Female Infertility

What was studied?

This study investigated the causal relationships between gut microbiota and female reproductive tract inflammation and infertility, specifically employing Mendelian randomization (MR). MR is a method that utilizes genetic variants to elucidate the causal influence of modifiable exposures, specifically gut microbiota, on specific health outcomes, such as reproductive tract inflammation and infertility.

Who was studied?

The analysis utilized existing genome-wide association study (GWAS) datasets primarily involving individuals of European ancestry. It included genetic data from 18,340 participants in the MiBioGen consortium to analyze microbiome quantitative trait loci, which are host genetic variations influencing gut microbiota composition. The study evaluated causal relationships between 119 bacterial genera and female reproductive conditions using summary data predominantly from the FinnGen biobank, validated by additional datasets from the UK Biobank.

What were the most important findings?

This research provided robust evidence linking specific gut microbiota to female reproductive tract inflammation and infertility. Bacterial genera such as Lachnospiraceae and Ruminococcus were causally linked to an increased risk of pelvic inflammatory disorders. In contrast, Butyricicoccus and Prevotella were associated with a protective effect against inflammation. Detailed analyses further identified associations specific to reproductive organs: Coprococcus and Ruminococcus increased the risks of salpingitis and oophoritis, whereas Coprococcus reduced the risk. Similarly, Eubacterium (Fissicatena group) and Oscillospira increased the risk of uterine inflammation, while Haemophilus decreased the risk of cervical inflammation.

Faecalibacterium was associated with increased infertility risk. Conversely, genera such as Erysipelotrichaceae, Lactococcus, and Ruminococcus (torques group) had protective associations. Detailed subtype analyses revealed bacteria significantly associated with specific infertility types, including anovulation and tubal infertility. The findings were robustly validated through sensitivity analyses, showing no reverse causality, suggesting the microbiota directly influence these conditions rather than being merely correlated.

What are the greatest implications of this study?

This study’s findings have substantial implications for the diagnosis, prevention, and targeted treatment of reproductive health issues in women. Identifying gut bacteria associated with increased or decreased risks opens pathways for personalized probiotic therapies and nutritional interventions aimed at maintaining or restoring reproductive health. Clinicians can potentially leverage these insights to design preventive strategies tailored to the microbiome profile, thereby reducing the incidence of reproductive tract inflammations and infertility. Further research is encouraged to explore the microbiome's precise mechanisms and clinical applications.

What was studied?

This study utilized a two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between gut microbiota composition and infertility in males and females. Genetic variants associated with specific gut microbiota taxa served as instrumental variables (IVs) to assess their direct influence on the incidence of infertility. The researchers aimed to clarify whether variations in gut bacteria directly contribute to infertility or if these associations are merely correlational due to confounding factors or reverse causation.

Who was studied?

The study analyzed genetic data from the MiBioGen consortium, which included 18,340 participants across 24 international cohorts primarily from European descent. Infertility data came from the FinnGen consortium, with 994 male infertility cases and 100,050 controls, and 9,831 female infertility cases and 94,394 controls. The analysis excluded individuals with unclear sex, high genotype deficiency, excess heterozygosity, or non-Finnish ancestry.

What were the most important findings?

The MR analysis confirmed significant causal relationships between specific gut microbiota and infertility risks. For male infertility, five taxa (Bacteroidaceae, Bacteroides, Enterobacteriales, Romboutsia, Enterobacteriaceae) were associated with a reduced risk, whereas Allisonella genus increased infertility risk. For female infertility, beneficial associations (reduced risk) were found with multiple taxa, including Ruminococcus torques group, Desulfovibrio, Bifidobacterium, Family XIII AD3011 group, Ruminococcaceae NK4A214 group, Holdemania, Bifidobacteriales order, Actinobacteria phylum, Bifidobacteriaceae family, and Actinobacteria class. Conversely, Faecalibacterium was significantly linked to an increased risk of female infertility. The MR analysis was robust and well-supported by sensitivity tests, including Cochran Q and MR-PRESSO analyses, indicating reliable results free from major horizontal pleiotropy or heterogeneity.

What are the greatest implications of this study?

The study provides strong evidence that gut microbiota directly affects infertility risks in both males and females, highlighting potential microbiome-based targets for diagnostic, preventive, and therapeutic interventions. For clinicians, these findings emphasize the importance of assessing gut microbiota composition when managing infertility. Identifying protective and harmful bacterial taxa offers actionable insights for developing personalized probiotic treatments, nutritional recommendations, and lifestyle modifications aimed at optimizing fertility outcomes.

What was studied?

The study examined how chronic endometritis (CE) influences pregnancy outcomes in women experiencing infertility related to endometriosis. Specifically, it evaluated whether the coexistence of CE in these women affected their ability to conceive and carry pregnancies successfully. Researchers explored the incidence of pregnancy complications and live birth outcomes following combined laparoscopic and hysteroscopic surgical treatment.

Who was studied?

The study involved 685 women diagnosed with infertility associated with endometriosis. Among these participants, 318 women were diagnosed with chronic endometritis (CE group), while 367 women did not have CE (non-CE group). A subset consisting of 123 clinically pregnant women from the CE group and 369 from the non-CE group was analyzed in depth. These women underwent combined laparoscopy and hysteroscopy between January 2018 and December 2020. Data was meticulously gathered from medical records and telephone follow-ups over 24 months.

What were the most important findings?

The research revealed that chronic endometritis was highly prevalent (46.42%) in patients with endometriosis-associated infertility. Patients diagnosed with CE had increased rates of pregnancy complications compared to those without CE. Specifically, there was a significantly higher occurrence of placenta previa, gestational hypertension, and cesarean deliveries in the CE group. The cumulative pregnancy rate post-surgery was lower in patients with both EMS and CE compared to those without CE, although this difference was not statistically significant. However, notably, higher Endometriosis Fertility Index (EFI) scores (7-10) correlated strongly with improved pregnancy outcomes in both groups, suggesting that EFI scores remain reliable predictors of fertility success after surgical intervention.

What are the greatest implications of this study?

The study underscores the importance of identifying and treating chronic endometritis in patients suffering from endometriosis-related infertility. Clinicians should be particularly aware that CE significantly increases the risk of adverse pregnancy outcomes, including placenta previa, gestational hypertension, and higher rates of cesarean deliveries. The findings support incorporating routine diagnostic evaluations and proactive management of CE in fertility treatments. They also emphasize the value of combined hysteroscopic and laparoscopic surgical interventions to potentially improve pregnancy outcomes, with careful monitoring and counseling regarding possible complications post-surgery.

What was reviewed?

This review comprehensively examined current research on the microbiota of the female reproductive system, focusing specifically on its role in infertility and reproductive health. It analyzed literature investigating both the lower reproductive tract (vaginal microbiota) and the upper reproductive tract (uterus, fallopian tubes, and ovaries). The authors reviewed the microbial composition of these regions, highlighting the dominance of Lactobacillus species under normal conditions, and explored how deviations from this balanced microbial community—referred to as dysbiosis—might affect fertility outcomes and influence the success rates of assisted reproductive technologies (ART), particularly in vitro fertilization (IVF).

Who was reviewed?

The review summarized studies involving women across various reproductive statuses, including fertile women, infertile women, and women undergoing ART procedures. Literature assessing microbial differences between fertile and infertile groups, particularly in terms of vaginal and uterine microbiota composition, formed the basis of the review. The authors also incorporated evidence related to microbiome shifts associated with different life stages, hormone fluctuations, lifestyle influences, and environmental exposures, providing clinicians with an extensive view of factors affecting reproductive microbiota dynamics.

What were the most important findings?

The central findings of the review emphasized the critical role of Lactobacillus species in maintaining reproductive health through their dominance in the reproductive tract, particularly in the vagina. Lactobacilli were identified as crucial for creating an acidic environment that inhibits pathogen growth. Dysbiosis, characterized by reduced Lactobacillus abundance and increased prevalence of anaerobic bacteria like Gardnerella vaginalis, Atopobium vaginae, and Ureaplasma spp., was strongly linked to infertility, chronic inflammatory conditions, and notably poorer outcomes in IVF treatments, including lower implantation rates and increased pregnancy complications. The review highlighted a significant continuity of bacterial communities along the reproductive tract, suggesting a microbiological link from the lower to upper regions. Moreover, the potential influence of male partner semen microbiota on female reproductive health was underscored, suggesting that fertility evaluations should also consider the microbiome of the male partner.

What are the greatest implications of this review?

The review's greatest clinical implication is that clinicians should consider reproductive microbiota assessment as an integral part of fertility evaluations and infertility treatment strategies. Understanding the link between microbiota and infertility provides an opportunity to enhance reproductive outcomes by diagnosing and correcting microbial dysbiosis through targeted probiotics, lifestyle interventions, and possibly tailored antibiotic treatments. This approach could substantially improve IVF success rates and overall fertility management. Moreover, the identification of microbial signatures associated with fertility may facilitate personalized reproductive healthcare strategies, optimizing conditions not just for conception but also for the long-term reproductive health of couples and their offspring.

What was studied?

This study investigated the association between endometrial microbiota composition and reproductive outcomes in infertile patients undergoing assisted reproductive technologies (ART), including in vitro fertilization (IVF). Researchers specifically aimed to determine whether the presence or absence of specific bacterial taxa in the endometrial microbiota was linked to reproductive success, defined by live birth (LB), biochemical pregnancy (BP), clinical miscarriage (CM), or no pregnancy (NP). The study employed 16S rRNA sequencing to analyze both endometrial fluid and biopsy samples collected prior to embryo transfer.

Who was studied?

The study included 342 infertile women, aged 21 to 49, from 13 reproductive clinics across Europe, America, and Asia. These women were undergoing IVF or ovum donation treatments and had an average age of 36 years. The cohort consisted of patients with a variety of infertility causes, including advanced maternal age, male factor infertility, unexplained infertility, and ovarian pathology. All participants underwent a hormone replacement therapy cycle before embryo transfer, and their endometrial microbiota composition was analyzed to correlate it with reproductive outcomes.

What were the most important findings?

The study found significant differences in the endometrial microbiota composition between patients with successful reproductive outcomes (live birth) and those with unsuccessful outcomes (biochemical pregnancy, clinical miscarriage, or no pregnancy). Lactobacillus spp., particularly dominant in the endometrial microbiota, was consistently enriched in women who achieved live birth. In contrast, patients with unsuccessful outcomes exhibited a dysbiotic microbiota profile, characterized by higher levels of potentially pathogenic bacteria, including Gardnerella, Haemophilus, Klebsiella, Neisseria, Streptococcus, and Atopobium. These dysbiotic profiles were strongly associated with lower pregnancy rates and higher miscarriage rates. The study found that the microbiota composition of endometrial fluid (EF) and endometrial biopsy (EB) samples showed some discrepancies, though both sample types revealed similar associations with reproductive outcomes. The presence of Lactobacillus spp. was inversely correlated with pathogenic bacteria in successful pregnancies, highlighting its potential role in preventing microbial dysbiosis and ensuring a healthy reproductive environment conducive to embryo implantation.

What are the greatest implications of this study?

The study’s findings emphasize the importance of endometrial microbiota composition as a predictive biomarker for reproductive outcomes in infertility treatments. Clinicians can use this information to assess the microbial health of the endometrium before embryo transfer and potentially identify candidates who may benefit from interventions aimed at restoring a healthy microbiota. This may involve the use of probiotics, antimicrobial therapies, or other microbiome-modulating strategies to enhance the likelihood of a successful pregnancy, particularly in cases of recurrent implantation failure or unexplained infertility. Additionally, the results support the need for further research into the mechanisms by which specific pathogens disrupt implantation and pregnancy, potentially leading to improved diagnostic and treatment protocols for ART patients.

What was studied?

This study examined the vaginal and seminal microbiomes of couples with idiopathic infertility and their correlation with intrauterine insemination (IUI) outcomes. The researchers sought to determine whether the microbiomes of the vaginal and seminal fluids influence the success rate of IUI. They specifically focused on identifying any differences in the microbiota composition between women with successful and unsuccessful IUI outcomes, particularly in relation to Lactobacillus species, which are considered crucial for maintaining a healthy vaginal environment.

Who was studied?

The study involved 23 couples with idiopathic infertility undergoing their first IUI treatment at the Centro Scienze della Natalità in Milan, Italy. Both female and male partners participated, with vaginal swabs taken from the female participants and seminal fluid samples from the male participants on the day of the IUI procedure. The female participants had a mean age of 33 years, and the male participants were approximately 34 years old. The couples were all Caucasian, and the women underwent a comprehensive clinical evaluation to exclude any other known causes of infertility, such as endometriosis or male factor infertility.

What were the most important findings?

The study found that the vaginal microbiome composition differed significantly between women who achieved pregnancy following IUI and those who did not. Women with successful IUI outcomes had a vaginal microbiome predominantly dominated by Lactobacillus crispatus, which is associated with a healthy and stable vaginal ecosystem. On the other hand, women who experienced IUI failure showed a greater diversity in their vaginal microbiota, including higher levels of Bifidobacterium and other non-Lactobacillus species, indicating a more dysbiotic environment. The presence of Lactobacillus species, especially L. crispatus, was strongly associated with a higher probability of successful pregnancy. Interestingly, no significant differences in the seminal microbiome were observed between men whose partners experienced success or failure in IUI, suggesting that male seminal microbiota might not play as critical a role in IUI success as vaginal microbiota does.

What are the greatest implications of this study?

The findings suggest that the vaginal microbiome, particularly the dominance of Lactobacillus crispatus, could serve as an important biomarker for predicting IUI success in couples with idiopathic infertility. This underscores the potential value of incorporating vaginal microbiome analysis into fertility assessments prior to IUI procedures. Clinicians might consider characterizing the vaginal microbiome in these patients and explore interventions, such as probiotics or other microbiome-targeted therapies, to restore a more optimal microbial balance and improve reproductive outcomes. However, given the study's relatively small sample size, further research with larger cohorts is necessary to confirm these findings and determine the clinical applicability of microbiome-based interventions.

What was reviewed?

This review explored the relationship between genital tract microbiota dysbiosis and infertility in both men and women. It discussed how microbial imbalances in the vaginal, endometrial, seminal, and placental microbiomes can impair fertility, leading to complications such as bacterial vaginosis, poor sperm quality, and pregnancy-related issues like preterm birth. The review also examined how these microbiota imbalances affect reproductive health, suggesting that hormonal influences and microbial exchanges between partners play critical roles in fertility outcomes. The authors aimed to provide insights into how microbiome alterations can be used for better personalization of infertility treatments.

Who was reviewed?

The review primarily focused on studies involving both male and female infertility, including those with unexplained infertility and those undergoing assisted reproductive technologies (ART). It incorporated data on microbial composition from both sexes, specifically examining how dysbiosis in vaginal, endometrial, seminal, and placental microbiota can contribute to infertility and affect the success of treatments like in vitro fertilization (IVF). The review also addressed how microbial imbalances influence reproductive outcomes, drawing from clinical findings related to sperm quality, bacterial vaginosis, and pregnancy complications.

What were the most important findings?

The review highlighted the critical role of Lactobacillus species in maintaining a healthy vaginal microbiome. A dysbiotic vaginal microbiome, characterized by low Lactobacillus dominance and an overgrowth of pathogens such as Gardnerella, Prevotella, Mobiluncus, and Ureaplasma, was strongly associated with infertility, bacterial vaginosis, and adverse pregnancy outcomes. It was noted that female microbiota composition directly impacts pregnancy, with non-Lactobacillus-dominated environments leading to an increased risk of preterm birth and recurrent miscarriage. Similarly, seminal microbiota imbalances, including the overgrowth of bacteria such as Ureaplasma and Enterococcus, negatively influenced sperm quality, including motility and morphology, thereby affecting male fertility. The review also emphasized the concept of microbial trade-off between partners, where microbial dysbiosis in one partner could influence the reproductive microbiota of the other, further complicating fertility issues.

What are the greatest implications of this review?

The review's findings suggest that clinicians should consider the role of genital tract microbiota when diagnosing and treating infertility. The identification of dysbiosis, particularly the loss of Lactobacillus dominance, can serve as a useful diagnostic marker for reproductive health. Interventions aimed at restoring a healthy microbiome, such as the use of probiotics or antimicrobial therapies, could improve fertility outcomes and reduce complications during pregnancy. Furthermore, the concept of microbial trade-off between partners indicates that both individuals in a couple should be assessed and treated for microbiome imbalances, enhancing the chances of successful conception. The review calls for further research into microbiome-based diagnostics and therapeutics to offer more personalized and effective treatments for infertility.

What was reviewed?

This systematic review explored the role of the genital tract microbiome in fertility, with a focus on its impact on both natural conception and assisted reproductive treatments (ARTs), such as in vitro fertilization (IVF). The review aimed to consolidate current research on the microbiome's correlation with infertility, discussing how dysbiosis in various areas of the genital tract, such as the vagina, cervix, endometrium, and even the fallopian tubes, affects fertility outcomes. The study involved an analysis of 26 selected articles published until February 2021, using methods like PCR and RNA sequencing to examine microbial diversity and its relationship with infertility.

Who was reviewed?

The review included studies on women and couples with infertility, focusing on those who were either attempting to conceive naturally or undergoing ART treatments. These studies compared the microbiomes of infertile women with those of fertile women and examined the differences in microbial compositions, particularly in the vaginal, cervical, and endometrial environments. Additionally, the review included studies that explored how microbial imbalances could affect ART success rates, such as implantation and pregnancy rates in IVF treatments.

What were the most important findings?

The review highlighted that the genital tract microbiome plays a pivotal role in fertility, particularly the vaginal microbiome. Lactobacillus species, especially Lactobacillus crispatus, were consistently identified as crucial for maintaining a healthy environment conducive to fertility. A Lactobacillus-dominated microbiota was associated with better fertility outcomes, while dysbiosis, characterized by a reduction in Lactobacillus and an overgrowth of pathogens like Gardnerella vaginalis, Ureaplasma species, and other Gram-negative bacteria, was linked to infertility and poor ART outcomes. Notably, the presence of pathogens such as Chlamydia trachomatis and Gardnerella vaginalis was associated with infertility, even in the absence of symptoms like bacterial vaginosis (BV), suggesting that asymptomatic infections still have a significant impact on fertility. The review also discussed how vaginal and endometrial microbiomes could differ, with non-Lactobacillus-dominated endometrial microbiomes correlating with lower rates of implantation and pregnancy in IVF cases. Importantly, no studies were identified that focused on the microbiome of the fallopian tubes, highlighting an area for future research.

What are the greatest implications of this review?

The greatest implication of this review is that clinicians should consider the genital tract microbiome as a factor in infertility assessments and treatments. Dysbiosis, particularly a lack of Lactobacillus dominance, could serve as a diagnostic marker for fertility issues, and addressing microbiome imbalances through interventions such as probiotics or antibiotics could improve fertility outcomes. The review also emphasizes the need for standardized microbiome sampling and analysis methods to allow for more consistent and reliable clinical applications. Additionally, the importance of the vaginal microbiome, specifically Lactobacillus crispatus, as a predictor for ART success points to potential personalized treatments based on individual microbiome profiles, enhancing the precision of fertility treatments.

What was reviewed?

This review article explored the crucial role of the microbiome in infertility, examining how microbial imbalances in both male and female reproductive systems contribute to infertility. The review synthesized findings from multiple studies that focused on the genital tract microbiome and its impact on fertility. The research emphasized the importance of understanding the microbiome's influence on reproductive health, particularly in conditions such as polycystic ovary syndrome (PCOS), endometriosis, and bacterial vaginosis, which are often linked to infertility.

Who was reviewed?

The studies reviewed in this article primarily focused on both male and female reproductive health, with particular attention to the microbiome’s role in infertility. Research on the female genital tract, including the vagina, endometrium, and uterus, was emphasized, as microbial imbalances in these areas are often associated with reproductive disorders. In men, the review covered how gut and urogenital microbiomes affect sperm quality and overall fertility. The review aimed to provide a comprehensive understanding of how microbial communities influence reproductive health and fertility outcomes.

What were the most important findings?

Key findings from this review highlighted the connection between microbial imbalances and infertility in both men and women. In females, the vaginal microbiome’s imbalance, particularly a reduction in Lactobacillus species, was associated with infertility, with bacteria like Gardnerella vaginalis and Atopobium vaginae contributing to conditions such as bacterial vaginosis. These imbalances lead to inflammation and reduced chances of successful implantation during IVF. In males, gut microbiome imbalances were linked to reduced sperm quality, with specific bacteria such as Mycoplasma genitalium being detrimental to sperm motility. The review also found that an unhealthy uterine microbiome contributes to recurrent implantation failure, signaling the need for microbiome management in fertility treatments.

What are the greatest implications of this review?

The review’s greatest implications lie in its potential to improve fertility treatments through microbiome-based interventions. The findings suggest that microbiome analysis could be incorporated into infertility diagnostics, helping healthcare providers identify microbial imbalances that affect fertility. Personalized treatments, including probiotics or targeted antibiotics, could be prescribed to restore microbial balance and improve fertility outcomes, particularly for patients undergoing ART like IVF. This approach could lead to more tailored, effective fertility treatments and better success rates in assisted reproductive technologies, marking a significant shift in fertility care.

What was reviewed?

This comprehensive narrative review synthesized current research on the interplay between diet, genetics, epigenetics, and the microbiome in female infertility, with a focus on the impact of dietary patterns and nutrients on reproductive health and assisted reproductive technology (ART) outcomes. It critically appraised evidence from observational studies, randomized controlled trials, and animal research, covering macronutrients (proteins, carbohydrates, fats), micronutrients (vitamins, minerals), dietary patterns (Mediterranean, Western), and specific dietary components, such as prebiotics and probiotics. The review also discussed how nutritional factors interface with genetic and epigenetic mechanisms and the gut and vaginal microbiome, ultimately influencing female fertility and ART success.

Who was reviewed?

The review encompassed studies involving a diverse range of populations, including healthy women of reproductive age, women experiencing infertility, those undergoing ART procedures (e.g., IVF, ICSI), and relevant animal models (mice, rats, cattle, macaques, Drosophila). The reviewed evidence included large cohort studies (e.g., Nurses’ Health Study II), randomized controlled trials, and mechanistic studies exploring molecular and microbial pathways. The analysis particularly focused on women with different dietary patterns, micronutrient statuses, and genetic backgrounds, as well as those with specific reproductive disorders such as PCOS.

Most important findings

The review found that dietary patterns and specific nutrients play a significant role in female reproductive health and ART outcomes. Adherence to the Mediterranean diet, rich in plant-based foods, PUFAs, whole grains, and micronutrients, was consistently associated with improved ovulatory function, higher pregnancy rates, and enhanced ART outcomes, potentially mediated by anti-inflammatory and antioxidant effects. Conversely, Western diets high in trans fats, refined sugars, and red meat were linked to ovulatory disorders and lower fertility. Micronutrients such as folate, vitamin D, zinc, and selenium were positively associated with reproductive hormone profiles, oocyte quality, and ART success, though evidence on vitamin D was mixed. Genetic polymorphisms influenced folate metabolism and ART outcomes, highlighting the potential for personalized nutrition. Epigenetic modifications such as DNA methylation changes induced by dietary folate or histone modification by micronutrients were implicated in oocyte and embryo quality. Microbiome studies revealed that dietary fiber and prebiotic supplementation improved ART outcomes by enriching beneficial gut bacteria and reducing potentially harmful taxa. Higher follicular fluid levels of the microbial metabolite TMAO were associated with poorer embryo quality, implicating the gut microbiome in reproductive success. Favorable vaginal microbiome profiles, dominated by Lactobacillus species, were predictive of higher ART pregnancy rates.

Key implications

The review underscores the importance of considering diet, genomics, epigenetic status, and the microbiome in the management of female infertility and ART. Personalizing nutritional interventions based on genetic and microbial signatures holds promise for optimizing fertility treatments. Clinicians should be aware that dietary counseling, favoring Mediterranean-style diets, adequate intake of key micronutrients, and possibly prebiotic/probiotic interventions may improve reproductive outcomes. However, the heterogeneity of study designs and populations, as well as limited interventional evidence, means that further research is needed to establish precise, individualized nutritional guidelines for women seeking to conceive, particularly those undergoing ART.

What was studied?

This study investigated alterations in vaginal microbiota among women with infertility who were infected with Chlamydia trachomatis (CT), specifically examining microbiome profiles before and after antibiotic treatment. The researchers performed metagenomic analysis of sequenced 16S rRNA gene amplicons to identify microbiota variations and assess potential microbiome signatures predictive of CT infection in women experiencing tubal infertility.

Who was studied?

The study involved 25 women from Chenzhou, China, categorized into four distinct groups: healthy women without CT (CT-C), infertile women negative for CT (CT-N), infertile women positive for CT (CT-P), and infertile women who were CT-positive but post-treatment with azithromycin (CT-PT). All women were aged 20-49 years, non-pregnant, and had no other sexually transmitted infections at enrollment. Vaginal swabs were taken to perform microbial analyses and measure cytokine levels, providing comprehensive profiles of their vaginal microbiomes and inflammatory status.

What were the most important findings?

The study demonstrated clear differences in vaginal microbiota between infertile women infected with CT and those who were not. Women with infertility and CT infection exhibited significant vaginal microbiota dysbiosis characterized by reduced microbial diversity and distinct microbial profiles. Notably, CT-positive infertile women exhibited vaginal microbiota dominated by Lactobacillus iners, contrasting sharply with the typical Lactobacillus crispatus dominance observed in healthy vaginal environments. Other beneficial microbes, such as Bifidobacterium, Enterobacter, Atopobium, and Streptococcus, were significantly reduced in women infected with CT. Elevated levels of cytokines, particularly interferon (IFN)-γ and interleukin (IL)-10, were also observed, indicating a heightened inflammatory response. Post-treatment analysis revealed a substantial recovery of the vaginal microbiota, characterized by increased Lactobacillus abundance and the disappearance of CT genomic sequences, underscoring the effectiveness of azithromycin therapy.

What are the greatest implications of this study?

This study's greatest implication is the identification of specific microbiome signatures as predictive markers for CT infection in women experiencing infertility. This insight can enable clinicians to use vaginal microbiome profiles as diagnostic and predictive tools for CT infection, potentially guiding more targeted and personalized treatment strategies. The recovery of a healthy microbiome after antibiotic treatment highlights the possibility of using microbiome modulation (e.g., probiotics or other microbiota-directed therapies) to enhance fertility outcomes and reduce complications associated with CT infections. Such microbiome-based approaches could represent a new frontier in reproductive medicine, specifically targeting women at risk for infertility due to microbial dysbiosis and infections.

What was studied?

The study characterized the gut microbiota of women experiencing infertility and investigated the impact of supplementation with partially hydrolyzed guar gum (PHGG), a dietary fiber, on gut microbiota and pregnancy outcomes. Researchers compared the microbiota composition of infertile women against fertile controls and assessed changes following the administration of PHGG alongside assisted reproductive technology (ART).

Who was studied?

The study enrolled 36 women: 18 fertile women and 18 women diagnosed with infertility, matched by age. All participants were recruited from HORAC Grand Front Osaka Clinic, Osaka, Japan. Subsequently, 12 of the infertile women agreed to undergo combined treatment involving ART and dietary supplementation with PHGG. The participants' fecal samples were analyzed using 16S rRNA sequencing to determine microbiota composition.

What were the most important findings?

The study identified clear differences in gut microbiota composition between fertile and infertile women. Notably, infertile women exhibited decreased levels of beneficial bacteria such as Stenotrophomonas, Streptococcus, and Roseburia, while showing increased levels of the genera Unclassified [Barnesiellaceae] and Phascolarctobacterium. Additionally, an increased abundance of the phylum Verrucomicrobia was observed among infertile participants. These microbial differences suggest a potential dysbiosis associated with infertility. After dietary supplementation with PHGG, infertile women showed a significant shift in microbiota characterized by increased abundance of beneficial Bifidobacterium, particularly in women who successfully conceived. Predictive microbial signatures identified before treatment included lower levels of Paraprevotella and Blautia, coupled with increased Bifidobacterium abundance. Importantly, 7 out of 12 women (58.3%) who received PHGG supplementation alongside ART achieved pregnancy, indicating that dietary fiber could beneficially modulate the gut microbiome to enhance fertility outcomes.

What are the greatest implications of this study?

The greatest implications of this study for clinicians lie in recognizing that gut microbiota dysbiosis is linked to infertility and can potentially be modified through dietary interventions. Supplementing infertile women with dietary fiber, specifically PHGG, may improve fertility outcomes by correcting gut microbiota imbalances. This study highlights the potential for personalized nutritional strategies, emphasizing dietary fiber supplementation to enhance the efficacy of ART. Clinicians should consider evaluating gut microbiota composition in infertility assessments and incorporate dietary interventions aimed at modulating the gut microbiota to improve fertility outcomes. Further large-scale studies are needed to validate these preliminary findings and establish dietary supplementation as a standard adjunct treatment for infertility.

What was studied?

This study explored the relationship between microbiome imbalances in the vaginal and rectal environments and infertility in women experiencing repeated in vitro fertilization (IVF) failures. Researchers specifically investigated the expression levels of microRNAs (miRNAs), particularly miR-21-5p and miR-155-5p, alongside microbiota composition differences between infertile and fertile women. The study aimed to determine whether these microbiome alterations and miRNA levels could serve as potential biomarkers for unexplained infertility.

Who was studied?

The study included 287 women diagnosed with unexplained infertility who had experienced multiple IVF failures, along with 20 fertile women as controls. The infertile group was characterized by an average age of 40, had a history of at least two unsuccessful IVF attempts, and exhibited normal ovarian and tubal anatomy. The fertile group comprised women who had conceived naturally, were aged between 29 and 38, and had no infertility or autoimmune conditions. Vaginal and rectal swabs were collected for microbiota sequencing and miRNA expression analysis. Blood and saliva samples were also analyzed for immunometabolic markers.

What were the most important findings?

Significant microbiota differences between infertile and fertile groups emerged from this study. Infertile women showed reduced microbial diversity in their rectal microbiome, characterized by an increased ratio of Firmicutes to Bacteroidetes. This imbalance correlated with markers indicative of gut barrier dysfunction. In vaginal samples, infertile women demonstrated a unique microbial pattern, primarily an increased ratio of Lactobacillus brevis to Lactobacillus iners, which contrasts with the typical Lactobacillus dominance associated with healthy reproductive outcomes.

Two miRNAs—miR-21-5p and miR-155-5p—were notably elevated in both vaginal and rectal samples from infertile patients. MiR-21-5p was associated with increased gut permeability, fungal overgrowth, and reduced microbial diversity, whereas miR-155-5p correlated with inflammation and bacterial dysbiosis. Receiver operating characteristic (ROC) analyses confirmed that elevated levels of these miRNAs could reliably distinguish infertile women from fertile women, demonstrating their potential as effective biomarkers for infertility linked to microbiome imbalances.

What are the greatest implications of this study?

The greatest clinical implication is the potential use of microbiome profiling and miRNA expression levels as diagnostic and prognostic tools in managing infertility, especially in cases of unexplained repeated IVF failures. Identifying microbiome dysbiosis and associated inflammatory markers through miRNAs may allow clinicians to personalize treatment plans, potentially involving microbiota-modifying therapies such as probiotics or targeted nutritional interventions. This approach could significantly enhance fertility treatment outcomes by restoring microbiome balance and reducing inflammatory states that adversely affect fertility. Moreover, understanding the link between gut and reproductive tract microbiota suggests that comprehensive evaluation and management of microbiome health should be integral to infertility assessments.

What was studied?

This study investigated the composition and diversity of the vaginal microbiome in women experiencing secondary infertility who were undergoing in vitro fertilization and embryo transfer (IVF-ET). The researchers compared the vaginal microbiota of 30 women with secondary infertility to that of 92 healthy, reproductive-age women. They also evaluated whether hormone stimulation during IVF affected the vaginal microbiome in these infertile patients. By analyzing vaginal swab samples using 16S rRNA gene sequencing, the study aimed to clarify how the microbiome’s structure changes in infertile women, its sensitivity to hormonal manipulation, and the potential implications for IVF outcomes.

Who was studied?

The study included 30 Chinese women aged 23–42 years diagnosed with secondary infertility and scheduled for IVF-ET, alongside 92 age-matched healthy women with no history of infertility or reproductive complications. All participants were HIV negative, had regular menstrual cycles, and had not received significant treatments within four weeks prior to enrollment. Vaginal swabs from infertile women were collected both before ovulation induction and after hormone stimulation. Healthy controls provided samples during both the follicular phase and the ovulation period, allowing for assessment of natural cyclic changes versus those observed in infertile women during IVF.

What were the most important findings?

The study revealed that women with secondary infertility exhibited significantly reduced vaginal microbiome diversity and richness compared to healthy controls during the follicular phase. The vaginal microbiome of infertile women was notably less dynamic than that of healthy women, who displayed substantial microbial fluctuations during ovulation. Infertile women demonstrated a persistent alteration in their microbiome, with increased abundance of genera such as Atopobium, Aerococcus, and Bifidobacterium, and a decreased presence of protective genera like Lactobacillus and Leuconostoc. In contrast, healthy women experienced predictable microbiome shifts with hormonal changes, particularly an increase in beneficial bacteria during ovulation. Importantly, hormone stimulation with GnRH agonist and r-hCG during IVF had no significant effect on the vaginal microbiome of infertile women, indicating a form of hormone insensitivity. Further correlation analysis suggested that the altered microbiome in infertile patients involves synergistic dysbiotic interactions between various anaerobic bacteria, such as Atopobium, Prevotella, Bifidobacterium, and Megasphaera.

What are the greatest implications of this study?

This study strongly suggests that a stable, hormone-responsive vaginal microbiome is critical for female reproductive health and successful IVF outcomes. The finding that infertile women’s vaginal microbiota remain dysbiotic and largely unresponsive to hormonal stimulation points to an underlying microbiological barrier to fertility that current IVF protocols may not address. For clinicians, these results highlight the importance of evaluating and potentially modifying the vaginal microbiome in women undergoing IVF, particularly those with a history of secondary infertility. Personalized interventions, such as microbiome modulation through probiotics or targeted antimicrobials, could enhance the effectiveness of ART by restoring a healthy, Lactobacillus-dominated microbiota and improving receptivity to hormonal treatments. This study also underscores the need for future large-scale research to refine microbiome-targeted diagnostics and therapies as adjuncts to conventional infertility treatments.

What was reviewed?

This review article comprehensively examines the associations between bacterial vaginosis (BV), endometritis, pelvic inflammatory disease (PID), and infertility, with a particular focus on the underlying microbiome-related mechanisms. The paper synthesizes current evidence on how disruptions in the vaginal and endometrial microbiota, characterized predominantly by a loss of beneficial lactobacilli and an overgrowth of anaerobic bacteria, contribute to the pathogenesis of these gynecological conditions. The review covers diagnostic criteria, treatment options, recurrence issues, and the role of the vaginal and endometrial microbial signatures in affecting reproductive outcomes, both naturally and in assisted reproduction settings. It also explores potential mechanistic pathways linking these infections to infertility, including inflammation, immune responses, microbial toxin production, and increased susceptibility to sexually transmitted infections (STIs).

Who was reviewed?

The review synthesizes data from a broad range of studies involving women of reproductive age, particularly those diagnosed with BV, endometritis, or PID, as well as women experiencing infertility (including those undergoing fertility treatments such as in vitro fertilization [IVF]). It considers diverse populations, including women with tubal and non-tubal infertility, women with unexplained or idiopathic infertility, and those with recurrent implantation failure or miscarriage. The article also references clinical trials and meta-analyses, drawing on evidence from both symptomatic and asymptomatic women across multiple ethnic groups and geographic regions.

Most important findings

The review highlights that optimal vaginal health is typically characterized by a microbiota dominated by lactobacilli, which produce lactic acid and antimicrobial compounds, conferring protection against pathogenic bacteria. BV is marked by a depletion of these protective lactobacilli and an overgrowth of anaerobes such as Gardnerella vaginalis, Atopobium vaginae, Megasphaera spp., and others. This microbial imbalance is strongly associated with an increased risk of endometritis and PID, both of which are significant causes of infertility. Notably, more than 85% of PID cases are linked to BV-associated bacteria and/or STIs, but fewer than half involve classic pathogens like Neisseria gonorrhoeae or Chlamydia trachomatis, underscoring the importance of the broader vaginal microbiome.

BV increases the risk of acquiring STIs, which further amplify the risk of upper genital tract infections and infertility. Mechanistically, BV-related bacteria can induce genital tract inflammation, alter immune responses, produce enzymes that degrade cervical mucus, and facilitate pathogen ascension to the endometrium and fallopian tubes. Women with BV and non-lactobacillus-dominated endometrial microbiota have lower implantation and pregnancy rates, particularly in IVF settings. Chronic endometritis (CE) is highly prevalent among women with unexplained infertility and recurrent implantation failure, and cure of CE with antibiotics improves reproductive outcomes. Despite these associations, causality between BV and infertility is not fully established due to heterogeneity in diagnostic criteria, patient populations, and study designs.

Key implications

The review underscores the clinical importance of recognizing and treating BV, endometritis, and PID—especially in women with infertility or at risk of reproductive complications. Early diagnosis and appropriate antibiotic treatment for symptomatic BV and CE can improve fertility outcomes, particularly in IVF patients. The findings also call for a more nuanced understanding of the vaginal and endometrial microbiome, advocating for future research to refine the definitions of “normal” versus “abnormal” microbial states and to clarify the mechanisms linking microbial dysbiosis to infertility. Given the high recurrence rates and diagnostic challenges, integrating microbiome-based diagnostics and interventions (including probiotics) into preconceptional and fertility care may offer new avenues for improving women’s reproductive health.

What was studied?

This study conducted a bibliometric analysis to elucidate the global research trends, collaborations, and evolving focal points regarding polycystic ovary syndrome (PCOS) and infertility. The authors systematically searched the Science Citation Index Expanded (SCI-E) database using the terms "polycystic ovary syndrome" and "infertility," extracting all relevant literature up to September 21, 2021. The aim was to quantify publication outputs, citation trends, authorship, institutional and country contributions, journal significance, and the evolution of research keywords within this field. The bibliometric approach, utilizing CiteSpace software, enabled visualization of collaborations and shifts in research emphasis, offering an in-depth overview of the current landscape, gaps, and future directions in PCOS and infertility research.

Who was studied?

The study did not directly involve patient populations or experimental cohorts; rather, it analyzed 2,716 published documents (after deduplication) on PCOS and infertility. These documents encompassed original research articles, reviews, proceedings papers, editorials, and other scholarly outputs. The contributing researchers originated from 105 countries, with the United States, China, the United Kingdom, Italy, and Australia leading in publication volume. Institutional analysis highlighted the University of Adelaide, Monash University, and the University of Pennsylvania as key contributors. The analysis also identified top publishing authors, including Legro RS and Zhang HP, and mapped collaborative patterns across countries and institutions.

Most important findings

The bibliometric analysis revealed a consistent annual increase in both the number of publications and citations in the PCOS and infertility field, indicating growing scientific interest and knowledge generation. The United States dominated in terms of research output and collaborative centrality, while the University of Adelaide was the leading institution in both publication count and collaboration. Top journals such as Fertility and Sterility and Human Reproduction published the majority of studies, but highly impactful papers also appeared in comprehensive and endocrinology journals. Keyword analysis uncovered evolving research interests: in earlier years, focus centered on diagnostic criteria and ovulation induction; more recently, meta-analysis, follicular fluid, oxidative stress, and new therapeutic strategies gained prominence. Insulin resistance, obesity, and metabolic factors repeatedly emerged as key terms, reflecting the recognized metabolic-microbiome axis in PCOS.

Key implications

This study highlights the increasing global research activity in PCOS and infertility, but also exposes regional imbalances, with most research concentrated in developed countries. The evolving research focus toward metabolic, inflammatory, and therapeutic dimensions, many of which are intimately linked to the gut and reproductive tract microbiome, signals an opportunity for deeper integration of microbiome insights into PCOS research. The identification of key authors, institutions, and journals can inform clinicians and researchers seeking collaborative networks or authoritative sources. Additionally, the bibliometric trends help prioritize research questions and resource allocation, emphasizing the need for multicenter, international studies (especially in underrepresented regions) and for systematic evaluations of adjunctive therapies, including those targeting metabolic-microbiome pathways. For clinicians, understanding these trends supports evidence-based practice and highlights the emerging role of metabolic and potentially microbial factors in PCOS-related infertility.

What was reviewed?

This narrative clinical review discusses the pathogenesis, clinical evaluation, and management of pelvic inflammatory disease (PID) with a dedicated focus on fertility-related long-term sequelae. The article synthesizes current knowledge regarding PID’s microbial etiologies, diagnostic approaches, complications such as tubal infertility, and both medical and surgical management strategies. Special attention is given to the role of the microbiome in PID development and progression, particularly regarding upper genital tract infection by various microorganisms and their contribution to reproductive morbidity.

Who was reviewed?

The review synthesizes data and recommendations relevant to women of reproductive age who are at risk for, or have a history of, PID. It draws on evidence from studies involving women with clinically and laparoscopically diagnosed PID, women undergoing infertility evaluation, and specific population groups with higher reported PID incidence, such as those in developing nations and Indigenous Australian communities. The microbiological data reviewed come from studies isolating pathogens from women with PID and related infertility.

Most important findings

PID is a polymicrobial infection of the upper female genital tract, initiated by pathogens that disrupt the cervicovaginal barrier. Chlamydia trachomatis and Neisseria gonorrhoeae are implicated in 33–50% of cases, but other significant contributors include Mycoplasma genitalium, bacterial vaginosis-associated anaerobes, as well as respiratory and enteric organisms. The progressive ascent of these microbes, facilitated by alterations in the cervicovaginal microenvironment and host factors (e.g., menses, loss of mucus plug), leads to upper tract inflammation and damage. Despite adequate antimicrobial therapy, long-term sequelae are common: infertility (18%), ectopic pregnancy (0.6–2%), and chronic pelvic pain (30%). Tubal infertility, largely attributable to microbial damage and subsequent fibrosis or adhesions, is responsible for 25–35% of female infertility cases, with PID as the primary cause in over half. Notably, risk escalates with recurrent PID episodes and severity of tubal damage. The review underscores that even subclinical PID can have major reproductive consequences, and that the diversity of implicated microbes should be considered in diagnosis and management.

Key implications

For clinicians, this review emphasizes the importance of early suspicion, diagnosis, and treatment of PID to mitigate long-term reproductive sequelae, particularly tubal infertility. The polymicrobial nature of PID, including both classical sexually transmitted pathogens and diverse anaerobic and facultative organisms, highlights the need for comprehensive microbial assessment and broad-spectrum empirical therapy. The findings suggest that a history of PID should prompt early fertility evaluation and counseling, and that public health efforts in STI prevention and early intervention could substantially reduce infertility rates. From a microbiome perspective, the article reinforces the critical role of cervicovaginal microbial communities and their disruption in PID pathogenesis, supporting the inclusion of these microbial signatures in reproductive health databases for risk stratification and targeted interventions.

What was studied?

This population-based nested case-control study investigated the associations between female genital tract infections, selected comorbidities, and infertility using data from the Taiwan National Health Research Database (NHIRD) between 2000 and 2013. The study specifically evaluated whether infections such as pelvic inflammatory disease (PID), bacterial vaginosis (BV), and endometritis, as well as comorbid conditions like obesity, lipid metabolism disorders, and abortion history, were linked to an increased risk of diagnosed infertility. The research leveraged the large scope of the NHIRD, which includes nearly the entire Taiwanese population, to provide robust epidemiological insights. The analysis involved both univariate and multivariate conditional logistic regression to adjust for confounding variables and to isolate the independent associations of different infections and comorbidities with infertility risk in women, stratified by age groups (≤40 and >40 years).

Who was studied?

The study included 18,276 women newly diagnosed with infertility and 73,104 age-matched controls without infertility, all identified from the NHIRD. Controls were matched by age (within three years) and index year and were required to have a history of pregnancy but no prior diagnosis of infertility or use of ovulation stimulants or gonadotropins. Exclusion criteria covered prior hysterectomy, bilateral oophorectomy, cancer, prior chemotherapy or radiotherapy, polycystic ovary syndrome, ovarian failure, endometriosis, adenomyosis, amenorrhea, and Turner syndrome. The mean age of the cohort was 31 years, and the population was predominantly Han Chinese women residing in Taiwan. Patients were further stratified into two age groups (≤40 and >40 years) to assess potential age-related interactions with infertility risk factors.

Most important findings

The most significant finding was a robust association between upper and lower genital tract infections and increased risk of infertility, evident even after controlling for comorbidities and other confounders. Specifically, pelvic inflammatory disease involving the ovary, fallopian tube, pelvic cellular tissue, and peritoneum showed odds ratios (OR) of 4.82 and 6.03 for infertility. Cervical, vaginal, and vulvar inflammation had even higher associations, with ORs of 7.79 and 6.65. Clinicians found that BV and endometritis were associated with infertility in univariate analysis, but multivariate models did not confirm these associations, indicating that other factors or confounders may mediate their effect. Comorbidities such as obesity, lipid disorders, dysthyroidism, and abortion initially showed associations with infertility, but these did not persist after adjustment. Importantly, the study did not examine specific pathogens, but referenced the role of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Ureaplasma urealyticum, and Trichomonas vaginalis as potential microbial contributors to tubal factor infertility.

Key implications

These findings reinforce the central role of female genital tract infections, particularly upper tract involvement and lower tract inflammation, in the pathogenesis of infertility. The lack of an independent association with bacterial vaginosis and endometritis after adjustment suggests that not all genital infections contribute equally to infertility risk and highlights the importance of distinguishing between associative and causal relationships. For clinicians, this underscores the need for vigilant screening, diagnosis, and management of PID and lower genital tract inflammation as part of infertility workups. The study’s population-based design adds weight to these recommendations, advocating for targeted prevention and early intervention strategies that could mitigate the risk of infertility associated with genital tract infections. These microbiome-related insights are particularly relevant for developing microbiome signatures and risk-stratification tools in reproductive medicine.

What was studied?

This letter to the editor presents a detailed clinical case of premature ovarian insufficiency (POI) in a young woman, highlighting the diagnostic challenges, clinical course, and a rare instance of spontaneous pregnancy following a POI diagnosis. While primarily focused on the clinical aspects of POI, the article references current understanding of POI etiopathology, noting the associations with autoimmune diseases, chromosomal abnormalities, and environmental factors. The letter underscores the unpredictable nature of ovarian function in POI, stressing the possibility of intermittent ovarian activity and spontaneous conception even after apparent ovarian failure.

Who was studied?

The subject of this report is a 28-year-old woman presenting with primary infertility of 16 months’ duration, with a background of regular menses and no prior relevant medical or surgical history. After unsuccessful attempts at conception via intrauterine insemination (IUI) and in vitro fertilization (IVF), she was diagnosed with POI based on laboratory findings (FSH >65 mIU/mL, low estradiol, and undetectable anti-Müllerian hormone). Despite being listed for oocyte donation, she experienced spontaneous resumption of menses and subsequently conceived, ultimately delivering a healthy child.

Most important findings

The case illustrates several key points regarding POI. First, the diagnosis is often complex, relying on a combination of clinical and laboratory criteria, and is frequently made after failed fertility treatments. The underlying causes of POI remain poorly defined but include genetic, autoimmune, and environmental contributors. The report describes the possibility of spontaneous ovarian function resumption and pregnancy in women previously diagnosed with POI, a phenomenon supported by literature but uncommon in clinical practice. From a microbiome perspective, although this case report does not directly investigate microbial associations, the referenced etiologies (autoimmune mechanisms and environmental triggers) are areas where the microbiome may exert influence, warranting further investigation into the role of gut or reproductive tract microbiota in the pathogenesis or reversibility of POI.

Key implications

Clinically, this case emphasizes the need for ongoing counseling regarding the potential for spontaneous ovarian activity and conception in women with POI, even post-diagnosis. It highlights the limitations of current POI diagnostic criteria and the unpredictable course of the disease. This unpredictability suggests that, in select cases, natural conception remains possible, underscoring the importance of individualized patient management. For future research and microbiome signature databases, the case reinforces the value of investigating immune and environmental factors, including the microbiome, as possible contributors to both POI onset and its occasional reversibility.

What was studied?

This cross-sectional study investigated the perception prevalence of the relationship between pelvic inflammatory disease (PID) and infertility among women of reproductive age in Rivers State, Nigeria. The primary aim was to assess awareness and understanding of the established link between PID, an ascending genital tract infection often caused by sexually transmitted infections (STIs) like Chlamydia trachomatis, and infertility, which is recognized globally as a major public health concern. The study evaluated awareness levels regarding PID, infertility, and their interrelationship, with particular interest in how education and age might influence these perceptions. Data were collected from women attending an enlightenment campaign hosted by the Mother and Baby Care Global Foundation and analyzed using SPSS.

Who was studied?

The study population comprised 250 women of reproductive age (20–49 years) who participated in a local health campaign in Port Harcourt, Rivers State, Nigeria. The mean age was 24 ± 4 years, with 46% aged 20–29, 34% aged 30–39, and 20% aged 40–49. Educational attainment was high in this cohort, with 80% holding tertiary qualifications and the remaining 20% having secondary education. All participants provided informed consent, and those under 15 or over 49 years were excluded from the study.

Most important findings

Despite high educational status among participants, only 30% were aware of PID and 45% were aware of infertility. Notably, only 10% recognized the relationship between PID and infertility, a figure that is low given the well-documented association between these conditions. The highest perception prevalence of the PID-infertility link was observed in women aged 30–39 years (6%). Microbiologically, the study reinforces that Chlamydia trachomatis and Neisseria gonorrhoeae are the primary pathogens implicated in PID, with Chlamydia infection alone accounting for up to 45% of tubal infertility in referenced literature. Approximately 85% of PID cases globally are attributable to STIs. The low perception prevalence found here suggests a significant gap in patient awareness, which is critical given the preventable nature of many PID-related infertility cases.

Key implications

The findings highlight an urgent need for targeted public health education and community-based interventions to raise awareness about PID and its reproductive consequences. Despite high levels of formal education, knowledge gaps persist, underlining that educational campaigns must be tailored and recurrent. From a microbiome perspective, recognizing the microbial etiology of PID, especially the role of Chlamydia trachomatis, should inform both clinical practice and public health messaging to improve screening, early diagnosis, and treatment. Enhanced awareness could contribute to reducing infertility rates attributable to PID, particularly in similar populations and settings.

What was reviewed?

This comprehensive review explores the pathogenesis of endometriosis and its impact on infertility, focusing on the mechanisms by which endometriosis impairs fertility and the current and emerging treatment modalities. The article synthesizes evidence on the etiology of endometriosis, including retrograde menstruation, coelomic metaplasia, altered immunity, stem cell involvement, and genetics, and details how these factors culminate in altered pelvic anatomy, inflammatory microenvironments, and molecular changes in reproductive tissues. The review also evaluates the effects of endometriosis on gametes, embryo development, fallopian tube function, and endometrial receptivity, and discusses the effectiveness of treatments such as surgery, medical therapy, superovulation with intrauterine insemination (IUI), and in vitro fertilization (IVF). Future directions, including novel medical therapies, immune modulation, and stem cell-based approaches, are also considered.

Who was reviewed?

The review synthesizes data from a broad range of studies involving women of reproductive age, primarily aged 25–35, affected by endometriosis with and without infertility. It references epidemiologic data showing an increased prevalence of endometriosis among infertile women (up to 50%) and discusses animal models, such as baboons and mice, to elucidate mechanisms relevant to human disease. The populations reviewed include women with varying stages of endometriosis (minimal/mild to advanced), including those participating in surgical, medical, and assisted reproductive intervention trials. Data on genetic and stem cell contributions are drawn from both human and animal research.

Most important findings

Endometriosis is confirmed as a multifactorial, estrogen-dependent inflammatory disease with a robust association with infertility. Mechanistically, infertility arises from both mechanical disruption (e.g., adhesions, distorted pelvic anatomy) and complex molecular interactions involving immune dysregulation, increased inflammatory cytokines, altered gene expression (notably HOXA10 and Wnt signaling), and oxidative stress. These disrupt ovulation, gamete quality, embryo viability, tubal transport, and endometrial receptivity. Aberrant microbiome or microbial signatures are not a primary focus, but the inflammatory milieu, rich in cytokines and altered immune cell populations, could suggest potential secondary impacts on local microbial communities. Treatments are stage-dependent; surgery is most beneficial for minimal-moderate disease, while IVF remains the most effective for advanced cases. There is limited benefit from medical suppression unless used adjunctively before ART. Emerging approaches, such as stem cell therapy and immune modulation, hold promise for restoring endometrial function and correcting epigenetic alterations.

Key implications

For clinicians, this review underscores the need for individualized management in endometriosis-associated infertility, integrating disease stage, patient age, and reproductive goals. The multifactorial pathogenesis, including immune, genetic, and molecular disruptions, highlights the complexity of diagnosis and treatment, and supports the exploration of targeted, non-hormonal therapies and regenerative approaches. Recognizing the altered inflammatory and possibly microbial environment in the pelvis may inform future research and therapeutic strategies, especially for developing microbiome-informed diagnostic or treatment tools.

What was reviewed?

This paper is a detailed review of the current knowledge on endometriosis-associated infertility, synthesizing recent advances in understanding the pathophysiology, diagnosis, and management of this complex and multifactorial condition. The review highlights that endometriosis is not only a localized pelvic disease but also a systemic condition with pleiotropic effects on reproductive health. The review scrutinizes the interactions between inflammation, hormonal dysregulation, altered pelvic anatomy, diminished ovarian reserve, impaired endometrial receptivity, and systemic immune changes, all of which collectively contribute to infertility in women with endometriosis. The authors further discuss animal models, molecular mechanisms, including genetic and epigenetic influences, and the role of stem cells and microRNAs in disease pathogenesis and clinical presentation.

Who was reviewed?

The review focuses on women of reproductive age affected by endometriosis, with particular attention to those experiencing infertility. It draws from a heterogeneous population including both clinical and experimental (animal) models, and examines evidence from diverse phenotypes, ranging from women with minimal, mild, or advanced disease to those with specific subtypes such as ovarian, peritoneal, or deep infiltrating endometriosis. The paper also reviews findings from meta-analyses, randomized controlled trials, cohort studies, and basic science research, ensuring a broad and representative scope of current evidence.

What were the most important findings?

Endometriosis-associated infertility is multifactorial, with the most important mechanisms involving a persistent pro-inflammatory microenvironment, hormonal imbalances, particularly estrogen dominance and progesterone resistance, and anatomical disruption from adhesions and fibrosis. The review underscores that only half of women with endometriosis-associated infertility have typical macroscopic lesions, which contributes to underdiagnosis and delays in treatment. A core finding is that chronic inflammation, stemming from elevated cytokines and immune cell dysfunction, distorts the follicular and endometrial microenvironments, ultimately impairing ovulation, fertilization, embryo development, and implantation. Diminished ovarian reserve, especially in women with ovarian endometriomas, is linked to oxidative stress, stromal fibrosis, and accelerated follicular depletion, which can be exacerbated by surgical interventions.

At the molecular level, the review identifies major microbial associations (MMA) and signatures such as dysregulation of specific genes (e.g., HOXA10, PR isoform B), aberrant DNA methylation, and microRNAs that alter gene expression and promote disease progression. The immune signature of the eutopic endometrium in affected women is notably pro-inflammatory, with increased type I macrophages and impaired regulatory T cell function. Stem cell trafficking and inappropriate differentiation play significant roles in lesion formation at both pelvic and extra-pelvic sites. On the diagnostic front, the review highlights promising advances in non-invasive biomarkers, particularly panels of serum-derived miRNAs with high sensitivity and specificity for disease detection. Treatment recommendations are increasingly individualized, combining surgical, medical, and assisted reproductive strategies tailored to disease severity, ovarian reserve, age, and patient preferences. Novel molecular diagnostic tools, such as transcriptomic-based endometrial receptivity assays and BCL6 testing, are emerging as potential game-changers for clinical decision-making.

What are the greatest implications of this review?

This review has major implications for clinical practice. It clarifies that endometriosis-associated infertility cannot be addressed with a single, uniform approach; rather, it demands individualized, multidisciplinary care informed by an understanding of both systemic and local pathophysiology. The integration of molecular and microbiome signatures into diagnostic and therapeutic protocols holds promise for earlier detection and more precise interventions. The review also calls attention to the significant impact of diagnostic delays, emphasizing the need for validated, non-invasive tests such as miRNA panels for timely diagnosis and intervention. The authors advocate for collaborative, specialized care in referral centers, incorporating both reproductive surgery and assisted reproductive technologies (ART). The review also recognizes the ongoing need for research to further elucidate molecular mechanisms, optimize biomarker panels, and refine therapeutic algorithms, particularly as new insights into the microbiome, genetics, and immune modulation emerge.

What Was Reviewed?

This review presented a comprehensive analysis of the multifactorial causes, pathophysiology, and therapeutic approaches for polycystic ovary syndrome (PCOS). It placed particular emphasis on the role of gut microbiota dysbiosis and its systemic effects on insulin resistance, hyperandrogenism, and chronic inflammation. In addition to outlining traditional treatments, the paper critically evaluated emerging therapies such as probiotics, prebiotics, fecal microbiota transplantation (FMT), miRNA modulation, and IL-22 therapy. This review serves as a key resource for clinicians seeking a holistic understanding of PCOS, connecting microbiome research with endocrine and metabolic interventions.

Who Was Reviewed?

The review synthesized findings from a wide array of clinical studies, animal models, and experimental trials. It referenced data involving women of reproductive age diagnosed with various phenotypes of PCOS, including both obese and lean individuals. It incorporated rodent models, especially those induced by androgens or letrozole, to simulate PCOS pathology and examine microbiome manipulation outcomes. In its assessment of microbiota, the review drew from sequencing studies and intervention trials using specific probiotic strains such as Lactobacillus acidophilus, L. casei, Bifidobacterium bifidum, and prebiotics like inulin and resistant dextrin. These references grounded its recommendations in translational and mechanistic evidence.

What Were the Most Important Findings?

The review outlined several critical findings that directly connect gut microbiota dysbiosis with the clinical hallmarks of PCOS. A key mechanism involves increased gut permeability due to decreased populations of beneficial bacteria like Lactobacillus and Bifidobacterium, alongside an overgrowth of pro-inflammatory species such as Escherichia coli and Shigella. This dysbiosis allows lipopolysaccharides (LPS) to enter systemic circulation, stimulating immune responses that impair insulin receptor function and exacerbate insulin resistance. Hyperinsulinemia then stimulates androgen production by ovarian theca cells and reduces SHBG levels, increasing free testosterone and fueling PCOS symptoms.

The review also addressed microbial metabolites, particularly short-chain fatty acids (SCFAs) and bile acids. Women with PCOS showed reduced production of SCFAs like butyrate, which are vital for maintaining gut integrity and regulating inflammation. Moreover, altered bile acid profiles—especially reductions in glycodeoxycholic and tauroursodeoxycholic acid—were linked to disrupted hormonal balance and metabolic dysfunction. These major microbial associations (MMAs) illustrate how gut microbiota interact with ovarian steroidogenesis, glucose homeostasis, and the immune axis in PCOS.

Importantly, the review highlighted the therapeutic potential of microbiota restoration. Probiotic supplementation with specific strains led to improvements in insulin sensitivity, lipid profiles, and androgen levels. Prebiotics such as resistant dextrin demonstrated similar metabolic benefits. FMTs in animal models reversed hyperandrogenism and restored menstrual cycles, suggesting strong translational potential. Additionally, novel pathways involving IL-22 and miRNA regulation offer future targets for microbial and metabolic rebalancing in PCOS.

What Are the Implications of This Review?

This review has profound implications for the clinical management of PCOS. It reframes the condition as a microbiota-linked systemic disorder rather than solely an endocrine one. By mapping specific microbial patterns to the hallmarks of PCOS—including hyperandrogenism, insulin resistance, and anovulation—the authors offer a rationale for gut-targeted diagnostics and treatments. Clinicians may soon assess microbiome composition as part of a diagnostic workup, particularly in patients with metabolic dysfunction but unclear hormonal profiles.

Furthermore, the review validates a multi-pronged therapeutic strategy, integrating microbiota restoration with hormonal, metabolic, and reproductive targets. The demonstrated success of Lactobacillus and Bifidobacterium supplementation in improving PCOS biomarkers supports the clinical use of probiotics. Similarly, FMT, while currently limited to preclinical studies, presents a compelling intervention with the potential to reset dysregulated metabolic-hormonal loops. Lastly, novel therapies like IL-22 and miRNA modulation could personalize treatment, especially for patients with inflammatory or resistant phenotypes. Overall, this review builds a clear and actionable bridge between microbiome science and PCOS clinical care.

What was reviewed?

This narrative review comprehensively examined the associations between metabolic risk factors and female fertility disorders, focusing on obesity, the female athlete triad (low energy intake, menstrual dysfunction, decreased bone density), and oxidative stress as potential contributors to infertility. The authors aimed to clarify how these metabolic conditions, alongside major infertility-related disorders such as polycystic ovary syndrome (PCOS) and endometriosis, impact women's reproductive health. The review synthesized evidence from 50 selected studies published between 2006 and 2020, integrating pathophysiological, genetic, lifestyle, and epidemiological perspectives. It also highlighted the prevalence, mechanisms, and clinical consequences of metabolic risks with female infertility and discussed gaps in current knowledge, especially regarding idiopathic infertility and the need for robust molecular markers.

Who was reviewed?

The review focused on studies involving women of reproductive age experiencing infertility. It included populations affected by PCOS, endometriosis, obesity, and those displaying characteristics of the female athlete triad. The selected studies varied in design but excluded animal research and clinical trials of pharmaceutical treatments. The review encompassed diverse geographic regions and considered women with both known and idiopathic infertility, as well as those undergoing assisted reproductive technology (ART). The aim was to gather data relevant to women at risk for or experiencing infertility due to metabolic and lifestyle factors.

Most important findings

The review established a clear and direct association between obesity and increased risk of female infertility, with obese women exhibiting up to a three-fold higher risk compared to those with normal body mass index (BMI). Obesity was linked to anovulation, reduced ART success rates, and increased miscarriage risk. Mechanistically, excess body fat disrupts ovarian steroidogenesis, induces hyperandrogenism, and promotes chronic low-grade inflammation, all of which impair reproductive function. PCOS was highlighted as a central metabolic-endocrine disorder, often comorbid with obesity, insulin resistance, and increased cardiovascular risk. Endometriosis risk showed a more complex relationship with BMI, with evidence suggesting both inverse and direct associations, possibly due to genetic and hormonal influences. The female athlete triad, though less well-studied in this context, was associated with hypothalamic suppression, menstrual dysfunction, and reduced fertility, primarily through chronic energy deficiency and altered estrogen signaling. Oxidative stress, driven by lifestyle factors (e.g., smoking, alcohol, drug use), was identified as a pervasive mediator, damaging DNA and germ cells, increasing risks for PCOS and endometriosis, and contributing to idiopathic infertility. The review emphasized a lack of large-scale population studies and molecular biomarker research linking metabolic status and infertility.

Key implications

For clinicians, the review underscores the necessity of assessing metabolic risk factors, especially obesity and undernutrition, when addressing female infertility. Interventions targeting weight management, healthy nutrition, and lifestyle modification may improve hormonal balance and reproductive outcomes, particularly in women with PCOS. The review also calls for interdisciplinary collaboration to integrate molecular, metabolic, and psychosocial approaches to infertility. Given the anticipated rise in obesity prevalence among women, proactive metabolic assessment and the development of diagnostic molecular signatures are critical for improving ART outcomes and reducing unexplained infertility. Further, the establishment of consensus definitions and large-scale biobank studies will be pivotal for advancing personalized infertility care.

What was studied?

This original research investigated the metabolic profile of follicular fluid (FF) in women undergoing in vitro fertilization (IVF) to determine whether specific biochemical alterations correlate with female infertility and IVF outcomes. Using a targeted metabolomics approach, the study quantified 55 low molecular weight compounds, encompassing energy metabolites, purines, pyrimidines, antioxidants, oxidative/nitrosative stress markers, and amino acids, in FF samples. The research aimed to identify distinct metabolic signatures in infertile women compared to controls (fertile women whose partner’s infertility was the only impediment to conception), and to evaluate the relationship between these metabolic patterns and clinical IVF outcome measures, including oocyte development, embryo quality, and pregnancy rates. A cumulative Biomarker Score, based on deviations in 27 key FF metabolites, was developed to distinguish between fertile and infertile women and to predict IVF success.

Who was studied?

The study cohort consisted of 180 women attending a fertility clinic in Rome, Italy, from 2018 to 2020. The control group (n=35) was composed of women whose infertility was exclusively due to a male factor, ensuring their reproductive competence. The infertile group (n=145) included women diagnosed with endometriosis (n=19), polycystic ovary syndrome (PCOS; n=14), age-related reduced ovarian reserve (AR-ROR; n=58), reduced ovarian reserve (ROR; n=29), unexplained infertility (UI; n=14), and genetic infertility (GI; n=11). All participants underwent standardized ovarian stimulation and IVF/ICSI protocols, with FF collected during oocyte retrieval. The study excluded women with mechanical reproductive barriers, cancer history, or premature ovarian failure, and controlled for confounding lifestyle and nutritional factors.

Most important findings

The metabolomic analysis revealed that 27 of 55 measured metabolites significantly differed between infertile and control groups. Infertile women generally exhibited lower FF glucose, higher lactate, elevated purine and pyrimidine catabolites (hypoxanthine, xanthine, uracil, pseudouridine), decreased antioxidants (ascorbic acid, glutathione, vitamin A, vitamin E, coenzyme Q10, carotenoids), increased oxidative/nitrosative stress markers (malondialdehyde, 8-hydroxy-2′-deoxyguanosine, nitrite, nitrate), and reduced levels of several amino acids (notably serine, threonine, arginine, valine, methionine, tryptophan, isoleucine, leucine). These metabolic anomalies were largely consistent across different infertility diagnoses, though some subgroup-specific patterns emerged (e.g., PCOS and GI showed normal FF glucose). The composite Biomarker Score robustly discriminated between control and infertile groups, with scores correlating inversely with key IVF outcomes—number and quality of oocytes/blastocysts, clinical pregnancy, and healthy live birth rates. The Biomarker Score showed high specificity and sensitivity in predicting fertility status and IVF success.

Key implications

This study underscores the central role of FF metabolic composition in female fertility and IVF outcomes. The identification of a 27-metabolite signature and its integration into a Biomarker Score offers a powerful, noninvasive tool for distinguishing fertile from infertile patients and predicting assisted reproduction success. The findings suggest that metabolic profiling of FF could inform personalized interventions to optimize the follicular environment, enhance oocyte quality, and improve IVF success rates. Furthermore, these metabolomic biomarkers could be incorporated into microbiome-multimetabolite databases, facilitating personalized reproductive medicine and potentially guiding future research into the interplay between follicular metabolites, the ovarian microenvironment, and the local microbiome.

What was studied?

This study investigated the combined effects of co-exposure to phenols and phthalates on infertility risk among women of reproductive age. Specifically, it examined whether the mixture of these endocrine-disrupting chemicals (EDCs) is associated with an increased risk of infertility. Data from the National Health and Nutrition Examination Survey (NHANES) 2013–2016 were used, including 857 women aged 18-45 years. The study measured urinary metabolites of phenols and phthalates, along with reproductive health data, to explore their relationships with self-reported infertility.

Who was studied?

The study focused on 857 women of reproductive age (18-45 years) from the NHANES 2013–2016 data set. These women had available information on urinary phenol and phthalate metabolites, reproductive health questionnaires, and relevant covariates. The study excluded pregnant women, those who had undergone hysterectomy or oophorectomy, and those without full data on infertility history or other covariates.

What were the most important findings?

The study found significant associations between the combined exposure to phenols and phthalates and an increased risk of infertility. Higher levels of bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) metabolites were positively linked to infertility risk. The analysis showed that the DEHP-BPA factor, derived through principal component analysis (PCA), had a strong positive association with infertility. Specifically, women in the higher quartiles of this DEHP-BPA mixture component had a significantly higher likelihood of infertility compared to those in the lower quartiles. Furthermore, the Bayesian kernel machine regression (BKMR) model confirmed that exposure to specific metabolites, including MEOHP, MEHHP, and BPA, significantly contributed to the increased risk of infertility. The study also highlighted that the risk of infertility grew with increasing concentrations of these pollutants, underscoring the cumulative effects of mixed exposures to environmental chemicals. These findings indicate that combined exposure to multiple EDCs, such as phenols and phthalates, rather than individual compounds, has a more profound impact on female fertility.

What are the greatest implications of this study?

The most significant implication of this study is the recognition that environmental pollutants have a substantial impact on reproductive health in women. This study suggests that it is crucial to evaluate the combined effects of multiple pollutants, as exposure to these chemicals frequently occurs simultaneously in real-life settings. The findings highlight the need for more comprehensive regulations and preventive measures to reduce exposure to these EDCs, especially for women of reproductive age. Clinicians and researchers should consider the potential cumulative effects of these pollutants when diagnosing and treating infertility. Furthermore, future studies are needed to establish causal links and investigate the underlying biological mechanisms, such as epigenetic changes and hormone disruption, to better understand how these chemicals contribute to infertility.

What was studied?

This original research article investigated the association between exposure to heavy metals, specifically cadmium (Cd), lead (Pb), mercury (Hg), and arsenic (As), and female infertility in a representative sample of American women. Using data from three cycles of the National Health and Nutrition Examination Survey (NHANES, 2013–2018), the study measured blood and urinary levels of these metals and examined their correlation with self-reported infertility. The primary aim was to clarify whether elevated levels of these toxic metals are linked to increased risk of infertility, adjusting for relevant demographic and health covariates.

Who was studied?

The study population consisted of 838 American women aged 20–44 years, selected from NHANES 2013–2018 cycles based on availability of laboratory and questionnaire data. Women with a history of hysterectomy, bilateral oophorectomy, or incomplete data were excluded. Infertility was defined via self-report, using the question: “Have you ever attempted to become pregnant for at least a year, without becoming pregnant?” The cohort was diverse in terms of ethnicity, education, and marital status, with significant differences in age and BMI between infertile and control women.

Most important findings

The study found that urinary arsenic (As) and cadmium (Cd) levels were significantly higher in infertile women compared to controls. After controlling for several covariates, including age, ethnicity, education, marital status, poverty index ratio, BMI, regular menstrual periods, pelvic infection, and smoking history, urinary arsenic remained significantly associated with infertility. Women with higher urinary As levels had a substantially increased risk of infertility. Urinary Cd was also associated with infertility in less-adjusted models, but this association weakened with full adjustment. Blood and urinary Pb levels were not associated with infertility overall, but stratified analyses revealed that both blood and urinary Pb were positively correlated with infertility in women aged 35–44 and in those with BMI ≥25, highlighting age and obesity as effect modifiers. Blood Hg was not significantly associated with infertility in any model.

Key implications

This study highlights the potential reproductive health risks posed by environmental exposure to heavy metals among women of reproductive age. The robust association between urinary arsenic and infertility suggests that arsenic exposure (likely from contaminated water or certain foods) may disrupt female reproductive function, potentially through oxidative stress and endocrine disruption. The findings also indicate that older and overweight/obese women may be more susceptible to the adverse reproductive effects of lead. From a clinical and public health perspective, these results support the need for routine monitoring of heavy metals in at-risk populations and for interventions aimed at reducing environmental exposures, especially in vulnerable subgroups. The study also highlights the value of using urine measurements to assess chronic exposure, as opposed to blood levels that may reflect only recent exposure.

What was reviewed?

This review comprehensively evaluated the effects of toxic heavy metals on the epidemiology of male and female infertility. The authors systematically searched and synthesized findings from articles published between 1982 and 2021 in databases such as PubMed, Google Scholar, Scopus, and others, focusing on the mechanistic and epidemiological associations between these metals and reproductive dysfunction. The review explores the multifaceted ways that heavy metal exposure, both environmental and occupational, influences reproductive health, including hormonal disruption, impaired gametogenesis, and direct damage to reproductive tissues. Special attention is given to the biochemical mechanisms by which these metals exert toxic effects, such as oxidative stress, enzyme inhibition, and endocrine disruption, all of which are highly relevant to clinicians concerned with environmental determinants of infertility.

Who was reviewed?

The review encompasses a broad range of human and animal studies, including epidemiological research on general populations and occupational groups, as well as controlled laboratory investigations in animal models. Human studies included both men and women from diverse geographic and occupational backgrounds, such as industrial workers, smokers, and populations with high environmental exposure. Animal research provided mechanistic insights, particularly regarding gamete quality, hormonal changes, and reproductive organ pathology following heavy metal exposure. Some studies included in the review also examined the reproductive health of non-human species to elucidate underlying biological processes and to support observed epidemiological trends in humans.

Most important findings

The review identifies strong associations between exposure to lead, cadmium, and copper and increased risk of infertility in both sexes. Cadmium, widely distributed in the environment, is linked to direct damage to the ovaries and testes, reduced sperm count, motility, and viability, as well as impaired oocyte maturation. It acts as a reproductive toxin by replacing zinc in enzymes and altering protein function, leading to oxidative stress and cytotoxicity. Lead exposure disrupts hormonal balance by interfering with calcium-mediated cellular activities and is associated with decreased sperm quality, impaired oocyte development, increased risk of miscarriage, and stunted fetal growth. Occupational and environmental exposures, such as working in lead mines or exposure to cigarette smoke, exacerbate these effects. Elevated copper levels, while copper is essential in trace amounts, are correlated with oxidative damage and sperm dysfunction at higher concentrations. The review highlights the impact of heavy metals on key microbiome-modulated processes (e.g., oxidative stress, inflammation) and notes that heavy metal exposure may alter the host's microbiome, which can further influence reproductive health outcomes.

Key implications

Clinicians should be aware of the significant impact that environmental and occupational exposures to lead, cadmium, and copper can have on reproductive health. The review supports incorporating environmental exposure histories into infertility assessments, particularly for patients with unexplained infertility or those with relevant occupational risks. The evidence also suggests that heavy metal-induced oxidative stress and endocrine disruption might be compounded or modulated by changes in the reproductive tract microbiome, indicating a potential avenue for future diagnostic and therapeutic interventions. Surveillance of heavy metal exposure, coupled with targeted interventions to reduce environmental risk, could improve fertility outcomes and inform public health strategies. Furthermore, the recognition of microbiome–heavy metal interactions opens the door to novel research on microbial biomarkers and microbiota-targeted therapies in infertility management.

What was studied?

This cross-sectional study investigated the association between blood concentrations of lead (Pb), cadmium (Cd), and arsenic (As) and risk factors for infertility in women of childbearing age in Taiwan. The study aimed to elucidate whether exposure to these environmental toxic metals, commonly found as contaminants in the environment and traditional Chinese herbal medicines, correlates with infertility. Researchers compared the levels of Pb, Cd, and As in blood samples of infertile and pregnant women and examined how lifestyle factors, including use of Chinese herbal medicine, alcohol consumption, and physical activity, might influence metal body burdens. Additionally, the study assessed possible associations between blood metal levels and reproductive hormone concentrations (FSH, LH) in the infertile group.

Who was studied?

Three hundred and sixty-seven women aged 18–45 years were recruited from the Department of Obstetrics and Gynecology at Taiwan Adventist Hospital between 2008 and 2010. Of these, 310 infertile women (defined as failing to conceive after one year of regular intercourse) and 57 pregnant women (confirmed by ultrasound in the first trimester) were included after applying exclusion criteria (e.g., excluding women with PCOS, diabetes, IVF pregnancies, and other confounders). Sociodemographic data, lifestyle habits, and reproductive histories were collected via structured interviews. Blood samples for metal and hormone analyses were collected under standardized conditions, ensuring comparability between the groups.

Most important findings

The study found that blood levels of Pb and As, but not Cd, were significantly higher in infertile women compared to pregnant women. Median Pb concentrations were 15.7 μg/L in infertile versus 11.6 μg/L in pregnant women; As levels were also higher in the infertile group. Use of Chinese herbal medicine was more prevalent among infertile women and was associated with higher blood Pb levels in both infertile and pregnant women, with a clear dose-response relationship: more frequent herbal medicine use correlated with greater Pb burden. Alcohol consumption was also higher among infertile women, while regular physical activity was more common in pregnant women. Physical activity showed a trend toward reducing blood Pb accumulation. No significant correlations were observed between blood metal concentrations and reproductive hormone levels in infertile women, potentially due to overall metal exposures being below recognized toxicity thresholds.

Key implications

This study highlights that environmental and lifestyle exposures to heavy metals may contribute to increased Pb body burden in women of childbearing age, potentially impacting fertility. While the absolute metal levels observed were below acute toxicity thresholds, the data support the need for caution regarding the use of herbal preparations that may contain heavy metals, especially for women planning pregnancy. Regular physical activity may have a protective effect against Pb accumulation. Clinicians should consider environmental and cultural factors when assessing infertility and counsel patients on potential risks associated with traditional medicine use. These findings underscore the importance of monitoring metal exposures and integrating environmental health perspectives into reproductive care.

What was reviewed?

This comprehensive review examined the impact of various environmental pollutants, including heavy metals, air pollutants, and endocrine disruptors, on female fertility. The authors analyzed the mechanisms by which these contaminants disrupt ovarian function, hormonal regulation, and oocyte quality, ultimately leading to reduced fertility. Special attention was given to the fixed, non-renewable nature of the female oocyte pool, which increases vulnerability to environmental insults. The paper also explored how pollution-induced oxidative stress, endocrine disruption, and epigenetic changes can impair oogenesis, follicular development, and embryo viability. Additionally, the review discussed the influence of environmental factors on the placental barrier, fetal development, and the potential for transgenerational effects. The article highlighted emerging concerns such as climate change, thermal stress, and the interaction between pollution and the microbiome as contributors to declining reproductive health.

Who was reviewed?

The review synthesized evidence from human epidemiological studies, animal experiments, and in vitro research. Human data included women of reproductive age, pregnant women, and those undergoing assisted reproduction, as well as population-level studies from polluted regions. Key animal models were referenced to elucidate mechanistic insights not easily obtained in humans. The review also incorporated studies on fetal and placental tissues and, where relevant, included cross-species data to highlight conserved biological responses to pollutants.

Most important findings

The review identified several key mechanisms by which environmental pollutants impair female fertility. Heavy metals such as lead, cadmium, and mercury accumulate in the body and can cross the placental barrier, leading to epigenetic modifications, oxidative stress, and disruption of steroidogenesis. These metals act as endocrine disruptors, affecting the hormonal milieu required for oocyte maturation and ovulation. Air pollution was associated with decreased ovarian reserve, lower rates of fertilization, increased miscarriage, and adverse IVF outcomes. Endocrine disruptors like bisphenol A (BPA) and phthalates were shown to alter gene expression, induce oxidative stress, and interfere with estrogen and androgen receptors, with strong evidence of negative effects on folliculogenesis, embryo development, and increased risk of conditions such as polycystic ovarian syndrome (PCOS). The review also highlighted the compounding effects of multiple pollutants and the role of the microbiome in modulating susceptibility to environmental toxins—an area of emerging relevance for microbiome signatures databases.

Key implications

For clinicians, this review underscores the critical importance of environmental exposures as modifiable risk factors in the management of female infertility. The findings advocate for thorough patient histories that include environmental, occupational, and lifestyle exposures. There is a strong rationale for patient education on minimizing contact with pollutants, advocating for public health policies that reduce environmental contamination, and counseling regarding timing and mode of assisted reproduction, particularly in high-pollution contexts. The mechanistic links between pollutants and reproductive dysfunction also suggest avenues for biomarker development, including the use of AMH and specific microbial signatures to assess exposure and risk. The review calls for further research on pollutant-microbiome interactions and the cumulative effects of pollutant mixtures, as well as expanded epidemiological studies to inform guidelines and interventions.

What was studied?

This original research article investigated the association between blood levels of lead and cadmium (two common environmental heavy metals) and self-reported infertility among women in the United States. The study leveraged data from the 2013–2014 and 2015–2016 cycles of the National Health and Nutrition Examination Survey (NHANES), focusing on reproductive-aged women. The researchers measured blood concentrations of lead and cadmium using inductively coupled plasma mass spectrometry and compared these levels between women who reported infertility (defined as attempting to conceive for at least one year without success) and women who were currently pregnant. Statistical analyses, including logistic regression adjusted for multiple confounders (age, ethnicity, income, education, marital status, smoking, alcohol use, physical activity, BMI), were performed to evaluate whether higher blood metal levels corresponded to increased odds of infertility.

Who was studied?

The study included 124 sexually experienced women aged 20–39 years who participated in the NHANES 2013–2016 cycles and had complete data on blood lead, cadmium, and relevant covariates. Of these, 82 were classified as “infertile” based on self-report, and 42 were “pregnant” at the time of the survey. Women with a history of hysterectomy or bilateral oophorectomy were excluded to ensure reproductive potential. The sample was demographically diverse, but no significant differences were found between infertile and pregnant groups regarding ethnicity, socioeconomic status, education, marital status, health behaviors, or BMI; the infertile group was, however, significantly older.

Most important findings

The study found that even low levels of blood lead and cadmium were associated with significantly increased odds of infertility. After adjusting for confounders, each two-fold increase in blood lead was associated with a 2.6-fold higher odds of infertility, and each two-fold increase in cadmium was associated with a 1.84-fold higher odds. A dose-response relationship was observed for blood lead, with higher tertiles corresponding to higher infertility odds (adjusted ORs for tertiles 2 and 3 vs. tertile 1: 5.40 and 5.62, respectively). Adjusted mean blood lead and cadmium levels were significantly higher in the infertile group compared to the pregnant group. These findings support the hypothesis that environmental exposure to lead and cadmium, even at low levels, may impair female reproductive function. Although the study primarily focused on heavy metal exposure, it is important to note that heavy metals can alter the gut and systemic microbiome, which may further impact reproductive health, though this was not directly assessed in this study.

Key implications

This study provides important evidence that low-level environmental exposure to lead and cadmium is associated with increased infertility risk among US women of reproductive age. These results challenge current safety thresholds for these metals and highlight the need for further population-based research to clarify reproductive toxicity at low exposure levels. Clinicians should consider environmental exposures, including heavy metals, as contributing factors in unexplained female infertility. While not directly examining microbiome profiles, the study’s findings are relevant to a microbiome signatures database, as heavy metal exposures are known to disrupt microbial communities and reproductive hormone regulation, which can influence fertility outcomes.

What was reviewed?

This comprehensive review article examines the current clinical evidence and mechanistic insights for complementary and alternative medicine (CAM) approaches in the management of infertility associated with polycystic ovary syndrome (PCOS). The review synthesizes findings from clinical trials, animal studies, and mechanistic research to evaluate the safety, efficacy, and potential mechanisms of traditional Chinese medicine (TCM), acupuncture (including electroacupuncture, moxibustion, and related modalities), nutrient supplementation (vitamins and trace elements), and lifestyle interventions such as diet, exercise, Tai Chi, yoga, and Qigong. The review emphasizes both the clinical outcomes and the biological pathways involved, particularly those relevant to metabolic, endocrine, and inflammatory regulation.

Who was reviewed?

The article analyzes a broad spectrum of studies, including randomized controlled trials (RCTs), cohort studies, and preclinical animal research. The reviewed populations primarily consist of reproductive-age women diagnosed with PCOS and infertility, as well as animal models (mainly rats) induced with PCOS-like phenotypes for mechanistic studies. The included studies span diverse geographic regions, with a heavy emphasis on Chinese clinical practice and research, but also incorporate international evidence on CAM use in PCOS. Subpopulations considered include patients with insulin resistance, obesity, or poor ovarian response, and studies often include comparison groups receiving conventional Western medical therapy.

Most important findings

The review identifies strong evidence that CAM modalities, particularly TCM herbal formulas and acupuncture, can improve reproductive and metabolic outcomes in women with PCOS-related infertility. Key TCM monomers such as berberine, cryptotanshinone, and quercetin, as well as compound prescriptions like Liu Wei Di Huang, Gui Zhi Fu Ling, Shou Tai Pill, and Zi Shen Yu Tai Pill, demonstrate efficacy in clinical trials by improving insulin resistance (IR), regulating sex hormone levels, reducing inflammation, and promoting follicle development. Several studies report that these interventions also modulate the gut microbiome and metabolic pathways (e.g., PI3K/AKT/mTOR, IRS-1/PI3K/GLUT4), suggesting a microbiome-endocrine-immune axis relevant to PCOS pathophysiology.

Notably, some studies link improvements in insulin sensitivity and reduction in inflammatory markers to alterations in the intestinal flora, providing a basis for further microbiome signatures research. Nutrient supplementation (vitamins D, E, and trace elements) and lifestyle modifications (weight loss, exercise, Tai Chi, yoga) also offer measurable benefits in ovulation, metabolic parameters, and psychological well-being.

Key implications

For clinicians, this review supports the integration of CAM as adjuncts to conventional fertility treatments for PCOS, particularly in patients with metabolic disturbances, poor response to ovulation induction, or those seeking alternatives due to adverse reactions to standard therapies. The mechanistic evidence for microbiome involvement highlights new avenues for personalized medicine and database development of microbial signatures associated with improved reproductive outcomes. While the safety profile for most CAM interventions is favorable, the review calls for greater standardization, larger-scale RCTs, and rigorous monitoring of potential adverse effects. Overall, CAM offers a promising, multifaceted approach to improve fertility outcomes and quality of life in PCOS, meriting further clinical adoption and research.

What was reviewed?

This review comprehensively examines the role of vaginal microbiota dysbiosis, primarily the loss of Lactobacillus dominance and increased microbial diversity, in the pathogenesis and progression of a wide range of gynecological diseases, both infectious (e.g., bacterial vaginosis [BV], vulvovaginal candidiasis, trichomonal vaginitis, atrophic vaginitis, sexually transmitted infections including HPV, HSV-2, HIV, Neisseria gonorrhoeae, Mycoplasma genitalium, and Chlamydia trachomatis) and non-infectious (e.g., miscarriage, preterm birth, infertility, polycystic ovarian syndrome [PCOS], uterine fibroids, menstrual disorders, and intrauterine adhesions). The review also evaluates current and emerging interventions, including antibiotics, probiotics, and the novel approach of vaginal microbiota transplantation (VMT), to restore healthy microbial balance and mitigate disease risk and recurrence.

Who was reviewed?

The review encompasses studies involving a diverse population of women across different reproductive stages and clinical conditions, including those with various gynecological infections, infertility, endocrine disorders, and other non-infectious diseases. It references observational, clinical, and interventional research, from healthy women (to characterize community state types of the vaginal microbiome) to patients suffering from BV, recurrent infections, PCOS, and other gynecological pathologies. The included studies span multiple age groups, menopausal statuses, and geographic regions, offering a broad perspective on vaginal microbiota's clinical significance.

Most important findings

A healthy vaginal microbiota is typically dominated by Lactobacillus species, primarily L. crispatus, L. gasseri, L. jensenii, and L. iners, which maintain vaginal acidity, produce antimicrobials, and modulate immune responses, thereby protecting against pathogens. Dysbiosis is characterized by a reduction in Lactobacillus and an increase in diverse anaerobes such as Gardnerella, Atopobium, Prevotella, Megasphaera, Leptotrichia, Sneathia, and fungi like Candida. This shift is strongly associated with increased susceptibility to infections (BV, VVC, trichomoniasis, STIs), adverse reproductive outcomes (miscarriage, preterm birth, infertility), and endocrine/metabolic disorders (PCOS, uterine fibroids, menstrual disorders). The review highlights that antibiotic use, while effective, is limited by recurrence and resistance; probiotics show promise, particularly strains restoring Lactobacillus dominance, but clinical outcomes are variable. Notably, the review details the first clinical application of VMT, with promising results in refractory BV, suggesting its potential as a robust restorative therapy. Altered vaginal microbial signatures, such as decreased Lactobacillus and increased Gardnerella/Prevotella in BV, or increased Mycoplasma/Prevotella and decreased L. crispatus in PCOS, could serve as important biomarkers for clinical risk stratification and therapeutic targeting.

Key implications

The clinical management of gynecological diseases can be significantly improved by integrating strategies to modulate the vaginal microbiota. While antibiotics remain the standard of care, their limitations necessitate adjunctive or alternative therapies. Probiotics, particularly those containing key Lactobacillus species, can reduce recurrence and improve outcomes in both infectious and non-infectious gynecological conditions. VMT emerges as a highly promising intervention, capable of re-establishing a resilient, healthy vaginal microbiota, particularly for recurrent or treatment-resistant BV. However, broader clinical adoption requires larger trials, standardized protocols, and robust safety assessments. For clinicians, understanding the microbial signatures associated with specific diseases allows for more personalized, microbiome-informed therapeutic approaches and risk prediction.

What was reviewed?

This comprehensive narrative review explores the human reproductive tract microbiome and its significance in infertility and reproductive outcomes. It synthesizes recent research on microbial communities inhabiting both female and male reproductive systems, highlighting the use of next-generation sequencing techniques to characterize these microbiota. The review delves into the role of specific microbial taxa, particularly Lactobacillus species, and their influence on reproductive tract health, the success of assisted reproductive technologies (ART), and the pathogenesis of infertility-related disorders. It also discusses the impact of microbial dysbiosis on conditions such as bacterial vaginosis (BV), chronic endometritis (CE), endometriosis, and adverse pregnancy outcomes, including preterm birth and preeclampsia. The therapeutic potential of antibiotics and probiotics for restoring reproductive tract eubiosis and improving fertility outcomes is critically evaluated.

Who was reviewed?

The review encompasses a wide spectrum of studies involving women and men of reproductive age, with a focus on both fertile and infertile populations. It draws on data from healthy individuals, infertility patients (including those undergoing ART such as IVF), and individuals with specific gynecological or obstetric pathologies. The populations studied span various ethnicities and geographic backgrounds, as inferred from referenced multicenter and international studies. The review also includes evidence from both cross-sectional and longitudinal research, as well as meta-analyses, providing a broad perspective on microbial associations across reproductive health and disease states.

Most important findings

The review highlights that the reproductive tract harbors a complex microbiome, with Lactobacillus species dominating in healthy females and contributing to an acidic, protective environment. Dysbiosis is strongly linked to BV, infertility, adverse ART outcomes, and pregnancy complications such as preterm birth and preeclampsia. In males, seminal microbiota composition (notably the presence of Lactobacillus vs. Anaerococcus, Pseudomonas, or Prevotella) correlates with sperm quality. The endometrial and follicular microbiomes, though less studied, also appear to influence implantation success and embryo development. The presence of pathogenic or dysbiotic communities in the reproductive tract can impair fertilization, implantation, and pregnancy maintenance, potentially resulting in ART failure or reduced live birth rates. Importantly, the review discusses how biofilm formation and the three-dimensional structure of microbial communities may shield pathogens from host immune responses and antimicrobial interventions, complicating treatment.

Key implications

This review underscores the emerging clinical importance of assessing and modulating the reproductive tract microbiome in infertility management. For clinicians, it emphasizes that microbial profiling, especially using sequencing-based methods, can identify dysbiosis not detectable by standard cultures, and may inform personalized interventions. The dominance of beneficial Lactobacillus strains is associated with higher fertility and ART success, while dysbiotic states predict poorer outcomes. Probiotic therapies and targeted antibiotics show promise but require further validation; indiscriminate antibiotic use may disrupt beneficial microbes. Future directions include integrating microbiome analysis into reproductive health assessments and developing microbiota-based therapeutics to optimize reproductive outcomes. A nuanced understanding of microbial signatures could enable precision medicine approaches in infertility and pregnancy care.

What was reviewed?

This review article comprehensively examines the emerging role of probiotics in the context of human infertility, focusing on both male and female reproductive health. The authors synthesize current evidence on how the human microbiome, particularly the urogenital and gastrointestinal microbiota, influences fertility, and detail the mechanisms by which probiotics, especially strains of Lactobacillus and Bifidobacterium, may contribute to fertility restoration. The review covers the historical development of probiotic therapy, the interaction between probiotics and prebiotics (synbiotics), and the multi-faceted ways in which probiotics maintain immune homeostasis, suppress pathogenic bacteria, and support reproductive tract health. Special emphasis is placed on infertility related to bacterial vaginosis, oxidative stress, obesity, hormonal disturbances, and complications during IVF or pregnancy, highlighting the microbiome’s pivotal role in reproductive success.

Who was reviewed?

The review synthesizes studies involving a broad spectrum of populations relevant to infertility: reproductive-age men and women, including those with obesity, advanced age, bacterial vaginosis (BV), polycystic ovary syndrome (PCOS), and those undergoing assisted reproductive technology (ART) such as IVF. Both human clinical trials and animal model studies are included to elucidate probiotic effects on sperm quality, testicular histopathology, vaginal microbiota balance, pregnancy outcomes, and menopausal infections. The article integrates findings from diverse ethnic, age, and health backgrounds, reflecting the complex interplay between host factors, microbiome composition, and fertility outcomes.

Most important findings

The review highlights that a balanced microbiome, particularly the dominance of Lactobacillus species in the female genital tract, is strongly associated with reproductive health and fertility. In women, disruption of this balance (dysbiosis) and overgrowth of pathogens such as Gardnerella vaginalis are linked to BV, infertility, increased risk of pre-term birth, and complications in ART. Probiotic supplementation demonstrates efficacy in restoring vaginal microbiota, reducing BV recurrence, and promoting favorable reproductive outcomes. In men, probiotics can mitigate the negative effects of obesity and oxidative stress on sperm quality and testosterone levels, potentially enhancing fertility. Notably, animal and human studies show that probiotics can reverse testicular tissue injury, improve sperm parameters, and maintain reproductive hormone levels. Furthermore, probiotics are associated with reduced inflammation in PCOS, improved IVF outcomes, and better management of menopausal vaginal infections. The review underscores the need to identify precise probiotic strains, optimal dosing regimens, and combination strategies for maximal clinical benefit.

Key implications

The findings suggest that probiotics could serve as adjunct or alternative therapies for infertility management in clinical settings, offering a microbiome-targeted approach to both prevention and treatment. For women, maintaining a Lactobacillus-dominant vaginal microbiota may reduce infertility risk, improve ART success, and prevent recurrent BV and related complications. For men, probiotics offer a natural means to counteract infertility associated with metabolic dysfunction and aging. However, the review also notes that further in vivo studies are necessary to standardize administration methods, dosing, strain selection, and combination therapies before widespread clinical adoption. Integration of microbiome analysis into fertility assessments and treatment personalization could significantly advance reproductive medicine.

What was studied?

This randomized, double-blind clinical trial investigated the comparative efficacy of a herbal regimen, Nigella sativa (black seed) combined with black pepper, versus standard pharmacological ovulation induction (letrozole plus tamoxifen) in treating infertility among women with polycystic ovarian syndrome (PCOS). Over three menstrual cycles, participants received either the herbal combination or the pharmaceutical agents during days 3–7 of their cycle. The primary outcomes measured were endometrial thickness, dominant follicle size, and follicle count, as assessed by transvaginal ultrasound. The secondary outcomes included pregnancy rates and incidence of ovarian hyperstimulation syndrome (OHSS). The study aimed to determine whether the herbal regimen could offer a comparable or superior alternative to standard pharmacological treatments, with potential implications for safety, cost, and patient acceptability.

Who was studied?

The study enrolled 90 infertile women with PCOS, aged 18 to 42 years, who were referred to an infertility clinic associated with Jahrom University of Medical Sciences, Iran. Participants were diagnosed with PCOS according to the Rotterdam criteria, requiring two out of three features: oligo/amenorrhea, clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasound. Exclusion criteria included underlying medical conditions (e.g., endocrine disorders, liver/renal disease), abnormal laboratory results, and prior or ongoing use of fertility medications or relevant surgeries. Rigorous randomization and double-blinding ensured comparability between the intervention (Nigella sativa + black pepper) and control (letrozole + tamoxifen) groups, which were closely matched for age, BMI, and baseline hormonal profiles.

Most important findings

The intervention group (Nigella sativa + black pepper) demonstrated a significantly higher pregnancy rate compared to the letrozole + tamoxifen group. By the 12th day of the menstrual cycle, the herbal group also exhibited greater endometrial thickness and dominant follicle size, as well as increased follicle numbers, all with statistically significant differences. Importantly, the incidence of OHSS did not differ significantly between groups, suggesting that the herbal regimen did not increase the risk of this notable adverse effect. While the study did not directly assess microbiome composition, it is notable that both Nigella sativa and black pepper possess well-documented antioxidant and anti-inflammatory properties, which may beneficially influence the metabolic and inflammatory milieu characteristic of PCOS, a condition that has been linked in other research to alterations in the gut and reproductive tract microbiota. The study also noted a significant reduction in serum LH levels in the herbal group, which is relevant given the role of LH/FSH imbalance in PCOS pathogenesis.

Key implications

This study suggests that Nigella sativa combined with black pepper may serve as an effective, low-cost, and low-side-effect alternative to standard pharmaceutical ovulation induction in infertile women with PCOS. The herbal regimen improved pregnancy rates and key reproductive parameters, with a safety profile comparable to conventional agents. The findings support further research into the mechanisms of action, including possible modulation of metabolic and inflammatory pathways relevant to PCOS and potentially mediated by the microbiome. If corroborated by larger and longer-term studies, these results could expand the therapeutic options for PCOS-related infertility, particularly where accessibility, cost, or side-effect profiles limit the use of standard medications.

What was reviewed?

This editorial provides an alternative perspective on the use of metformin in treating female infertility associated with polycystic ovary syndrome (PCOS), challenging the conservative stance of the 2007 ESHRE/ASRM consensus. The review critically evaluates the evidence base behind current recommendations, which suggest restricting metformin use to women with glucose intolerance. Nestler discusses pharmacological distinctions between metformin and clomiphene, evaluates the outcomes of landmark randomized controlled trials and meta-analyses, and considers patient-specific factors such as the urgency of conception and risk of multiparity. The editorial also addresses the potential benefits of metformin alone, combination therapy with clomiphene, and pre-treatment strategies, highlighting the need for individualized approaches to ovulation induction in PCOS patients.

Who was reviewed?

This editorial reviews data from women with PCOS, specifically those experiencing anovulatory infertility. The populations considered in the referenced trials and meta-analyses include both obese and non-obese women, with varying degrees of insulin resistance and diverse reproductive goals. The review pays particular attention to subgroups, women seeking immediate pregnancy (often seen by reproductive endocrinologists) versus those with a longer fertility timeline (frequently managed by gynecologists or medical endocrinologists), and distinguishes between those with and without glucose intolerance. The editorial also references studies with large and well-defined cohorts, such as the 1,639 subjects in the cited meta-analysis, and incorporates clinical experience from academic centers.

Most important findings

The key findings revolve around the nuanced role of metformin in PCOS-related infertility. The editorial notes that while clomiphene is more effective for rapid ovulation induction, metformin is associated with improved ovulation rates over longer treatment periods, especially in women not seeking immediate conception. Meta-analyses demonstrate that metformin enhances ovulation in a significant proportion of women with PCOS (up to 69% improvement in menstrual cyclicity, with 88% of responders achieving normal cycles). The addition of metformin to clomiphene increases cumulative ovulation and pregnancy rates, though the impact on live birth rates remains statistically inconclusive, possibly due to insufficient study power. Notably, metformin appears to reduce the risk of multiparity compared to clomiphene, an important consideration in clinical decision-making. The editorial also explores the benefit of pre-treatment with metformin, particularly in obese women, as a means to improve weight loss, ovulation induction success, and potentially reduce pregnancy complications.

Key implications

This review underscores the importance of individualized therapy in managing PCOS-related infertility. Metformin should not be restricted solely to women with glucose intolerance; rather, its use should be tailored according to patient fertility timelines and risk profiles. For women desiring rapid conception, clomiphene remains first-line, but adding metformin can boost ovulation rates. For those with a longer horizon, metformin (with lifestyle modification) offers a lower-risk approach that may restore ovulatory cycles and reduce the likelihood of multiple gestations. The editorial highlights the need for further research on metformin’s long-term reproductive outcomes and its role in combination or sequential therapy. Clinicians are encouraged to consider patient preferences, metabolic status, and the evolving evidence base to optimize fertility treatments in PCOS.

What was reviewed?

This narrative review synthesized evidence from seven observational studies addressing the association between preconception adherence to the Mediterranean Diet and outcomes in assisted reproductive technologies (ART), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). The review emphasized the Mediterranean Diet as a holistic dietary pattern, high in plant-based foods, olive oil, and moderate fish/poultry, with low red/processed meat, rather than focusing on individual food components. Study selection spanned publications up to July 2023, with data extracted on Mediterranean Diet adherence (mainly via various food frequency questionnaires and scoring systems), ART protocol details, and primary fertility and ART outcomes, including oocyte and embryo quality, clinical pregnancy, live birth rates, and ovarian response. The review critically appraised methodological strengths and limitations, particularly the heterogeneity in Mediterranean Diet assessment and ART protocols, and lack of standardization across studies.

Who was reviewed?

The review encompassed 2,321 women experiencing infertility and undergoing ART, with individual study sample sizes ranging from 161 to 590 participants. Most participants were aged between their late 20s and early 40s, with studies from Europe (Netherlands, Greece, Italy), the USA, and China. All studies included women preparing for or undergoing IVF or ICSI; some focused on subgroups, such as non-obese women or those with normal BMI and ovarian reserve. Notably, male partners and their dietary habits were largely excluded from analysis, and studies focusing on specific infertility-related pathologies (e.g., PCOS, endometriosis) were not included.

Most important findings

Findings indicate that higher Mediterranean Diet adherence may be associated with modest improvements in ART outcomes: three studies reported increased clinical pregnancy rates or live birth rates, while others found improved embryo yield or ovarian response. However, the effect was not universal; two studies showed no significant associations with ART success rates, oocyte, or embryo quality. One cross-sectional study linked lower Mediterranean Diet adherence to an increased risk of poor ovarian response. Effects were sometimes age-dependent, with benefits seen predominantly in women under 35. Microbiome-related mechanisms are not directly studied, but the Mediterranean Diet’s anti-inflammatory and antioxidant properties are hypothesized to support fertility by promoting a favorable endometrial environment, potentially modulating the reproductive tract microbiome, reducing oxidative stress, and enhancing implantation. The major limitation is heterogeneity in Mediterranean Diet scoring, ART protocols, and lack of randomized controlled trials, which constrains causal inference and generalizability.

Key implications

While the Mediterranean Diet appears promising as a supportive intervention for women undergoing ART, current evidence is inconsistent and limited by methodological variability. Clinicians may consider recommending the Mediterranean Diet as part of preconception counseling for infertile couples, given its broad health benefits and potential to improve ART outcomes. However, robust randomized controlled trials with standardized dietary assessment tools are necessary to establish causality and clarify the magnitude of benefit. Understanding microbiome-mediated mechanisms could further inform personalized dietary recommendations to optimize reproductive success.

What was reviewed?

This comprehensive review synthesized current evidence regarding the protective roles of honey in reproductive health, focusing on both male and female fertility, menopause-related symptoms, reproductive toxicity, and vulvovaginal candidiasis. The review explored honey’s biochemical composition, rich in antioxidants, phytoestrogens, and antimicrobial components, and its traditional and emerging therapeutic applications. Emphasis was placed on honey’s impact on reproductive organ health, hormonal balance, microbial modulation (particularly vaginal microbiota), antioxidant defenses, and its utility as a natural alternative or adjunct to conventional therapies.

Who was reviewed?

The review encompassed a broad range of studies involving both animal models (primarily rats) and humans. Included were in vivo and in vitro experiments, randomized clinical trials, and epidemiological data. The populations reviewed spanned healthy and diseased states: men and women of reproductive age, postmenopausal women, pregnant women, and individuals with vulvovaginal candidiasis. Both traditional and modern clinical contexts were considered, making the findings broadly applicable to diverse patient groups.

Most important findings

Honey demonstrates multifaceted benefits in reproductive health through several mechanisms, many of which intersect with microbiome dynamics. Notably, honey’s antioxidant-rich composition (including flavonoids like quercetin and kaempferol) confers protection against oxidative stress in reproductive tissues, an effect substantiated in animal models exposed to toxins such as bisphenol A and cigarette smoke. Honey has shown efficacy in improving sperm quality, motility, and testosterone levels, and serves as a natural cryoprotectant in semen preservation across multiple species. In females, honey supplementation (notably Tualang and Manuka varieties) mitigates menopausal atrophy of the vagina and uterus, likely due to its phytoestrogenic and prebiotic properties, which help maintain mucosal integrity and possibly support beneficial Lactobacillus populations.

A particularly significant microbiome-related detail is honey’s selective antimicrobial action: it inhibits Candida albicans (the main cause of vulvovaginal candidiasis) without suppressing commensal Lactobacillus, thus preserving or restoring a healthy vaginal microbiota. Clinical trials comparing honey (alone or combined with yogurt) to conventional azole antifungals found similar or superior symptom resolution with honey, and no significant adverse effects. Furthermore, honey’s acidity and osmolarity create an environment unfavorable for pathogenic microbes while supporting microbial homeostasis.

Key implications

For clinicians, this review highlights honey as a promising natural adjunct or alternative for managing reproductive health conditions. Its antioxidant and estrogenic activities suggest utility in mitigating toxin-induced reproductive damage, supporting fertility, and managing menopause-related vaginal symptoms without the risks associated with hormone replacement therapy. Notably, honey’s selective antimicrobial properties make it an attractive candidate for treating recurrent vulvovaginal candidiasis, especially amid growing antifungal resistance. Incorporating honey into clinical practice could support microbial health (especially in the vaginal ecosystem), reduce reliance on pharmaceuticals, and offer patients a well-tolerated, cost-effective therapeutic option. Further research is warranted to establish standardized dosing, identify optimal honey varieties, and elucidate detailed mechanisms of microbiome modulation.

What was reviewed?

This review article examines current evidence on the use of medical-grade honey (MGH) as a novel therapy for bacterial vaginosis (BV), a prevalent condition among women of reproductive age characterized by a dysbiosis of the vaginal microbiome. BV is associated with a reduction in protective, lactic acid-producing lactobacilli and an overgrowth of pathogenic anaerobes, often resulting in recurrent symptoms even after standard antibiotic treatment. The authors explore the multifaceted antimicrobial, anti-biofilm, prebiotic, probiotic, anti-inflammatory, antioxidant, and immunomodulatory properties of MGH, and how these may address the shortcomings of conventional therapies. The review synthesizes in vitro, animal, and limited clinical evidence, highlighting the mechanisms by which MGH can selectively inhibit BV-associated pathogens while supporting beneficial microbial populations.

Who was reviewed?

The review encompasses research involving a range of populations and experimental models: in vitro studies on pathogenic and commensal vaginal microbes; animal models, including rats and rhesus macaques, investigating the effects of honey or its constituents on vaginal flora and tissue; and small-scale clinical studies and case series with women experiencing BV or related gynecological disorders. The clinical evidence includes a pilot study using MGH in women with vaginal complaints (including BV), trials on honey-based therapies for cervicitis, and preclinical models examining the impact of honey on vaginal microbiota and tissue health. The reviewed populations predominantly comprise women of reproductive age, but also incorporate data from non-human models to elucidate mechanisms of action.

Most important findings

The review underscores that MGH exhibits broad-spectrum antimicrobial activity through multiple mechanisms—osmotic effects, acidic pH, hydrogen peroxide production, and diverse bioactive compounds (e.g., phenolics, flavonoids). Importantly, MGH's antimicrobial impact is selective: while it significantly inhibits BV-associated pathogens such as Gardnerella vaginalis and Atopobium vaginae, it generally spares or even promotes lactobacilli, which are central to a healthy vaginal microbiome. MGH also disrupts biofilms, a critical factor in BV recurrence and antibiotic resistance, by breaking down the extracellular matrix and preventing biofilm formation. Unlike antibiotics, which can further disrupt the microbiome and drive resistance, MGH supports restoration of the vaginal ecosystem via prebiotic and probiotic effects, encouraging growth of beneficial bacteria. Additional anti-inflammatory, antioxidant, and immunomodulatory properties may promote mucosal healing and reduce recurrence. Clinical evidence, though limited, suggests symptomatic and microscopic improvement in BV and related conditions with intravaginal MGH application.

Key implications

MGH represents a promising alternative or complementary therapy for BV, offering broad-spectrum antimicrobial action without promoting resistance and with the potential to restore a healthy vaginal microbiome. Its ability to eradicate biofilms and modulate inflammation gives it distinct advantages over conventional antibiotics, which are plagued by high recurrence rates, microbiome disruption, and increasing resistance. The favorable impact of MGH on lactobacilli and the microenvironment suggests a paradigm shift toward therapies that restore ecological balance rather than merely suppressing pathogens. However, robust clinical trials are urgently needed to confirm efficacy, optimal formulations, and long-term outcomes before routine clinical adoption.

What was studied?

This original research investigated the long-term effects of dietary quercetin supplementation on female fertility and ovarian physiology in mice, with a specific focus on the role of the enzyme transglutaminase 2 (TG2). Quercetin, a widely consumed flavonoid supplement, is known for its antioxidant properties, but its effects on female reproductive health remain poorly characterized. The study evaluated birth outcomes (number and size of litters, birth spacing) and detailed ovarian histology (folliculogenesis) in mice administered quercetin (5 mg/kg/day) for nine months. Two breeding periods were analyzed: one during prime reproductive age (2–6 months) and another during later reproductive age (8–11 months). The researchers also compared wild-type mice with TG2-null mice to determine whether the observed effects were mediated through TG2 inhibition.

Who was studied?

The subjects were C57BL/6 female mice, either wild-type or genetically modified to lack TG2 (TG2-null), and their offspring. Each experimental group consisted of four females and two males, with both wild-type and TG2-null genotypes represented. Mice were randomly assigned to receive either quercetin or vehicle via drinking water, and breeding outcomes were monitored during two distinct reproductive periods. The offspring of these dams were also analyzed for ovarian morphology and follicle counts at four weeks of age. Additionally, male fertility was assessed by mating quercetin-exposed males with untreated females to exclude male-mediated effects.

Most important findings

Dietary quercetin supplementation produced complex, age-dependent effects on female fertility and ovarian physiology in mice. In young wild-type females, quercetin reduced the total number of litters by approximately 60% and increased the interval between births (birth spacing), indicating a reduction in overall reproductive potential. Paradoxically, these same young females exhibited a nearly 70% increase in average litter size, a change associated with significantly enhanced ovarian folliculogenesis—specifically, an increase in mature antral follicles and a corresponding depletion of primordial and primary follicles. In older females, quercetin reversed its effect, reducing litter size. Importantly, TG2-null mice displayed similar changes in follicle development and litter size as quercetin-treated wild-type mice, and were unresponsive to additional quercetin, indicating that quercetin’s effects are predominantly mediated via TG2 inhibition.

Key implications

This study demonstrates that chronic dietary quercetin, at doses relevant to human supplementation, can adversely affect female reproductive potential by accelerating follicle maturation and depleting ovarian reserves, likely through inhibition of TG2. The findings suggest a risk of premature ovarian aging and reduced fertility with long-term quercetin use in females of reproductive age. The data also highlight TG2 as a novel regulator of ovarian aging and folliculogenesis. These insights are clinically relevant for counseling women considering quercetin supplementation and inform potential mechanisms underlying reproductive disorders, such as those observed in TG2-targeting autoimmune diseases like celiac disease. For microbiome signatures databases, the study underscores the importance of tracking host-microbe interactions influenced by dietary polyphenols and their systemic enzymatic targets.

What was reviewed?

This comprehensive narrative review focused on the relationship between dietary factors, nutritional supplementation, and female fertility, with an emphasis on how dietary patterns and specific nutrients influence reproductive outcomes. The authors synthesized current evidence regarding the effects of macronutrients (carbohydrates, fats, proteins), micronutrients (vitamins, minerals), phytoestrogens, gluten, antioxidants, caffeine, alcohol, and the gut microbiota on female fertility. Special attention was given to the Mediterranean versus Western-style dietary patterns and their associations with ovulatory health, metabolic disorders such as polycystic ovary syndrome (PCOS), endometriosis, and assisted reproductive technology (ART) outcomes. The review also detailed how specific nutrients and bioactive food components interact with underlying hormonal, metabolic, and inflammatory pathways relevant to the reproductive system.

Who was reviewed?

The review encompassed a broad population of reproductive-aged women, including those planning pregnancy, experiencing infertility (of both known and idiopathic causes), and those undergoing ART. Studies drawn upon in the review included healthy women, women with metabolic and reproductive disorders (notably PCOS and endometriosis), and subgroups with dietary deficiencies or excesses. The review also referenced evidence regarding women with specific conditions such as celiac disease and those with varying levels of micronutrient status. While primarily focused on the female population, some comparative insights referenced male fertility or lifestyle factors, though male infertility was not the core subject.

Most important findings

The review underscores that dietary patterns have a significant impact on female fertility. Diets high in trans fats, refined carbohydrates, and added sugars are associated with higher risks of ovulatory disorders, insulin resistance, PCOS, and reduced ART success. Conversely, adherence to the Mediterranean diet, rich in dietary fiber, plant-based proteins, omega-3 fatty acids, vitamins, and minerals, is linked to improved ovulatory function, better metabolic profiles, and higher fertility rates, including among women undergoing ART. Micronutrients such as folic acid, vitamin D, iodine, and iron are particularly important, with deficiencies in these linked to impaired fertility, increased time to conception, and adverse pregnancy outcomes. The review highlights inconsistent findings regarding dairy fat, protein sources, and phytoestrogens, noting the need for individualized dietary recommendations. Importantly, the composition of the gut microbiota emerges as a potentially critical mediator of fertility, with Western diets promoting dysbiosis and inflammation, while fiber-rich, plant-based diets foster beneficial microbial shifts (notably increased Bifidobacteria and Prevotella). The review also finds limited evidence for the routine exclusion of gluten in non-celiac women and suggests routine supplementation of folic acid and vitamin D for women planning pregnancy.

Key implications

For clinicians, the review highlights the necessity of a holistic and individualized approach to female fertility, integrating dietary assessment and intervention as core components of preconception and infertility care. The findings support recommending Mediterranean-style dietary patterns, ensuring adequate intake (and, if necessary, supplementation) of key micronutrients such as folic acid, vitamin D, and iodine, and promoting gut health through fiber-rich, plant-based foods. Given the intricate links between diet, metabolic health, reproductive hormones, and the gut microbiome, multidisciplinary collaboration, including the involvement of clinical dietitians, is crucial. The review also suggests the importance of monitoring micronutrient status and considering celiac disease screening in infertile women. Current evidence does not support universal exclusion of gluten, caffeine (within recommended limits), or moderate alcohol prior to conception, but underscores the risks of excess. Future research should focus on clarifying the roles of specific nutrients, gut microbiota signatures, and developing standardized dietary recommendations for women planning pregnancy.