Endometriosis is a complex chronic condition, driven by estrogen, characterized by the growth of endometrial-like tissue outside the uterus. This often-debilitating disease affects millions of women globally, manifesting as severe pelvic pain, significant subfertility, and a profound reduction in the quality of their lives. These clinical problems need advancements in both diagnostic tools and therapeutic strategies. This article delves into the intricate relationship between endometriosis-derived lactic acid and a specific subset of immune cells, known as myeloid-derived suppressor cells (MDSCs). We aim to elucidate the nuanced biological pathways that affect this significant interaction. Lactates subsequently drive the expansion and activation of MDSCs, which then increase immune suppression through key signaling molecules such as hypoxia-inducible factor 1-alpha, signal transducer and activator of transcription 3, and nuclear factor kappa-light-chain-enhancer of activated B cells. Beyond its role in immune modulation, this complex interplay between lactic acid and MDSCs is emerging as a pivotal factor in the multifaceted pathogenesis of endometriosis. It significantly contributes to the disease’s bad progression, including its invasive spread, the development of new blood vessels (angiogenesis), and the characteristic formation of fibrotic, scar-like tissue. This review hypothesizes that targeted modulation of lactate metabolism could serve as a promising therapeutic strategy to regulate MDSC activity. The purpose of this study is to clarify these intricate cellular and molecular events.
Background: Non-obstructive azoospermia (NOA) is a severe form of male infertility characterized by impaired spermatogenesis. Although chromosomal abnormalities and Y-chromosome microdeletions are known causes, many cases remain idiopathic, suggesting that other genetic factors may be involved. RAD54 like (RAD54L) is a key component of the homologous recombination pathway required for DNA double-strand break repair and meiotic progression. Objective: To identify the potential genetic cause of NOA using whole-genome sequencing (WGS) in affected individuals from consanguineous families. Materials and Methods: For performing this experimental study, 10 NOA men who were referred to Infertility Center of the Yazd Reproductive Sciences Institute, Yazd, Iran underwent clinical, hormonal, and genetic evaluations. Genomic DNA was extracted from peripheral blood and was subjected to WGS. Variants were filtered and prioritized based on allele frequency, predicted pathogenicity, inheritance pattern, and gene expression data. In silico splicing analyses were performed using SpliceAI and Human Splicing Finder. Results: WGS identified an ultrarare homozygous splice-site variant, c.1375+1G>T, in the RAD54L gene. The variant affects a canonical donor splice site and is predicted to cause loss of normal splicing, likely resulting in exon 12 skipping, frameshift, and premature termination codon formation. RAD54L shows the highest expression in testicular tissue and plays a critical role in homologous recombination and meiotic DNA repair. The patient exhibited hormonal findings consistent with primary testicular failure. Conclusion: This study proposes RAD54L as a potential novel candidate gene linked to NOA and underscores the efficacy of WGS in identifying rare genetic etiologies of idiopathic male infertility. Further functional and clinical studies are needed to validate this association.
More than 40% of infertility causes are attributed to women. Polyendocrine metabolic ovarian syndrome (PMOS) is one of the important and common causes of infertility in women. Recurrent miscarriage is defined as the occurrence of 2 or 3 consecutive spontaneous miscarriages before the 20th wk of pregnancy. The origin of recurrent miscarriage is unknown in 50% of cases, which are called idiopathic recurrent miscarriage. The present study aims to investigate the relationship between gene polymorphisms and infertility, PMOS, and recurrent miscarriage in Iranian women. This review study was conducted by examining reliable domestic and foreign sources between 2000 and 2026. For this purpose, 80 articles were selected and reviewed using the Scientific Information Database, Scopus, ScienceDirect, and PubMed databases, with an emphasis on the most relevant and newest sources. The results of the studies indicate the effective association of some of these gene polymorphisms with infertility, PMOS, and recurrent miscarriage in Iranian women. Some gene polymorphisms also showed no association with the aforementioned diseases. To better understand the association of these polymorphisms with infertility and recurrent miscarriage in women, there is a need for larger populations with more numbers and to study all environmental and climatic aspects of the populations. Investigating the role of different genes in the body’s response to various drugs is of great importance in determining appropriate treatment methods and can also be important in population screening.
This is a Letter to the Editor and does not have an abstract. Please download the PDF or view the article in HTML.
Background: Progestogen/progestin supplementation is favorable in threatened miscarriage. However, comparative data on the efficacy, safety, and immunomodulatory functions of types/routes of administration are limited. Objective: This study compares oral dydrogesterone (DYD) vs. oral micronized progesterone (MP) in threatened miscarriage. Materials and Methods: This ongoing, investigator-initiated, randomized controlled trial includes eligible, consenting, pregnant women who had vaginal bleeding and/or abdominal pain during first trimester. Participants are treated up to 14 gestational wk with DYD (40 mg stat followed by 10 mg thrice daily) or MP (200 mg twice daily). The following outcomes till 20 gestational wk are presented: miscarriage rate (primary); change in serum cytokines (interferon gamma [IFN-γ], tumor necrosis factor alpha [TNF-α], interleukin [IL]-4, IL-10), time to symptom resolution (secondary); treatment-emergent adverse events (AEs; safety). Results: Interim analysis includes 116 participants (DYD, 62; MP, 54). Miscarriage rate in DYD (14.52%) was statistically comparable to, but numerically lower than, that in MP (20.37%; p = 0.558). The mean time to symptom resolution in DYD and MP was, respectively, 6.49 and 7.38 days for vaginal bleeding, and 7.15 and 7.67 days for abdominal pain. Numerically, IFN-γ and TNF-α decreased and IL-4 increased with DYD, while IFN-γ decreased and IL-4 and IL-10 increased with MP. Considering Th1:Th2 ratio, numerical decreases in IFN-γ:IL-4, IFN-γ:IL-10, and TNF-α:IL-4 were evident with DYD but not with MP. No AE was related to study medication. Conclusion: Compared to oral MP, oral DYD resulted in a numerically lower miscarriage rate and time to symptom resolution, concomitant to favorable decrease in Th1:Th2 ratio.
Background: Poor ovarian response remains one of the most challenging problems in assisted reproductive technology. Various stimulation protocols have been proposed to improve outcomes, including combined gonadotropin-releasing hormone (GnRH) agonist and antagonist strategies. Objective: To compare the effectiveness of a stop GnRH-agonist protocol combined with a GnRH-antagonist protocol vs. a standard GnRH-antagonist protocol in poor ovarian responder (POR) cases. Materials and Methods: This randomized clinical trial was conducted on 100 women aged 18–44 yr diagnosed as POR according to the Bologna criteria. Participants were randomly allocated to either a GnRH-antagonist protocol (control group) or a combined Stop GnRH-agonist/GnRH-antagonist protocol (intervention group). The primary outcome was the clinical pregnancy rate. Secondary outcomes included the number of retrieved oocytes, embryo quality, chemical pregnancy, and live birth rate. Results: No statistically significant differences were observed between the 2 groups regarding chemical pregnancy, clinical pregnancy, or live birth rates. Laboratory outcomes, including the number of retrieved oocytes, metaphase II oocytes, and embryo quality, were also comparable. The intervention group required a significantly higher gonadotropin dose and had a longer stimulation duration (p < 0.01). Conclusion: The stop GnRH-agonist protocol did not demonstrate superiority over the GnRH-antagonist protocol in terms of laboratory or clinical outcomes in POR cases.
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Infertility is a significant challenge in today’s industrialized world, affecting approximately 15% of couples of reproductive age. Around 10% of infertility cases worldwide remain unexplained. As a result, extensive research has focused on exploring natural resources and innovative approaches to preventing and treating infertility. One traditional remedy used since ancient times to enhance sexual potency and fertility in both men and women is date palm pollen (DPP). This study examines the various bioactive compounds in DPP that hold nutritional and therapeutic significance, including phenolic acids, flavonoids, proteins, fatty acids, vitamins, and minerals, which may contribute to fertility. It further analyzes the mechanisms and therapeutic effects of DPP. Evidence from animal and human studies suggests that DPP positively impacts hormonal balance, including estrogen, progesterone, and follicle-stimulating hormone levels, enhances ovarian function, improves egg quality, reduces oxidative stress, alleviates menopausal symptoms such as vaginal dryness and dyspareunia, and boosts women’s sexual health. The mechanism of action of DPP appears to involve modulation of the hypothalamic-pituitary-gonadal axis, enhancement of steroidogenesis, and activation of antioxidant defenses. Additionally, it regulates nitric oxide signaling, modulates dopaminergic pathways, suppresses inflammation, and activates key signaling cascades, including PI3K/Akt, MAPK, and Nrf2/ARE. However, challenges remain in this advanced technological era, including variability in composition, pre-purification requirements, and a lack of standardized clinical protocols. Despite these challenges, DPP shows considerable potential for improving fertility. Future studies in the field should prioritize the systematic isolation of bioactive components, detailed mechanistic investigations, rigorous clinical validation, and integration into sustainable bioeconomy strategies.
Background: One significant concern during pregnancy is the possibility of chromosomal malformations. While prenatal screenings are intended to reassure parents about the health of their unborn child, how reliable are these results when deemed suspicious? Objective: This study aimed to evaluate the predictive accuracy of non-invasive prenatal screening tests in comparison with amniocentesis as the gold standard diagnostic method for chromosomal abnormalities. Materials and Methods: This retrospective descriptive-analytical study was performed using medical records of 490 pregnant women who underwent amniocentesis between 2018 and 2023. Data related to first- and second-trimester maternal serum screening results, ultrasound markers, and fetal karyotype findings were extracted and analyzed. Results: Among 490 pregnant women who underwent amniocentesis, 79 cases were suspected of chromosomal abnormalities based on combined first-trimester ultrasound criteria. Cytogenetic analysis confirmed abnormalities in only 20 of these suspected cases (25.3%). After excluding very low-risk results (≥ 1:300), amniocentesis confirmed abnormalities in only 5.1% (12/234) of first-trimester and 4.5% (7/155) of second-trimester screen-positive cases. All comparisons between screening results and amniocentesis showed significant differences (p < 0.05). Conclusion: These findings suggest that a more appropriate clinical approach involves the integrated use of multiple screening tools combined with genetic counseling and clear communication for prenatal care, as well as using validated noninvasive methods such as non-invasive prenatal testing before amniocentesis, thus rationally supporting parents when making decisions. Ultimately, although amniocentesis remains the most accurate diagnostic tool, the goal should be to use all available methods judiciously to minimize unnecessary interventions and psychological harm.
Background: Given concerns regarding changing puberty ages globally, examining current trends in specific societies is essential. Objective: This study aimed to determine secular changes in the age at menarche among Iranian girls in central Iran using the Probit model. Materials and Methods: This cross-sectional study utilized data from the entry phase of the Shahedieh cohort study, Yazd, Iran. In total, fertility information and menarche data were extracted from 4,854 women (aged 35–70 yr). Based on the menarche age data of these individuals, the proportion of those who had reached menarche in each of the 3 birth decades (1946–1957, 1958–1969, and 1970–1981) was calculated. To calculate this proportion, a hypothetical time origin was considered for each decade, and the Probit model was employed to calculate the probability of menarche at each age. Results: Findings indicate that approximately 10% of Iranian girls experienced menarche before age 11, while 90% reached menarche by age 14.89, with a median age of 12.89 yr. A significant downward trend in the age at menarche was observed; girls born between 1946–1957 experienced significantly later menarche compared to those born in the 1958–1969 and 1970–1981 cohorts at the 10th, 25th, 50th, and 75th percentiles. Conclusion: The observed downward trend in menarche age in central Iran aligns with results from similar studies in developing countries. This declining trend has historically been attributed to lifestyle-related variables. Today, this decreasing trend (acceleration of puberty) can be attributed to poor nutritional habits, sedentary lifestyles, or a physiological response to increased physical and mental stress.
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The DNA damage response (DDR) is a fundamental cellular network that preserves genomic integrity, and its dysregulation drives initiation, progression, and therapeutic response in female reproductive system and breast cancers. This narrative review provides a comparative analysis of DDR alterations across ovarian, endometrial, cervical, and breast cancers, synthesizing molecular studies, clinical trials, and international guidelines from PubMed/MEDLINE, Scopus, and Web of Science. DDR alterations vary substantially among these cancers, reflecting differences in tissue origin, hormonal regulation, and viral oncogenesis. Homologous recombination repair defects, particularly in breast cancer susceptibility 1/2, partner and localizer of BRCA2, ataxia telangiectasia mutated, and checkpoint kinase 2), are prevalent in ovarian, endometrial, and breast cancers, predicting sensitivity to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors. In endometrial cancer, homologous recombination deficiency predominates in high-grade tumor protein p53-mutated subtypes, while Fanconi anemia pathway alterations characterize aggressive serous carcinomas. Cervical cancer exhibits virus-induced DDR disruption and replication stress. Quantitative biomarkers, including tumor mutational burden, microsatellite instability, Radiation sensitive 51, Fanconi anemia complementation group D2, excision repair cross-complementation group 1, and DDR-related microRNAs enable patient stratification. Emerging ataxia telangiectasia and Rad3-related and WEE1 inhibitors show promise in combination regimens. Understanding of tumor-specific DDR enables rational therapeutic stratification, providing a framework for precision oncology.
Recent advancements in 3-dimensional (3D) in vitro culture systems for follicles, oocytes, and embryos represent a paradigm shift in assisted reproductive technologies and reproductive biology. By mimicking the native physiological microenvironment more faithfully than conventional 2-dimensional systems, these innovative platforms directly address critical limitations of current in vitro embryo production protocols, including low blastocyst development rates, compromised embryo quality, and concerning epigenetic aberrations. This comprehensive review examines a spectrum of emerging 3D strategies, microfluidic devices, dynamic culture conditions, spheroid/organoid models, and advanced co-culture systems with supportive somatic and stem cells. Accumulating evidence demonstrates that these technologies (by preserving 3D follicular and embryonic architecture, enhancing nutrient and gas exchange, and restoring vital cell-cell and cell-matrix interactions) significantly improve oocyte maturation rates, embryo developmental competence, and overall in vitro fertilization outcomes. Nevertheless, challenges such as species-specific optimization, scalability, high costs, and the imperative for clinical standardization remain significant hurdles. Future directions to overcome these obstacles involve the development of smart, physiologically responsive biomaterials, the integration of cutting-edge technologies, such as artificial intelligence and organ-on-a-chip platforms, and the creation of cost-effective systems for widespread application. This review underscores the transformative potential of 3D culture systems as a foundational new approach in reproductive research and fertility treatments.
The publisher has been informed of an error that occurred on page 961 in which the authors affiliations must be changed as: Ezri Chow1 M.Sc., Elean To1 M.D., Tony Kun Fai Chow2 M.D. 1. Manningham General Practice, Templestowe Lower, Victoria, Australia. 2. Australia and New Zeeland College of Anaesthetists, Melbourne, Victoria, Australia. On behalf of the author, the publisher wishes to apologize for this error. The online version of article has been updated on 30 June 2026 and can be found at https://doi.org/10.18502/ijrm.v23i11.20551.
Background: Cell-free DNA (cfDNA) in spent culture medium (SCM) offers a non-invasive option for preimplantation genetic testing, but its low concentration and fragmentation reduce clinical reliability. Combining genetic assessment with metabolomic profiling may provide complementary information about embryo competence. Objective: This study assessed pre-analytical cfDNA processing workflows and examined whether SCM amino acid metabolic patterns could act as practical markers of embryo quality. Materials and Methods: In this case-control study (2021–2023), 90 embryos were evaluated using fluorescence in situ hybridization or array comparative genomic hybridization. SCM samples underwent rapid boiling, silica-based purification, or whole-genome amplification (WGA). Sex determination was performed using quantitative polymerase chain reaction (qPCR). For cfDNA quality control and aneuploidy screening, the multiplex IRFiling kit and quantitative fluorescent polymerase chain reaction (QF-PCR) were used. Amino acid profiles across embryonic developmental stages and quality grades were quantified via liquid chromatography-tandem mass spectrometry. Results: Rapid boiling resulted in complete failure of DNA amplification. Conversely, silica-based purification yielded 70.0% concordance for qPCR-based sexing and 56.7% for QF-PCR. WGA achieved the highest efficacy (73.3% qPCR and 56.7% QF-PCR concordance), although quality control checks flagged occasional misclassifications. LC-MS/MS profiling revealed significantly elevated alanine and arginine levels in tripronuclear embryos. Furthermore, high-quality blastocysts exhibited elevated glutamic acid levels alongside a pronounced overall depletion of extracellular amino acids compared to low-quality counterparts and controls. Conclusion: WGA improves cfDNA detectability and qPCR accuracy compared with boiling or purification, but remains inadequate as a standalone screening approach. SCM amino acid profiling provides informative, complementary metabolic signatures of developmental competence, supporting a multimodal strategy for non-invasive embryo assessment.
Background: Recurrent implantation failure remains a challenge in assisted reproduction. Intralipid has been proposed as an immunomodulatory intervention to improve outcomes, although evidence remains inconsistent. Objective: This study aimed to evaluate the effect of intralipid on pregnancy outcomes in women with a history of at least 2 failed embryo transfer cycles. Materials and Methods: In this retrospective cohort study, data of 270 women with ≥ 2 failed embryo transfer cycles, who underwent a subsequent frozen embryo transfer (FET) at Avicenna Fertility Center, Tehran, Iran, from March 2021–2022 were extracted from medical records. Participants were allocated to the intralipid group (n = 132), receiving 100 mL intravenous intralipid 20% 1 wk before FET, if beta-human chorionic gonadotropin was positive, the same dose was given every 4 wk until the end of the first trimester, or to the control group (n = 138), undergoing routine FET treatments. Outcomes included biochemical, clinical, and ongoing pregnancy, abortion, and live birth. Results: Biochemical pregnancy rate was significantly higher in the intralipid group compared with controls (51.5% vs. 37.7%, p = 0.022). Clinical pregnancy (43.2% vs. 36.2%), ongoing pregnancy (28.8% vs. 18.8%), and live birth (25.8% vs. 17.4%) also favored the intralipid group, although these differences did not reach statistical significance (p > 0.05). Abortion rates were comparable between groups (25.8% vs. 21.0%, p = 0.357). Conclusion: Intralipid may improve biochemical pregnancy rates and shows a non-significant positive trend in other pregnancy outcomes in recurrent implantation failure cases, warranting confirmation in larger randomized controlled trials.
Background: Individuals with spinal cord injury (SCI) face fertility concerns due to various causes, such as low sperm quality and ejaculatory dysfunction. Consequently, different sperm retrieval techniques are used for these cases, including testicular sperm extraction (TESE) and electroejaculation (EE). Clinical and neonatal outcomes have been reported inconsistently between these 2 methods. Objective: This study aimed to compare the chemical pregnancy, clinical pregnancy, and live birth rate in men with SCI undergoing intracytoplasmic sperm injection using sperm obtained via EE vs. TESE. Materials and Methods: This retrospective cohort study was conducted between 2017 and 2023. 37 men with SCI underwent 2 different sperm retrieval techniques. Sperm was retrieved using EE in 18 cycles, while TESE was performed in 36 cycles. Then, chemical, clinical, and live birth rates were reported. Results: Overall, 21 (38.8%) chemical pregnancies were obtained. Moreover, 19 (35.18%) clinical pregnancies were achieved. The live birth rate was 20.3%. No statistically significant differences were observed between the EE and TESE groups in terms of chemical pregnancy (44.4% vs. 36.1%, p = 0.55), clinical pregnancy (33.3% vs. 36.1%, p = 0.89), or live birth rates (22.2% vs. 19.4%, p = 0.81). Conclusion: Both retrieval techniques, EE and TESE, can be applicable strategies for intracytoplasmic sperm injection procedures in men with SCI with no discrepancy in pregnancy outcomes.
Background: Endometriosis is one of the most common gynecological conditions, and the gold standard for its diagnosis is laparoscopy. Cytokeratin fragment 21-1 (CYFRA 21-1) has emerged as a potential biomarker candidate due to its strong association with endometriosis. The mechanisms underlying the cleavage of cytokeratin-19 into CYFRA 21-1 remain unclear. Tumor necrosis factor alpha (TNF-α) may play a regulatory role in this process. Objective: This study aimed to analyze the correlation between intraperitoneal TNF-α levels and CYFRA 21-1 expression levels in women with endometriosis. Materials and Methods: This was an analytical study with a cross-sectional study design, involving 38 women diagnosed with endometriosis and 35 non-endometriosis women as controls. Both CYFRA 21-1 and TNF-α concentrations were measured using the Enzyme-Linked Immunosorbent Assay method. Urine creatinine was measured using the Electrochemiluminescence Immunoassay method, while clinical data were collected through medical records. Results: The mean intraperitoneal TNF-α level was significantly higher in the endometriosis group compared to controls (p < 0.001). A significant positive correlation was found between intraperitoneal TNF-α concentrations and CYFRA 21-1 levels (p < 0.001; r 0,662 [95% CI: 0.426-0.814]), indicating a strong association. Furthermore, a strong positive correlation was observed between the urinary CYFRA 21-1 to creatinine ratio and intraperitoneal TNF-α levels, particularly during the proliferative phase of the menstrual cycle. Conclusion: These findings suggest that TNF-α may influence CYFRA 21-1 expression in a cycle phase-dependent manner, supporting the potential role of CYFRA 21-1 as a non-invasive biomarker for endometriosis, particularly during the proliferative phase.
Background: Cyclophosphamide (CP), a commonly used chemotherapy drug, induces oxidative stress and damages testicular tissue, leading to impaired spermatogenesis. Objective: This study aimed to evaluate the effects of selenium, a potent antioxidant, on sperm parameters in adult mice treated with CP. Materials and Methods: In this experimental study, 32 adult male NMRI mice were randomly divided into 4 groups (n = 8/each): A) control, B) CP (100 mg/kg/wk, intraperitoneally), C) selenium (1 mg/kg/day, intraperitoneally), and D) CP + selenium. After 35 days of treatment, spermatozoa were collected from the caudal epididymis. Basic sperm parameters (motility, count, viability, morphology, and tail length), and functional parameters (plasma membrane integrity, nuclear maturity, and DNA damage) were evaluated. Daily sperm production was evaluated using the left testis. Serum levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) were also measured. Results: In the CP group, sperm motility, count, viability, membrane integrity, normal morphology, tail length (p < 0.001), nuclear maturity (p < 0.05), DNA integrity, daily sperm production (p < 0.001), and TAC (p < 0.001) were significantly reduced, while MDA levels increased (p < 0.001) vs. controls. In the CP + selenium group, motility (p < 0.001), count (p < 0.01), viability (p < 0.001), membrane integrity, normal morphology (p < 0.01), tail length (p < 0.05), DNA integrity, daily sperm production (p < 0.001), and TAC (p < 0.05) significantly improved, with reduced MDA levels (p < 0.001) compared to CP group. Conclusion: CP impaired sperm quality and antioxidant status through oxidative stress in mice, whereas selenium co-administration mitigated these adverse effects by improving sperm parameters, enhancing antioxidant capacity, and reducing lipid peroxidation, indicating protection against CP-induced reproductive toxicity
Background: Oligoasthenoteratozoospermia (OAT) is one of the most common multifactorial causes of male infertility. Platelet-rich plasma (PRP), a biological product, has emerged as a promising regenerative therapy in various fields of medicine, including reproductive health. Therefore, we investigated the effect of PRP administration on sperm DNA fragmentation in OAT men. Objective: The aim was to evaluate the effect of intratesticular injection of PRP on DNA fragmentation index (DFI) in men with idiopathic OAT and assess its potential as a novel therapeutic intervention to enhance sperm DNA integrity. Materials and Methods: This randomized controlled trial study involved 160 infertile men diagnosed with OAT without underlying diseases who were referred to the infertility center of Fatemieh Infertility Center, Hamadan, Iran, from July 2023 to July 2024. The participants were randomly assigned to intervention and control groups using a block randomization method. The intervention group received 1-2 cc of PRP in each testicle. Sperm parameters and DFI were measured; a hormonal study was also performed before and after the procedure. Results: The results revealed a significant difference in concentration (p = 0.030), progressive motility (p < 0.001), DNA fragmentation (p < 0.001), normal morphology (p < 0.001), and also testosterone levels (p <0.001) between groups after PRP injection. Conclusion: PRP Injection into the testis appears to be a safe, minimally invasive, and potentially effective therapeutic approach in enhancing sperm quality and reducing DFI in men with OAT.
