PJZ_58_2_955-967

INTRODUCTION

Recently, female infertility has been a serious health issue around the whole world (Tomaiuolo et al., 2020). Infertility, a complicated medical condition, can affect an infertile individual’s physical, mental, and psychological health. Both female and male infertility can cause variofertility-related conditions. Though male fertility is a serious and prevalent factor in infertility studies this review paper only summarizes different bacterial infection-related infertility conditions in women (Walker and Tobler, 2022). According to the World Health Organization (WHO), infertility is defined as failure to achieve pregnancy after 12 months or more of regular unprotected sexual intercourse. At the same time unable to get pregnant after the very first successful pregnancy is called secondary infertility. It may present in both male and female individuals, affecting a million people worldwide. WHO reported that 186 million people and 48 million couples suffer from infertility (WHO, 2020). In the United States, nearly 6% of married women in the reproductive age group (15 to 44 years) currently have infertility and 12 % of the total married women population faces impaired fecundity problems and other pregnancy difficulties. In the United States, the male factor is one of the main reasons behind infertility. 8% of infertility is because of male partners only over there (CDCP, 2021a). In India, a wide range of lifestyle diversity like working patterns, traditions, hygiene patterns, health care facilities, customs, traditions, and external environmental conditions leads to different infertility rates within the different regions and groups of people. Recently, in India, infertility is between 10 and 14%. The burden is higher in urban areas (approximately 1 in 6 couples suffer from infertility). Infertile women face psychological, social, and physical ignorance and trauma daily of the phenomenon. These mental and physical issues are more severe in India within patriarchal societies. Female infertility can put women into marital insecurity, and the consequences can exert massive emotional instability for women. Women used to face lots of disrespect, rejection, teasing, and abusive words at home and in society. Centres for Disease Control and Prevention (CDCP) have started a National Public Health Action Plan to prevent, manage and detect infertility. This plan covers some essential points regarding this infertility field, like promoting healthy behaviours to control infertility rate, early diagnosis, preventive measures, and therapeutic remedies to control infertility, and lastly, avoiding external exposures including infectious pathogens, environment, hygiene, and iatrogenic agents to secure fertility possibility (Kalidasan et al., 2020).

Vagina is an appropriate place for microbial growth due to its humid and warm environment and the presence of nutritional sources. 9% of the total microbiota inside the human body is occupied by vaginal microbiota. Lactobacillus has been found abundantly in the vaginal microbiota, and along with Lactobacillus, many other bacterial species such as Bifidobacterium, Prevotella, Gardnerella, Megasphaera, Atopobium, Anaerococcus, Sneathia are also found (Amabebe and Anumba, 2018; Sirota et al., 2014). Normal vaginal microbes can prevent pathogenic growth by using their anti-microbial and anti-inflammatory compounds. Lactobacillus use to produce L-lactic acid and D- lactic acid that maintains the normal vaginal acidic pH (4.5) (Tomaiuolo et al., 2020). The normal vaginal pH of a healthy female is near about 4.5. However, dysbiosis of the vaginal microbiota may increase the pH value inside the vagina, which is directly associated with a higher risk of preterm birth and female infertility. One descriptive study by Lykke et al. (2021) detected an elevation of the pH value in the lower vagina of the female with abnormal vaginal microbiota than the women with normal vaginal microbiota by selecting both pregnant and nonpregnant women for this study. This study also identified some pathogens like Atopobium vaginae, Leptotrichia amnionii, Sneathia sanguinegens, bacterial vaginosis-causing bacteria, Prevotella spp., TM7 among women with abnormal vaginal microbiota by using PCR technique (Lykke et al., 2021). Lactobacillus also produces bactericidal peptides, bacteriocins which can form pores on the pathogen’s cell membrane and consequently rupture it. The balance between normal vaginal microbes and unwanted facultative pathogens in the vaginal microbiome plays an essential role in women’s reproductive health, including fertility chances. Disbalance in the vaginal microbiota can damage the first-line defense mechanisms against pathogens. Bacterial vaginosis, an excess number of facultative anaerobes inside the vaginal microbiota instead of Lactobacillus, urinary tract infections, sexually transmitted infections, and preterm birth are some common reasons for vaginal microbial dysbiosis (Tomaiuolo et al., 2020). Infertility-causing pathogenic microbes used to enter the upper genital tract through the vagina. The vaginal microbiota is composed of many anaerobic as well as aerobic bacteria; any external factors, including medications, antibiotics, systematic hormones, douching process, contraceptives, frequent sexual intercourse, poor socio-economic status, and stress level can hamper typical vaginal ecosystem after a specific period. Sometimes, lactobacillus dominant vaginal microbiota is replaced by several harmful anaerobic and aerobic microbes (Sirota et al., 2014; Lykke et al., 2021). Babu et al. (2017) conducted one cross-sectional study in India by selecting 200 females (84 healthy + 116 infertile) aged 18 to 45 years. Study collected swab samples for microbiological analysis. This study showed a significant amount of Lactobacillus present in the vaginal samples among 27.8% (n= 40) of healthy women. Remaining 15.3% (n= 22), 11.1% (n= 16), and 8.3% (n= 12) of healthy women’s vaginal samples were dominated by Micrococcus, Enterococcus, and Staphylococcus, respectively. At the same time, among the infertile patient group, 26.5% (n= 30), 23% (n= 26), and 14.1% (n= 16) of infertile women showed Candida, Enterococcus, and Escherichia coli dominated vaginal microbiota. A low level of Lactobacillus count was detected among infertile female patients. The result of the experiment also identified asymptomatic vaginosis among 27.6% of infertile patients and 7.1% of healthy females. This study recommended routine screening of the vaginal microbial system during infertility treatment (Babu et al., 2017). Some internal factors including age, immune power, hormonal status, and external factors such as infectious microbial exposure, antibiotic exposure, can facilitate the vaginal microbial disbalance process (dysbiosis). Vaginal microbiota dysbiosis is strongly associated with bacterial vaginosis, which further directly associated with women reproductive health disorders, HIV (human immunodeficiency virus), human papillomavirus (HPV), pelvic inflammatory disease risk. Some common factors like douching, variation in intercourse, stress, race, regional disparity can also chance the vaginal microbiome composition (Babu et al., 2017). This review aims to summarize the adverse effect of different bacterial infections on female reproductive health and infertility.

Chlamydia trachomatis

Chlamydia trachomatis is an obligate intracellular Gram-negative bacterium (Witkin et al., 2017). C. trachomatis (under the genus Chlamydophila) is responsible for Chlamydia, one kind of sexually transmitted infectious state. C. trachomatis, mainly serovars A-C are responsible for human blindness, serovars L1-L3 are responsible for lymphatic system infection and sexually transmitted infections C. trachomatis serovars D-K are especially responsible (Witkin et al., 2017). C. trachomatis can transmit directly through the vagina, oral and anal sex. The fetus can also get this infection during childbirth from the mother. This infection is widely prevalent around the United States as well as around the world. C. trachomatis is responsible for cervicitis, proctitis, urethritis, and trachoma, one kind of ocular infection that consequently leads to permanent blindness if remains untreated (CDCP, 2021b). Sexually transmitted infections like C. trachomatis, Neisseria gonorrhoeae, Mycoplasma, and Treponema pallidum can impair normal reproductive functions (Witkin et al., 2017). Persistent C. trachomatis infection can induce infertility and ectopic pregnancy chance. Young women usually get Chlamydia infection rapidly, increasing the chance of tubal infertility, pelvic inflammatory diseases, obstetrics consequences, and chronic pelvic pain. 10% to 15% of women infected with Chlamydia show symptomatic pelvic inflammatory disease (CDCP, 2021b; Srivastava et al., 2008). Most of the patients with chlamydial infection are asymptomatic. According to the Centers for Disease Control and Prevention, 4 million people were infected by C. trachomatis (CDCP, 2021b). In the United States, Chlamydia infection is the most common, followed by Gonorrhea infection cases. Centres for Disease Control and Prevention estimated 1808703 Chlamydia infection cases and 616392 Gonorrhea infection cases from fifty states of the United States and the District of Columbia in 2019 (CDCP, 2021c). Chlamydia infection also has some disadvantages, such as antibiotic resistance and side effects on urogenital microbiota (Mohseni et al., 2022; Debonnet et al., 2021). Parpillewar and Singh (2021) conducted one cross-sectional study to determine the prevalence of female infertility due to C. trachomatis infection. Seventy-five infertile women (with and without pelvic inflammatory disease) and 75 women with no infertility symptoms were enrolled in this study.

The study collected cervical swab samples from recruited women to detect C. trachomatis infection. A sudy detected 14 C. trachomatis infections from the infertile women group (42.85 were asymptomatic and 57.14 were symptomatic) and 4 from the control group. This study also agreed that C. trachomatis infection harms female fertility processes (Parpillewar and Singh, 2021). Sharaf et al. (2021) selected 50 female patients with primary and secondary infertility and 25 healthy pregnant ladies for their prospective randomized clinical study. The study analyzed the anti-chlamydial IgG level of the enrolled females and reported a higher level of IgG in infertile women (46%) compared to the normal pregnant women group (12%). Studies strongly suspect C. trachomatis is one of the major reasons for tubal factor infertility (Sharaf et al., 2021). A retrospective cohort study investigated 253 tubal factor infertile women (who went for tubal flushing) and showed that C. trachomatis infection significantly decreased the pregnancy chance and live birth rate. Therefore, the findings of the study suggest that C. trachomatis infection screening before the tubal flushing procedure (Kayiira et al., 2019). Another experimental study by Rashidi et al. (2013) was performed to measure the burden of C. trachomatis infection among fertile and non-fertile women group using PCR and ELISA techniques.

The study took 223 pregnant and 234 infertile women for the study purposes. The study showed that 12.4 % of the infertile women and 8.5% of the fertile women were C. trachomatis infected. Studies failed to show any significant difference in C. trachomatis infection rate between the pregnant and non-fertile groups of women. A study suggested the C. trachomatis infection diagnosis during infertility condition and recommended molecular techniques for determination of the infection (Rashidi et al., 2013). One more cross-sectional study in India investigated the C. trachomatis infection rate in infertile women. Mania-Pramanik et al. (2012) took 896 female patients and performed a PCR technique to determine the presence of C. trachomatis infection. Studies showed a significant negative effect of C. trachomatis infection on female fertility. The study also revealed that the C. trachomatis infection rate is much higher among women with ectopic pregnancy (25%) and infertility (18.6%). De Lima Freitas et al. (2011) used the polymerase chain reaction technique for C. trachomatis infection identification among 106 infertile women. After analysis study revealed that 52.8% of infertile women had C. trachomatis infection and out of this 51.8% were above 30 years old.

The study also reported that among 56 C. trachomatis infection cases, 55.4% were infertile permanently, and 16 % of women faced fetal death during pregnancy (de Lima Freitas et al., 2011). Another prospective study in India by Malik et al. (2009) also confirmed the presence of Chlamydia infection among women with secondary infertility. The study selected 40 women with secondary infertility and 30 healthy women as controls. Study results indicated that the Chlamydia infection rate among secondary infertile women was significantly high. The study also recommended the immunoglobulin G antibody detection process as a diagnosis tool for Chlamydia infection. The study also indicated the positive advantages of the ELISA technique such as inexpensiveness, ease of measurement, and early process for antibody and antigen diagnosis during Chlamydial infection (Siemer et al., 2008). Srivastava et al. (2008) collected vaginal swab samples from 133 infertile female patients to detect sexually transmitted infections. After analysis, the study identified 25 patients and 23 patients who had C. trachomatis and Mycoplasma infection, respectively. Apart from this, the study did not find any Neisseria gonorrhoeae and Treponema pallidum infection cases. At the end of the experiment, the study concluded that frequently, C. trachomatis and Mycoplasma infection detection is necessary in case of infertility treatment. India-based study with 368 female patients identified the effect of chlamydial heat shock proteins (cHSP) 60 and 10 on infertility and ectopic pregnancy. Chlamydial heat shock proteins (cHSP) 60 and 10 could stimulate the production of IL-10, Interferon-gamma, and tumor necrosis factor-alpha from cervical mononuclear cells, and this phenomenon is related to C. trachomatis infection-mediated infertility and ectopic pregnancy.One retrospective study by Siemer et al. (2008) (191 with primary and secondary infertility, 248 healthy pregnant women) women did not show any significant association between C. trachomatis infection and infertility rate, but this study observed infection-specific IgG and IgA antibodies within both primary and secondary infertile women. Al-Ramahi et al. (2008) conducted one Jordan-based prospective controlled study. The study aimed to check the burden of C. trachomatis infection among infertile women over a specific area. The study recruited 146 healthy women as control and 152 infertile patients and collected endocervical swab samples for infection detection by polymerase chain reaction technique. No significant effect of C. trachomatis infection on infertility rate was reported. Malik et al. (2009) conducted one study to observe the effect of C. trachomatis on female infertility. The study recruited 110 women with primary and secondary infertility and 30 healthy pregnant women as control. The findings of the study stated that 28.1% of the infertile women and 3.3% of the control population had Chlamydia infection (detection of C. trachomatis infection). The study detected more C. trachomatis infection cases from the infertile women group, especially from asymptomatic cases.

The study recommended an early screening process for C. trachomatis infection to establish preventive, therapeutic measures against this infection as soon as possible (Malik et al., 2009). Lucisano et al. (1992) isolated C. trachomatis from 105 women who underwent laparoscopy. The study collected urethral, cervical, endometrial, and peritoneal samples for C. trachomatis isolation. Out of 42 tubal infertilities, 41 were unexplained infertility, 4 were salpingitis, and 18 were endometriosis cases 13, 5, 1, and 1 female patient were infected with C. trachomatis infection, respectively. However, the study confirmed the association of C. trachomatis infection with tubal damage (Lucisano et al., 1992).

Mycoplasma genitalium

Mycoplasma comes under the Mollicutes class (Ljubin-Sternak and Meštrović, 2014). Genus Mycoplasma consists of more than 100 different strains (Mycoplasma infections-statpearls- NCBI Bookshelf, 2022). Mycoplasma genitalium infection can lead to abnormal inflammatory conditions like cervicitis, urethritis, salpingitis, pelvic inflammatory disease (Afrasiabi et al., 2015), and endometritis and ultimately increase the chances of getting female infertility. M. hominis infection is associated with bacterial vaginosis (Plummer et al., 2021), pyelonephritis, cervicitis, tubal inflammation, pelvic inflammatory disease, endometritis, and postpartum septicemia. Another genital mycoplasma, Ureaplasma urealyticum infection can induce preterm delivery, bacterial vaginosis, cervicitis, urethritis, and chorioamnionitis (Afrasiabi et al., 2015). Women’s reproductive health can be altered due to various genital mycoplasma infections. Some species like M. genitalium, Mycoplasma hominis, Ureaplasma parvum, M. spermatophilum, M. primatum, M. penetrans, Ureaplasma urealyticum are commonly known as genital Mycoplasma.

Ma et al. (2021) studied the potential role of genital mycoplasmas on female infertility and pregnancy outcomes. Based on the previous 35 electronic databases, the study concluded that genital Mycoplasma, M. genitalium infection was one of the significant causative factors for preterm delivery and female infertility. However, there was no role of M. genitalium infection in spontaneous abortion. Whereas, M. hominis increased female infertility, stillbirth, and preterm membrane rupture chances. The study found no potential role of Ureaplasma urealyticum on female infertility (Ma et al., 2021). Peipert et al. (2021) used proportional hazards models and found that age, low socio-economic status, black race, and previous record of M. genitalium infection could lower the chances of conception. The study confirmed the impact of M. genitalium infection on fertility and conception rate (delayed conception) by performing a serological analysis process on 461 participants (Peipert et al., 2021). Tantengco et al., (2021) performed a meta-analysis to confirm the impact of genital Mycoplasma on female infertility status. This meta-analysis also selected M. genitalium, M. hominis, Ureaplasma parvum, and Ureaplasma urealyticum as potent genital mycoplasmas. This meta-analysis confirmed the potential effect of M. genitalium, M. hominis, and Ureaplasma urealyticum infection on female reproductive health (female infertility) and suggested Mycoplasma diagnosis during infertility management (Tantengco et al., 2021). Doroftei et al. (2021) proved the negative impact of M. genitalium infection on women’s fertility process. This study recruited 51 infertile patients and 23 females with normal fertility. 19.6 % and 4.4% of infertile and fertile women had M. genitalium infection in their cervical canal, respectively. The study also identified M. genitalium infection in the abdominal cavity of 5.8% of infertile women (Doroftei et al., 2021). Another related study also checked the burden of Ureaplasm aurealyticum and M. hominis infection within 411 registered infertile women. As per the study, 28.46%, 2.91%, and 0.48% of the infertile women had Ureaplasm aurealyticum, coinfection, and M. hominis infection respectively (Doroftei et al., 2021).

One Iran-based descriptive study investigated the infection rate of C. trachomatis, M. genitalium, and Neisseria gonorrhoea within infertile women. The study collected 65 infertile women to collect vaginal swab samples from them. PCR and DNA extraction techniques were performed and it ultimately found that out of a total of 65 female samples, 23 patients were infected with bacterial infection (2 patients had mixed infection). 16.9%, 13.8%, and 6.2% of infertile patients had M. genitalium, C. trachomatis, and Neisseria gonorrhea infection, respectively. The study confirmed the significant presence of C. trachomatis, M. genitalium, Neisseria gonorrhea infections among women with infertility (Sameni et al., 2022). Another experimental study was conducted to determine M. genitalium, M. hominis, and Ureaplasma urealyticum infection prevalence among infertile women candidates. The study recruited 104 infertile women and collected their cervical swab samples for further analysis. Multiplex-PCR techniques detected Ureaplasma urealyticum infection among 37.5% of the selected females. Only 2.9% had M. genitalium, M. hominis infection. The study found no association between infertility and the patient’s education, age, employment nature, first intercourse age, or abortion history (Mousavi, et al., 2014). Baczynska et al. (2006) conducted an in vitro experiment. They detected the moderate effect of M. genitalium infection on normal human fallopian tubes. However, they observed massive alteration of the epithelium of normal human fallopian tubes after exposure to C. trachomatis and Neisseria gonorrhea infection (Baczynska et al., 2006). Baczynska et al. (2005) suspected M. hominis infection as one of the major risk factors for infertility due to damaged fallopian tubes. Their study analyzed sera for M. hominis specific antibody detection by selecting 304 infertile women. This study identified M. hominis-specific antibodies in the sera sample of 97 infertile women. The result of the study indicated a potent relation between insufficient fallopian tube passage-related infertility and M. hominis infection rate (Baczynska et al., 2005). Figure 1 lists seven significant Mycoplasma strains together with each one’s harmful characteristics.

Bacterial vaginosis

A change in the vaginal microbiota’s delicate equilibrium is the main contributor of BV. The vagina naturally harbours many microorganisms, including helpful lactobacilli that support the vagina’s acidic pH balance and inhibit the growth of potentially hazardous bacteria. Although BV is not considered an STI, it is more prevalent in people who engage in sexual activity, particularly those with several sexual partners. Frequent douching increases the risk of BV and disturbs the vaginal flora. Soaps, scented goods, or vaginal deodorants can interfere with the typical vaginal environment. Smoking has been linked to a higher chance of developing BV. According to certain studies, using an intrauterine device (IUD) is associated with BV.

Typical signs included in vaginal discharge that is greyish-white, a strong, fishy smell, especially after sexual activity, itching or discomfort in the vagina and a burning feeling when urinating. A combination of clinical evaluation and laboratory tests are used to diagnose BV. Medical history and clinical exam, evaluation of vaginal discharge, and microscopic analysis of the vaginal discharge are some common methods to detect BV. Treatment including antimicrobial therapy, which tries to reduce the excess of dangerous bacteria and reestablish the normal vaginal flora is commonly use. During bacterial vaginosis, lactobacillus-dominated vaginal microbiota is replaced by a wide range of harmful pathogens like Gardenella vaginalis, Mobiluncus, Atopobium, Prevotella, Dialister, Mycoplasma, Streptococcus, Ureaplasma, Bacteroides and many more. These anaerobes decrease antimicrobial peptides amount and normal vaginal pH by inhibiting lactic acid concentration and exhibit the level of short-chain fatty acids (butyrate, acetate, succinate, propionate) and immune mediators (interferon, IL- 2, IL- 6, IL- 8, IL- 10, IL-1β, TNFα RANTES) (Amabebe and Anumba, 2018; Sirota et al., 2014). Vaginal amylase can split complex carbohydrates into glycogen, serving as bacterial food for normal vaginal bacterial growth and survival. The vaginal amylase content gets low during bacterial vaginosis; therefore, normal bacteria cannot grow and survive. Additionally, the human body becomes deprived of antimicrobial peptides during bacterial vaginosis. Bacterial vaginosis can trigger female infertility by elevating inflammatory responses, hampering immune system potentiality, damaging normal vaginal cells and sperm, damaging the production of cervical mucus at the time of ovulation, and clogging the fallopian tube by infections mediated scar tissues, decreasing sperm and egg meeting process in a fallopian tube (Nunn et al., 2020; APA, 2022). About 67 species are available that cause bacterial vaginosis. Name of some common bacterial vaginosis-causing bacteria are Gardnerella vaginalis, Dialister spp., Megasphaera spp., Atopobiumvaginae, Sneathiaamnii, Sneathiasanguinegens, Porphyromonas spp., Prevotella spp., Mobiluncus spp. (Ravel et al., 2021). Many studies proved the association between idiopathic infertility and bacterial vaginosis, elevated vaginal pro-inflammatory cytokines (IL- 8, IL- 1 β) levels.

Bacterial vaginosis is directly associated with poor reproductive health, tubal factor infertility, implantation failure, pregnancy loss, and other sexually transmitted infection’s chance. At the same time, some infectious conditions in the female reproductive organs, like pelvic inflammatory disease, Bacterial vaginosis, (Mania-Pramanik et al., 2012), and endometritis, can put a woman into various reproductive health-related issues, including infertility. A common symptom of bacterial vaginosis is whitish or grey vaginal discharge with a fishy odour. Other symptoms are dyspareunia, dysuria, vaginal pruritus, etc. Patients with bacterial vaginosis are more prone to get other sexually transmitted infections like gonorrhea, and chlamydia; even pregnant women with bacterial vaginosis may have a higher risk of preterm delivery. Bacterial vaginosis is not transmitted from person to person. Bacterial vaginosis induces endotoxin secretion, further triggering prostaglandin and cytokine production in the vagina. Simultaneously, bacterial vaginosis inhibits the potentiality of the host leukocytes against infectious diseases. The presence of clue cells, the cervix’s epithelial cells is the main indicator of bacterial vaginosis. Douching, antibiotic treatment, multiple sexual partners, frequent use of intrauterine devices, and cigarette smoking contribute to bacterial vaginosis (Kairys and Garg, 2022). Wee et al. (2018) performed one initial pilot study (case-control study) to check the vaginal and cervical microbiota composition of women with infertility and normal fertile women. The study selected 31 women (15 infertile and 16 fertile) for sample collection and performed 16 rRNA gene amplicon sequencing techniques to analyze the collected samples. The study stated that Ureaplasma and Gardenella were most abundantly present in the vaginal and cervical samples of the selected infertile women, respectively. Babu et al. (2017) checked the difference between the prevalence of bacterial vaginosis in healthy and infertile women by establishing one cross-sectional study in India. The study considered only 200 women (84 healthy females, 116 infertile females) in the reproductive age group for the study purpose. Studies showed a greater number of Lactobacillus (27.8%) within the vaginal flora of the healthy women group. At the same time, the vaginal flora of the infertile women group was dominated by Candida spp. (26.5%), Enterococcus (23%), Escherichia coli (14.1%). The study detected the significant presence of bacterial vaginosis and asymptomatic vaginosis among the infertile women population compared to healthy females. Systematic literature reviews from PubMed, CINAHL, EMBASE, ISI Web of Knowledge, and Cochrane Library showed that women with bacterial vaginosis are more prone to get tubal factor infertility. The incidence rate of bacterial vaginosis was higher among tubal factor infertile women and was often associated with preclinical pregnancy loss (van Oostrum et al., 2013). A cohort study once conducted by Salah et al. (2013) and the study considered 382 asymptomatic fertile women (control) and 874 infertile women to investigate the presence of bacterial vaginosis in the vaginal samples of the mentioned women and the effect of bacterial vaginosis on fertility and pregnancy rate. The study’s findings showed that 45.5% of the infertile women had bacterial vaginosis, whereas only 15.4% of the fertile women had bacterial vaginosis. As per the regression model, bacterial vaginosis is one of the major significant factors for adverse pregnancy outcomes and faulty fertility processes (mainly unexplained infertility). Casari et al. (2010) investigated the present rate of pathogens among asymptomatic infertile and symptomatic fertile women (a total of 952 patients). The study investigated the genital discharge of recruited females and showed that 19.7%, 12.1%, and 8.6% of infertile patients had Gardenella vaginalis, Enterococci, and Streptococcus agalactiae in their genital discharge, respectively. A study mentioned the decreased number of vaginal Lactobacillus and increased polymorphonucleates number as indicative parameters to determine female urogenital tract health status. Nwaziri et al. (2010) conducted one in vivo study to detect the Gardenella vaginalis effects on pregnancy and infertility by using albino rat models. A study found a 20-40% decrease in impregnation and a 70-80% reduction of offspring production ability by rats after being infected with Gardenella vaginalis (105CFU/ml). This study concluded that Gardenella vaginalis negatively affects rats normal fertility process and pregnancy outcomes. One experimental study also investigated the effect of vaginal microbiota on early pregnancy failure and conception rate in women who went for in-vitro fertilization (IVF). The study only enrolled 91 female patients for this study. The study analyzed and confirmed that IVF patients with bacterial vaginosis and a low amount of hydrogen peroxide synthesizing Lactobacillus within vaginal microbiota are more vulnerable to early pregnancy loss and lower conception chance (Eckert et al., 2003). One cross-sectional study with 749 confirmed bacterial vaginosis was more common among tubal infertile women than endometriosis, male factors infertility, and unexplained infertility (Wilson et al., 2002). Spandorfer et al. (2001) conducted one masked study with 331 IVF patients, and the findings showed that bacterial vaginosis was strongly linked with a higher level of IL-1 beta and IL-8 in the cervix. The pro-inflammatory cytokines production by the vaginal microbial community might increase the risk of idiopathic infertility.

Chronic endometritis

Chronic endometritis (CE) is an inflammatory condition where plasma cells are detectable inside the endometrial stroma during diagnosis. Alteration of the endometrial microbiota composition leads to chronic endometritis (CE), which enhances the chance of bacterial vaginosis and preterm delivery. Intracellular gram-negative microbes like Mycoplasma, Enterococcus faecalis, Chlamydia, Ureaplasma, Staphylococcus, and Escherichia coli are primarily responsible for altering endometrial microbiota. Low Lactobacillus content is very natural within the endometrial cavity during chronic endometritis. Buzzaccarini et al. (2020) summarized fifteen original electronic articles stating that CE can consequently inhibit fertility rate in females by infection-mediated inflammation, altering the endometrium microbial environment, altering the permeability of the endometrium vascular system, altering leukocytes and cytokines expression, and injuring viability of the embryo. Symptomatic and asymptomatic chronic endometritis is directly related to pregnancy failure, miscarriage, and other associated gynaecological problems. Chronic endometritis has been found in approximately 40% of infertile patients (Holzer et al., 2021). Elnashar (2021) suggested chronic endometritis diagnosis in infertile females to improve the clinical management of asymptomatic patients in whom chronic endometritis is not suspected or diagnosed. Many immunocompetent cells in the endometrium can regulate immune and inflammatory associated responses and trophoblast implantation. However, immunogenic cell alteration is common during endometritis, further responsible for immune cell infiltration, hamper immune and inflammatory responses of endometrial cells, and ultimately, embryo implantation and growth endometrium (Ravel et al., 2021). For their study, Hirata et al. analyzed 53 female patients (26 were diagnosed with CE, and 27 patients had no CE during diagnosis).

Studies showed that patients with CE were more prone to miscarriage risk. CE also harmed the live birth rate and pregnancy rate among selected women. Live birth rate pregnancy and miscarriage rate among female patients with CE were 7.7%, 30.8%, and 75%, respectively, whereas live birth rate pregnancy and miscarriage rate among female patients without CE were 51.9%, 63.0%, and 17.7%, respectively. This study advised specific diagnostic criteria for CE: the detection of > = one plasma cell in 10 power fields (Hirata et al., 2021). Wiesenfeld et al. (2012) conducted one prospective observational cohort study with 418 women. Those selected women were either at risk of gonorrhea, Chlamydia, or bacterial vaginosis. No women had pelvic inflammatory disease. A study showed a 40% reduction in the pregnancy rate among women with subclinical pelvic inflammatory disease (endometritis) compared to women without subclinical pelvic inflammatory disease. The study report showed that Chlamydia and Neisseria gonorrhoeae infection without the subclinical pelvic inflammatory disease did not affect infertility risk. The study also suggested that recent preventive therapies for sexually transmitted infections related to infertility problems are insufficient to prevent infertility rate (Wiesenfeld et al., 2012). Li et al. (2017) selected 100 infertile women for a prospective, monocentral pilot study. The expert group detected chronic endometritis among 13 infertile women (13%), and they had associated unilateral or bilateral fallopian tube blockage and endometriosis. The study specified that stages of endometriosis depended upon the presence of syndecan-1- 1 (CD138) positive plasma cells within endometrial tissue. One randomized controlled trial showed a 2.8% rate of chronic endometritis among 606 asymptomatic infertile women using a biopsy test. The study stated that chronic endometritis had minimal effect on the reproductive outcome of infertile women after IVF/ ICSI treatment (Kasius et al., 2011).

Endometriosis

Endometriosis is one type of vaginal microbiota dysbiosis condition among reproductive-aged women, further contributing to women’s infertility. 40% to 50% of the reproductive age female with endometriosis may face infertility in their reproductive life. In endometriosis, endometrial tissue formation is common outside of the uterine cavity. Endometriosis is one of the major causes of infertility (Kasius et al., 2011). Nearly 30 to 71% of infertile women are generally detected with endometriosis, and approximately 30 to 50% of the women with endometriosis are diagnosed as infertile (López-Moreno and Aguilera, 2021). Microbes responsible for endometriosis are Gardnerella, Prevotella, Staphylococcus, Escherichia coli, Cornybacterium, Actinomyces, Enterococcus, Streptococccus, Propionibacterium (Tomaiuolo et al., 2020). Shi et al. (2021) took 226 female infertile patients (176 patients completed the experiment) and found that both adenomyosis and endometriosis harmed reproductive activity and pregnancy outcome. This study also suggested the IVF technique and laparoscopic surgery to improve the pregnancy outcome in patients with adenomyosis and endometriosis. Corachán et al. (2021) identified some significant consequences within female patients with endometriosis such as dysregulation of the cell cycle (impaired quality of oocyte and embryo, poor folliculogenesis process and IVF outcomes), oxidative stress and inflammatory response, biosynthesis and metabolism of steroid (impaired quality of oocyte and embryo), and angiogenesis process into the oocyte and follicular environment by using 123 endometriosis-related previous data (from 1992- 2020) available in PubMed database. This study indicated endometriosis as one of the main reasons for female infertility problems due to those, as mentioned above, endometriosis-associated clinical factors. Campisciano et al. (2017) took 27 infertile female patients and 69 fertile average women and collected cervical-vaginal fluid samples from them for the experiment. A study found that endometriosis is the primary cause of infertility among selected infertile women group, and they did not have normal vaginal Lactobacillus in their vaginal microbiota. After performing the V3-16rDNA sequencing technique study, they indicated Lactobacillus as a biomarker for a normal healthy vaginal ecosystem.

Pelvic inflammatory disease

In pelvic inflammatory disease, the inflammatory condition has been seen in the uterus, fallopian tubes and ovaries, and pelvic part of the female reproductive system due to pathogenic infection. This inflammation-causing infection can enter through the vagina and infect up to the endometrium portion or beyond. Sometimes, clinical symptoms of pelvic inflammatory disease are asymptomatic. However, this inflammatory condition usually leads to several clinical consequences like parametritis, endometritis, oophoritis, salpingitis, pelvic peritonitis, tubo-ovarian abscess, perihepatitis, and ovarian cancer. Pelvic inflammatory disease is becoming a public health burden because nearly 30% of female infertility cases and 50% of ectopic pregnancy cases are due to pelvic inflammatory disease (Al-Kuran et al., 2021). Pelvic inflammatory disease (PID) is a serious infectious disease that directly affects women’s fertility capacity (Witkin et al., 2017). Pelvic inflammatory disease (PID) is an infection (mainly sexually transmitted infections like C. trachomatis and Neisseria gonorrhoeae) mediated inflammatory condition among women that starts to develop from the lower genital tract and gradually spread to the uterus, fallopian tube, and ovaries (DM, 2022). Cervicitis is also an inflammatory condition that affects uterine endocervix epithelium. It can happen from both infectious and non-infectious sources (Iqbal et al., 2025). Infection in the female reproductive organs (endometrium, fallopian tube, peritoneum) leads to pelvic inflammatory disease. This infection state often occurs by sexually transmitted infectious pathogens invading Gonorrhea, Chlamydia. Pathogens transmit to the upper genital tract through the vagina and cervix.

According to the National Health and Nutrition Examination Survey, 2013-2014 report, the lifetime pelvic inflammatory disease rate among sexually active women in the United States is 4.4%, almost 2.5 million females across the United States. This number is far higher than the 2001-2004 report (21.2 million women). The pelvic inflammatory disease ultimately leads to female infertility, lower pregnancy outcomes, pelvic pain, ectopic pregnancy, and many other reproductive health-related issues (Kreisel et al., 2017; CDCP, 2020). Anti-cancerous role of Flavonoids, Catechin, β-sitosterol, and Lignin Glycosides from Saracaasoca (Ashoka) have been discussed with reference to the female reproductive system (Ahmad and Ghosh, 2022). A group of researchers from different countries had worked on the Antineoplastic action of sulforaphane on HeLa cells by modulation of signaling pathways and epigenetic pathways. It showed how cancer call can be controlled by chemical interventions (Sundaram et al., 2021). Nanotechnology can completely alter cancer treatment by providing cutting-edge medication delivery, diagnostics, and imaging options, among other problems. While nanotechnology cannot be used to cure cancer directly through food, it can be used to improve the efficacy of cancer treatment when added to medicinal formulations or medical equipment (Ahmad and Ghosh, 2020).

CONCLUSION

Microbial dysbiosis may stimulate various kinds of bodily malfunctions, including hormonal dysfunction, metabolic dysfunction, reproductive organ dysfunction, and so on. From this review study on the female infertile condition, vaginal microbiota significantly contributes. The vaginal microbiota is essential in maintaining female reproductive health and preventing gynaecological problems. Generally, a normal healthy vaginal contains a very few pathogenic microbes. Lactobacillus has a direct role behind this because Lactobacillus maintains vaginal pH around 3.5 to 4.5 by producing lactic acid which helps to reduce pathogens (Gardnerella vaginalis, Pepto-streptococci, Anaerobic rods, and mycoplasma species) growth and multiplication. Antibacterial compounds like H2O2 bacteriocins and bacteriostatic compounds are also produced by Lactobacillus, which helps in the bacterial lysis process. Lactobacillus can prevent various pathogenic infection-related gynaecological problems such as pelvic inflammatory disease, endometriosis, chronic endometritis, and cancer. Vaginal microbial dysbiosis and exposure to any pathogenic microorganisms can lead to infertility. This review paper concluded that pathogens, like sexually transmitted infection-causing bacteria (Treponema pallidum, Neisseria gonorrhoeae, Mycoplasma, C. trachomatis) and a wide range of reproductive organs associated with inflammatory conditions like pelvic inflammatory disease, endometriosis, and chronic endometritis, may hamper normal fertility process in the women population. The location of the onset or occurrence of bacterial vaginosis is depicted in Figure 2. Figure 3 demonstrates how various microbial strain infections cause an imbalance that results in a condition known as microbial dysbiosis in the vagina.

Declarations

Acknowledgments

We, Ahmad, Husain, and Pritha, express our profound gratitude to the Almighty, whose blessings have inspired, strengthened, and sustained us throughout this endeavor. We hope that our work will contribute meaningfully to scientific understanding and the advancement of society. We also extend our sincere thanks to the Deanship of Research and Gr`aduate Studies at King Khalid University, KSA, for their financial support.

Funding

All authors, especially Dr. Izhar Husain, would like to extend their gratitude to the Deanship of Research and Graduate Studies at King Khalid University, KSA, for their financial support through project number RGP1/331/45.

Statement of conflict of interest

The authors have declared no conflict of interest.

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