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Background: Endometriosis is a chronic disease that can compromise fertility in up to 30-50% of affected patients, and it is estimated that patients affected by endometriosis represent about 10% of patients undergoing ART treatments. The hypothesized underlying mechanisms explaining infertility are various, but great attention has been given to the relationship between ovarian endometriomas and reduced ovarian reserve.

Objective and rationale: Infertility in patients with endometriosis does not have univocal management, since surgical therapy can increase the chances of natural conception, but at the same time increases the risk of damage to the ovarian reserve. In some cases, IVF procedures should be considered instead of surgery, within a personalized strategy. It has therefore been proposed that patients with endometriosis are eligible for fertility preservation.

Search methods: This article is based on a critical review of literature on peer-reviewed article indexing databases including PubMed, Scopus and Medline, using as keywords: 'fertility preservation', 'oocyte vitrification', 'endometriosis', 'endometrioma', 'ovarian reserve' and 'in vitro fertilization'.

Outcomes: Data regarding the feasibility of oocyte cryopreservation in patients with endometriosis have increased over recent years, indicating that these patients seem to have the same number of oocytes retrieved and IVF outcomes similar to those who perform fertility preservation for other indications. However, probably due to a reduced ovarian reserve, several cycles of ovarian stimulation may be needed to gather a suitable number of retrieved oocytes per patient. Age, ovarian reserve, and previous ovarian surgery are the main factors affecting the success of fertility preservation. Bilateral endometriomas, a history of unilateral endometrioma surgery with a contralateral recurrence, and preoperative reduced ovarian reserve are the most common indications for fertility preservation. The choice between primary surgery and ART is often complex, requiring a therapeutic strategy tailored to the patient's clinical characteristics and needs, such as age, type and severity of endometriosis lesions, presence of symptoms, surgical history, and desire for pregnancy.

Limitations reasons for caution: The development of endometriosis-related infertility and the severity of ovarian damage due to endometriosis lesions per se or their surgical treatment are difficult to predict, and data are lacking concerning which subgroups of patients with endometriosis might benefit most from fertility preservation.

Wider implications: Women with endometriosis, and in particular women with bilateral ovarian endometriomas or recurrent surgery on the ovaries, should be advised about risk of ovarian reserve damage. Oocyte cryopreservation is an established technique t

Study question: Does the molecular composition of uterine fluid extracellular vesicles (UF-EVs) reflect endometrial tissue changes across the menstrual cycle?

Summary answer: Concordance between endometrial tissue and UF-EVs exists on miRNA and mRNA levels along the menstrual cycle phases and UF-EV surface proteomic signatures suggest EVs originate from several major endometrial cell populations.

What is known already: The clinical value of endometrial receptivity testing is restricted by invasiveness and the use of only one omics level of input. There is promising evidence that UF-EVs can reflect changes in mid-secretory endometrium, highlighting the potential to establish endometrial receptivity testing right before embryo transfer. However, the dynamic changes of UF-EVs molecular cargo have not been directly compared to endometrial tissue on multiple omics levels.

Study design size duration: This cross-sectional study included fertile women from four menstrual cycle phases: proliferative and early-, mid-, and late-secretory phases. In total, 26 paired samples of UF and endometrial tissue were collected. mRNA and miRNA were sequenced, and differential analysis was performed on consecutive phases. UF-EVs were profiled for various protein surface markers associated with different cell types. EVs from epithelial endometrial organoid-conditioned culture media were used as a reference of pure epithelial endometrial EVs.

Participants/materials setting methods: Paired UF and endometrial tissue samples were collected from 26 fertile, reproductive-age women. EV isolation from UF was validated using electron microscopy and western blotting, and particle numbers were measured by nanoparticle tracking analysis. The transcriptome and miRNome of UF-EVs and endometrial tissue were sequenced, and differential expression analysis was conducted on consecutive phases of the menstrual cycle. Bead-based EV flow cytometry targeting 37 surface protein markers was used to characterize EVs from UF and endometrial organoids.

Main results and the role of chance: Surface proteome analysis revealed that UF-EVs from the mid-secretory phase had significantly increased expression of natural killer cell marker CD56 (P < 0.005), pan-leukocyte marker CD45 (P < 0.005), pan-T-cell marker CD3 (P < 0.005), and coagulation-related protein CD142 (P < 0.005) compared to those from the proliferative phase, whereas markers associated with endometrial epithelial cells (CD29, CD133, and CD326) did not significantly change across the menstrual cycle. Transcriptomic analysis highlighted differential expression of histone and metallothionein genes that correlated between paired UF-EVs and endometrial tissues in each tested menstrual cycle phase. Principal component analysis of miRNomes of paired UF-EVs and endometrial tissue samples

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.