Reviews of physiology, biochemistry and pharmacologyUndurti N Das
AA is known to play a significant role in male fertility. AA metabolites, prostaglandins (PGs), were first discovered in the seminal fluid. It was assumed at the time of its discovery that PGs were formed by the prostate and hence were named as prostaglandins. PGs are crucial for sperm function. Lower PGE2 in the semen was found in those who are infertile. NSAIDs (nonsteroidal anti-inflammatory drugs such as ibuprofen) are known to affect male fertility, sperm function, and semen parameters. These results suggest that potential use of AA and PGE2 to enhance male fertility needs to be studied.
Reproduction, fertility, and developmentNeslihan Hekim, Sezgin Gunes, Ramazan Asci
CONTEXT: The epigenetic factors underlying varicocele and idiopathic infertility are still poorly understood, despite established pathophysiological mechanisms. AIMS: This study assessed sperm miR-574 expression in infertile males with or without varicocele and fertile controls, evaluating its relationship with semen parameters and chromatin condensation. METHODS: Thirty-eight participants were included, comprising idiopathic infertile men (n = 14), varicocele patients (n = 9), and fertile controls (n = 15). Aniline blue staining evaluated chromatin condensation; quantitative RT-PCR determined miR-574 expression. In silico analysis predicted target genes. RESULTS: Idiopathic infertile men exhibited significantly lower expression of sperm miR-574, indicated by significantly higher ΔCq levels, than fertile controls (P = 0.031). The idiopathic group also showed a significantly higher ratio of aniline blue-positive, histone-rich spermatozoa than the controls (P = 0.002). Across the entire study cohort, a significant negative correlation was established between miR-574 ΔCq levels and the proportion of spermatozoa with normal morphology (ρ = -0.465, P = 0.022). In silico analysis predicted that miR-574 targets key genes involved in chromatin regulation (H1FNT, CHD7), mitochondrial function (MRPS23, MARC2), and spermatogenesis (DAZL, SOHLH2). CONCLUSIONS: These findings suggest a potential biological association where miR-574 downregulation may be a feature of idiopathic male infertility, potentially influencing gene networks involved in sperm formation and nuclear organization. Its precise regulatory mechanisms in male infertility subgroups warrant further large-scale validation. IMPLICATIONS: Sperm miR-574 targets critical spermatogenesis and mitochondrial genes, representing a potential epigenetic factor involved in germ cell differentiation. Although its direct utility as a diagnostic biomarker requires further validation, it provides a valuable conceptual framework for understanding the molecular complexity of idiopathic male factor infertility.
FASEB journal : official publication of the Federation of American Societies for Experimental BiologyHuihui Wang, Chaoying Wang, Shuaishuai Guo, Guang Yang, Junnan Fang, Jingyi Hu, Ran Jiang, Jun Zhai, Haixia Jin, Wenyan Song, Senlin Shi, Xianju Huang, Lin Qi,…
Obesity triggers ovarian dysfunction and female infertility accompanied by granulosa cell damage. Ferroptosis, iron-dependent lipid peroxidation-mediated cell death, participates in multiple reproductive diseases, yet the molecular cascade linking metabolic obesity to granulosa ferroptosis remains undefined. Using high-fat diet obese mice, primary human granulosa cells from obese infertile patients, and KGN cell lines, we identified the nuclear receptor NR4A1 as a key mediator of obesity-induced ferroptosis downstream of PI3K/AKT signaling. Elevated NR4A1 was associated with upregulated ACSL4 and suppressed GPX4, accompanied by iron overload, lipid peroxidation, and mitochondrial collapse, impairing folliculogenesis and oocyte quality. Metformin reduced NR4A1 activation in association with PI3K/AKT signaling modulation, thereby attenuating ferroptotic injury and contributing to the restoration of ovarian function. In vivo NR4A1 agonist administration attenuated the protective effects of metformin, while ovarian-specific NR4A1 knockdown alleviated HFD-triggered ovarian ferroptosis. Single-cell RNA-seq further suggested that metformin remodels oocyte redox and folliculogenic transcriptional networks. These findings support a role for the PI3K/AKT-NR4A1 signaling pathway in driving ferroptosis during obesity-related ovarian dysfunction and suggest a potential anti-ferroptotic mechanism of metformin in this context.
Embryo implantation is a critical and complex process that requires coordination between the embryo and the receptive endometrium for its success. However, a multitude of factors have the potential to contribute to implantation failure. Among these factors, bacterial infections in the uterine environment are of particular concern and are increasingly being considered as a contributing factor to implantation failure. The presence of pathogenic bacteria has been demonstrated to stimulate inflammatory responses, alter the endometrial microbiome, interfere with critical signaling pathways, and finally change the uterus microenvironments that are required for implantation. We aimed to review bacterial infection as an important potential etiology of chronic endometritis pathophysiology and its correlation with implantation failure.
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical geneticsYingwen Liu, Lulu Yan, Haibo Li, Changshui Chen, Yongjun Wang
OBJECTIVE: To explore the clinical phenotype and genetic etiology of a male with Multiple morphological abnormalities of sperm flagella (MMAF) combined with sperm head abnormalities due to compound heterozygous variants of DNAH1 gene, with an aim to provide guidance for assisted reproductive technology in his family. METHODS: A man with MMAF combined with sperm head abnormalities who visited Women and Children's Hospital of Ningbo University in October 2024 was selected as study subject. Clinical data of the patient's family were retrospectively collected. Peripheral blood samples were collected from the patient and his spouse, and G-banding karyotyping and whole exome sequencing (WES) were carried out. Candidate variants were validated by Sanger sequencing. Conservation of the DNAH1 protein was queried on the UCSC website. The difference between wild type and variant DNAH1 proteins were analyzed using AlphaFold v3.0.1 and PyMOL v2.5.6. The pathogenicity of variant was rated based on the guidelines from American College of Medical Genetics and Genomics (ACMG). Previous literature was searched using keywords "DNAH1 gene" and "multiple morphological abnormalities of the sperm flagella" on CNKI, Wanfang Data Knowledge Service Platform, and PubMed database to identify cases of MMAF attributed to biallelic DNAH1 gene variants. The retrieval period was set from the establishment of the databases to December 31, 2025. The genotypes and clinical phenotypes of patients with biallelic DNAH1 mutations were analyzed. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2023-094). RESULTS: The 30-year-old patient and his 30-year-old wife had infertility for 2 years. Semen analysis revealed no motile sperm and a 99.0% abnormal morphology rate. Typical MMAF was observed with phase-contrast microscopy. Sperm morphology analysis revealed abnormalities of the head, neck, and tail with an approximate ratio of 9:5:1. The patient's karyotype was 46,XY, and his wife's karyotype was 45,X[4]/47,XXX[1]/46,XX[84]. WES and Sanger sequencing revealed that the patient harbored compound heterozygous variants of the DNAH1 gene, namely c.1435_1444+3del and c.12204_12206del (p.Asn4069del), but their origin remained unidentified. UCSC genome browser query results showed that the amino acid residue at position 4 069 of the DNAH1 protein is highly conserved across various species. Protein structure prediction reveals that, in the wild-type DNAH1 protein, the Asparagine at position 4 069 (Asn4069) can form hydrogen bonds with the Leucine on the main chain at position 4 086 (Leu4086) and the Serine on the side chain at position 4 087 (Ser4087). The c.12204_12206del variant, resulting in deletion of Asn4069, disrupts these hydrogen bonds and does not generate any compensatory interactions. Based on the ACMG guidelines, the c.1435_1444+3del variant was predicted to be likely pathogenic (PM2_Supporting+PVS1), and the c.12204_12206del(p.Asn4069del) variant was rated as likely pathogenic (PM2_Supporting+PM4+PM3+PP4). The couple had elected for in vitro fertilization using donor sperm. During this cycle, 12 oocytes were retrieved, 10 oocytes were successfully fertilized, 1 embryo and 6 blastocysts were obtained. Following the first transfer of a frozen-thawed blastocyst, implantation of an empty gestational sac occurred, which led to a miscarriage. After the second transfer of a high-quality blastocyst, the embryo split into twins following implantation, and the spouse had selected fetal reduction. The gestational age was 33+3 weeks on June 1, 2026. Literature review identified three studies reporting biallelic mutations of the DNAH1 gene in association with MMAF combined with sperm head abnormalities. Together with the patient from this study, a total of 20 patients were included in the analysis. The rate of sperm flagellar abnormalities in these patients was above 80.0%, while the rate of sperm head abnormalities has ranged from 12.0% to 100.0%. In four patients, the genetic basis was unknown. In the remaining 16 patients, 35 mutations were detected, with c.8626-1G>A being the most common (22.9%, 8/35). CONCLUSION: This patient showed MMAF with frequent sperm head defects. Compound heterozygous variants of the DNAH1 gene probably underlay these abnormalities, which in turn has led to his primary infertility. This study revealed the phenotypic variability of MMAF and broadened the mutational spectrum of the DNAH1 gene.
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical geneticsXiaobin Zhong, An Zhong, Yu Zhou, Shenghui Zhu, Zhiyou Guo, Zijian Peng, Qinyi Huang, Cui Wang, Lvyuan Fan, Shiqi Liu, Yongxia Wang, Jia Tang
OBJECTIVE: To explore the clinical and genotypic characteristics of a patient with Sertoli cell-only syndrome (SCOS) due to variants of MOV10L1 gene. METHODS: A 27-year-old patient with Non-obstructive azoospermia (NOA) underwent routine semen analysis. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E2), prolactin (PRL), and testosterone (T) were determined by chemiluminescence assays. Peripheral blood samples were collected for G-banded karyotyping analysis. Multiplex PCR fluorescence detection was used to screen for AZF gene microdeletions. Whole exome sequencing (WES) and Sanger sequencing were performed simultaneously. Testicular biopsy tissues were subjected to Hematoxylin-Eosin (HE) staining to assess seminiferous tubule cell composition, and MOV10L1 protein expression was detected by immunohistochemical staining. Bioinformatics tools were employed to predict the pathogenicity of variants and their impact on protein structure and function. This study was approved by the Medical Ethics Committee of the Guangdong Institute of Reproductive Sciences [Ethics No.: 2023(01)]. RESULTS: The patient's two semen analyses had failed to detect any sperm. Hormone tests indicated elevated FSH (22.32 mIU/mL) and PRL (397.6 mIU/mL), while T (3.68 nmol/L) and E2 (38.32 pmol/L) were reduced. Chromosomal karyotyping revealed 46,XY, and no AZF gene deletion was detected. WES and Sanger sequencing detected compound heterozygous variants of the MOV10L1 gene, including a c.345C>A (p.C115X) nonsense variant and a c.3323C>T (p.T1108I) missense variant, with the former being unreported previously. HE staining showed only Sertoli cells in the seminiferous tubules, confirming the diagnosis of SCOS. Immunohistochemical staining revealed absent MOV10L1 protein expression in the testicular tissue. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the c.345C>A (p.C115X) was classified as a pathogenic variant (PVS1+PM2_Supporting+PP4), while the c.3323C>T (p.T1108I) was deemed variant of uncertain significance (PM2_Supporting+PP3_Supporting+PP4). Bioinformatics analysis demonstrated that c.345C>A (p.C115X) may cause premature termination of protein translation, while c.3323C>T (p.T1108I) may disrupt the hydrophobicity of the RNA helicase domain, reducing the active pocket volume and decreasing its affinity for MILI protein. CONCLUSION: This study has diagnosed a case of SCOS due to compound heterozygous variants of the MOV10L1 gene, which also enriched its mutational spectrum.
Journal of psychosomatic obstetrics and gynaecologySwati Dhar, Vidyashree Ganesh Poojari, Prashanth Adiga, Anjali Mundkur, Akash Tomar, Pratap Kumar
OBJECTIVE: To explore how professional women undergoing assisted reproductive technology (ART) experience and manage conflicts between treatment demands and professional identity; and to identify ways healthcare professionals can support them. METHODS: Following COREQ guidelines, semi-structured, in-depth interviews were conducted with 18 professional women undergoing ART in a tertiary care hospital. Reflexive Thematic Analysis bolstered by interdisciplinary investigator triangulation (clinical and basic science) ensured thematic confirmability. RESULTS: Analysis revealed Gendered Occupational Asymmetry (female occupational burden regardless of clinical aetiology), the Insider Paradox (the role reversal for healthcare professionals) and the Workplace Panopticon (constant self-surveillance to preserve professional authority). Interestingly, work simultaneously often acted as a Sanctuary of Competence, providing psychological respite. Finally, narratives exposed an Existential Rumination (mourning past personal-professional decisions) and permanent temporal career stalling. These themes were further mapped onto a 'A Day in the Life' structural framework to illustrate compounding daily burdens. CONCLUSIONS: Current clinical lifestyle directives inadequately account for the rigid psycho-socioeconomic structures governing professional women. Based on identified themes, we propose targeted measures for healthcare professionals to deliver patient-centric care by integrating occupational awareness and identity-sensitive counselling into routine ART practice, thereby potentially reducing distress and improving treatment experience.
The Journal of international medical researchRongze Sun, Jian Liu, Xiaoyu Liu, Boning Liu, Xinyu Zhang, Enzhi Fan
ObjectiveTo examine the association between adherence to the Planetary Health Diet Index and self-reported infertility among U.S. women of reproductive age and, secondarily, to explore adiposity-related indirect associations involving the body mass index, waist-to-height ratio, weight-adjusted waist index, and body roundness index.MethodsThis cross-sectional study included 2256 women aged 18-44 years from the 2013-2018 National Health and Nutrition Examination Survey. Planetary Health Diet Index scores were derived from two 24-h dietary recalls, and infertility was identified based on self-reported Reproductive Health Questionnaire responses. Associations were estimated using multivariable logistic regression that incorporated survey weights, strata, and primary sampling units. Restricted cubic spline analyses were performed to assess functional form. Exploratory survey-replicate statistical decompositions were used to evaluate adiposity-related indirect probability contrasts.ResultsAmong the 2256 female study participants, 310 reported infertility. In the fully adjusted model, a 10-point higher Planetary Health Diet Index score was associated with an odds ratio of 0.895 for self-reported infertility (95% confidence interval, 0.768-1.043; p = 0.149). Compared with women in the lowest weighted Planetary Health Diet Index quartile, those in the highest quartile had lower odds of self-reported infertility (odds ratio, 0.536; 95% confidence interval, 0.309-0.931; p = 0.028). Restricted cubic spline analyses did not provide clear evidence of a nonlinear association. Exploratory statistical decompositions yielded negative indirect estimates through all four adiposity indices; however, every corresponding 95% confidence interval included the null.ConclusionsHigher Planetary Health Diet Index scores demonstrated an inverse association with self-reported infertility, with the clearest evidence observed for the highest-versus-lowest weighted quartile; however, the continuous association was imprecisely estimated, and no clear exposure-response pattern was identified. Adiposity-related indirect estimates were exploratory and imprecise. Given the cross-sectional design, causal and temporal interpretations cannot be derived. Prospective studies are needed to clarify the temporality and potential explanatory processes.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in CancerPaige W Lake, Yayi Zhao, Rossybelle P Amorrortu, Gwendolyn P Quinn, Dana E Rollison, Susan T Vadaparampil
PURPOSE: Adolescent and young adult (AYA) patients (18-39) with cancer experience psychosocial challenges upon being diagnosed with cancer. AYAs are also at risk of potential infertility due to certain cancer treatments. We examined factors associated with desire for future children among AYAs. Among those interested in having future children or were unsure if they wanted children, we examined factors associated with interest in fertility consultations. METHODS: Patients completed an electronic patient questionnaire (EPQ) which included items assessing physical/mental health, desire for future children, and interest in fertility consultations. Cancer registry data comprised cancer characteristics (e.g., cancer and treatment type). Multinomial regression analysis examined factors associated with desire for future children. Binary regression examined factors associated with interest in fertility consultations. RESULTS: AYAs (n = 4847) were majority female (62%) and on average, 32 years old. In multinomial analysis, females (vs. males) (OR [95% CI] = 0.56 [0.48-0.71]), older AYAs (OR [95% CI] = 0.81 [0.80-0.83]), and those with children (OR [95% CI] = 0.34 [0.26-0.45]) were less likely to report wanting future children. Among AYAs wanting children, older patients (OR [95% CI] = 1.04 [1.01-1.06]), females (OR [95% CI] = 1.39 [1.00-1.94]), breast cancer (OR [95% CI = 2.65 [1.38-5.10]) or lymphoma patients (OR [95% CI] = 1.99 [1.12-3.56]), and receiving hormone therapy (OR [95% CI] = 1.73 [1.06-2.81]) or transfusions (OR [95% CI] = 3.23 [0.86-12.21]) were more likely to desire consultations. CONCLUSIONS: There is a need to systematically address and offer fertility consultation for all AYA patients prior to treatment initiation. Sociodemographic, clinical, and psychosocial factors warrant additional study and future intervention development to ensure fertility needs are met.
PeerJJiguang Gao, Wenwen Hou, Heli Wang, Shuo Xu, Guoxian Chen
Psychological stress is a risk factor for male infertility, and adolescence is a critical period of vulnerability to stress. However, the effects of psychological stress on spermatogenesis in adolescent males remain unclear. To investigate this, we used a restraint stress model in adolescent Kunming mice, where animals were restrained for 2 and 4 h per day from postnatal day 28 to 56. Restraint stress resulted in a decreased sperm concentration and serum testosterone levels, together with increased sperm abnormalities, synaptonemal complex protein3 (SYCP3)-positive germ cells in the epididymis, and serum corticosterone levels in adult mice. Additionally, restraint stress altered seminiferous tubule histoarchitecture and the distribution of spermatogenic stages. Restraint-stressed mice exhibited increased proportions of zygotene- and pachytene-stage spermatocytes and a reduced proportion of diplotene-stage spermatocytes. Further analysis showed altered γH2AX and ataxia-telangiectasia and rad3-related (ATR) localization patterns together with increased frequencies of chromosomal synapsis abnormalities and abnormal chiasma formation, which were accompanied by increased spermatocyte apoptosis. The mRNA expression levels of key meiotic genes, including SPO11 initiator of meiotic double stranded breaks (SPO11), DNA meiotic recombinase 1 (DMC1), synaptonemal complex protein1 (SYCP1) and SYCP3, were reduced in stressed mice. In addition, restraint stress increased germ cell apoptosis and reduced litter size in adulthood. In conclusion, adolescent exposure to psychological stressors such as restraint stress is associated with impaired spermatogenesis and reduced reproductive capacity in adult male mice.
The journal of obstetrics and gynaecology researchSatomi K Doi, Aya Isumi, Mai Ohashi, Hiroyuki Fujiwara, Seung Chik Jwa
AIM: We examined the association between family support during fertility treatment and loneliness at the first clinical consultation. METHODS: Data from 204 women with infertility who first visited the Reproduction Center of a university hospital in Tochigi Prefecture between May 2024 and December 2025 and completed both a medical intake questionnaire and a web-based survey were analyzed. Family support from partners, own parents, and parents-in-law was assessed. Loneliness was measured using the three-item UCLA Loneliness Scale. Multivariable regression analyses were adjusted for sociodemographic, clinical, and psychosocial covariates, including adverse childhood experiences. RESULTS: Among participants, 30.9% and 46.6% had not disclosed infertility treatment to their own parents and parents-in-law, respectively. Lower perceived support from parents-in-law and nondisclosure to parents-in-law were significantly associated with greater loneliness, whereas support from partners and own parents was not. CONCLUSION: Disclosure to and support from parents-in-law may be particularly associated with lower level of loneliness at the initial consultation among women undergoing infertility treatment.
Reproduction & fertilityFlorence Abou, Netanel Waldenberg, Shany Kravat, Moran Gershoni, Sandra E Kleiman, Naama Steiner, Atef Zeadna, Guy Bar, Oshri Barel, Snir Dekalo, Ruti Parvari,…
ABSTRACT: Non-obstructive azoospermia (NOA) due to spermatogenic failure is one of the most challenging conditions for surgical sperm retrieval (SSR). Complete AZFa deletions on Yq11 typically lead to a uniform Sertoli-cell-only (SCO) phenotype, rendering testicular sperm extraction futile. Current EAA/EMQN guidelines rely on sequence-tagged site (STS)-based PCR to detect multi-kilobase AZFa deletions; however, by design, they do not capture intragenic loss-of-function (LoF) variants in key AZFa genes. Recent exome studies have identified DDX3Y as the critical spermatogenic factor within AZFa, showing that isolated DDX3Y LoF variants can reproduce the classical AZFa-like SCO phenotype despite an apparently normal AZFa STS profile. We present a case of a man with idiopathic NOA and an AZFa-like phenotype; elevated FSH, normal karyotype, negative standard AZFa/b/c STS testing, and microdissection testicular sperm extraction (micro-TESE) showed complete SCO syndrome with no sperm retrieved. Whole exome sequencing (WES) subsequently revealed a novel likely pathogenic LoF variant in DDX3Y in one of its coding exons, a defect not detectable by routine AZFa PCR. This case adds to the small number of published DDX3Y loss-of-function variants associated with NOA and SCO syndrome and illustrates an important diagnostic limitation of STS-based AZF testing. We suggest that DDX3Y should be considered in exome or targeted-panel interpretation for selected men with NOA and an AZFa-like presentation despite negative microdeletion testing. Prospective cohorts are required before routine testing algorithms, SSR contraindications, or cost-effectiveness conclusions can be established. Upon validation, such an approach would avoid unnecessary, low-yield SSR while enhancing prognostic counseling and resource utilization. LAY SUMMARY: Some men have no sperm in the semen because sperm production in the testis has failed. In selected patients, surgical sperm retrieval may be performed, in which small pieces of testicular tissue are examined to look for rare sperm that could be used for intracytoplasmic sperm injection, a form of IVF in which a single sperm is injected into an egg. Before surgery, men are usually tested for large missing regions on the Y chromosome, including the AZFa region. Complete AZFa deletions are associated with a very poor chance of finding sperm. In this case report, we describe a man with no sperm in the semen, negative standard AZF deletion testing, and no sperm found during microdissection testicular sperm extraction. Later exome sequencing identified a previously unreported stop-gain variant in DDX3Y, a gene located within AZFa and now considered to have moderate evidence for involvement in severe sperm production failure. Together with previously published cases, this finding illustrates a limitation of standard deletion testing: it cannot detect small gene-level variants. In carefully selected men with an AZFa-like clinical picture, DDX3Y sequence analysis may improve counseling and may help avoid low-yield surgery, but larger studies and economic evaluation are needed.
The journal of obstetrics and gynaecology researchTuangsit Wataganara, Eiko Yamamoto, Somsook Santibenchakul, Ninlapa Pruksanusak, Jitti Hanprasertpong, Suthee Panichkul, Supitchaya Surasereewong
AIM: Obstetricians and gynecologists (OBGYNs) are high-risk, surgically intensive, and emergency-driven specialists. Women are the majority of OBGYNs, but their representation in decision-making roles remains disproportionately low. This narrative review explores the empirical evidence and aims to narrow gender gaps among OBGYNs. METHODS: We included 154 publications from 2000 to 2025 on gender inequity, career progression, women physicians, OBGYNs, academic promotion, leadership, workforce, and regional variation from Asia, Europe, North America, Africa, South America, and the Caribbean. Eligible studies either (1) focused on OBGYNs or female surgeons, (2) reported gender disparities in academic, administrative, or service domains, or (3) provided regional data. Qualitative and quantitative studies, policy reports, and professional society publications were included. RESULTS: There were insufficient data from South America and the Caribbean. For the other regions, we identified cultures, societal norms, and the structures of health systems as contributors to gender barriers in OBGYNs. These barriers are not at the entry levels, but rather in career ascension. In high-income countries, implicit biases persist despite established work-life policies and legislative protections. In low and middle-income countries, disparities are shaped by sociocultural expectations, fewer institutional supports, and rigid hierarchical structures. Men also face distinct barriers, such as limited patient acceptance and unequal distribution of out-of-hours duties. CONCLUSIONS: There is an urgent need to acquire high-quality data on stereotypic biases, structural, and cultural barriers to gender inequities among OBGYNs. Without timely intervention, gender gaps within the OBGYN workforce will likely be widened over time.
International journal of gynecological cancer : official journal of the International Gynecological Cancer SocietyRadwa Hablase, Alexander Shushkevich, Ana Tatiana Palacios Torres, Anisa Mburu, Houssein El Hajj, Nicolò Bizzarri, Stamatios Petousis, Joanna Kacperczyk-Bartni…
OBJECTIVE: Gynecologic oncology surgery is delivered by clinicians with diverse specialty backgrounds and varied training pathways. The Q-GOAL (Quality in Gynecologic Oncology Advancement for Learning) study aimed to explore the heterogeneity of these training experiences, identify common training structures and surgical exposure profiles, evaluate self-reported surgical confidence, and compare these findings across income levels. METHODS: An open, cross-sectional, web-based survey was conducted between July and September 2025 using convenience and snowball sampling. The survey was distributed globally to trainees and consultants in obstetrics and gynecology, general surgery, gynecologic oncology, and surgical oncology. Descriptive statistics and exploratory unsupervised multi-variate analyses were performed. RESULTS: A total of 1,035 clinicians participated (92% completion rate), of whom 64% were from low- and middle-income countries. Most respondents had an obstetrics and gynecology background, with general surgeons contributing a greater proportion in low- and middle-income countries than in high-income countries (23% vs 5.5%). Training pathways included dedicated sub-specialty programs, rotation-based training, and a small proportion reporting no formal training. Rotation-based training was associated with a less structured training environment in the latent class analysis. Multiple correspondence analysis identified distinct low-, intermediate-, and high-volume training profiles. Increased surgical exposure was associated with higher self-reported confidence, and income status remained an independent predictor of surgical confidence. CONCLUSIONS: The study demonstrated the diversity of the workforce delivering gynecologic oncology surgery globally. These findings highlight the need for internationally harmonized training standards and a minimum level of surgical exposure, while recognizing the differences among health care systems worldwide.
Mymensingh medical journal : MMJH H Pervin, F Huq, K F Begum, F Noor, K Fatema, B Chakma, N Sultana
Polycystic ovary syndrome (PCOS) is a common endocrine disorder and a leading cause of infertility in reproductive-aged women. Emerging evidence suggests that vitamin D deficiency may exacerbate PCOS-related reproductive and metabolic disturbances. This study aimed to assess the prevalence of vitamin D deficiency among infertile women with PCOS and explore its association with subfertility. This cross-sectional study was conducted at the Department of Infertility, Bangladesh Medical University (BMU), from November 2019 to April 2025. Total 155 infertile women aged 18-40 years; diagnosed with PCOS using the revised Rotterdam criteria (2003) were enrolled. Participants with other known causes of infertility were excluded. Data on demographic variables, clinical features, hormonal profile, glucose metabolism and serum 25(OH) vitamin D levels collected and analyzed. The mean age of participants was 28.34±3.5 years, with a mean BMI of 23.46±3.2 kg/m². Primary subfertility was observed in 69.68% (n=108) of cases. Vitamin D deficiency (<20 ng/ml) was present in 47.10% (n=73) and 40.65% (n=63) had insufficient levels (20-29 ng/ml); only 12.26% (n=19) had sufficient vitamin D (>29 ng/ml). The mean HOMA-IR was 1.88, indicating prevalent insulin resistance. Most participants were normoglycemic with a mean HbA1c of 5.42%. A high prevalence of vitamin D deficiency and insufficiency observed among infertile women with PCOS, particularly among those with primary subfertility. Vitamin D status may represent a modifiable factor in the management of PCOS-related infertility.
The Australian & New Zealand journal of obstetrics & gynaecologyYael Yagur, Orla Donohoe, Sarah Choi, Jessica Robertson, Danny Chou, David Rosen
BACKGROUND: Robotic-assisted gynaecologic surgery has expanded globally, yet its adoption in Australasia remains variable. AIM: To evaluate the current attitudes, practice patterns, and perceived barriers surrounding robotic-assisted gynaecologic surgery among clinicians in Australia and New Zealand (Australasian). MATERIAL AND METHODS: A cross-sectional, anonymised electronic survey was distributed to all RANZCOG-certified obstetrician-gynaecologists practicing in Australasian. The survey assessed demographics, access to and use of robotic platforms, perceived advantages and limitations, and willingness to expand robotic practice. Associations between years of clinical experience and access, utilisation, and attitudes toward robotic surgery were analysed. RESULTS: A total of 276 clinicians responded. Most (62.2%) had more than 10 years of clinical experience. 37.5% reported access to robotic-assisted surgery, and among those, 34% currently performed robotic procedures mostly for < 25% of major operations. Willingness to expand usage remained low even if access improved (42.8%). Ergonomic benefit and surgeon longevity were the most cited advantages, while fewer than half believed robotics improved patient outcomes. Main barriers were high cost, longer operative time, limited evidence of benefit, and scarce training opportunities. Clinicians with ≤ 10 years of experience were more likely than senior colleagues to perceive advantages (68.3% vs. 38.8%) and to express willingness to adopt robotics if given access (56.9% vs. 33.7%). CONCLUSIONS: As of 2025, robotic surgery remains limited in Australasian gynaecology, with adoption shaped by practical concerns, limited evidence, cost, and access. Nevertheless, greater enthusiasm among early-career clinicians suggests future practice may evolve. Ongoing evaluation and evidence-based decision-making will be essential as the field advances.
International journal of gynecological cancer : official journal of the International Gynecological Cancer SocietyAudrey Tieko Tsunoda, Angelica Nogueira-Rodrigues, Glauco Baiocchi Neto, Bruno Roberto Braga Azevedo, Renato Moretti-Marques, Rosilene Jara Reis, Vanessa Alvar…
Access to gynecologic oncology care varies substantially across health care systems and is influenced by organizational, geographic, workforce, and referral network factors that extend beyond the availability of specialized services. Using Brazil as an illustrative case of a large middle-income country with a mixed public-private health system, we performed a narrative policy and health-systems analysis, integrating evidence from global cancer surgery, gynecologic oncology, health-system organization, and international models of cancer care delivery. The objective was to examine access to gynecologic oncology from a health-systems perspective and to develop a conceptual framework describing the organizational dimensions of access that may be applicable across diverse health care settings. The literature was examined to identify recurrent concepts related to the organization of gynecologic oncology care. These concepts were grouped into broader themes and progressively consolidated into the nine domains of the Brazilian-informed Gynecologic Oncology Access and Sustainability Framework: burden, geography, organization, workforce, quality, financing, education, digital integration, and sustainability. Building on the Global Cancer Surgery framework, we also propose an expanded model that considers safe, equitable, timely, and networked care as complementary dimensions of access. To support the interpretation of the proposed framework, we developed the Gynecologic Oncology Network Maturity Framework, a conceptual framework for network organizational development, together with a scalable four-tier model linking local services, regional cancer units, specialized referral hubs, and centers of excellence. The Brazilian-informed Gynecologic Oncology Access and Sustainability Framework is intended as a conceptual model to support the description, discussion, and planning of gynecologic oncology networks. The Gynecologic Oncology Network Maturity Framework is proposed as a conceptual framework for describing network organizational development and requires prospective validation before benchmarking applications. Together, these frameworks should be interpreted as a foundation for future empirical evaluation, refinement, and implementation across different health-system contexts.
International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and ObstetricsElizabeth Tunney, Daniel Kane, Mike Geary
The practice of obstetrics and gynecology (O&G) is frequently regarded as one of the most demanding medical specialties, with physicians being called to duty at any hour of the day or night, with acute patient demands requiring prompt management. Consequently, high levels of physician burnout and psychological distress have been reported among O&G healthcare professionals, with these challenges further compounded by the COVID-19 pandemic. Despite the prevalence of mental health difficulties, many healthcare professionals do not seek out professional intervention and support. Within O&G, trainees appear vulnerable, with studies reporting significant rates of stress, anxiety, depression, and burnout. These mental health challenges contribute to reduced job satisfaction, increased intentions to leave specialist training programs, and growing concerns regarding physician attrition and workforce retention. In this context, physician resilience (i.e., the ability to excel in the face of adversity) emerges as an area worthy of exploration. This narrative review explores the multifaceted emotional and practical elements of physician resilience and grit in contemporary obstetrics and gynecology practice. A comprehensive literature search was conducted using PubMed and the Royal College of Surgeons in Ireland library database, employing terms related to physician wellbeing, burnout and interventions specifically related to obstetrics and gynecology. Inclusion criteria were limited to full text, English-language articles published within the past 10 years to ensure relevance to contemporary practice. The review examines the interrelationship between physician burnout, mental health challenges among O&G trainees, and their impact on attrition rates. We aim to highlight the need for practical interventions at institutional levels with consideration of environmental/workplace factors, which might improve physician wellbeing and grit, strengthen workforce retention, and ultimately optimize patient care.
JMIR formative researchCüneyt Destan Cenger, Giray Kolcu, Mehmet Ali Malkoç, Birgül Tüzün, Meral Çevik Doğan, Tuğba Saraç Sivrikoz
BACKGROUND: Defensive medicine (DM) is particularly relevant in obstetrics and gynecology (OB/GYN), where physicians face substantial medicolegal risks and malpractice-related pressures. Defensive practices may involve cost-increasing diagnostic or therapeutic behaviors and avoidance of high-risk patients or procedures. Identifying factors independently associated with DM may help inform organizational and medicolegal interventions. OBJECTIVE: This study aimed to evaluate DM attitudes among physicians working in OB/GYN clinics in Istanbul, Türkiye, and to identify professional, organizational, and medicolegal factors independently associated with these attitudes. METHODS: A cross-sectional analytical study was conducted among resident physicians, specialists, and faculty members working in OB/GYN departments in Istanbul between June 2023 and February 2024. Participants were recruited using nonprobability convenience sampling through on-site visits and an online survey. DM attitudes were assessed using the 14-item Turkish Defensive Medical Practice Attitude Scale (TDMPAS). Multivariable linear regression models with heteroscedasticity-consistent HC3 SEs were used to identify factors independently associated with the total and subscale scores. Sensitivity analyses were used to assess the potential influence of the data collection modality. RESULTS: A total of 1069 physicians participated in the study. The mean total TDMPAS score was 48.12 (SD 10.59), with mean scores of 15.65 (SD 5.21) for cost-increasing behavior, 16.07 (SD 3.24) for defensive behavior, and 16.40 (SD 5.22) for avoidance behavior. Internal consistency was good for the total TDMPAS (Cronbach α=0.880), cost-increasing behavior (α=0.879), and avoidance behavior (α=0.879) and acceptable for defensive behavior (α=0.780). In the multivariable model, dissatisfaction with working conditions (B=6.62, 95% CI 4.19 to 9.05; P<.001), partial satisfaction (B=3.90, 95% CI 1.60 to 6.20; P<.001), and a history of administrative investigation (B=3.44, 95% CI 1.37 to 5.50; P=.001) were independently associated with higher total DM scores. Malpractice training (B=-2.18, 95% CI -3.54 to -0.82; P=.002), professor status compared with resident physician status (B=-7.53, 95% CI -12.22 to -2.83; P=.002), and longer experience in OB/GYN (B=-0.15 per y, 95% CI -0.29 to -0.01; P=.03) were associated with lower mean scores. The total-score model explained 17.6% of the variance (R²=0.176; adjusted R²=0.154). The data collection modality was not independently associated with the total TDMPAS score or any subscale score and did not materially alter the primary findings. CONCLUSIONS: DM attitudes were prominent among physicians working in OB/GYN and were independently associated with professional and organizational factors. Dissatisfaction with working conditions and previous administrative investigations were associated with stronger DM attitudes, whereas malpractice training and greater professional seniority showed inverse associations with these attitudes. These findings suggest that interventions addressing working conditions, medicolegal education, and institutional support for physicians may complement financial liability protection strategies. Prospective multicenter studies are required to clarify the causal relationships and evaluate the effectiveness of such interventions.
Reproduction, fertility, and developmentNatalie A Trigg, Nicole O McPherson, Lucy A Bartho
Male fertility is primarily assessed using descriptive semen parameters, such as sperm concentration, motility and morphology. These conventional parameters provide an initial assessment of male reproductive health and may explain why a couple is struggling to conceive; however, they are not a direct measure of fertility potential. Growing evidence suggests that spermatozoa transmit far more than paternal DNA. Alongside the genome, spermatozoa deliver proteins, RNA and epigenetic information that are responsive to environmental and lifestyle exposures, and can influence embryo development, pregnancy outcomes and offspring health. This emerging concept challenges the view that male fertility is defined solely by successful conception. Here, we discuss evidence that spermatozoa act as carriers of environmental and lifestyle 'memories', transmitting molecular information shaped by paternal health to the next generation. We further consider the implications for assisted reproductive technologies, which select spermatozoa largely on their capacity to move while overlooking the molecular cargo they transmit. Recognising spermatozoa as vectors of environmental information reframes male fertility and highlights the need for biomarkers that assess molecular integrity alongside conventional clinical parameters.
Reproduction, fertility, and developmentLuchen Xu, Wei Ma, Chunyan Liu, Qinglian He, Zaoya Zhao, Xiaoli Qu, Qianxing Zou
CONTEXT: Inhibiting phosphodiesterase (PDE) activity to increase cyclic adenosine monophosphate (cAMP) concentrations is a core strategy in artificial sperm activation. PDE3, a key member of the PDE family, comprises two subtypes, PDE3A and PDE3B. However, their specific expression patterns and functions in human sperm remain incompletely understood. AIMS: To analyze the expression characteristics of PDE3A and PDE3B in human sperm and investigate the regulatory effects of PDE3 inhibitor milrinone on asthenozoospermic sperm function and the related mechanisms. METHODS: The expression of PDE3A and PDE3B was detected using reverse transcription polymerase chain reaction (RT-PCR), western blot and immunofluorescence. Changes in asthenozoospermic sperm functions after milrinone treatment were detected using computer-assisted sperm analysis (CASA), methylcellulose viscous penetration assay, and fluorescein isothiocyanate-conjugated peanut agglutinin (FITC-PNA) staining. Moreover, intracellular factors closely correlated with sperm function regulation were measured using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and metabolome analysis. KEY RESULTS: PDE3B expression level was greater than was the expression level of PDE3A in human sperm. Sperm function analysis showed that milrinone significantly enhanced asthenozoospermic sperm motility, mucus penetration ability, and the acrosome reaction. With respect to intracellular signals, milrinone activated the cAMP‒protein kinase A (PKA) signaling pathway, and metabolomic analysis showed that milrinone-induced differentially abundant metabolites (DAMs) were associated with the citrate cycle and fatty acid degradation pathways, suggesting that it regulates energy metabolism. CONCLUSIONS: These results demonstrated that milrinone primarily targets PDE3B to improve asthenozoospermic sperm function by regulating cAMP‒PKA signaling pathway and energy metabolism. IMPLICATIONS: The present study has gained new insight into the molecular basis of cAMP signaling regulation in human sperm and provides theoretical and experimental support for the potential application of milrinone for asthenozoospermic sperm activation.
Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologicaAndrea Fabiani, Pasquale Scarano, Alessandra Filosa
OBJECTIVES: To evaluate the efficacy of a specific synbiotic formulation in improving genital environment, sperm quality, and reproductive outcomes in infertile couples with a history of persistent post-antibiotic dysbiosis. METHODS: This prospective, single-arm pilot study enrolled 33 infertile couples who had completed antibiotic therapy at least three months prior without success in conceiving. Couples received the synbiotic treatment for 90 days. A strategic sexual behavior protocol (barrier contraception for the first 45 days) was adopted. Primary endpoints were changes in Sperm DNA Fragmentation (DFI via Sperm Chromatin Dispersion - SCD test), vaginal pH, and spontaneous pregnancy rates. RESULTS: At T1 (90 days), a significant reduction in mean Sperm DFI was observed (from 32.4% +/- 6.1% to 16.8% +/- 4.2%, p < 0.001). Female partners showed a significant decrease in vaginal pH (from 5.2 +/- 0.4 to 4.1 +/- 0.2, p < 0.001) and restoration of vaginal Lactobacillus dominance. The cumulative spontaneous pregnancy rate was 33.3% (11/33), with 10 pregnancies reaching full term and 1 early miscarriage. CONCLUSIONS: Modulation of the Gut-Gonad Axis via synbiotics represents a promising restorative strategy, overcoming the "biological stasis" often observed after antimicrobial treatments.
BACKGROUND: Oligoasthenozoospermia (OAS) is a major cause of male infertility. 2,8-Dihydroxyquinoline (2,8-DHQ), an endogenous antioxidant metabolite, remains unexplored in OAS. This study identified 2,8-DHQ as a bioactive XHBG metabolite and elucidated its mechanisms in improving OAS. METHODS AND RESULTS: Male BALB/c mice received glycosides of Tripterygium wilfordii (GTW) (140 mg/kg/day, oral gavage) for 4 weeks to induce OAS, confirmed by marked reductions in testicular/epididymal weights, sperm concentration, serum testosterone, and severe seminiferous tubule disruption. Then, mice were treated with XHBG (10.4, 20.8, 41.6 g/kg/day) or 2,8-DHQ (50 mg/kg/day) for another 4 weeks. Integrative network pharmacology and serum metabolomics identified 2,8-DHQ as a key bioactive metabolite of XHBG, with 137 overlapping targets with OAS. In H2O2-challenged GC-1 spermatogonia, the DARTS assay confirmed direct binding of 2,8-DHQ to Mitogen-Activated Protein Kinase 14 (MAPK14), and Western blot revealed its downregulation. 2,8-DHQ enhanced GC-1 cell viability and, in OAS mice, restored testicular weight, sperm count, testosterone, and histological architecture. Mechanistically, 2,8-DHQ lowered ROS and MDA, elevated GSH/GSSG ratio, reduced Fe2+ levels, and upregulated SLC7A11 and GPX4, indicating suppression of oxidative stress and ferroptosis. Importantly, MAPK14 overexpression abolished these protective effects both in vitro and in vivo, confirming that 2,8-DHQ acts via targeting MAPK14 to inhibit ferroptosis. CONCLUSION: 2,8-DHQ, an active metabolite of XHBG, ameliorates OAS by targeting MAPK14 to inhibit spermatogonial ferroptosis. These findings provide a scientific basis for the clinical use of XHBG and highlight 2,8-DHQ as a potential lead compound for male infertility.
MedicineQigui Chen, Lizhi Lu, Wenwen Zhou, Jiyu Meng, Chao Xiao, Gang Liu
This study explores the global burden of female infertility across 204 countries and 21 regions from 1990 to 2021. The population-based study analyzed was conducted using data from the Global Burden of Disease 2021. We assessed age-standardized prevalence rate (ASPR), age-standardized incidence rate, disability-adjusted life years rate, and trends via average annual percent change, with projections to 2035 using the Bayesian age-period-cohort model. The outcomes revealed that female infertility sustained a global rise in ASPR (0.66% annually) and disability-adjusted life years (0.68% annually), driven by population growth and aging. Notably, while the 35 to 39 age group exhibited the highest prevalence, the 20 to 29 age group showed the fastest growth rate (average annual percent change = 1.04%), signaling a younger-onset trend. Socioeconomic disparities were prominent: low-middle sociodemographic index regions experienced the steepest ASPR increases (1.23% annually), contrasting with high sociodemographic index areas. During 2019 to 2021, ASPR stabilized, potentially linked to COVID-19-related population shifts rather than direct biological effects. Projections indicate a persistent burden, with ASPR reaching 6458.26/100,000 by 2035. These findings underscore the urgent need for targeted interventions addressing socioeconomic inequities, younger demographic risks, and sustainable reproductive health policies to mitigate the escalating global challenge of female infertility.
Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologicaAhmed M Hjazi
BACKGROUND: Male reproductive dysfunction reflects the interaction of endocrine, metabolic, genetic, environmental, oxidative, and immune-related factors. Although semen analysis remains the principal laboratory assessment, it is largely descriptive and provides limited insight into the systemic biological context in which semen abnormalities arise. Complete blood count (CBC)-derived inflammatory indices may offer a practical, low-cost approach to characterizing this context, but their relationship with semen-analysis phenotypes remains unclear. OBJECTIVE: To examine whether conventional haematological variables and leukocyte-derived immune-inflammatory indices differ across semen-analysis phenotypes and whether these markers are related to individual semen parameters. METHODS: This retrospective cross-sectional study analysed anonymised semen-analysis and complete blood count data from Royal Diagnostics Medical Laboratory, Riyadh, Saudi Arabia, collected between February and May 2025. The final analytical cohort comprised 245 matched records. Conventional haematological parameters, leukocyte percentages, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) were compared across the principal semen phenotypes. Correlation analyses and exploratory logistic regression models were used to assess parameter-level associations and predictive performance. RESULTS: Normozoospermia was the most common phenotype (49.8%), followed by asthenozoospermia (31.4%). Conventional haematological parameters were broadly comparable across phenotype groups. In contrast, neutrophil percentage (p = 0.013), lymphocyte percentage (p = 0.007), and NLR (p = 0.008) differed significantly across the principal semen phenotypes. The pattern of variation was heterogeneous rather than progressively graded across groups. PLR and SII did not differ significantly. Immune-inflammatory markers showed no meaningful correlations with sperm concentration, progressive motility, or morphology, and exploratory regression models found no independent predictive effects. Conclusions: Leukocyte-derived inflammatory markers varied across semen-analysis phenotypes, whereas conventional haematological parameters remained broadly comparable. However, these markers showed no meaningful correlations with individual semen parameters and no independent predictive value in exploratory models. They should therefore be interpreted as descriptive indicators of immune-haematological context rather than diagnostic biomarkers of semen quality or male infertility.
Journal of molecular medicine (Berlin, Germany)Rafael Santos, Beatriz Marinheiro, Margarida Ramos, Pedro F Oliveira, Pedro O Corda, Margarida Fardilha, Joana Santiago
Male infertility is a multifactorial condition accounting for 50% of infertility cases. Although conventional semen analysis remains the standard method for male infertility diagnosis, it fails to explain 30% of the cases and their underlying molecular causes. Metabolomics offers valuable insights into sperm metabolic dysfunction, enabling the identification of deregulated pathways involved in male infertility. Here, a systematic review including metabolomic studies that compare the seminal plasma metabolome of healthy and infertile men was conducted. A literature search was conducted in PubMed, Scopus, and Web of Science databases following PRISMA guidelines. Twenty metabolomic studies published until December 2025 were included and categorized into four groups: asthenozoospermia, oligozoospermia, obesity, and overall male infertility. A total of 284 metabolites were retrieved, of which eleven (down: L-tyrosine, D-fructose, L-valine, phenylalanine, proline, D-glucose, L-alanine, leucine, sorbitol, L-aspartic acid; up: uridine), six (down: D-fructose, glycine, maleic acid, L-valine, proline, and lysine), and ten (down: L-carnitine, L-tyrosine, L-valine, L-alanine, phenylalanine, proline, D-glucose, leucine, malic acid, and citraconic acid) were altered in asthenozoospermia, obesity, and overall infertility groups, respectively. These metabolites were associated with phenylalanine/tyrosine metabolism, fructose and mannose degradation, and β-oxidation of long-chain fatty acids. A bioinformatic analysis of the enzymes possibly involved in these pathways revealed associations with male infertility phenotypes and key sperm functions, including motility, vitality, and energy metabolism. This study provides a list of metabolites altered in the seminal fluid of infertile men, highlighting their potential as biomarkers of male infertility, and gives insights into the metabolic pathways affected in these conditions.
Reproductive biology and endocrinology : RB&ERaoul Orvieto
This report explores the case of a young, normal-responder nulligravida with peritoneal endometriosis and recurrent implantation failure, with poor embryo quality during multiple failed attempts at IVF treatment. The patient underwent Dienogest (Visabelle®) pretreatment followed by a combination protocol of Stop GnRH-agonist/GnRH-antagonist for controlled ovarian stimulation, culminating in a natural cycle frozen-thawed embryo transfer with modified luteal phase support. This combined approach produced several high-quality embryos leading to a successful singleton pregnancy. These findings provide new insights into addressing endometriosis-associated infertility and repeated IVF failure.
OBJECTIVE: To identify disproportionality signals linking androgenetic alopecia (AGA) drugs (finasteride, dutasteride, and minoxidil) with male infertility-related adverse events and to explore infertility-related biological features using testicular transcriptomic datasets. METHODS: A dual-database replication design was employed using FAERS (2004-2025) and EudraVigilance (2002-2025). Disproportionality analysis with multiple signal detection metrics assessed drug-infertility associations. Multi-level bioinformatic analyses-including toxicity prediction, drug-associated target screening, testicular transcriptomic analysis, single-cell RNA sequencing, intercellular communication analysis, gene set enrichment analysis (GSEA), and immune infiltration analysis-were integrated to explore biological features potentially relevant to male infertility. RESULTS: Disproportionality analyses detected signals for all three drugs, with finasteride demonstrating the most prominent reporting signal, followed by dutasteride and minoxidil. Multi-level bioinformatic analysis identified HIF1A as an overlap-derived candidate under the specified datasets and screening criteria, and HIF1A expression was higher in testicular tissue from patients with male infertility. Single-cell analysis showed higher HIF1A expression in late spermatocytes, Leydig cells, and myoid cells from infertility samples, together with group-dependent inferred communication patterns for selected VEGF-, PDGF-, IGF-, and FGF-related signaling axes. GSEA associated higher HIF1A expression with immune-response-, wound-healing-, and cell-adhesion-related processes, whereas lower HIF1A expression was associated with spermatid-development- and cilium/flagellum-dependent motility-related processes. ssGSEA-based analysis showed positive correlations between HIF1A expression and several immune-cell signature scores. CONCLUSION: This study systematically evaluated associations between AGA drugs and male infertility using real-world pharmacovigilance data and integrated bioinformatic analyses. The HIF1A-related transcriptomic findings provide a hypothesis-generating biological context for male infertility but do not establish a shared or drug-specific mechanism linking the three medications to infertility. The pharmacovigilance findings indicate reporting signals rather than incidence or causality.
Besides providing nutrients, Sertoli cells support spermatogenic cells development by maintaining seminiferous epithelial polarity, forming the blood-testis barrier (BTB), and phagocytosing residual bodies. Beclin1, a core component of the autophagy initiation complex, is critical for autophagic flux in many cell types. However, its role in Sertoli cells remains unclear. Here, we generated a Sertoli cell-specific Becn1 knockout (cKO) mouse model and found that 9-week-old male cKO mice exhibited reduced fertility with decreased sperm quality and vacuolated seminiferous tubules, and became completely infertile by 12 weeks of age. These defects were associated with disrupted BTB integrity and reduced expression of Claudin-11 in the testes. Further analysis revealed that loss of Beclin1led to impaired autophagosome formation, evidenced by reduced LC3-II/LC3-I ratio. In summary, these findings demonstrate that Beclin1 in Sertoli cells is vital for spermatogenesis and male fertility.
International medical case reports journalMohammad Fahim Sarwary, Mahbobullah Sediqi, Mohammad Hussain Modabber, Mohammad Ibrahim Kamal, Amjadzia Bawarzai, Maiwand Marofi, Abdul Ghaffar Mukhlis, Latifa…
BACKGROUND: Tuberculosis (TB) is an infectious disease that most commonly affects the lungs and remains among the top 10 causes of death worldwide. Isolated ovarian tuberculosis is a rare form of extrapulmonary TB that usually presents with atypical symptoms and infertility. It brings significant diagnostic challenges and may mimic ovarian malignancy. CASE PRESENTATION: A 23-year-old nulliparous Afghan woman underwent laparotomy for suspected ovarian adnexal masses/ovarian tumor after presenting with pelvic pain, prolonged low-grade fever, and infertility for five years following marriage. Intraoperatively, bilateral ovarian cysts were noted; subsequently, bilateral cystectomies were done. Postoperative Histopathology of surgical specimens confirmed the diagnosis of tuberculosis lesions, and the patient was referred for anti-tuberculous therapy. CONCLUSION: Isolated ovarian tuberculosis can present as adnexal masses with elevated CA-125 and could closely mimic ovarian malignancy. This case highlights the need to consider ovarian tuberculosis in the differential diagnosis, particularly in endemic regions. It emphasizes the value of histopathological confirmation to prevent misdiagnosis and to recommend early initiation of antitubercular therapy for favorable clinical outcomes.
British journal of hospital medicine (London, England : 2005)Zao Cen, Jie Cai, Yi Zheng
AIMS/BACKGROUND: Male infertility accounts for 30%-50% of infertility cases. Sperm mitochondrial membrane potential (MMP) and seminal plasma zinc are crucial for sperm motility and function, while seminal elastase reflects infection and inflammation of the reproductive system. This study aimed to explore the roles of sperm MMP, seminal plasma elastase, and seminal plasma zinc in the outcomes of in vitro fertilization-embryo transfer (IVF-ET) among male infertility patients. METHODS: Clinical data from 179 male infertility patients who visited the hospital between November 2022 and July 2023 were retrospectively analysed. Of these, 85 cases underwent fresh embryo transfer (ET) after in vitro fertilization (IVF). According to the pregnancy outcomes, the 85 ET cycles were divided into a pregnancy group (n = 42) and a non-pregnancy group (n = 43). Sperm MMP, seminal plasma elastase, and seminal plasma zinc levels were measured. Spearman correlation analysis was used to assess the correlation between fertilization rate and sperm MMP, seminal plasma elastase, and seminal plasma zinc. Binary logistic regression was performed to identify independent factors influencing pregnancy outcomes. Receiver operating characteristic (ROC) curves were constructed to predict diagnostic values of these factors for pregnancy outcomes. RESULTS: The fertilization rate of IVF was positively correlated with sperm MMP (r = 0.362) and seminal plasma zinc (r = 0.415), and negatively correlated with seminal plasma elastase (r = -0.379) (all p < 0.001). Among the 85 ET cycles, the clinical pregnancy rate and live birth rate were 49.41% (42/85) and 41.18% (35/85), respectively. Compared to the non-pregnancy group, the pregnancy group had significantly higher sperm MMP and seminal plasma zinc levels (p < 0.001 and p = 0.009, respectively), and lower seminal plasma elastase levels (p = 0.002). Multivariate analysis identified sperm non-progressive motility (p = 0.013, odds ratio [OR] = 0.478, 95% confidence interval [CI] = 0.267-0.856), sperm MMP (p < 0.001, OR = 1.114, 95% CI = 1.047-1.184), seminal plasma elastase (p = 0.006, OR = 0.996, 95% CI = 0.993-0.999), and seminal plasma zinc (p = 0.024, OR = 1.188, 95% CI = 1.023-1.381) as independent factors affecting pregnancy outcome. ROC analysis showed that sperm MMP (area under the curve [AUC] = 0.748, 95% CI = 0.644-0.851, p < 0.001), seminal plasma elastase (AUC = 0.698, 95% CI = 0.587-0.809, p < 0.001), seminal plasma zinc (AUC = 0.664, 95% CI = 0.549-0.779, p = 0.005), and the combined indicators (AUC = 0.832, 95% CI = 0.747-0.916, p < 0.001) had good predictive values for pregnancy outcomes. CONCLUSION: Sperm MMP, seminal plasma elastase, and seminal plasma zinc are significantly correlated with fertilization rates in IVF. Combined detection of these three indicators provides strong predictive value for pregnancy outcomes in IVF-ET among male infertility patients.
BACKGROUND: Infertility is not only a medical condition but also a reproductive health issue with significant psychological, social, and cultural consequences for women. Gender perception may influence women's attitudes toward infertility; however, evidence regarding this relationship remains limited. This study aimed to examine the relationship between gender perception and attitudes toward infertility among women and to determine whether gender perception predicts attitudes toward infertility. METHODS: This cross-sectional study included 346 women aged 18-60 years who were registered at the Çerkeş Family Health Center. Data were collected using the Introductory Information Form, the Infertility Attitude Scale, and the Gender Perception Scale. Descriptive statistics, independent samples t-test, one-way analysis of variance, Pearson correlation analysis, and multiple linear regression analysis were used to examine the association between gender perception and attitudes toward infertility while accounting for relevant sociodemographic and pregnancy-related characteristics. RESULTS: The mean Infertility Attitude Scale score was 48.23 ± 7.55, and the mean Gender Perception Scale score was 97.45 ± 18.22. A moderate positive correlation was found between attitudes toward infertility and gender perception (r = 0.634, p < 0.001). Multiple linear regression showed that gender perception was positively associated with attitudes toward infertility (B = 0.262, β = 0.621, 95% CI: 0.218-0.306, p < 0.001), with the model explaining 46.8% of the variance (R² = 0.468; adjusted R² = 0.440). Employment status, marital status, and pregnancy history were also significantly associated with infertility attitudes (p < 0.05). CONCLUSIONS: Gender perception was positively associated with women's attitudes toward infertility. These findings highlight the potential value of gender-sensitive approaches in reproductive health education and counselling.
Women's health (London, England)Patricia L Jackson, Peter Saunders, Simone Mizzi, Karen Tracey Hallam
BackgroundInfertility-related distress is associated with elevated rates of anxiety, depression, grief, and identity disruption. While existing frameworks often conceptualise infertility distress through stress and coping paradigms, these approaches may not fully explain the cumulative and reactivating experience of infertility distress. Trauma-informed perspectives, including the Adaptive Information Processing (AIP) model, may offer an alternative framework for understanding infertility-related distress.ObjectivesTo explore how women experiencing infertility describe and make meaning of their experiences, and whether their narratives reflect processes consistent with trauma-informed and AIP frameworks.DesignQualitative study embedded within a randomised controlled trial of Eye Movement Desensitisation and Reprocessing (EMDR) therapy for infertility-related distress, using baseline pre-intervention session transcripts.MethodsEighteen women experiencing infertility-related distress participated in an initial EMDR assessment and case conceptualisation session. Sessions were audio-recorded, transcribed verbatim, and analysed using Reflexive Thematic Analysis within an experiential and contextualist framework informed by trauma-informed perspectives and the AIP model.ResultsFive interconnected themes were identified: (1) The Burden of Responsibility, (2) Defectiveness and Diminished Worth, (3) Loss of Autonomy and Suspended Futures, (4) Threat, Vulnerability and Mistrust, and (5) Isolation and Disconnection. Participants described infertility as a cumulative, unresolved experience, often characterised by shame, self-blame, uncertainty, diminished agency, loss of trust, and relational disconnection. Infertility generated distress and reactivated broader beliefs about responsibility, worth, safety, control, and belonging. Interpreted through the AIP model, these findings suggest distress may be maintained by the repeated activation of inadequately processed experiences organised around of shame, helplessness, threat, and loss.ConclusionFindings suggest that infertility may be experienced as both a traumatising and a re-traumatising process that disrupts identity, agency, safety, and belonging. A trauma-informed framework informed by the AIP model may provide a useful lens for understanding the enduring psychological impact of infertility and informing interventions that address unresolved experiences underlying infertility-related distress.
Journal of medical Internet researchDou Liu, Ying Long, Sophia Zuoqiu, Di Liu, Kang Li, Kaipeng Xie, Runze Yang, Yiting Lin, Hanyi Liu, Rong Yin, Tian Tang
BACKGROUND: Large language models (LLMs) have been proposed as decision-support tools in assisted reproductive technology (ART), but it remains unclear whether posttraining alignment strategies translate into clinically acceptable decision support. Outcome-based benchmarks may reward token-level correctness while overlooking the reasoning quality that clinicians rely on. OBJECTIVE: This study aimed to evaluate whether 4 mainstream alignment paradigms for medical LLMs (supervised fine-tuning [SFT], direct preference optimization [DPO], group relative policy optimization [GRPO], and in-context learning [ICL]) produce comparable algorithmic and clinical alignment (SFT vs GRPO) when used for infertility diagnosis and treatment planning. METHODS: This retrospective single-center study used 8201 deidentified electronic health records from West China Second University Hospital, collected between January 2020 and December 2022 (mean age 31.79, SD 4.63 y). All 4 strategies were built on a shared open-source biomedical backbone. Evaluation comprised the following 2 tiers: (1) automatic field-level metrics (accuracy, macro-F1, and mean absolute error [MAE]) on 5 structured decision fields (infertility type, initial diagnosis, ART strategy, controlled ovarian stimulation [COS] regimen, and gonadotropin starting dose); and (2) blinded independent expert review by 2 reproductive medicine specialists on 100 paired cases across 4 clinical dimensions (reasoning capability, diagnostic accuracy, treatment feasibility, and hallucination). Automatic field-level evaluation included all 4 strategies, whereas blinded expert review was restricted to the SFT versus GRPO contrast. RESULTS: GRPO achieved the highest average automatic performance (eg, infertility type accuracy=92.57%, COS regimen accuracy=62.36%, ART strategy accuracy=76.49%, and gonadotropin dose MAE=44.94). However, in blinded expert review, the conservative SFT baseline showed directionally higher expert ratings than GRPO on reasoning capability and treatment feasibility; diagnostic-accuracy differences were not significant. In the 3-way best-response comparison including the original physician-charted plan, the SFT baseline was selected as the best response in 51.2% (102.3/200) of cases compared with 26.2% (52.4/200) for GRPO, and 22.6% (45.3/200) for the charted plan. This result reflects preference within the standardized review format, not evidence that model-generated decisions are clinically superior to physician decision-making. Hallucination rates were 15% (GRPO) and 18.5% (SFT), indicating that higher automatic performance did not eliminate clinically unsupported content and that neither model is ready for clinical deployment. Subgroup analyses showed GRPO improved F1 in in vitro fertilization (IVF) and preimplantation genetic testing (PGT) but decreased F1 in intracytoplasmic sperm injection (ICSI) cases, where male-factor information was largely captured only in unstructured fields. CONCLUSIONS: Outcome-based metrics alone are insufficient proxies for clinical utility in ART decision support. Algorithmic improvement and clinical alignment suggest a possible decoupling; a phenomenon we term the alignment paradox. However, because the clinical review was based on 2 reproductive medicine specialists with marginal interrater agreement, the clinical-alignment findings should be interpreted as exploratory. External multicenter validation is required before clinical deployment.
Systems biology in reproductive medicineSeth Parks, Ryan Miller, Lily Millar, Berlin Barnett, Timothy Jenkins, Kristin Brogaard, Paul J Turek
Male fertility supplements reduce oxidative stress, but whether they improve fertility is controversial. Since sperm epigenetic patterns correlate with fertility potential, we investigated whether a male fertility supplement (AlphaSperm®) impacts semen parameters or sperm epigenetics. In a prospective, multi-institutional, within-subject study, 3 groups were evaluated: young healthy men < 25 years old (C, n = 11), young infertile men < 40 years old (YI, n = 10), and older infertile men > 40 years old (OI, n = 10). While on daily AlphaSperm® supplementation, subjects provided serial semen samples. Conventional WHO semen parameters, sperm DNA fragmentation, and sperm DNA methylation were assessed at baseline and after 9 months of treatment. Beta values were generated from methylation array data, and differences in regional sperm DNA methylation with treatment were reported as differentially methylated regions (DMRs) by paired sliding-window analyses. The Stanford GREAT gene ontology tool revealed biological pathways associated with DMRs. SpermQT, a clinical diagnostic, was performed on all subjects. AlphaSperm® supplementation did not significantly alter semen parameters or sperm DNA fragmentation within groups. Regional sperm DNA hypermethylation was observed in all groups (eFDR < 0.0001), and mean methylation changes at DMRs ranged from 0.1% to 4.3%. Gene ontological analysis revealed 29 biological pathways significantly altered with treatment in the OI group (adjusted p < 0.05), though their functional significance needs validation. Supplement-induced DMRs included 5 genes whose methylation statuses are correlated with male infertility that were hypermethylated in the OI group; 1 was hypermethylated in the C group. Thus, although semen parameters and DNA fragmentation were largely unaltered, male fertility supplementation induced novel regional sperm DNA hypermethylation, most obvious in older infertile men. This study provides novel insights into the potentially large epigenetic effects of nutritional supplements occurring independent of semen analysis changes. Limitations include small sample size and lack of placebo controls.
Zoological researchXu Ha, Shu-Jin Li, Ru-Lian Zhao, Lan-Yao Yang, Yun-Qi He, Li Peng, Li-Ting Lv, Xian-Jun Zhu, Mu Yang, Zheng-Lin Yang
Infertility affects approximately 10%-20% of couples worldwide, with male factors accounting for roughly half of all cases. Teratozoospermia, defined by the occurrence of abnormally shaped sperm, is a significant contributor to male infertility. Here, by analyzing a publicly available RNA array dataset comparing teratozoospermia patients and normal controls, we uncovered disrupted adherens junction (AJ)-associated signaling and defective spermatogenesis within germ cells of teratozoospermia patients. In adherens junctions (AJs), α-catenin ( CTNNA1) anchors the cadherin-catenin complex to the actin cytoskeleton and regulates actin organization, but its role in germ cell development and sperm function remains unknown. We generated a germ cell-specific Ctnna1 conditional knockout mouse model ( Ctnna1 cKO). Homozygous Ctnna1-deficient mice exhibited male infertility with abnormal structure and function of spermatozoa. Single-cell RNA sequencing of control and Ctnna1 cKO testes revealed an accumulation of spermatogonia with impaired differentiation and abnormal acrosome structure in Ctnna1-deficient mice, likely caused by disrupted splicing and meiotic processes through dysregulated vinculin. Additionally, loss of α-catenin disrupted both direct and indirect interactions between spermatogenic cells and Sertoli cells, as evidenced by N-cadherin internalization that mediates their adhesion and by reduced Cyclophilin A/CD147 paracrine signaling essential for spermatogenesis. Mechanistically, loss of α-catenin results in disorganization of the α-catenin/vinculin/N-cadherin complex, leading to defective cell-cell interactions and impairment of spermatogenesis. Collectively, our study establishes α-catenin as a critical regulator of spermatogenesis and germ cell development and highlights its potential as a prognostic biomarker and therapeutic target for male infertility, particularly teratozoospermia.
Infertility is one of the great paradoxes of reproductive health in Africa. The continent has some of the world's highest fertility rate1, yet it also carries a disproportionately high burden of infertility2. Despite this, infertility remains one of the least prioritised components of sexual and reproductive health and rights (SRHR) on the continent, receiving far less attention than contraception, maternal health, HIV, sexually transmitted infections (STIs), abortion. and adolescent pregnancy.In 2026, 32 years after the 1994 International Conference on Population and Development (ICPD) included infertility as one of its platforms of action3, this neglect is no longer defensible. L'infertilité constitue l'un des grands paradoxes de la santé reproductive en Afrique. Le continent affiche certains des taux de fécondité les plus élevés au monde1, tout en supportant un fardeau disproportionné lié à l'infertilité2. Malgré cela, l'infertilité demeure l'un des aspects les moins prioritaires de la santé et des droits en matière de sexualité et de reproduction (SDSR) sur le continent, recevant bien moins d'attention que la contraception, la santé maternelle, le VIH, les infections sexuellement transmissibles (IST), l'avortement et les grossesses chez les adolescentes. En 2026, soit 32 ans après que la Conférence internationale sur la population et le développement (CIPD) de 1994 a inscrit l'infertilité dans son programme d'action3, cette négligence n'est plus justifiable.
Annals of medicineDandan Xiong, Guangli Mao, Jianwu Zhao, Dan Zi, Fang Qiu
BACKGROUND: Intrauterine adhesions (IUA), particularly moderate to severe cases, is a leading cause of decreased menstrual flow and secondary infertility in women, affecting an estimated 2.8%∼46% of infertile women. Hysteroscopy remains the gold standard for diagnosis, with high sensitivity and specificity (both exceeding 90%), while three-dimensional ultrasonography offers a non-invasive alternative with a reported sensitivity of 86% and specificity of 90% for detecting intrauterine abnormalities. The success of surgical management via transcervical resection of adhesions (TCRA) is primarily gauged by the resumption of normal menstrual flow and the absence of significant adhesions on second-look hysteroscopy or ultrasonography. However, the high recurrence rate postoperatively, especially in severe cases (up to 60%), and the persistently thin endometrium significantly impair patients' reproductive outcomes. Existing adjuvant treatments such as high-dose oestrogen, uterine stents and hydrogels have failed to substantially improve patients' fertility outcomes. Platelet-rich plasma (PRP), as an autologous biological preparation rich in various growth factors, has demonstrated remarkable application prospects in recent years for the adjuvant and combined treatment of IUA due to its potent pro-angiogenic, anti-inflammatory and tissue repair/regeneration-promoting properties. OBJECTIVE: This review aims to summarize the mechanisms and clinical efficacy of PRP as an adjuvant therapy for IUA, providing new perspectives for the comprehensive management of this condition. DISCUSSION: We explore the mechanisms of action and clinical outcomes of PRP monotherapy following IUA surgery and evaluate the safety and application advantages of PRP and autologous PRP. The mechanisms of the synergistic effects of PRP combined with mesenchymal stem cells(MSCs), uterine scaffolds and hydrogels, as well as the efficacy of these combination therapies, were discussed. In most studies, favourable feedback was obtained, while a few studies suggested that PRP alone or in combination failed to improve the reproductive outcomes of IUA patients. CONCLUSION: Current evidence suggests that PRP, both as a standalone and adjunctive therapy, shows promise in promoting endometrial regeneration and improving certain clinical outcomes, such as endometrial thickness and menstrual flow, in patients with IUA. However, the clinical efficacy remains inconclusive due to significant heterogeneity in study designs, patient populations and PRP preparation protocols. High-quality, large-scale randomized controlled trials with standardized methodologies and long-term follow-up are urgently needed to definitively establish its impact on critical reproductive outcomes, such as live birth rates, before its widespread clinical adoption can be recommended.
BACKGROUND: Previous studies have confirmed that changes in semen microbiota are closely related to male oligoasthenospermia(OA). However, current research only qualitatively describes the differences in the microbial community, fails to screen out core markers with independent discriminatory value, and also fails to quantitatively evaluate the diagnostic efficacy of the microbial community, resulting in insufficient research on the diagnostic value of the semen microbiota in oligoasthenospermia. METHODS: A total of 40 untreated patients with idiopathic oligoasthenospermia (IOA) and 30 fertile control (FC) were recruited for this study. The semen samples were sequenced using 16S rRNA sequencing technology to assess the differences in microbial diversity and abundance. Subsequently, three machine learning algorithms were employed to further identify the core microorganisms and to further evaluate the diagnostic performance. Then, the SHapley Additive exPlanations(SHAP)analysis method was used to explain the contribution of these core microbiota to the disease. Additionally, the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2) algorithm was used to predict the functions of the core microorganisms. RESULTS: The analysis of the microbial community in semen revealed that there were differences in the internal composition structure of the semen microbiota between the IOA group and the FC group. Machine learning algorithms identified a total of 5 core bacterial genera. The area under the curve (AUC) of this model was 0.773, with a 95% confidence interval (CI) of 0.661-0.885, indicating that the model has strong discriminatory power. SHAP analysis further revealed the direction of the association between the abundance of the microbiota and disease prediction. Additionally, KEGG pathway prediction revealed that the 5 core genera were predominantly enriched in carbohydrate and nucleic acid metabolism pathways, most notably glycolysis/gluconeogenesis (P = 6.67 × 10-3). CONCLUSION: This study employed a variety of machine learning algorithms to conduct a systematic characterization study on the semen microbiota of patients with idiopathic oligoasthenospermia. This method overcomes the limitations of traditional microbiota analysis and can This approach overcame the limitations of traditional microbiota analysis and constructed a risk prediction model based on core bacterial genera. It preliminarily explored the potential of the semen microbiota as a non-invasive screening candidate marker for IOA, providing a reference for subsequent research on non-invasive diagnostic markers and mechanisms., providing a basis for non-invasive precise diagnosis of the disease and the analysis of the pathogenic mechanism of the microbiome.
International journal of molecular sciencesGiulia Garbin, Loris Marin, Chiara Sabbadin, Giuseppe Gullo, Decio Armanini, Luciana Bordin, Eugenio Ragazzi, Guido Ambrosini, Alessandra Andrisani
Chronic endometritis (CE) is a persistent inflammatory disorder of the endometrium that is histopathologically characterized by CD138-positive plasma cells within the endometrial stroma. This study evaluated components of the renin-angiotensin-aldosterone system (RAAS) and interleukin-6 (IL-6) in infertile women with CE. Thirty-nine infertile women undergoing diagnostic hysteroscopy with endometrial biopsy were included. A total of 21 women were classified as CE-positive and 18 as CE-negative. Fasting blood samples were collected 48 h before hysteroscopy (t1) and approximately 2.5 h before the procedure (t2) to assess plasma renin, serum aldosterone, the aldosterone-to-renin ratio (ARR), sodium, potassium, progesterone, thyroid-stimulating hormone (TSH), and IL-6. Exploratory analyses were performed according to the extent of CD138-positive plasma-cell infiltration (plasma-cell burden, stratified as <20 or ≥20 cells/high-power field) and persistence versus resolution of CE after antibiotic treatment. Baseline characteristics, including body mass index (BMI), infertility duration, and anti-Müllerian hormone (AMH), were comparable between groups. No significant differences in the parameters were observed between CE-positive and CE-negative women. No consistent RAAS or inflammatory differences emerged according to plasma-cell burden or CE persistence after treatment. These findings suggest that CE is not associated with measurable systemic RAAS activation or IL-6 changes, supporting the hypothesis of local CE alterations.