carlo simulations for each age and AMH combination, incorporating age-based euploidy rates and IVF/PGT-A cost assumptions.ResultsThe cost to attain a 50% likelihood of a euploid blastocyst ranges from approximately $15,000 U.S. dollars (USD) for younger women with higher AMH values (≥ 2 ng/mL) to > $150,000 for the oldest women (44 years) with the lowest AMH values (< 0.1 ng/mL) in this cohort. The cost to attain a 75% versus 90% likelihood of a euploid blastocyst is similar (~ $16,000) for younger women with higher AMH values, but varies for the oldest women with low AMH values (~ $280,000 and > $450,000, respectively). A typical patient (36–37 years, AMH 2.5 ng/mL) should expect to spend ~ $30,000 for a 90% likelihood of attaining a euploid embryo.ConclusionsThis tool can serve as a counseling adjunct by providing individualized cost information for patients regarding PGT-A.

ContextRecent clinical and laboratory studies suggested that women with BRCA mutations have lower ovarian reserve and their primordial follicle oocytes may be more prone to DNA damage; however, direct proof is lacking.ObjectiveTo determine whether women with germline BRCA mutations have reduced primordial follicle reserve and increased oocyte DNA damage.DesignA comparative laboratory study of ovarian tissue obtained from unaffected BRCA mutation carriers (BMCs) vs age-matched organ donor cadavers.SettingTwo academic centers.Patients or Other ParticipantsOf the 230 ovarian specimens from BMCs, 18 met the study inclusion criteria. Healthy ovaries from 12 organ donor cadavers served as controls.InterventionHistology and immunohistochemical analysis on paraffin-embedded ovarian sections.Main Outcome Measure(s)Primordial follicle density and the percentage of DNA double-strand break (DSB)−positive primordial follicle oocytes.ResultsOvaries from BMCs had significantly lower primordial follicle densities than those of controls (11.2 ± 2.0 vs 44.2 ± 6.2 follicles/mm3; P = 0.0002). BRCA mutations were associated with increased DNA DSBs in primordial follicle oocytes (62% ± 5.2% vs 36% ± 3.4%; P = 0.0005). In subgroup analyses, both BRCA1 and BRCA2 mutations were associated with lower primordial follicle density (P = 0.0001 and 0.0030, respectively), and BRCA1 mutations were associated with higher DNA DSBs (P = 0.0003) than controls. The rates of follicle decline (R2 = 0.74; P = 0.0001) and DNA DSB accumulation (R2 = 0.70; P = 0.0001) appeared to be accelerated, particularly in primordial follicle oocytes of BMCs over age 30 years.ConclusionsWe provide direct evidence of diminished ovarian reserve as well as accelerated primordial follicle loss and oocyte DNA damage in women with BRCA mutations. These findings may further our understanding of ovarian aging, and be useful when counseling BMCs.Comparison of BRCA mutation carrier ovaries with controls showed that BRCA mutations were associated with accelerated loss of primordial follicle reserve and increased oocyte DNA damage with age.

BackgroundInfertility history may have important implications for clinical practice and scientific discovery. Previous research on the validity of self-reported infertility measurements has been limited in scope and duration (< 5 years). In this study, we validated self-reported infertility history measures 15–23 years after fertility treatment initiation among women who utilized assisted reproductive technology (ART).MethodsWomen who received ART treatments from three Boston infertility clinics and who enrolled in a prior study (1994–2003) were re-contacted in 2018 for the AfteR Treatment Follow-up Study (ART-FS). Infertility history was collected from clinical records and two self-report questionnaires (at ART initiation and at ART-FS enrollment). Treatment history included specific details (fresh or frozen embryo transfers, number of cycles) and treatment recall prior to ART initiation. Self-reported infertility diagnoses included polycystic ovary syndrome (PCOS), endometriosis, uterine factor infertility, tubal factor infertility, diminished ovarian reserve/advanced maternal age, male factor infertility, and other/unknown. We compared self-reported measures from 2018 to self-reported and clinical data from prior study initiation, using Cohen’s kappa, sensitivity, specificity, and 95% confidence intervals.ResultsOf 2644 women we attempted to recontact, 808 completed the ART-FS, with an average follow-up of 19.6 years (standard deviation: 2.7). Recall of fertility treatment usage had moderate sensitivity (IVF = 0.85, Clomiphene/Gonadotropin = 0.81) but low specificity across different infertility treatment modalities (IVF = 0.63, Clomiphene/Gonadotropin = 0.55). Specific IVF details had low to moderate validity and reliability with clinical records. Reliability of recalled infertility diagnosis was higher when compared to self-report at ART initiation (PCOS K = 0.66, Endometriosis K = 0.76, Tubal K = 0.73) than when compared to clinical records (PCOS K = 0.31, Endometriosis K = 0.48, Tubal K = 0.62) and varied by diagnosis.ConclusionsThe ability of women to recall specific IVF treatment details was moderately accurate and recall of self-reported infertility diagnosis varied by diagnosis and measurement method.

The use of preimplantation genetic testing for aneuploidy (PGT-A) in poor responders undergoing assisted reproductive technology has been a topic of debate with controversial results. It is critical to note the denominators used in data presented. Herein, we comment on the results found in the study by Kahraman et al. on the utility of PGT-A in poor responders with a single, good-quality blastocyst.

PurposeThe objective of this study was to assess if very-low–dose Lupron (VLDL) and ultra-low–dose Lupron (ULDL) protocols can have comparable cycle outcomes when compared to other “poor responder” stimulation protocols based on POSEIDON classification groups 3 (PG3) and 4 (PG4).MethodsA retrospective cohort study at a single, large academic center was performed. Women in PG3 (age < 35, AMH < 1.2 ng/mL) or PG4 (age ≥ 35, AMH < 1.2 ng/mL) undergoing in vitro fertilization using an ULDL (Lupron 0.1 to 0.05 mg daily), VLDL (Lupron 0.2 to 0.1 mg daily), microflare (Lupron 0.05 mg twice a day), estradiol priming/antagonist, antagonist, or minimal stimulation protocols from 2012 to 2021 were included. The primary outcome was the number of mature oocytes (MII) obtained. The secondary outcome was live birth rate (LBR).ResultsThe cohort included 3601 cycles. The mean age was 38.1 ± 3.8 years. In the PG3 group, ULDL and VLDL protocols produced a comparable number of MIIs (5.8 ± 4.3 and 5.9 ± 5.4, respectively) and live births (33.3% and 33.3%, respectively) when compared to other protocols. In the PG4 group, ULDL and VLDL protocols resulted in a higher percentage of MIIs when compared to microflare or minimal stimulation (Microflare/ULDL: adjusted relative risk (aRR) 0.78 (95% CI 0.65, 0.95); min stim/ULDL: aRR 0.47 (95% CI 0.38, 0.58); microflare/VLDL: aRR 0.77 (95% CI 0.63, 0.95); min stim/VLDL: aRR 0.47 (95% CI 0.38, 0.95)). There were no significant differences in LBR.ConclusionDilute Lupron downregulation protocols have comparable outcomes to other poor responder protocols and are reasonable to use.

Cancer treatments may compromise the fertility of children, adolescents, and young adults, and treatment-related infertility represents an important survivorship issue that should be addressed at diagnosis and in follow-up to ensure optimal decision-making, including consideration of pursuing fertility preservation. Risk of infertility varies substantially with patient and treatment factors. The ability to accurately assess fertility risk for many patients is hampered by limitations of the current literature, including heterogeneity in patient populations, treatments, and outcome measures. In this article, we review and synthesize the available data to estimate fertility risks from modern cancer treatments for both children and adult cancer survivors to enable clinicians to counsel patients about future fertility.

Serum human chorionic gonadotropin (hCG) levels are essential for diagnosing and monitoring early pregnancy. Obesity is a health care epidemic; however, the performance of this vital serum hormone in women with an elevated body mass index (BMI) is unknown. To investigate the association of BMI with serum hCG values and rate of hCG increase. Retrospective cohort study. University-based infertility clinic. Women undergoing fresh vs frozen in vitro fertilization cycles with single-day three or five embryo transfers resulting in singleton live births (≥24 weeks' gestational age) from 2008 to 2015. None. The initial hCG (mIU/mL, 16 days after oocyte retrieval) and 2-day percentage of hCG increases among BMI categories were compared using multivariable linear and logistic regression, adjusted a priori for the day of embryo transfer. The initial serum hCG values correlated inversely with the BMI (P < 0.0001, test for trend). Low initial hCG values (<100 mIU/mL) were significantly more common across increasing BMI classes, from 1.4% of normal weight patients to 15.6% of those with a BMI ≥40 kg/m2 (P = 0.001, test for trend). The mean 2-day hCG increases were similar and normal (≥53%) across the BMI groups. Patients with obesity achieving live births had statistically significantly lower initial serum hCG values compared with patients who were nonobese. However, the mean 2-day percentage of increases in hCG were similar across BMI categories. The initial hCG values might lack sensitivity for live births in patients with obesity. The rate of hCG increase remains the mainstay of monitoring very early pregnancies after in vitro fertilization. Future studies should investigate whether serum analyte ranges should be adjusted according to the BMI.

PurposeIn 2015, assisted reproductive technology (ART) accounted for 1.7% of all U.S. births, donor eggs accounted for over 17,000 started cycles in 2015, and donor sperm accounting for 6.2% of all cycles started in 2014. With increasing utilization of donor gametes as a method of assisting patients with infertility, the number of babies born each year utilizing gamete donation will also continue to increase. This study aimed to elucidate factors impacting decision to donate, amongst a representative national population.MethodsA survey was distributed via the internet utilizing SurveyMonkey Enterprise with HIPAA compliance. Univariate regressions and frequencies were conducted between each demographic and personal characteristic and the willingness to donate. Log Binomial and linear regression was used categorical and continuous variables, and Risk ratios were calculated.ResultsIn this large survey study, 64% of men and 50% of women reported they would be willing to donate gametes, with the majority desiring monetary compensation. Men with a high Consumer Financial Protection Bureau score were less likely to report that they would consider donating sperm compared to a medium high CFPB score. No other financial indicators were associated with considering donating sperm. There were no associations between CFPB score and egg donation outcomes. Black or African American women were less likely to consider donating their eggs compared to other groups, and more likely to desire > $5000 in compensation.ConclusionsIn this large survey study, a small minority of participants reported they would be willing to donate to an unknown infertility patient for reproductive purposes. High and very high CFPB scores were associated with willingness to donate games, but not with desire for monetary compensation or amount.