Search Results (1,148)

Background/Objectives: This study aims to assess changes in seminal parameters and sperm DNA fragmentation (SDF) index after empirical oral antibiotic therapy in infertile men with baseline SDF index > 15%. Methods: This retrospective, paired, uncontrolled pre- and post-intervention study included 98 infertile men with elevated baseline SDF index. Semen samples were obtained before treatment and at least two months after simultaneous oral treatment with ciprofloxacin 1000 mg/day for 21 days and doxycycline 100 mg/day for 10 days. Semen volume, sperm concentration, total sperm count, progressive motility, sperm morphology, round cell concentration, and SDF index were assessed before and after treatment. Results: After treatment, conventional semen parameters did not change significantly. Round cell concentration decreased from 0.3 to 0.2 × 10⁶/mL (p = 0.003), and median SDF index decreased from 30% to 20% (p < 0.0001). Conclusions: Empirical oral antibiotic therapy was associated with reductions in the SDF index and round cell concentration in this cohort. Because microbiological confirmation and an untreated control group were lacking, causality cannot be established, and controlled studies are required before routine clinical adoption. Full article

Background: Polycystic ovary syndrome (PCOS) is a leading cause of anovulatory infertility and a frequent indication for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Multivariable regression estimates adjusted associations, whereas association rule mining (ARM) can describe frequently co-occurring attributes; however, ARM outputs are unadjusted and may be sensitive to analytic specification. Objectives: We used ARM alongside multivariable logistic regression and internal robustness analyses to describe combinations of clinical and treatment-related variables that co-occurred with clinical pregnancy failure among women with PCOS undergoing IVF/ICSI. Methods: We retrospectively analyzed 733 deidentified patients with PCOS from the Reproductive Hospital of Guangxi. The original one-hot-encoded analytic file was linked to a supplemental clinical record file containing continuous age, BMI, infertility duration, anti-Müllerian hormone, total gonadotropin dose, fertilization method, embryo-transfer day, number of embryos transferred, and embryo score. Embryo quality was derived from D3 cleavage-stage and blastocyst morphology records. Multivariable logistic regression was used to estimate adjusted associations. ARM results were assessed using Fisher’s exact test, Benjamini–Hochberg false discovery rate (FDR) correction, 1000 bootstrap resamples, fivefold cross-validation, and threshold/cutoff sensitivity analyses. Results: In the multivariable model (n = 730), age remained associated with clinical pregnancy failure (adjusted odds ratio [aOR] = 1.04 per year, 95% CI 1.00–1.08, p = 0.031), whereas BMI was not independently associated with failure (aOR = 1.00 per kg/m², 95% CI 0.96–1.05, p = 0.860). Transfer of two embryos (aOR = 0.55, 95% CI 0.35–0.85, p = 0.008), D5 blastocyst transfer (aOR = 0.49, 95% CI 0.32–0.75, p = 0.001), and transfer of at least one high-quality embryo (aOR = 0.63, 95% CI 0.43–0.93, p = 0.020) were associated with lower odds of failure. Under the primary host-factor specification, age > 35 years + BMI ≥ 24 kg/m² + pelvic adhesion defined 48 patients, 30 of whom had clinical pregnancy failure (support = 0.07; confidence = 0.63; lift = 1.38; FDR q = 0.098). In the secondary treatment-inclusive analysis, infertility duration > 5 years + no high-quality embryo transferred defined 43 patients with 30 failures (support = 0.06; confidence = 0.70; lift = 1.54; FDR q = 0.026). Lift represents the subgroup failure proportion divided by the overall failure proportion and is not an adjusted risk ratio. The rule composition and the number of FDR-supported rules changed under alternative cutoffs and confidence thresholds. Conclusions: ARM described transparent but specification-sensitive co-occurrence profiles that complement, rather than compete with, regression. Treatment-inclusive profiles combine baseline and downstream cycle characteristics and are therefore especially exploratory. These findings require prospective multicenter validation before any clinical decision-support use. Full article

Background/Objectives: Maternal vitamin D deficiency has been associated with preeclampsia, but evidence regarding preconception partner-specific vitamin D biomarkers is limited. We evaluated associations between preconception maternal and paternal vitamin D biomarkers and the odds of preeclampsia. Methods: This secondary prospective cohort analysis used data from the Folic Acid and Zinc Supplementation Trial (FAZST), a multicenter study conducted in the United States between 2013 and 2017. Of the 2370 enrolled couples who were seeking infertility treatment, 1054 couples achieved a documented pregnancy. Because preeclampsia can only be ascertained among pregnancies progressing beyond 20 weeks of gestation, the primary analytic population was restricted to 826 pregnancies that reached ≥20 weeks, including 98 with preeclampsia and 728 without preeclampsia. Preconception serum total 25-hydroxyvitamin D (25(OH)D), vitamin D-binding globulin (VDBG), albumin, free 25(OH)D, and bioavailable 25(OH)D were assessed in both partners. Multivariable logistic regression models estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Results: In categorical analyses, maternal total 25(OH)D findings were consistent with a possible U-shaped pattern. Compared with concentrations of 30–< 50 ng/mL, concentrations ≤20 ng/mL were associated with higher odds of preeclampsia (aOR = 2.58, 95% CI: 1.13–5.88), as were concentrations ≥50 ng/mL (aOR = 5.45, 95% CI: 1.71–17.41). Similar categorical patterns were observed for maternal free 25(OH)D, with higher odds at concentrations ≤8.25 pg/mL (aOR = 2.23, 95% CI: 1.13–4.43) and ≥12.5 pg/mL (aOR = 4.71, 95% CI: 1.97–11.29), and for maternal bioavailable 25(OH)D concentrations ≤3.5 ng/mL (aOR = 2.61, 95% CI: 1.19–5.72) and ≥5.0 ng/mL (aOR = 5.38, 95% CI: 2.15–13.46). Lower paternal bioavailable 25(OH)D was associated with lower odds of preeclampsia in the fully adjusted model (aOR = 0.50, 95% CI: 0.28–0.89); however, this finding should be considered exploratory. Conclusions: Among pregnancies progressing to ≥20 weeks, lower and higher categories of maternal total, free, and bioavailable 25(OH)D were associated with the odds of preeclampsia relative to intermediate categories. These categorical findings are consistent with a possible U-shaped pattern but do not establish a nonlinear dose–response relationship. Paternal findings were limited and should be considered exploratory. Full article

Endometriosis is a chronic inflammatory disorder characterized by the ectopic growth of endometrial-like tissue, leading to pelvic pain and infertility. Although cepharanthine has well-established anti-inflammatory properties, its therapeutic potential and underlying mechanisms in endometriosis remain largely unexplored. In this study, the effects of cepharanthine were evaluated using a surgically induced mouse model and immortalized human endometrial stromal cell models. Cepharanthine treatment significantly reduced the calculated lesion volume, whereas wet lesion weight did not differ significantly between the groups. Cepharanthine was also accompanied by reduced spleen weight and alterations in the CD4+ helper T-cell population in vivo. In immortalized human ovarian endometriotic stromal cells (ihOESCs), cepharanthine significantly decreased cell viability, induced apoptosis, and disrupted cell-cycle progression. Cepharanthine altered autophagy-related signaling, accompanied by increased acidic vesicle-associated signals and accumulation of LC3B-II and p62/SQSTM1; however, the direction of autophagic flux remains unclear. These changes were associated with elevated reactive oxygen species production, intracellular Ca²⁺ redistribution, and mitochondrial dysfunction. Collectively, these findings indicate that cepharanthine reduces calculated lesion volume in vivo and alters mitochondrial function, autophagy-related signaling, apoptosis and cell-cycle progression in ihOESCs, supporting its potential as a therapeutic candidate. Full article

Background/Objectives: Varicocele is usually clinically left-sided, but imaging and mechanistic studies suggest that contralateral venous reflux or bilateral testicular effects may be more common than physical examination indicates. This narrative review critically examines whether varicocele-associated infertility is better conceptualized as an asymmetric disorder with potential bilateral anatomical or functional involvement and considers the implications for diagnosis and treatment. Methods: PubMed/MEDLINE and Scopus were searched from inception to 21 June 2026 for studies on varicocele laterality, bilateral and subclinical disease, color Doppler ultrasonography, venography, and unilateral versus bilateral repair. Reference lists and contemporary clinical guidelines were also reviewed. Because the included studies differed substantially in patient selection, age, operator technique, diagnostic criteria, and reference standards, reported bilateral rates were not interpreted as head-to-head estimates of diagnostic sensitivity or as pooled prevalence estimates. Results: Physical examination identifies predominantly left-sided clinical disease. Bilateral involvement is reported more frequently when both sides are assessed using Doppler ultrasonography or venography, but estimates vary widely across referral-enriched and highly selected cohorts. Human and experimental evidence supports several mechanisms by which a clinically unilateral lesion may have bilateral functional effects, including shared scrotal hyperthermia, oxidative stress, endocrine disturbance, and venous cross-communication. Bilateral repair is consistent with standard treatment criteria when both varicoceles are clinically palpable. In men with a clinical left varicocele and non-palpable right-sided reflux, comparative evidence is mixed, and current guidelines do not support routine treatment of imaging-only disease. Conclusions: Varicocele is best viewed as an asymmetric disorder that may be anatomically or functionally bilateral in selected men, rather than as a universally bilateral disease. Deliberate bilateral clinical assessment and standardized bilateral ultrasonography when imaging is clinically indicated may improve phenotyping and operative planning. However, contralateral imaging abnormalities should not automatically be converted into a surgical indication. Full article

The widespread adoption of in vitro fertilization (IVF) has profoundly transformed the management of infertility and established IVF as the most effective assisted reproductive technology for many clinical indications. Nevertheless, intrauterine insemination (IUI) remains widely used because of its lower invasiveness, reduced treatment burden, lower costs, and broader accessibility. The contemporary role of IUI in an IVF-dominated era remains a subject of ongoing debate. This narrative review aims to critically evaluate the current role of IUI in modern reproductive medicine by examining its clinical indications, effectiveness, limitations, cost-effectiveness, and patient-centered implications in comparison with IVF. A narrative review of the literature was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Relevant studies, systematic reviews, meta-analyses, randomized controlled trials, and international guidelines published primarily between 2010 and 2025 were identified and synthesized. Particular attention was given to recommendations from the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM). Current evidence supports the use of IUI, particularly when combined with ovarian stimulation, as an appropriate first-line treatment in selected couples with unexplained infertility, mild male-factor infertility, and minimal-to-mild endometriosis. Although IVF generally provides higher live birth rates per treatment cycle and remains the preferred option for several infertility diagnoses, IUI continues to offer meaningful clinical benefits in appropriately selected patients. Beyond effectiveness, treatment decisions should also consider cost-effectiveness, accessibility, treatment burden, safety, and patient preferences. Recent evidence increasingly supports individualized and prognosis-based approaches to fertility treatment selection. Evidence also highlights the importance of female age, infertility duration, and ovarian reserve in determining the relative benefit of IUI versus IVF. Despite the clinical dominance of IVF, IUI remains an evidence-based and clinically relevant component of contemporary fertility care. Rather than being viewed as competing interventions, IUI and IVF should be considered complementary treatment options within a personalized infertility management strategy. Appropriate patient selection, particularly considering female reproductive prognosis, remains essential to maximize reproductive outcomes while minimizing treatment burden and healthcare costs. Full article

Background and Objectives: Superficial peritoneal endometriosis (SPE) remains one of the most difficult endometriosis phenotypes to diagnose non-invasively, because lesions are frequently small, multifocal, and poorly detectable using conventional imaging. Diagnostic laparoscopy therefore remains the reference standard for direct visualization of superficial peritoneal lesions. However, the inconsistent relationship between visible lesion burden and pain severity, together with the multifactorial nature of chronic pelvic pain, highlights the limitations of a purely lesion-based diagnostic model. This narrative review reassesses SPE from a cautious functional and molecular perspective, focusing on clinically established evidence, emerging but incompletely validated tools, and hypothesis-generating concepts. The novelty of this review lies in its specific focus on SPE as an unresolved diagnostic phenotype and in the proposed integration of surgical diagnosis, expert imaging, pain phenotyping, empirical treatment response, and molecular research within a non-replacement framework. Materials and Methods: A narrative literature review was performed using PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library for English-language articles published between January 2010 and April 2026. The search focused on SPE, diagnostic laparoscopy, dynamic transvaginal ultrasound, sliding sign, chronic pelvic pain, hormonal treatment response, neuroinflammation, liquid biopsy, circulating biomarkers, epigenetics, and microbiome research. Results: Dynamic transvaginal ultrasound, sliding sign assessment, pelvic organ mobility evaluation, and tenderness-guided examination may provide indirect functional information in selected patients with suspected SPE, but they remain operator-dependent and insufficiently standardized for this phenotype. Response to hormonal therapy may support clinical reasoning, but it has low specificity and may also reflect improvement of adenomyosis, primary dysmenorrhea, ovulation-related pain, abnormal uterine bleeding, or other estrogen-sensitive conditions. Liquid biopsy and molecular biomarkers, including circulating microRNAs, extracellular vesicles, cell-free DNA, inflammatory mediators, epigenetic signatures, adipokine-related markers, and microbiome-related signals, remain investigational and require phenotype-specific validation. Conclusions: Functional and molecular stratification of suspected SPE represents a promising research direction rather than a current clinical standard. Laparoscopy remains essential when definitive diagnosis or surgical treatment is required, particularly in patients with infertility, refractory symptoms, suspicious imaging, or suspected complex disease. Future validated models may help integrate clinical phenotype, expert imaging, treatment response, pain mechanisms, and molecular profiles to support more individualized and selective diagnostic pathways. Full article

Introduction: Leukemia is the most common childhood malignancy. Treatment requires urgent polychemotherapy and may escalate to hematopoietic stem cell transplantation (HSCT) with or without total body irradiation (TBI). Due to the frequently young age at diagnosis, time limitations and unpredictable course, fertility preservation (FP) is especially challenging and may not be feasible prior to treatment, particularly in females. Methods: We conducted a systematic review and meta-analysis of fertility outcomes in leukemia survivors using MEDLINE, Embase, and Cochrane databases (search date: 13 June 2024). Results: Forty-two studies with 2048 patients were included. Overall infertility was 37% (95% CI 23–54%) with substantial heterogeneity. The highest infertility rates were observed after HSCT (68%) and after testicular irradiation (92%) or TBI ≥ 10–12 Gy (66%). Chemotherapy alone was associated with lower infertility (4%). Sex-specific differences were noted, with higher infertility in males following chemotherapy-only regimens (18% vs. 6% in females), while females were more affected after HSCT (70% vs. 59% in males). Subfertility affected about one-fifth of survivors. Conclusions: While standard chemotherapy is associated with relatively low gonadotoxicity, HSCT and irradiation confer substantial risk. These findings support individualized fertility counseling and long-term reproductive follow-up based on treatment exposure. Full article

Background: Sperm DNA fragmentation (SDF) is increasingly recognized as a clinically relevant marker of male reproductive potential and has been associated with impaired embryo development, miscarriage, and suboptimal assisted reproductive technology outcomes, particularly in selected infertile populations. Because conventional sperm-preparation methods do not directly target molecular sperm damage, combined selection strategies such as density gradient centrifugation (DGC) and annexin V-based magnetic-activated cell sorting (MACS) have been proposed to enrich spermatozoa with improved DNA integrity before intracytoplasmic sperm injection (ICSI). Regardless of their more favorable functional characteristics, the optimal sequence for combining these methods remains uncertain. Methods: This study presents a hybrid analysis combining a structured review of 25 published studies with original prospective observational laboratory data. The review examined the effects of DGC, MACS, and sequential combined protocols on SDF, conventional semen parameters, and reported assisted reproduction outcomes, with particular attention to the unresolved question of sequencing order. In parallel, a blinded observational cohort of 67 infertile men with baseline SDF of at least 30% underwent sequential DGC followed by MACS, with SDF measured before and after processing using the sperm chromatin dispersion test (Halosperm ^® assay). Results: Across the reviewed literature, combined DGC/MACS approaches generally reduced SDF more than single-step preparation, although the magnitude of benefit varied across assays, patient populations, and laboratory protocols. Some studies also reported improvements in embryo quality and pregnancy-related outcomes, but these data were derived mainly from retrospective or small comparative cohorts, and no large randomized head-to-head trials were identified comparing DGC→MACS with MACS→DGC for fertilization, miscarriage, or live-birth outcomes. In the observational cohort, DGC→MACS was associated with a significant mean absolute SDF reduction of 19.42% +/− 9.4% (p < 0.0001). Most patients (85.1%) achieved post-treatment SDF values below the 30% threshold. Conclusions: Combined DGC/MACS sperm preparation, supported by the data in our study sequence, appears promising for reducing SDF in selected infertile men, particularly those with elevated baseline SDF. However, the optimal sequencing strategy and its impact on major reproductive endpoints remain uncertain and require better standardized comparative clinical studies. Full article

Male infertility affects a substantial proportion of couples worldwide, with oxidative stress recognized as one of its most prevalent and potentially treatable mechanisms. This review critically analyzes current diagnostic and therapeutic approaches for oxidative stress-related male infertility, highlighting the necessity of advancing from descriptive semen analysis to mechanism-based clinical care. The biological basis of reactive oxygen species generation in spermatozoa, the dual physiological and pathological roles of redox signaling, and the contributions of leukocytes, lifestyle factors, infections, varicocele, metabolic disease, environmental exposures, and transition metals in amplifying oxidative injury are examined. Laboratory methods for assessing oxidative stress, including chemiluminescence, flow cytometry, oxidation-reduction potential, and total antioxidant capacity assays, are evaluated with respect to biological relevance, technical limitations, standardization, and clinical applicability. Evidence suggests that indiscriminate antioxidant use, without prior confirmation of oxidative stress or identification of its cause, may account for inconsistent clinical trial outcomes and could induce reductive stress. Conversely, individualized management based on comprehensive andrological evaluation, treatment of underlying conditions, and quality-controlled functional sperm testing is more rational and potentially effective. Oxidative stress should therefore be regarded as a diagnosable and monitorable clinical entity in male infertility, necessitating validated diagnostics and personalized therapeutic strategies rather than empiric supplementation alone. Full article

Background/Objectives: Letrozole combined with intrauterine insemination (IUI) is a common first-line treatment for unexplained and anovulatory infertility; however, the optimal dominant follicle size at human chorionic gonadotrophin (hCG) triggering remains uncertain. We evaluated associations of follicle size with biochemical pregnancy, clinical pregnancy, and live birth. Methods: This retrospective cohort included 596 letrozole–IUI cycles from 454 women aged <40 years treated between May 2024 and August 2025. Cycles were grouped by dominant follicle diameter at trigger (17.0–18.9, 19.0–21.0, and >21.0 mm). Mixed-effects logistic regression accounted for repeated cycles. Results: Biochemical pregnancy, clinical pregnancy, and live-birth rates differed across groups and were highest at 19.0–21.0 mm; live-birth rates were 3.4%, 15.1%, and 8.6%, respectively (p = 0.008). Compared with 17.0–18.9 mm, the 19.0–21.0 mm group had higher adjusted odds of clinical pregnancy (aOR 5.58, 95% CI 1.31–23.84; p = 0.020) and live birth (aOR 15.15, 95% CI 1.74–131.95; p = 0.014), although both estimates were imprecise. Adjusted live-birth probabilities were 3.5%, 16.1%, and 9.1%, respectively. The direction of the live-birth association was preserved in the single-cycle sensitivity analysis (aOR 3.85, 95% CI 1.22–12.13; p = 0.021). Continuous linear and quadratic follicle-diameter models were not significant. Conclusions: The 19.0–21.0 mm category was associated with higher reproductive outcome rates, including live birth; however, the observational design, sparse events, wide confidence intervals, and null continuous analyses preclude defining an optimal trigger threshold. These findings are hypothesis-generating and require prospective multicenter confirmation. Full article

Background: The aim of this study was to investigate the impact of intraovarian platelet-rich plasma (PRP) treatment on ovarian reserve markers, hormonal profiles, oocyte yield, fertilization potential, and pregnancy outcomes in infertile women with diminished ovarian reserve. Methods: This retrospective single-center study was conducted at a tertiary referral center between January 2021 and December 2024 in the Department of Obstetrics and Gynecology, IVF Clinic, Private Diyarlife Hospital, Diyarbakır, Turkey. A total of 78 infertile women with diminished ovarian reserve (DOR) were included. DOR was defined in the present study as an AMH level < 1.1 ng/mL and/or an antral follicle count (AFC) < 5 follicles. Pre-PRP and post-PRP measurements were compared in the same patients. Hormonal and clinical parameters, including prolactin, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), estradiol, endometrial thickness, gonadotropin dosage, antral follicle count (AFC), mature metaphase II (MII) oocyte count, and two-pronuclear (2PN) zygote count, were evaluated before and after PRP treatment. Results: Significant increases were observed in AMH and prolactin levels, whereas FSH levels significantly decreased following PRP treatment (all p < 0.001). Post-PRP AFC, MII oocyte count, and 2PN zygote count were significantly higher than pre-PRP values (all p < 0.001). A total of 21 pregnancies (26.9%) were achieved, including 17 clinical pregnancies (81.0% of pregnancies; 21.8% of all patients), 4 biochemical pregnancies (19.0% of pregnancies; 5.1% of all patients), 11 miscarriages (52.4% of pregnancies; 14.1% of all patients), and 6 live births (28.6% of pregnancies; 7.7% of all patients). Significant positive correlations were identified between post-PRP AFC and MII oocyte count (r = 0.803, p < 0.001), post-PRP AFC and 2PN zygote count (r = 0.624, p < 0.001), and MII oocyte count and 2PN zygote count (r = 0.728, p < 0.001). Conclusions: Intraovarian PRP administration was associated with improvements in ovarian reserve markers, oocyte maturation, and fertilization-related outcomes in women with DOR. Significant increases in AFC, MII oocyte count, and 2PN zygote count were observed after PRP treatment. However, these improvements in ovarian reserve markers were not associated with significant differences between women who achieved pregnancy and those who did not. Because of the retrospective design and the absence of a control group, these findings should be interpreted as associations rather than evidence of a causal treatment effect. Although clinical pregnancies and live births were observed during follow-up, larger, multicenter randomized controlled trials are required to confirm these findings and to further evaluate the effect of PRP on reproductive outcomes. Full article

Polycystic ovary syndrome (PCOS), newly named as Polyendocrine Metabolic Ovarian Syndrome (PMOS) is the most common endocrinopathy affecting women of reproductive age, which often leads to infertility due to anovulation and poor oocyte quality. Poor oocyte quality is a major reason for women’s infertility in humans and a barrier to efficient assisted reproduction technology (ART) treatment. Supplementation of melatonin, a free radical scavenger, has been reported to show satisfactory results in women undergoing ART. This review investigates whether the endogenous melatonin or supplementation of melatonin impact on oocyte/embryo quality and pregnancy rate in PCOS patients undergoing ART treatment. Articles published between 2010 and 2025 were reviewed to perform a comprehensive search on observational studies and clinical trials that evaluated the use of melatonin in PCOS patients undergoing in vitro fertilization (IVF) or intrauterine insemination (IUI) or intracytoplasmic sperm injection (ICSI). The databases searched included PubMed, Google Scholar, Science Direct, and Cochrane Library. This systematic review indicates that the group that received melatonin had significantly higher clinical pregnancy probabilities than the control group. Similarly, the melatonin administration significantly enhanced the endometrium thickness (p < 0.001) and the chemical pregnancy rate (30% versus 18%, p = 0.012). Additionally, in comparison to the control group that received metformin alone, the group that received melatonin (3 mg) significantly increased the proportion of top-quality embryos (40.3% vs. 29.9%; p < 0.001). According to this systematic review, melatonin significantly improves endometrial thickness, mature oocytes, high-quality embryos, and pregnancy rates, all of which improve ART outcomes in PCOS patients. Because of its safety, affordability, and efficacy, it is a useful supplement to ART procedures. The most popular and well-tolerated dosage is still 3 mg per day, despite variations in research. Full article

Iron overload is a recognized risk factor for female reproductive dysfunction, yet the underlying cellular and molecular mechanisms remain incompletely understood. In this study, the effects of iron overload on ovarian granulosa cells were investigated, and a protective role of the steroid biosynthesis pathway against ferroptosis was identified. A mouse model of ovarian iron overload was established by daily gavage of ferric citrate (FC, 120 mg/kg for 40 days). Iron-overloaded female mice exhibited disrupted estrous cycles, reduced serum estradiol levels, impaired antral follicle development, and decreased pregnancy rates and litter sizes. Metabolomic analysis of freshly isolated granulosa cells revealed significant depletion of unsaturated glycerophospholipids and fatty acids, along with reduced antioxidants such as glutathione, vitamin E, and coenzyme Q6, and enrichment of the ferroptosis pathway. Transcriptomic analysis showed marked upregulation of genes involved in steroid biosynthesis, including Hmgcr and Fdft1, and their master transcription factor Srebf2. In cultured KK1 granulosa cells, FC treatment increased intracellular Fe²⁺ and reactive oxygen species, decreased glutathione content and NADPH/NADP⁺ ratio, elevated malondialdehyde levels, and induced lipid peroxidation and plasma membrane rupture, all of which were attenuated by the iron chelator deferoxamine. Knockdown of Srebf2 suppressed Hmgcr and Fdft1 expression, exacerbated lipid peroxidation, and increased membrane damage in iron-overloaded cells, confirming that SREBF2-driven steroid biosynthesis acts as an endogenous anti-ferroptotic mechanism. Collectively, these findings demonstrate that iron overload triggers ferroptosis in granulosa cells, leading to follicular arrest and reduced fertility, and that activation of the steroid biosynthesis pathway counteracts ferroptosis, likely through the production of protective intermediates. This study provides a mechanistic basis for iron overload-induced female infertility and identifies the steroid biosynthesis pathway as a potential therapeutic target. Full article

Endometriosis is a chronic inflammatory disease characterized by the ectopic growth of endometrial-like tissue and is closely associated with pain and infertility. This review summarizes current evidence on immune dysregulation and emerging immunomodulatory therapies in endometriosis. Relevant clinical and mechanistic studies were identified through a structured literature review and qualitatively synthesized. Increasing evidence suggests that immune dysregulation plays a critical role in disease pathogenesis. Within the immune microenvironment, innate and adaptive immune cells—including macrophages, dendritic cells, neutrophils, mast cells, T cells, and B cells—collectively promote inflammation, angiogenesis, fibrosis, and immune evasion. Emerging immunotherapeutic strategies, including macrophage repolarization, NK cell restoration, dendritic cell modulation, neutrophil extracellular traps inhibition, immune checkpoint blockade, and cytokine/chemokine targeting, have shown promising preclinical and early clinical potential. However, disease heterogeneity, reproductive safety concerns, and the lack of validated biomarkers remain major barriers to clinical translation, highlighting the potential of immunomodulatory therapies as future non-hormonal treatment strategies. Full article