Search Results (91)

Background: Matrix metalloproteinases (MMPs) have been found to be associated with reproductive complications, including female infertility. This study was conducted to explore the link between MMPs in non-obese women with unexplained infertility (UI) in comparison to women with male factor infertility (MFI) as controls. Methods: This pilot exploratory study was carried out on 25 women, 11 with UI and 14 with MFI, undergoing IVF. Blood was drawn on day 21 of the luteal phase. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was undertaken for 12 matrix metalloproteinase proteins. Welch’s t-test and a permutation test were used to compare group means, and Pearson’s correlations to examine relationships with matrix metalloproteinases. Results: No significant differences were seen for baseline demographics and hormonal parameters between the groups, and parameters of the response following IVF did not differ. In the UI group, MMP-3 levels were lower (p = 0.045), while MMP-1 and MMP-17 levels were higher (p = 0.007 and p = 0.010, respectively) compared to the MFI group. In MFI alone, MMP-1 positively correlated with vitamin D₃ (p < 0.05). Conclusions: This exploratory study suggests altered circulating MMP-1, MMP-3, and MMP-17 profiles in women with unexplained infertility. These findings require confirmation in larger cohorts and in studies examining endometrial tissue expression and MMP functional activity. Full article

Background: Chronic endometritis (CE) is a subtle, often asymptomatic endometrial inflammation marked by CD138⁺ plasma cell infiltration and linked to recurrent implantation failure (RIF), recurrent pregnancy loss (RPL), and unexplained infertility. Emerging evidence implicates endometrial microbiome dysbiosis in CE. Objective: To systematically review and conduct meta-analysis on the association between CE and endometrial microbiome alterations and their reproductive implications. Methods: We searched MEDLINE, Embase, Web of Science, Scopus, Cochrane CENTRAL, and Google Scholar for studies diagnosing CE via CD138 immunostaining, assessing microbiota with molecular techniques. Data extraction, quality assessment, and meta-analysis were performed. Results: Twenty-two studies including 4022 women were analyzed. CE was associated with reduced prevalence of Lactobacillus-dominated microbiota and increased detection of non-Lactobacillus species, particularly Streptococcus spp., Enterococcus spp., Escherichia coli, Staphylococcus spp., Ureaplasma spp., and Gardnerella vaginalis. In the meta-analysis (2947 women), Enterococcus spp. and Ureaplasma spp. were significantly more prevalent in women with CE, whereas Streptococcus spp., E. coli, Staphylococcus spp. and G. vaginalis showed non-significant trends. Only E. coli and Streptococcus spp. showed significant heterogeneity between-studies. Conclusions: CE is linked to microbial dysbiosis with reduced Lactobacillus dominance and enrichment of potentially pathogenic taxa, notably Enterococcus and Ureaplasma spp. These findings suggest that the endometrial microbiome contributes to chronic inflammation and adverse reproductive outcomes, yet heterogeneity and limited evidence call for standardized diagnostics and robust trials before clinical implementation. Full article

Semen parameters, including sperm counts, have rapidly declined in men across the globe over the last five decades. Although this decline remains unexplained, lifestyle factors may affect male fertility. Recently, several studies highlighted a potential link between non-steroidal anti-inflammatory drug (NSAID) usage, such as naproxen and ibuprofen, and declining male fertility. However, the mechanisms by which these common analgesics affect male fertility, including their effects on the blood–testis barrier (BTB), remain poorly characterized. Utilizing an in vitro rhesus macaque non-human primate (NHP) BTB model, we demonstrate that serum levels of naproxen and ibuprofen alter the function of BTB. Following short-term naproxen and ibuprofen treatment of NHP primary Sertoli cells, we show that these NSAIDs increase the transepithelial electrical resistance, indicating an overall strengthening of the Sertoli cell junctions. Furthermore, naproxen and ibuprofen treatment alter the expression of genes involved in maintaining the BTB. Specifically, the genes that were significantly expressed in response to ibuprofen exposure were enriched for human phenotypic abnormalities linked to male factor infertility. Together, these results suggest that short-term naproxen and ibuprofen treatment disrupt the function of the BTB by altering the integrity of the Sertoli cell junctions, proposing a potential role of NSAIDs in male factor infertility. Full article

Background/Objectives: To evaluate the diagnostic yield of phenotype-guided cytogenetic and targeted molecular genetic testing in patients referred for infertility and reproductive disorders within a tertiary medical genetics referral pathway. Methods: This retrospective study included 900 consecutive patients (473 males, 427 females) referred to a tertiary medical genetics center between January 2020 and December 2024. Conventional karyotyping was performed in all patients. Additional targeted molecular tests were applied based on clinical indication: Y chromosome microdeletion analysis in azoospermia or oligospermia, CFTR sequencing in suspected congenital bilateral absence of the vas deferens, and F2/F5 genotyping in recurrent pregnancy loss (RPL). Diagnostic yield was analyzed in a predefined subgroup of 566 patients with RPL, unexplained infertility, azoospermia, or oligospermia; remaining referrals were included in descriptive cytogenetic analyses only. Results: Chromosomal abnormalities were identified in 3.22% (29/900) of the total cohort and in 5.12% (29/566) of the diagnostic-yield cohort. Targeted testing yields were 3.75% (6/160) for Y chromosome microdeletions, 9.38% (3/32) for CFTR variants, and 3.31% (4/121) for F2/F5 variants. Diagnostic yield varied markedly by phenotype, being highest in azoospermia (33.3%), followed by oligospermia (6.6%), RPL (5.3%), and unexplained infertility (3.1%). In unexplained infertility, all chromosomal abnormalities were detected in female patients. Conclusions: In a tertiary referral setting, phenotype-guided genetic testing provides the greatest diagnostic value in well-defined infertility phenotypes, particularly azoospermia. Lower yields in other referral groups support a targeted, indication-based approach to genetic evaluation and highlight the need for advanced genomic strategies in persistently unexplained cases. Full article

Multimorbidity is a key global trend across healthcare fields, including gynecology. It is strongly associated with an overall poorer health status. Statistics indicate that in the 21st century most women experience at least one gynecological disease. Meanwhile, there is a consistent increase in the prevalence of obesity associated with chronic inflammation and hyperestrogenism. Alongside other factors, it leads to a growing prevalence of hyperproliferative diseases of the female reproductive system (FRS), encompassing both benign and malignant conditions. While advanced-stage malignant tumors can be linked to missed detection and wrong checkup strategies, benign neoplasms can compromise the ovarian reserve and thus cause major concerns. The prevailing benign FRS tumors are uterine fibroids (UFs) and benign ovarian tumors (BOTs), including serous and mucinous cystadenomas. It appears that an increase in certain benign FRS tumors is occurring in parallel with a rise in infertility (especially “unexplained infertility”) and reproduction failures, potentially associated with endometrial dysfunction. Thus, the endometrium is currently considered a critical area of research due to its vital role as the site of blastocyst adhesion and implantation, especially in patients with comorbidities. In this context, this article highlights the significance and pathophysiological characteristics of UFs and BOTs and their impact on defective endometrial receptivity. Full article

Oxidative stress (OS) and sperm DNA fragmentation (SDF) are complementary contributors to male infertility. OS characterizes a compromised seminal redox status, whereas SDF quantifies downstream genomic damage. Human sperm are highly susceptible to redox damage due to lipid-rich membranes and disrupted post-meiotic DNA-repair capacity. Excess reactive oxygen species (ROS) can cause lipid peroxidation, oxidative base lesions, and DNA strand breaks that impair fertilization, embryo development, and pregnancy outcomes. This review explains how OS promotes genomic instability and summarizes the main laboratory assays that assess redox status and SDF in semen. These include direct ROS chemiluminescence assay, oxidation–reduction potential, total antioxidant capacity/ferric reducing antioxidant power, and lipid peroxidation biomarkers, alongside SDF platforms (Sperm Chromatin Structure Assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling, alkaline/neutral Comet, and sperm chromatin dispersion). Additionally, guideline-aligned indications are highlighted to clarify the conditions for testing OS and SDF. OS testing is most relevant in men with leukocytospermia or suspected genital tract infection or inflammation, including dysbiosis; in cases of major modifiable exposures such as smoking or heat; and for early monitoring after treatment. SDF testing is particularly informative in couples with recurrent pregnancy loss and in unexplained infertility with normal semen parameters. Combined OS and SDF testing is recommended in clinical varicocele, repeated in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) failure, poor embryo development, and follow-up after targeted therapy. Management centers on treating infection and inflammation, improving lifestyle and environmental factors, considering varicocelectomy when indicated, using targeted antioxidant therapy in men with documented OS, and selectively applying sperm selection technologies or testicular sperm for ICSI when SDF remains high. Priorities include assay standardization, etiologic attribution of DNA damage, and trials testing OS/SDF-guided pathways with live birth as the primary endpoint. When used selectively and in the appropriate context, OS and SDF testing can help refine diagnosis, improve counseling, and help personalize care of infertile couples. Full article

Background/Objectives: Infertility is a major public health concern, affecting one in six individuals worldwide and nearly one-quarter of couples in France. While a male, female, or combined factor can be identified in approximately 75% of cases, infertility remains unexplained in 10–25%. Genital tract infections account for roughly 15% of male infertility cases and are often asymptomatic, being detected incidentally during routine evaluation prior to assisted reproductive technology (ART). Emerging evidence suggests that the seminal microbiota may contribute to sperm quality and male reproductive health. This systematic review aims to evaluate whether specific microbial profiles are associated with alterations in semen parameters. Methods: A comprehensive literature search was conducted in PubMed and ScienceDirect, yielding 165 and 1418 records, respectively. In the end, 20 articles were included in this systematic review. Results: Men with normal semen parameters commonly exhibited a higher abundance of Lactobacillus and Bifidobacterium, whereas Prevotella was more frequently observed in individuals with impaired semen quality. Several taxa—such as Gardnerella, Corynebacterium, and Staphylococcus spp.—were detected in both normal and altered semen profiles, suggesting that their impact on sperm quality may depend on reaching a pathogenic threshold. Conclusions: Current evidence supports an association between seminal microbiota composition and sperm quality. However, the heterogeneity of available studies and the lack of standardized methodologies limit the ability to draw firm conclusions. Further well-designed studies are required to clarify causal relationships and to determine the clinical relevance of seminal microbiota assessment in male infertility. Full article

Background: Optimizing pregnancy outcomes while minimizing gonadotropin exposure and treatment burden remains a major goal in ovulation induction for intrauterine insemination (IUI), particularly for patients with polycystic ovary syndrome (PCOS) or high ovarian reserve. Sequential protocols combining early letrozole with late-onset recombinant FSH (rFSH) have been proposed to enhance efficiency while reducing medication requirements. However, real-world comparative data adjusting for baseline differences are limited. Methods: This retrospective comparative cohort study included 764 IUI cycles performed between January 2022 and October 2025. Cycles were stimulated either with conventional rFSH (n = 372) or letrozole plus late-onset rFSH (n = 392). The primary outcome was pregnancy per cycle, defined by a positive serum β-hCG. Secondary outcomes included clinical pregnancy, total gonadotropin dose, endometrial thickness, cycle cancelation, and obstetric outcomes. Confounding was addressed using multivariable logistic regression, propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and doubly robust estimation. Results: The crude pregnancy rate was higher in the letrozole plus late rFSH group compared with conventional rFSH (14.8% vs. 9.9%, p = 0.042). Women in the sequential stimulation group had higher AMH levels, higher antral follicle counts, and a higher prevalence of PCOS (32.4% vs. 16.3%, p = 0.001). After adjustment for age, ovarian reserve, and other baseline characteristics using regression, PSM, and IPTW, the stimulation protocol was not independently associated with pregnancy (adjusted OR 1.09, 95% CI 0.68–1.74; p = 0.657). Female age remained the strongest predictor of pregnancy (adjusted OR 0.70 per year increase; p < 0.001). The sequential protocol required a significantly lower total gonadotropin dose (median 375 IU vs. 750 IU; p < 0.001) while maintaining comparable cycle cancellation and safety outcomes. Conclusions: Sequential stimulation with letrozole plus late-onset rFSH achieves pregnancy outcomes comparable to conventional rFSH stimulation while significantly reducing gonadotropin requirements. After adjustment for PCOS status and ovarian reserve, the protocol itself did not independently influence pregnancy, suggesting that crude differences reflected baseline imbalances rather than true treatment effects. This approach represents a clinically efficient, gonadotropin-sparing option for IUI, particularly in patients at risk for excessive ovarian response. Full article

Background/Objectives: The most prevalent benign tumors in women are uterine fibroids. Most patients—more than half—do not exhibit any symptoms, but the most common clinical signs include irregular uterine bleeding, pelvic pain, gastrointestinal problems, increased frequency of urination, and, in some cases, infertility. Venous thromboembolism is a very rare consequence, especially when significant uterine fibroids are present. This syndrome usually develops because of pelvic vascular systems being compressed, which causes venous stasis. Pharmacological treatment, minimally invasive procedures, and surgical techniques are examples of therapy alternatives. The purpose of this study is to present, compare, and potentially elucidate the underlying mechanisms of VTE development in fibroids. Methods: we have synthesized findings from 24 documented instances of venous thromboembolism (VTE) linked to uterine fibroids. Results: the principal mechanism underlying thromboembolic events was identified as the mechanical compression of pelvic venous structures due to mass effect. Additionally, we recognized other pertinent risk factors, including oral contraceptive use, May-Thurner syndrome, myomatous erythrocytosis, and intravenous leiomyomatosis. None of the reviewed case reports provided evidence of confirmed inherited thrombophilia in the patients under investigation. The femoral and popliteal veins, primarily in the left leg, were most frequently impacted by thrombosis and the ensuing blockage. Imaging techniques confirmed that individuals suffered pulmonary embolisms in half of the cases. When the right treatment was given as soon as possible, most of VTEs had favorable outcome. In almost half of the cases examined, the patient had a hysterectomy. Since all symptoms were alleviated and the chance of additional thromboembolic consequences was reduced, this treatment strategy turned out to be the most successful. Conclusions: Clinicians should maintain a low threshold for venous imaging in women with large pelvic masses and unilateral limb symptoms. Despite being uncommon, VTE associated with UFs can cause serious morbidity. Mechanical venous compression is the main mechanism, which is often exacerbated by additional prothrombotic variables. Clinicians should maintain a low threshold for venous imaging in women with significant pelvic masses and unilateral limb symptoms, look for concurrent thrombophilia, and investigate early surgical consultation to address compressive etiologies when VTE is still unexplained. It would be simpler to ascertain the actual incidence and pinpoint risk variables that can be altered with standardized reporting of fibroid-associated VTE and prospective registries. Full article

Background/Objectives: Endometriosis is a chronic, inflammatory, estrogen-dependent disease that has historically been underdiagnosed, especially in patients with unexplained infertility. On average, diagnosis is delayed by 11 years, underscoring the need for precision medicine to improve outcomes. To compare disease severity and anatomical distribution of endometriosis between patients with unexplained infertility who underwent noninvasive Receptiva BCL6 testing before surgery and those who did not. Methods: A cross-sectional analysis was conducted on 195 women with unexplained infertility and histologically confirmed endometriosis following diagnostic video laparoscopy, with or without robotic assistance. Disease severity was staged using updated guidelines. Anatomical sites of endometriosis were documented. Patients were grouped based on whether they had undergone the Receptiva BCL6 overexpression test prior to surgery. Results: Of the 195 patients, 43 underwent Receptiva testing; 41 of them tested positive and were confirmed to have endometriosis during surgery. These patients had fewer affected anatomical regions (3.14 ± 2.09) compared to those without testing (3.93 ± 2.26; p = 0.04). The No Receptiva group also had more high-stage cases (70.39% vs. 65.12%, p-value: 0.038). In both groups, endometriosis most frequently involved the periureteral region, rectovaginal septum, and ovaries, though ovarian tissue was rarely excised to preserve fertility. Conclusions: Among patients with unexplained infertility and confirmed endometriosis, those who had preoperative Receptiva testing showed lower disease burden and severity. These findings support the potential utility of noninvasive testing to enrich diagnostic accuracy and guide earlier, more targeted intervention. Full article

Unexplained infertility and idiopathic recurrent pregnancy loss (RPL) have a prevalence of 1–5% of women of reproductive age in different populations. There are a few reports comparing the circulating immune cell populations and subpopulations in these medical entities in admixed populations. The study aimed to assess the different leukocyte, mononuclear cell populations, and T lymphocyte subpopulations and HLADR expression, as a marker of activation, in an admixed group of Venezuelan women: 80 controls, 73 women with RPL (53 primary, 20 secondary), and 26 infertile (20 primary, six secondary). Endometriosis was clinically ruled out in all patients and controls. Total leukocytes were 10–12% higher (p < 0.0001) in the infertile group, while neutrophils were 11% in the infertility group (p < 0.0001). In contrast, lymphocytes, CD3CD4 cells, NK cells, and HLADR+ cells were elevated (10–15, 18–22, 50–60, and 700–800% increase, respectively) in all patient groups. Changes in B cell numbers and monocyte counts were also observed. HLADR expression was significantly increased (p < 0.0001) in T cells, CD56+ cells, and monocytes of all patients. In infertile patients, a correlation was recorded between HLADR and T memory cells. Marked differences in peripheral blood leukocytes, NK cells, monocytes, T-cell populations, and HLADR suggest a proinflammatory effect. HLADR can be used as a simple biomarker to monitor pharmacological treatment in these patients. Full article

Killer-cell immunoglobulin-like receptors (KIRs) play a crucial role in the cytotoxic activity of natural killer (NK) cells, encompassing both inhibitory and activating types. A higher ratio of cytotoxic to inhibitory receptors may harm successful pregnancies by disrupting the uterine environment. Ongoing debates surround the impact of KIR gene variations on recurrent pregnancy loss (RPL) and infertility across populations. This study aimed to explore KIR gene polymorphisms in RPL and infertility among the Venezuelan admixed population. The Venezuelan population exhibits a genetic mix of Caucasian, African, and local Amerindian ancestry, distinguishing it from other Latin American admixed populations. This study included 100 controls and 86 patients: 73 women with idiopathic RPL (53 primary and 20 secondary) and 13 infertile patients (4 primary and 9 secondary). The frequency of activating receptors KIR2DS2 and KIR2DS3 was significantly lower (p < 0.05) in the whole patient group compared to controls. However, when analyzing the haplotypes and genotypes, the significance between patients and controls was lost. When comparing RPL and infertile patients, KIR2DS2, KIR2DL3, 2DL5, and 3DL1 were significantly less frequent in infertile women. In infertile women, KIR2DS3 frequency was increased compared to controls and RPL. The results suggest that the frequency of inhibitory receptors may differentiate patients with RPL and infertility. Further studies should ascertain the expression and function of KIRs in uterine NK cells in patients with RPL and infertility. Full article

Background/Objectives: Infections of the urogenital tract have experienced renewed interest in recent years, due to their frequency and also their impact on sperm parameters and the fertilizing quality of spermatozoa. Chlamydia trachomatis (CT) represents an intracellular microorganism responsible for sexually transmitted infections (STIs) in men and women. A reliable method of diagnosing this infection is therefore necessary because of the rapid onset of infection and the increase in STI-related diseases and their treatment costs. Methods: We analyzed 2371 semen samples from infertile men and detected the presence anti-CT IgG antibodies by Enzyme-Linked Immunosorbent Assay (ELISA), followed by real-time PCR confirmation of CT DNA whose target is the lipopolysaccharide (LPS). We assessed the effect of CT infections on characteristic parameters of sperm quality, including concentration, motility, viability, and morphology. The impact on sperm DNA quality was assessed by DNA fragmentation index (S) and decondensation of chromatin index (SDI) by the TUNEL technique. Results: Analysis of the results showed significant differences in mobility, concentration, and morphology (p < 0.05) between the control group, positive CT infection with normal spermiogram status (CT+/Normal SG) group, and positive CT infection with abnormal spermiogram status (CT+/Abnormal SG) group. A significant increase in the DFI and the SDI was found between the control group and the case groups, respectively (p < 0.01). Conclusions: Our results confirm that CT infection is associated with significant alterations in sperm parameters and sperm DNA quality. Regular CT screening by qPCR should be encouraged in couples suffering from unexplained infertility. Full article

Complement (C) proteins have been linked to infertility and reproductive outcomes. This study was undertaken to determine the association of complement proteins in non-obese women before in vitro fertilization (IVF) with unexplained infertility (UI) compared to women with male factor infertility (MFI) as controls. We hypothesized that complement protein factors may provide evidence for the underlying mechanism in UI. In this exploratory pilot study, 25 women (UI = 14 and MFI = 11) undergoing IVF had blood drawn on day 21 of the luteal phase. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was undertaken for 25 complement pathway-related proteins. Student’s t-test was used to compare group means and Pearson’s correlations to examine relationships with complement proteins. Baseline demographics and hormonal parameters did not differ between groups, and parameters of the response following IVF did not differ. In the UI group compared to the MFI group, there were lower levels of properdin (p = 0.03) that may reduce endometrial receptivity and impact follicular development, lower C3a anaphylatoxin des arginine (C3adesArg) (p = 0.02) that may reduce endometrial vascularity, lower C4 (C4) (p = 0.04), indicating reduced alternate pathway activation, and lower C8 (C8) (p = 0.04) that also may affect the endometrium. In UI alone, properdin negatively correlated with high-density lipoprotein cholesterol (HDL-c), and C8 positively correlated with thyroid-stimulating hormone (TSH) and Free-triiodothyronine (Free-T3) (p < 0.05). These preliminary findings indicate reduced complement activity among UI women, warranting further mechanistic investigation. Full article

Background: Feminizing adrenocortical tumors (FATs) are an exceedingly rare subset of adrenal neoplasms, typically affecting adult men and characterized by an excess of estrogen, suppressed gonadotropins, and gynecomastia. Most FATs are malignant, with a poor prognosis and a high risk of recurrence. Case Presentation: We report the case of a 24-year-old male with bilateral gynecomastia, abdominal mass symptoms, and one year of unexplained infertility. A hormonal evaluation revealed elevated estradiol (90.1 pg/mL) and suppressed ACTH (2.6 pg/mL), with inappropriately normal cortisol levels (12.1 µg/dL). Imaging identified a right adrenal mass. The patient underwent open adrenalectomy, and histopathology confirmed stage II adrenocortical carcinoma (T2NxM0) with autonomous estradiol secretion, negative margins, and a Ki-67 index of 10%. Postoperatively, gonadal function normalized, and infertility resolved at two months. The multidisciplinary tumor board considered but did not initiate adjuvant mitotane, given the completely resected low-stage disease. Conclusions: This case illustrates the rare presentation of feminizing adrenocortical carcinoma with reversible infertility and highlights the importance of early recognition and close surveillance. In addition, our literature review of 12 male cases reported between 2015 and 2025 emphasizes gynecomastia as the hallmark presentation and discusses emerging evidence supporting active surveillance as a potential alternative to adjuvant mitotane in selected low-risk patients. Full article