14 Val Edwards Jones Men and women are continually exposed to large numbers of microorganisms (bacteria, viruses, fungi, and parasites (predominantly protozoa) and many coexist to form the normal flora in a microbial community or microbiome. The diversity of microbes at each body site under normal environmental conditions is reflective of the age, nutritional status, ecological niche, and immediate partners. Most of these microbes are nonpathogenic but occasionally pathogens can form part of the normal flora and can be problematic for both endogenous and exogenous carriage. As technology improves, so does the information we hold on the interaction of microbes with man and the Human Microbiome Project is using these technologies (16S ribosomal RNA analysis) to determine the diversity of microbial flora at certain body sites and their role in health and disease (metagenomics analysis) (http://hmpdacc.org/micro_analysis/microbiome_analyses.php). The genital tract has its own microbiome and extensive studies have determined that it plays a mutualistic role in the maintenance of genital health. The common bacteria found colonizing the terminal portion of the urethra of both male and female are Staphylococcus epidermidis, diphtheroids, streptococci, lactobacilli, Gram negative bacilli, occasionally yeasts (such as Candida albicans) and anaerobic bacteria. These microorganisms can also be found colonizing the foreskin. Internal organs in both male and female are thought to be sterile but recent studies have shown that microorganisms can be found in the uterine cavity (Vertraelen et al. 2016) and placenta postpartum (Aagaard et al. 2014). Implications of these findings have yet to be determined but demonstrate the interaction of microbes and people. The vaginal microbiome is very complex and diverse and it is known that an imbalance in this microbiome can lead to an unhealthy genital tract and the organisms involved can be sexually transmitted to partners. The microorganisms in the microbiome are attached to their host membranes and exist in a balanced aggregated state encased in mucus, termed a biofilm. The different species of bacteria, occasional fungi, and protozoa present are dependent upon the glycogen content of the vaginal epithelium, which is dependent upon ovarian activity. The predominant bacterium, lactobacillus, breaks down glycogen forming lactic acid, which alters the pH of the vaginal secretions, making it more acidic (Faro 1993). The vaginal microbiome before and after puberty is very similar (being predominantly aerobic bacteria such as staphylococci, enterococci, streptococci, diphtheroids, and coliform bacteria) and differs during parturition (which include predominantly lactobacilli, streptococci, anaerobic bacteria, and some yeasts) (Brotman 2011). The presence of lactobacilli appears to be important in maintaining the equilibrium of normal microflora and preventing overgrowth of potentially pathogenic microorganisms. The most commonly isolated Lactobacillus species associated with a healthy vaginal environment are L. crispatus and L. jensenii (Marrazzo 2011). Production of hydrogen peroxide by lactobacilli is toxic to anaerobic bacteria, which do not produce peroxidase. An imbalance of hormones can impact on the glycogen content and ultimately influence the composition of the vaginal microbiome. The alterations in the dynamics of the microbial community can lead to a shift in hydrogen ion concentration and hydrogen peroxide, allowing an overgrowth of anaerobic bacteria and the subsequent development of vaginitis (Faro 1993). In this instance, the infection is endogenously acquired from the individual’s own microflora. Exogenous organisms, which, result in infection, can be acquired during surgery or medical procedures. Occasionally, these microorganisms can be endogenously acquired if part of the microbiome and result from an imbalance in the environment during medical procedures. These infections are usually presented with overt symptoms and if appropriate treatment is administered then there are few sequelae. Genital infections are also acquired through sexual intercourse or other sexual practices and are termed sexually transmitted infection (STI) or sexually transmitted disease (STD). There are over 20 different infections described in man and a number can impact on reproduction: the most commonly described are Chlamydia trachomatis and Neisseria gonorrhoeae. Infertility is usually defined as the lack of a conception following at least 1 year of constant, unprotected sexual intercourse. There are a number of reasons for infertility but individuals who do become infertile as a result of infection do so because of the inflammatory response (humoral or cell mediated) in accessory organs and total blockage of Fallopian tubes (Pellati et al. 2008). These infertility problems are considered such an issue that the Centre for Disease Control (CDC) in the USA recommend that all sexually active women under the age of 25 are screened for C. trachomatis and N. gonorrhoeae as these two common STIs are associated with tubal inflammation and subsequent blockage (CDC 2014). Vaginitis is an inflammation of the vagina and is associated with an irritation or infection of the vulva. When the inflammation is the result of an infection, it usually has three major causes, namely bacterial (30–35% of cases), candidiasis (20–25%), and trichomoniasis (10–15%) (Faro 1993). It also may be due to a combination of these causes. Symptoms may vary with infection but include vaginal discharge, irritation, inflammation, pain during sexual intercourse, and possibly a foul odour. Bacterial vaginitis can be caused by a range of bacteria where there is resultant inflammation. Aerobic vaginitis caused by an overgrowth of Escherichia coli, S. aureus, Group B streptococci and enterococci (with or without anaerobes) in the absence of lactobacilli (Donders et al. 2005; Tempera and Furneri 2010) and is treated with a combination of antibiotics (often kanamycin or quinolones) and vaginal creams to reduce inflammation. Bacterial vaginosis (BV) is due to an overgrowth of Gardnerella vaginalis, Mobiluncus spp., other anaerobic Gram‐negative bacilli (e.g. Prevotella spp.) and genital mycoplasmas. BV is characterized by an abnormal discharge (often white or yellow) with a fishy odour (due to the production of amines), a vaginal pH >4.5 and the presence of clue cells (vaginal epithelial cells coated with bacteria). Diagnosis is made based on clinical examination and microscopy. It can be asymptomatic and is differentiated from aerobic vaginitis by the absence of succinate, increased sialidase activity, and increased production of cytokines such as interleukin‐1, ‐6 and ‐8 (Marrazo 2011). Detection of fatty acids (succinic and acetic) in vaginal fluid is indicative of BV, in contrast to lactic acid seen in a healthy vagina (Africa et al. 2014). In women of reproductive age there is an associated risk for adverse pregnancy outcomes such as preterm birth, recurrent abortions, postabortal sepsis, early miscarriages, and still births (Africa et al. 2014). Fungal vaginitis is caused by a dimorphic fungus Candida spp. with Candida albicans the most prevalent species (Figure 14.1). Other species such as C. glabrata or C. tropicalis have also been implicated. These organisms are found on moist skin and mucosal surfaces of the alimentary canal, intestine, and vagina. They can also be found colonizing the foreskin. Candida spp. can become prevalent as an endogenous infection following antibiotics (which causes an imbalance in bacterial flora allowing it to grow) and its overgrowth can also occur during an imbalance of hormones, either naturally or during treatment, when an individual is stressed or immunosuppressed. Candida spp. can be sexually transmitted and colonize the foreskin and glans of the penis. In its invasive form, C. albicans will produce hyphae as part of its virulence (Figure 14.1). The resultant inflammation results in itching and oedema and the production of a voluminous soft white cheesy exudate which can form plaques and biofilm on the mucosal surface from the macerated surface. C. albicans produce a wide range of virulence factors that are used during the development of genital infections including adhesion, hyphal formation, phenotypic switching, extracellular hydrolytic enzyme production, and biofilm formation (Achkar and Fries 2010). Figure 14.1 (a) Candidia albicans in culture on agar showing hyphae (arrow). (b) Vaginal wet mount in candidal vulvovaginitis with hyphae visible (arrow). Source: https://commons.wikimedia.org. Trichomonas vaginalis is a sexually transmitted flagellate protozoan causing genital infections in men and women (Figure 14.2). Symptoms develop within a month of infection, although 50% of infected men and women will be asymptomatic. It causes inflammation, soreness and itching around the vagina, and a green frothy discharge, whereas it manifests in men as urethritis with an associated thin white discharge from the penis, and can also cause prostatitis. T. vaginalis is found with increased frequency in infertile women compared with control subjects and is thought to interfere with cervical and tubal factor in female infertility (El‐Shazly et al. 2001). It has been shown that secreted factors from T. vaginalis interferes with sperm activity, and may contribute to fertility problems (Roh et al. 2015). Figure 14.2 Papanicolau stain (×400) showing infestation by Trichomonas vaginalis (circle). Source: https://commons.wikimedia.org. Recent molecular studies (using 16s RNA v6 sequencing) comparing healthy women with those with BV and vulvovaginal candidiasis (VVC) showed that the microbiome of normal controls and those with BV had typical patterns. However, a detailed comparison showed that the vaginal microbiota of VVC was complex. The mixed BV and VVC infection group had a unique pattern, with a higher abundance of Lactobacillus than the BV group and a higher abundance of Prevotella, Gardnerella, and Atopobium than the normal control. In contrast, the VVC‐only group could not be described by any single profile, ranging from a community structure similar to the normal control (predominated with Lactobacillus) to BV‐like community structures (abundant with Gardnerella and Atopobium) (Liu et al. 2013). Treatment is varied depending upon the cause but BV and trichomoniasis is commonly treated with metronidazole (with 2% clindamycin cream for BV) and candidiasis with a single oral dose of fluconazole supplemented with a topical clotrimazole or nystatin cream if necessary. Many women have a recurrence of BV within a few months and intravaginal metronidazole gel has been shown to be effective in these cases (Marrazo 2011). Probiotics (either a single strain or a cocktail of lactobacilli) have been used in a number of clinical trials (administered orally or intravaginally) for vaginitis and vaginosis and show some success, but suggest that preparations containing high doses of lactobacilli are required to be effective (Mastromarino et al. 2013). Unfortunately, some infected women are asymptomatic for vaginitis and vaginosis. If left untreated, pelvic inflammatory disease may develop, which can lead to fertility problems in future years. Pelvic inflammatory disease (PID) is caused by an ascending infection (which can be endogenous or sexually acquired) of the reproductive organs of women including uterus, Fallopian tubes, and adjacent pelvic structures that are not associated with surgery or pregnancy. The symptoms range from asymptomatic (silent) or subclinical to severe, symptomatic disease. Bilateral lower abdominal pain is the most common symptom but there are others including abnormal vaginal discharge, intermenstrual or postcoital bleeding, menorrhagia, dysuria, fever, and nausea. If left untreated major reproductive health problems can result. However, PID and its sequelae are largely preventable. In the USA it is estimated that there are approximately 780 000 cases annually (Banikarim and Chacko 2005; Paavonen 2005). The most important causative microorganisms are C. trachomatis, N. gonorrhoeae (which are sexually acquired) and bacteria associated with vaginitis and vaginosis, e.g. G.vaginalis and mixed anaerobic organisms. Ureaplasma urealyticum, Mycoplasma hominis and Mycoplasma genitalium have also been associated with PID (Banikarim and Chacko 2005; Paavonen 2005). Those at risk for acquiring PID are similar to those for STI. Adolescents who engage in high‐risk sexual behaviours, including unprotected sex, and females with multiple partners have an increased risk. There is a slight risk of developing PID following insertion of an intrauterine device if an STI is undiagnosed at the time (Banikarim and Chacko 2005). Risk factors that place an individual at increased risk from STI and PID have been identified: for example, those with cervical eversion (where there are more columnar epithelial cells present) are more at risk of acquiring N. gonorrhoeae and C. trachomatis; individuals engaging in sexual intercourse close to or during menses can lose the cervical mucus plug and the presence of blood allows growth of endogenous bacteria; and some studies have shown that douching can increase the risk of PID due to a change in environment and alteration of vaginal flora, promoting the development of bacterial vaginosis (Banikarim and Chacko 2005). The most common symptoms of PID are pain during sexual activity, lower abdominal pain, dysuria, menstrual spotting, and vaginal discharge. The dull abdominal pain can become quite severe and patients may have associated vomiting and fever. Silent PID, where a patient has mild or no symptoms, can lead to tubal scarring and infertility if left untreated (Paarvonen 2005). Most serological studies undertaken on these individuals show evidence of undiagnosed C. trachomatis (WHO 1995). Treatment of PID is with combination therapy using doxycycline plus metronidazole (Paarvonen 2005). Infections of the male genital tract are a correctable cause of male infertility, causing up to 12% of cases, and include prostatitis, epididymitis, and orchitis (Dohle et al. 2005). Deterioration in spermatogenesis, obstruction of the seminal tract, and defects in spermatozoa function may induced by immunological reactions (humoral and cellular) against microbial agents, as well as by direct influence of some bacterial strains on gametogenic cells (Keck et al. 1998). Candida spp. infections can negatively affect sperm function, as reported in a number of studies. Sperm from healthy volunteers, exposed to C. albicans, show decreased sperm motility and increased agglutination (Tuttle et al. 1997). Tian et al. (2007
The Impact of Infections on Reproduction and Fertility
Introduction
Normal Flora of the Genital Tract
Infection and Infertility
Female Genital Infections
Trichomoniasis
Treatment for Vaginitis and Vaginosis
Pelvic Inflammatory Disease
Clinical Presentation of PID
Male Genital Tract Infections
Candida Infections and Male Fertility
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