Human reproduction open最新文献

Study question: Does FSH induce free radical generation with substantial oxidative damage in human cumulus granulosa cells (cGCs) and mural granulosa cells (mGCs)?

Summary answer: FSH of both physiological and supraphysiological concentrations induced free radical generation on subcellular levels, most notably in the mitochondria, while the elevated free radical load caused neglectable oxidative damage in both cGCs and mGCs.

What is known already: FSH is fundamental for regulation of granulosa cell (GC) function and oocyte maturation, during which a physiological level of reactive oxygen species (ROS) is essential, while excessive amounts lead to oxidative damage. Potential adverse effects of high FSH doses on GCs may be mediated by ROS.

Study design size duration: This prospective experimental study included patients who attended a reproductive medicine center in 2023. cGC and mGC were separately isolated and brought into culture on the day of oocyte retrieval, 36 h after ovulation induction with recombinant hCG (250 mg). Recombinant FSH, at different concentrations, mimicking physiological (6 mIU/ml) and supraphysiological (60 and 600 mIU/ml) conditions, was applied (n = 4 in each group).

Participants/materials setting methods: Women aged 20-35 years, undergoing ICSI with at least three follicles, were included. Quantum sensing of cGC and mGC free radicals, detected by either cytoplasm-located fluorescent nanodiamonds (FNDs) or mitochondria-targeted FNDs, was tracked for 2 h following FSH treatment in a magnetometry setup. Mitochondrial function analysis, as well as oxidative damage to DNA/RNA, lipids, and proteins, upon FSH exposure, was examined.

Main results and the role of chance: FSH-induced cytoplasmic and mitochondrial ROS increases in cGC and mGC (P < 0.01 in all concentrations after 2 h) while showing different patterns along time: cGC showed significantly larger cytoplasmic ROS change compared with mGC to physiological (P < 0.01) and supraphysiological (P < 0.05) concentrations of FSH. Significantly larger free radical changes were observed in the mitochondria compared to the cytoplasm in response to FSH (all concentrations in cGCs with P < 0.05; supraphysiological concentrations in mGCs with P < 0.05, P < 0.001, respectively) after 2 h. Mitochondrial basal respiration and ATP production were significantly increased upon FSH exposure to supraphysiological concentrations in both cGCs (P < 0.01) and mGCs (P < 0.05). However, no oxidative damage to GC DNA/RNA, proteins, or lipids was found upon FSH exposure at any concentration except elevated lipid peroxidation in the FSH group of 600 mIU/ml (P < 0.05).

Large scale data: N/A.

Limitations reasons for caution: The GCs came from females of different

Study question: What are the clinical and ethical challenges of performing ovarian stimulation and oocyte cryopreservation in adolescents and the barriers to providing treatment?

Summary answer: Our study shows that, in one of the largest case series to date in this population, post-pubertal adolescents as young as age 13 years can undergo ovarian stimulation and oocyte cryopreservation with a response comparable to adults.

What is known already: Fertility preservation in adolescents has not been well studied, with little data available in the existing literature. Referrals for fertility preservation in adolescents are increasing due to developments in childhood cancer treatments, which have led to a growing population of children at risk of developing premature ovarian insufficiency. Those with certain benign conditions or gender incongruence also face this challenge. All established fertility preservation guidelines state that where there is a risk to fertility, oocyte cryopreservation should be offered to post-pubertal females. However, counselling and consenting young people about fertility decisions is an ethically complex area, and assessing capacity to consent in this age group is not straightforward.

Study design size duration: This was a retrospective observational cohort study of 182 referrals for fertility preservation counselling to a specialist unit, and we present outcomes for the 33 adolescents who underwent 36 cycles of ovarian stimulation and oocyte cryopreservation between January 2018 and January 2024.

Participants/materials setting methods: We included patients aged 13-18 years who underwent ovarian stimulation and oocyte cryopreservation for fertility preservation due to high or intermediate risk of gonadotoxicity from medical or surgical treatment at a public-funded specialist unit. The primary outcome was oocyte yield; secondary outcomes included oocyte maturity rate, complications, and dropout rate. Data were retrieved from a prospectively managed database.

Main results and the role of chance: There was a total of 182 referrals received, and of these, 33 patients underwent 36 cycles of ovarian stimulation and oocyte cryopreservation. Indications for fertility preservation included malignancy n = 19/36 (54%), ovarian cyst surgery n = 7/36 (19%), immunological disorders n = 4/36 (11%), benign haematological disease n = 2/36 (6%), gender reassignment treatment n = 3/36 (8%), and genetic conditions n = 1/36 (3%). The youngest child who underwent ovarian stimulation was aged 13 years and 10 months at the time of egg collection; the minimum time from menarche to ovarian stimulation was 4 months, the median AMH (anti-Müllerian hormone) was 16.7 pmol/l (range 2.8-36.9 pmol/l), and the antral follicle count (AFC) was 11 (3-36). The median number of cryoprese

Study question: Do activated fibroblasts expressing fibroblast activation protein-α (FAP) - which is traceable in positron emission topography/computed topography (PET/CT) - play a role in the microenvironment of endometriosis?

Summary answer: Activated fibroblasts expressing FAP are detectable in endometriotic lesions and correlate with iron and collagen content and infiltrating CD8-positive cytotoxic T cells and CD68-positive macrophages in the microenvironment endometriotic lesions.

What is known already: FAP-positive activated fibroblasts are found in various fibrosis-related pathologies and in the desmoplastic stroma of solid tumours; they can be traced in PET/CT but have not been investigated in the context of endometriosis, a chronic disease involving hormone-mediated repetitive tissue remodelling and fibrosis.

Study design size duration: We analysed a cohort of endometriosis patients (n = 159) who had undergone surgery with removal of endometriotic foci at our University Hospital (tertiary care centre) between 2018 and 2024. All patients provided written informed consent. The median age of the patients was 34 years. In total, 245 samples from different locations were analysed retrospectively.

Participants/materials setting methods: We investigated the expression of FAP and its relation to stroma composition and the immune microenvironment of endometriosis in 245 specimens from peritoneal lesions, ovarian endometriomas, deep infiltrating endometriosis, and extra-abdominal lesions using conventional histology and immunohistochemistry followed by digital image analysis. Tissue within a radius of 500 µm of ectopic endometrium-like epithelium was analysed. To measure FAP expression in the perilesional stroma, a histoscore (H-score) was calculated. Masson trichrome staining was used to determine collagen content. Prussian blue staining for iron was used for age-dating of lesions. The abundance of CD68-positive macrophages and CD8-positive cytotoxic T cells within the microenvironment of ectopic endometriotic glands was analysed. Extra-lesional tissue served as controls.

Main results and the role of chance: Distinct FAP expression (H-score >10) was observed in 84% of endometriotic lesions and in only 4% of extra-lesional controls. FAP expression was significantly higher in endometriotic lesions (mean H-score 61.8) than in extra-lesional tissue (mean H-score 3.8, P < 0.0001). There was a significant (P < 0.05) association with collagen content when comparing samples with low (H-score <100) and high (H-score ≥100) FAP expression, and a significant difference in FAP expression correlating with the tissue iron content when comparing strong staining intensity and negative samples (P < 0.0005) or samples with weak staining intensity (P < 0.005). Moreover, the abundance of CD8-positive and CD

Study question: What are the trial characteristics, geographic distribution, and selected methodological issues of randomized controlled trials (RCTs) in infertility published from 2012 to 2023?

Summary answer: Of the 1425 infertility RCTs, over two-thirds focused on IVF, nearly two-fifths did not use pregnancy or live birth as the primary outcome, a third lacked a primary outcome, a half were unregistered, and just over half were conducted in China (22%), Iran (20%), or Egypt (10%).

What is known already: RCTs are the main source of evidence on the effectiveness of interventions. Knowledge about RCTs in infertility from the recent past will help to pinpoint research gaps and prioritize the future research agenda. Here, we aim to present a descriptive analysis of trial characteristics, geographic distribution, and selected methodological issues in infertility trials published in the last decade.

Study design size duration: This is a systematic review. We systematically searched Embase, Medline, and Cochrane Central for RCTs in infertility from January 2012 to August 2023. RCTs involving subfertile women and women who reported pregnancy endpoints were eligible, while conference abstracts or secondary analyses were not. We did not limit our search based on the language of the articles.

Participants/materials setting methods: The full articles were text-mined and manually extracted for the description of trials' characteristics (e.g. sample size, blinding method, types of intervention), the country where the patients were recruited, and methodological issues (trial registrations and specification of primary outcomes). We extracted funding statements from Dimensions, a literature database chosen for its comprehensive and robust metadata. Gross domestic product (GDP) data were obtained from the United Nations' official website. The accuracy of extracted data was validated in a random sample of 50 articles, and false positivity and false negativity were all at or below 8%. We used descriptive statistics, including frequencies and percentages to illustrate the overall and temporal trends.

Main results and the role of chance: Among 8757 records, we found 1425 eligible RCTs, with a median sample size of 140, and 33.3% had a sample size <100. Most (69.6%) of the trials focused on IVF, with the rest focusing on ovulation induction (12.4%), intrauterine insemination (10.6%), surgeries (4.8%), or other interventions (2.6%). Regarding the geographic distribution, China (n = 310), Iran (n = 284), and Egypt (n = 138) contributed to 51% of the RCTs, followed by Turkey (n = 82), India (n = 71), and the USA (n = 69); mainland Europe produced 343 trials. Ranked by publications of trials per trillion GDP, Greece had the most papers with 4.6, followed by Iraq at 3.9, and Iran at 2.5. Regarding trial registration, 47.8% of trials were u

Nearly 200 million people worldwide suffer from infertility. Disparities exist between developed and developing countries due to differences in the availability of infertility care, different reimbursement policies and socio-cultural differences surrounding procreation. In low- and middle-income countries, specialized infertility centres are either scarce or non-existent, mostly in private settings, and accessible only to the fortunate few who can afford them. The success and sustainability of ARTs will depend on our ability to optimize these techniques in terms of availability, affordability, and effectiveness. A low-cost, simplified IVF system has been developed and shown to be safe, cost-effective, and widely applicable to low-resource settings. Combined with inexpensive mild ovarian stimulation protocols, this could become a truly effective means of treating infertility and performing assisted reproduction at affordable prices, but only if such programmes are sincerely desired and supported by all relevant stakeholders. A receptive political, governmental, and clinical community is essential.

Study question: Is there an association between dydrogesterone exposure during early pregnancy and the reporting of birth defects?

Summary answer: This observational analysis based on global safety data showed an increased reporting of birth defects, mainly hypospadias and congenital heart defects (CHD), in pregnancies exposed to dydrogesterone, especially when comparing to progesterone.

What is known already: Intravaginal administration of progesterone is the standard of care to overcome luteal phase progesterone deficiency induced by ovarian stimulation in ART. In recent years, randomized controlled clinical trials demonstrated that oral dydrogesterone was non-inferior for pregnancy rate at 12 weeks of gestation and could be an alternative to micronized vaginal progesterone. Safety profiles in both mother and child were similar. However, concerns have been raised regarding an association between dydrogesterone usage during early pregnancy and CHD in offspring.

Study design size duration: We performed a disproportionality analysis, also called case-non-case study, similar in concept to case-control studies, using the WHO global safety database, VigiBase. The study cohort consisted of individual pregnancy-related safety reports, using the ad hoc standardized query (SMQ 'Pregnancy and neonatal topics'). Cases of birth defects consisted of safety reports containing terms related to the 'congenital, familial and genetic disorders' System Organ Class from the Medical Dictionary for Regulatory Activities. Non-cases consisted of safety reports containing any other adverse event, in pregnancy-related safety reports.

Participants/materials setting methods: Considering reports since database inception to 31 December 2021, we first compared the reporting of birth defects with dydrogesterone to that of any other drug on the database, then to any other drug used for ART. Secondly, we performed a comparison on the reporting of birth defects for dydrogesterone with progesterone. Results are presented as reporting odds ratio (ROR) and their 95% CI. For each comparison, two sensitivity analyses were performed. Finally, a case-by-case review was performed to further characterize major birth defects and sort anomalies according to classification of EUROCAT.

Main results and the role of chance: Study cohort consisted of 362 183 safety reports in pregnant women, among which 50 653 reports were related to the use of drugs for ART, including 145 with dydrogesterone and 1222 with progesterone. Of these, 374 (0.7%) were cases of birth defects: 60 with dydrogesterone and 141 with progesterone, including 48 and 92 cases compatible with major birth defect cases according to EUROCAT classification, respectively. Major birth defects reported with dydrogesterone were mainly genital defects such as hypospadias and CHD. A significantly hi

Study question: Is there an association between different mitochondrial DNA (mtDNA) genotypes and female infertility or ovarian response, and is the appearance of variants in the oocytes favored by medically assisted reproduction (MAR) techniques?

Summary answer: Ovarian response was negatively associated with global non-synonymous protein-coding homoplasmic variants but positively associated with haplogroup K; the number of oocytes retrieved in a cycle correlates with the number of heteroplasmic variants in the oocytes, principally with variants located in the hypervariable (HV) region and rRNA loci, as well as non-synonymous protein-coding variants.

What is known already: Several genes have been shown to be positively associated with infertility, and there is growing concern that MAR may facilitate the transmission of these harmful variants to offspring, thereby passing on infertility. The potential role of mtDNA variants in these two perspectives remains poorly understood.

Study design size duration: This cohort study included 261 oocytes from 132 women (mean age: 32 ± 4 years) undergoing ovarian stimulation between 2019 and 2020 at an academic center. The oocyte mtDNA genotypes were examined for associations with the women's fertility characteristics.

Participants/materials setting methods: The mtDNA of the oocytes underwent deep sequencing, and the mtDNA genotypes were compared between infertile and fertile groups using Fisher's exact test. The impact of the mtDNA genotype on anti-Müllerian hormone (AMH) levels and the number of (mature) oocytes retrieved was assessed using the Mann-Whitney U test for univariate analysis and logistic regression for multivariate analysis. Additionally, we examined the associations of oocyte maturation stage, infertility status, number of ovarian stimulation units, and number of oocytes retrieved with the type and load of heteroplasmic variants using univariate analysis and Poisson or linear regression analysis.

Main results and the role of chance: Neither homoplasmic mtDNA variants nor haplogroups in the oocytes were associated with infertility status or with AMH levels. Conversely, when the relationship between the number of oocytes retrieved and different mtDNA genotypes was examined, a positive association was observed between the number of metaphase (MII) oocytes (P = 0.005) and haplogroup K. Furthermore, the presence of global non-synonymous homoplasmic variants in the protein-coding region was significantly associated with a reduced number of total oocytes and MII oocytes retrieved (P < 0.001 for both). Regarding the type and load of heteroplasmic variants in the different regions, there were no significant associations according to maturation stage of the oocyte or to fertility status; however, the number of oocytes retrieved correlated positively w