Study question: What are the outcomes of controlled ovarian stimulation (COS) in childhood cancer survivors (CCS) undergoing fertility preservation (FP) after cancer treatment?
Summary answer: CCS who have undergone chemotherapy often show poor outcomes with COS and may need multiple cycles to achieve an adequate number of oocytes for future pregnancy.
What is known already: Up to 65% of CCS experience infertility from gonadotoxic treatments. Although it is ideal to consider FP at diagnosis, age and oncological factors often limit this option. After recovery, pubescent survivors, especially those who could not preserve fertility earlier, may be offered oocyte cryopreservation.
Study design size duration: A retrospective study including 20 CCS who underwent COS for oocyte storage between 2015 and 2022.
Participants/materials setting methods: This study involved young CCS who had been previously treated with chemotherapy and were evaluated at an FP center in a tertiary medical center. CCS were encouraged to pursue endocrine surveillance after recovering from cancer and were offered oocyte storage in case diminished ovarian reserve was evident, as dictated by elevated basal FSH (>10 IU/l), decreased anti-Müllerian hormone (AMH; <25th percentile for age), or low antral follicle count (<7).
Main results and the role of chance: Mean age at cancer diagnosis was 13.24 ± 5.6 years. Seventeen patients (85%) had been treated with alkylating agents, with five receiving cumulative doses greater than 4000 mg/m2. At the time of FP, a median of 4.25 years after cancer diagnosis, the mean age of patients was 20.6 ± 3.56 years. Mean Day 3 FSH levels were 9.26 ± 3.4 IU/l, and 12 patients had AMH levels below 1 ng/ml. The first stimulation cycle lasted 9.4 ± 2.1 days, with a mean gonadotropin dose of 3246 ± 1057 IU and a median peak estradiol (E2) level of 3733 pmol/ml (IQR 1424-6796). The median number of oocytes retrieved in the first stimulation cycle was 5.5, with a median of four mature oocytes. By the end of the FP process, which involved 1-7 cycles per patient, the median number of oocytes stored was 13.5 (IQR 3.5-18.5). Twelve patients managed to store more than 10 oocytes.
Limitations reasons for caution: The study is exploratory in its nature, limited by its small sample size and its retrospective design.
Wider implications of the findings: Oocyte storage is feasible yet limited in young CCS. Despite their young age at the time of FP, CCS who have undergone chemotherapy often show poor outcomes with COS. Ongoing reproductive monitoring after recovery is crucial to identify those who would benefit from FP following cancer treatment.
Study funding/competing interests: The Fertility Preservation Unit funds (Sheba Medical Center) were used to suppor
Study question: Are the risks of adverse perinatal outcomes in singletons born from medically assisted reproduction (MAR) mainly associated with underlying parental infertility, or are they primarily linked to the MAR treatments?
Summary answer: While MAR-conceived singletons have increased risks of preterm birth, admission to neonatal intensive care unit (NICU), and hospital admission in early life, these risks are mainly associated with the underlying parental infertility that led to the use of MAR technologies.
What is known already: Children born from MAR are at increased risk for some adverse perinatal and infant outcomes. However, to what extent this risk is associated with infertility or MAR treatment remains unclear. This knowledge gap arises from the challenge in disentangling the effects of infertility and MAR treatment, given that parental infertility necessitates the use of MAR treatment.
Study design size duration: This is a statewide longitudinally data-linked population-based cohort study conducted in New South Wales, Australia, involving all singleton infants born (liveborn or stillborn) between 2009 and 2017.
Participants/materials setting methods: We applied two comparisons to isolate the associations of infertility from its treatment: (i) MAR infants versus naturally conceived infants from fertile parents (NC-fertile), and (ii) MAR infants versus naturally conceived infants from parents who had a history of infertility (NC-infertile). The study cohort consisted of 824 639 singleton infants, of whom 27 796 (3.4%) were conceived through ART and 13 574 (1.6%) through ovulation induction/intrauterine insemination (OI/IUI), while 783 269 (95.0%) of the infants were naturally conceived (747 018 NC-fertile controls and 36 251 NC-infertile controls). We used the inverse probability of treatment weighting method to make MAR infants comparable with each of the two NC control groups. We then calculated the adjusted risk differences (aRDs) in these propensity score-weighted cohorts. In the subgroup analyses of different forms of ART treatment (ICSI vs IVF and fresh vs frozen embryo transfer), we reweighted the study cohort and compared these subgroups with the two NC control groups separately.
Main results and the role of chance: Singletons conceived through ART had a higher risk for preterm birth (aRD 25.7 per 1000 infants, 95% CI 21.3-30.0), admission to NICU (aRD 8.4 per 1000 infants, 95% CI 1.2-15.6), and hospital admission within 2 years of life (aRD 24.6 per 1000 infants, 95% CI 17.2-32.0) compared to NC-fertile controls. These risks were notably reduced when compared to NC-infertile controls (aRD 9.5 per 1000 infants, 95% CI 4.8-14.2 for preterm birth; -0.7 per 1000 infants, 95% CI -8.0 to 6.6 for NICU admission; and 10.6 per 1000 infants, 95% CI 2.5-18.7 for hospital admission within 2 years of life
Study question: Do men diagnosed with testicular cancer (TC) exhibit increased pre-existing morbidity compared to matched controls?
Summary answer: Men with TC had a significantly higher risk of hospital contacts and medicinal use prior to diagnosis compared to controls, reflecting excess morbidity across multiple health domains.
What is known already: The testicular dysgenesis syndrome hypothesis suggests that, e.g. cryptorchidism, poor semen quality, and TC are all symptoms of a fetal gonadal dysgenesis. The association of TC with broader pre-existing morbidity remains unclear.
Study design size duration: This retrospective, national, registry-based cohort study included 1952 TC patients, identified via the nationwide prospective clinical Danish Testicular Cancer (DATECA) database from 1 January 2013 to 28 February 2019, as well as 19 431 controls.
Participants/materials setting methods: TC patients were matched with up to 10 randomly selected age-matched males from the background population. None of the controls were at any time registered in the DATECA database or with a TC diagnosis in either The Danish National Patient Register or The National Cancer Register. Hospital contact data and medication prescriptions were evaluated using national registries, categorized by the International Classification of Diseases, 8th edition (ICD-8) prior to 1993 and 10th edition (ICD-10) from 1993 onward, and the Anatomical Therapeutic Chemical (ATC) Classification, using data from birth until TC diagnosis. Negative binomial regression was used to compare 'Number of hospital contacts' within each ICD chapter for TC patients versus controls, and stratified Cox regression was used to compare 'time to first medicinal prescription' within each ATC-group.
Main results and the role of chance: Prior to the TC diagnosis, the overall risk of hospital contacts was higher among TC patients than controls (incidence rate ratio (IRR)=1.18, CI: 1.13-1.25). IRRs were significantly increased in 11/18 chapters of the ICD-10, including cryptorchism (IRR = 3.24, CI: 2.31-4.52), indeterminate sex (IRR = 13.1, CI: 2.4-70.5), and infertility (IRR = 1.45, CI 1.08-2.01), and there were increased risks of respiratory, digestive, musculoskeletal, and nervous system diseases.The overall risk of being prescribed any medication was also increased among TC patients before their diagnosis (hazard ratio (HR)=1.28, CI: 1.21-1.34) compared to controls. HRs were significantly increased in 8/14 chapters of the ATC Classification, including the genito-urinary, respiratory, alimentary, musculoskeletal, and nervous system chapters. Risk of androgen prescriptions was not increased, whereas risks of prescription of gonadotropins (HR = 2.90, CI: 1.38-6.08) and medications related to erectile dysfunction (HR = 1.21, CI: 1.00-1.45) were.
Limitations reason
Study question: How different is the global proteomic and metabolic profile of mouse blastocysts generated by IVF, cultured in optimal (5% O2) or stressful (20% O2) conditions, compared to in vivo generated blastocysts?
Summary answer: We found that in IVF-generated embryos: (i) the proteome was more sensitive to high oxygen levels than the global metabolomic profile; (ii) enzymes involved in splicing and the spliceosome are altered; (iii) numerous metabolic pathways, particularly amino acids metabolism, are altered (iv) there is activation of the integrated stress response (ISR) and downregulation of mTOR pathways.
What is known already: IVF culture conditions are known to affect the gene expression of embryos. However, comprehensive data on the global metabolic and proteomic changes that occur in IVF-generated embryos are unknown.
Study design size duration: Mouse embryos were generated by natural mating (in vivo control or flushed blastocyst-FB-group) or by IVF using KSOM medium and two distinct oxygen concentrations: 5% O2 (optimal) and 20% O2 (stressful). Proteomic and metabolomic analyses were performed using state-of-the-art mass spectrometry techniques in triplicate (n = 100 blastocysts per replicate), allowing for detailed profiling of protein and metabolite alterations in each group.
Participants/materials setting methods: Mouse blastocysts were collected from CD-1 and B6D2F1 strains as specified above. High-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomics, while high-performance liquid chromatography coupled with mass spectrometry (HILIC-MS) was used for metabolomics. In addition, Immunofluorescence was used to assess the activation of stress response pathways, including the ISR.
Main results and the role of chance: Proteomic analysis revealed significant changes in protein expression in embryos cultured under 20% O2 compared to 5% O2 and in vivo embryos. Compared to in vivo embryos, IVF embryos cultured under 20% O2 exhibited 599 differentially expressed proteins, with an increase in proteins involved in oxidative stress responses, aminoacyl-tRNA synthesis, and spliceosome pathways. In contrast, IVF embryos cultured under 5% O2 showed fewer changes, with 426 differentially expressed proteins, though still reflecting significant alterations compared to in vivo embryos. These results indicate that embryos in stressful conditions (20% O2) exhibit a stronger stress response and alterations in critical pathways for protein synthesis and DNA repair. Metabolomic analysis revealed that embryos cultured under 20% O2 showed changes in branch-chained amino acid levels, and decreased levels of key metabolites of the TCA cycle an
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