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 Table of Contents  
Year : 2020  |  Volume : 6  |  Issue : 3  |  Page : 189-196

The role of infections in infertility: A review

1 Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
2 Department of Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
3 Department of Microbiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Date of Submission08-Jun-2019
Date of Acceptance22-Apr-2020
Date of Web Publication26-Sep-2020

Correspondence Address:
Dr. Manju Ohri Pai
Department of Lab Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJAM.IJAM_44_19

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Reproduction is an essential part of a human life and being unable to conceive marks a great impact on mind and body of both males and females. Infertility being on a rise among the couples, urogenital infections are considered to be one of the major causes. A broad range of organisms including bacteria, fungi, virus, and parasites are well documented to interfere with the reproductive function in both the sexes. They affect different sites, in males, sperm morphology, its motility and eventually its function can be affected at different levels of their development, maturation, and mobility. In females, cervical areas, tubal obstruction, and peritoneal damage are the common sites that are affected by infections, thus, interfering with human fertility. Other than direct infections, co-infections are also nowadays suspected to be responsible for impairment of sperm quality, motility, and mobility. In light of these facts, this review aims to report the complex relation between infection and fertility.
The following core competencies are addressed in this article: Medical knowledge, Patient care.

Keywords: Bacteria, female, infections, infertility, male, mycoplasma

How to cite this article:
Pai MO, Venkatesh S, Gupta P. The role of infections in infertility: A review. Int J Acad Med 2020;6:189-96

How to cite this URL:
Pai MO, Venkatesh S, Gupta P. The role of infections in infertility: A review. Int J Acad Med [serial online] 2020 [cited 2023 Feb 7];6:189-96. Available from: https://www.ijam-web.org/text.asp?2020/6/3/189/296144

  Introduction Top

Fertility is a natural capability to produce an offspring. Since the growing world is booming with modernity and technology, a sharp decline in birth rate has been seen all over the world. So much so that many poorer and developing countries including India is now facing the same problems as Europe and America: Women want to have children, but cannot make it work. There can be a number of reasons: financial limitations, lack of a suitable partner, national instability, or infertility. Here, we focus on one of the important reasons of infertility, that is infections. Human infertility is defined as an inability of a female or a male to conceive and produce offspring after at least 12 consecutive months of unprotected sexual intercourse. Infertility is a situation of human health which is indeed difficult to explain where both the individual's body and mind is involved. The continuous stress of not achieving pregnancy also hinders an individual's health, thus contributing toward altering couple's quality of life. A report from the year 2010, shows 1.9%–10.5% of women of the age group of 20–44 years old were suffering from primary and secondary infertility. A high rate of infertility is noted in South Asia, Africa, the Middle East, Central Eastern Europe, and Central Asia.[1]

Globally, approximately 15% of the reproductive age women are afflicted with infertility.[2] Multiple factors are responsible for impairment of reproductive function in both men and women.[3] The list of factors can be either one or a combination of multiple factors such as: congenital or hormonal disorders, lifestyle changes, psychological stress and environmental hazards. These factors can in turn lead to alterations in functionality of genital organs; production of reproductive cells; sperm and semen quality; transport of sperm to oocyte; their fertilization followed by embryo implantation.[4],[5] Male genital infections that may preclude fertility include genital injury, infections of semen, testes and accessory glands, genital tract obstructions, variocele, genital malformations, endocrine and metabolic diseases, drug use and abuse, and allegedly psychiatric conditions. Autoimmune processes induced by inflammation and leukocytospermia impacts in the decrease in spermatozoa count, suppression of motility, changes in morphology, and fertilizing capacity. In female, factors leading to infertility are usually divided into endocrine, vaginal, cervical, uterine, tubal and pelvic-peritoneal. A form of infertility of immune origin has also been identified as a result of the presence of anti-sperm antibodies. A report by Centre for Disease Control has published data showing many factors that might be key players contributing towards infertility [Figure 1]. However, countless number of infertility cases still remain unexplained.[6]
Figure 1: Graph showing the probable factors contributing toward infertility. Source: Centre for Disease Control report *Source: Centre for Disease Control (CDC)

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The unexplained infertility further ponders to see the role of microflora of the genital tract. The role of abnormal microflora of the vagina and the lower genital tract plays an important part in conception. The healthy microflora is dominated by Lactobacillus alone with numerous other good bacteria which constitute the flora of the lower genital tract [Table 1]. These bacteria and their metabolic products help to maintain the microenvironment promoting a healthy conception. However, this microenvironment is constantly at threat by the external and internal factors, among which an important role is being played by the urogenital infections.[1],[3]
Table 1: Microbial flora of healthy vagina and normal semen samples

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With the above factors contributing, still there are missing links to find the cause of infertility. Ample literature is available showing the contribution of bacterial infections in fertility or even infertility [6]. Evidence shows that reproductive tract of both men and women are predisposed to infections that might impair the reproductive functions, respectively.[3],[7]

  Epidemiology Top

Since many years, the quest for source of infection and infertility has been chased and attempts to trace the source has always been an active area of the study. In 2001, the Human Genome Sequence paved a way for many such studies including reproductive studies because without knowledge of the “second genome” of the microorganisms that inhabit the human body, our understanding would be woefully incomplete.[8] Therefore, in 2007, a global exertion was made to sequence the human microbiome to understand the microbial community in states of good health and disease.[9] In the United States, the project was named the “Human Microbiome Project” by the National Institutes of Health (NIH). It was an initiative of the NIH Roadmap for Biomedical Research where characterization of the human microbiome from at least four body sites from healthy volunteers, including the vagina as a major site of study was done.[10]

Available data indicate that at least 50–80 million couples worldwide experience infertility.[11],[12] Out of these, it has been anticipated that about 15–20 million are from India only.[11] In India, the prevalence of unexplained infertility ranges from 8% to 37%.[13] According to the Indian Society of Assisted Reproduction, infertility currently affects about 10%–14% (approx. 27.5 million) of the Indian population, with higher rates in urban areas, wherein one out of six couples is affected. Controversies exist in literature regarding the role of bacterial infection in infertility. Chlamydia and gonorrhea being the old players in pelvic inflammatory disease (PID) and PID-related infertility, their impact on fertility has been well established.[14]

  Male Infertility Top

Male infertility is defined as a male's inability to cause a pregnancy after having regular intercourse (sex) with a fertile female without birth control for 1 year. About 35% of the male infertility cases have been associated with infections and inflammation of the male genitourinary tract including the testis, epididymis and accessory sex glands.[15] They may further deteriorate the functionality of spermatozoa by altering them in various ways like de-heading of sperms (decapitation), alterations in the sperm tail structure etc., alters the sperm function qualitatively and quantitatively.[16] Testicular damage, prostatitis, orchitis, and epididymitis in male reproductive system are also a few results of infections affect fertility in males.[15] Various microorganisms have been known to bring out the alterations through different pathomechanisms. However as such there are limited data on microbiota of semen. Recent studies from the West have deciphered that the presence of Anaerococcus might be a biomarker for low sperm quality [17] and Prevotella enriched sperm samples usually carry sperm defects.[18] Some of the deciphered and well documented mechanisms are agglutination of motile spermatozoa, immobilization of spermatozoa, impaired acrosome reaction, deterioration of spermatogenesis, autoimmune response due to inflammation, antisperm immunological reactions, and dysfunction of accessory sex glands.[16]

  Female Infertility Top

The National Institute of Health and Care Excellence guidelines state that: “A woman of reproductive age, who has not conceived after 1 year of unprotected vaginal sexual intercourse, in the absence of any known cause of infertility, should be offered further clinical assessment and investigation along with her partner (2013).” In reproductive age women, there are many factors which affect the vaginal microbiota such as the age, sexual activity, pregnancy, and exogenous hormones. The cervix plays a crucial role in ascent of sperms, and thus, it is always at a threat by unwanted microorgainisms which might inhibit the ascent of sperms to the uterus and finally going to  Fallopian tube More Detailss for fertilization. Ascending infections of female genital tract with microorganisms are introduced via sexual intercourse (STDs), which are a major cause of female morbidity, adverse pregnancy outcome, and infertility.[19] Fundamentally, all parts of the female reproductive system may be prone to infectious agents; however, some conditions may have direct impact on fertility.[20]

  Microorganisms and Infertility Top

Many microorganisms have been reported to affect sperm morphology and function while undergoing laboratory work up in infertility clinics. It has been reported that bacteriospermia is commonly detected in male and female partners of infertile couples. As mentioned earlier too that chlamydial and gonorrheal infections have been on the decline in the last decade however it still continues to be an increasing problem.[21] Reports from recent years have shed much light on the role of other bacteria such as  Escherichia More Details coli, Staphylococcus, Gardenella, Mycobacteria, Niesseria to name a few, as important causative agents for immobilization and agglutination of the sperms. The few important felons contributing to altercations in sperm morphology and function or are a part of vaginosis or are the causes of obstruction in cervical tract causing PID's are briefly enlisted below and a flowchart is shown in [Figure 2].
Figure 2: Flowchart showing the role of microbial flora in infection and other fertility related complications

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  Escherichia Coli Top

A number of studies have investigated the in vitro effect of E. coli, one of the most common uropathogen on sperm function.[22] Starting with the first report by Rosenthal et al. 1931[23] which showed the instant and irreversible sperm agglutination effect of E. coli was further followed by many reports revealing the same effects.[24] Microscopy revealed multiple adhesions of E. coli to spermatozoa, causing variable ultrastructural damage as probable cause of immobilization.[25] Thus indicating that such uropathogenic organisms can have more influence on oligospermic ejaculates than normal sperm specimens.[24] Further studies delineated the E. coli proteins pertaining the sperm inhibitory activity. Reports have shown various sperm immobilization factors immobilizing (71 KDa and 56 KDa) the sperms with their pre-incubation, but it did not kill them and was found reversible.[26] A study showed that E. coli serotype O6 but not with other serotypes effected sperm motility.[27] The above studies demonstrated the importance of the receptor-ligand interaction in the pathogenesis of urinary tract infection, which is well documented.[28] The uroepithelial receptors may be glycoproteins (as with type 1 fImbriae) or glycolipids (as with P-fimbriae).[29] A study by Monga et al. 1994,[30] identifies a receptor-ligand interaction between fimbriated E. coli and spermatozoa that results in spermagglutination and significant decreases in motile sperm count. Furthermore, the above reports show that surface of spermatozoa is rich in glycoproteins, therefore asymptomatic colonization of the male or female genitalia with Enterobacteriaceae may also result in similar interactions.

  Staphylococcus aureus Top

Staphylococcus aureus is an infrequent, but one of the most successful aerobic human pathogens found in female genital tracts and semen samples of normal and infertile males.[31] A number of other studies support the above observations like a study in Iran (2017), documented 26% prevalence of S. aureus in infertile males. Momoh et al., [32] reported that S. aureus was perhaps the most dominant microorganism in semen culture of infertile men with a prevalence rate of 75%. Emokpae et al.[33] found S. aureus as causative agent in 68.2% of seminal fluid infections. A recent report by Ruggeri et al.[2] also reported S. aureus as a major contaminant of both male and female genital fluids. Another study showed significant decrease in sperm motility and its agglutination with S. aureus coincubation and further its 70 KDa purified factor was tested in animals intravaginally for 10 days which resulted in a state of infertility.[34]

  Pseudomonas Aeruginosa Top

Pseudomonas aeruginosa, a Gram negative opportunistic pathogen, primarily associated with nosocomial infections have also been associated with urinary tract infections. Its quorum sensing signaling produced by lactone compound has been reported to have detrimental effects on spermatozoa. It reduces the sperm motility at sub lethal doses and can also lead to a probable calcium dependent premature acrosomal loss. In addition, it can also cause apoptosis and necrosis of spermatozoa at concentrations that do not affect immune cells.[35] Animal studies have shown the cytotoxic effect of Exotoxin A of P. aeruginosa, chromatin level crowning in mouse spermatozoal cells, namely amorphous head, banana head, two heads, head without hook, divided tail, coiled tail, and others abnormalities. Among all, divided tail abnormality was more than other abnormalities because of toxin's effect on tail composition.[36] The porins from Pseudomonas also induces apoptosis in an epithelial cell line derived from rat seminal vesicles as they have receptors for sperm plasma membrane and can have negative impact on sperm morphological parameters.[37]

  Candida Albicans Top

Being an opportunistic uropathogen C. albicans arresting sperm motility and leading to significant agglutination of human spermatozoa., is evident. Sasikumar et al.[38] also observed rapid motility loss and decreased survival time of spermatozoa when incubated with C. albicans. Tian et al.[39] reported a direct relation of yeast contact time with reduction in progressive motility of spermatozoa with significant signs of membrane alteration. In addition, they also reported that C. albicans as well as its cell free filtrates have an inhibitory effect on human sperm motility and impaired the ultrastructure of human spermatozoa and this could be associated with male infertility. Distinct adhesion of spermatozoa to C. albicans leading to sperm agglutination has been observed. Electron microscopic examinations have shown the decrease in motility could be due to C. albicans attachment to spermatozoa mainly through the head and lead to multiple ultrastructural lesions. Farnesol, a quorum sensing molecule produced by C. albicans, induces significant loss of progressive motility which coincided with multiple damages in spermatozoa due to apoptosis and necrosis.[38] It can also lead to premature acrosomal loss and DNA fragmentation of spermatozoa even at sublethal doses. Burrello et al.[40] have also shown that on incubation of C. albicans with spermatozoa, there is decrease in sperm motility with reduced mitochondrial membrane potential or phosphatidylserine externalization, thereby leading to apoptosis, which increased in a time-and concentration-dependent manner. It also led to increased DNA fragmentation in spermatozoa.

  Genital Mycoplasmas Top

These microorganisms are frequently present in genital tract and semen of both fertile and infertile men.[41] Ureaplasma ureolyticum and Mycoplasma hominis are commonly associated with orchitis, prostatitis and non-gonococcal urethritis (NGU). M. genitalium has been reported to attach to and carried away by human sperms. The same microorganisms may also cause fertility disorders in female with cervicitis and endometritis.[42] These microorganisms can be easily isolated and grown from clinical specimen in addition to other detection tools such as DNA probes and PCR.

  Niesseria Top

Niesseria is a well-known organism contributing to sexually transmitted infections (STI's) in humans worldwide. These STI's are thus known perpetrators of human infertility. This tendency of STIs to cause infertility is likely to reflect an evolutionary adaptation of such pathogens including Niesseria and Chlamydia.[43] Niesseria, a characteristic nonmotile diplococcus is a common entity responsible for urethritis which is rarely complicated by infection of other parts of the genital tract, including testes thus impairing male fertility. In females, the primary gonococcal infection is present in endocervix with concomitant urethral infection. About 10%–20% of infected women suffer from ascending infections resulting in PID. These PID's can further lead to other complications such as salpingitis, endometritis, and tubo-ovarian abscess, which promotes ectopic pregnancy, sterility, and chronic pelvic pain.[43] Apari et al.[44] have credibly discussed the molecular mechanisms of their pathogenesis which contribute to a state of infertility or infertility like conditions in humans. Among these mechanisms, one hypothesis states that, N. gonorrhoeae destroys the uninfected nonciliated cells of the tubal mucosa, thus ceasing them for transportation of fertilized egg toward the uterus. This type of effect is led by gonococcal lipopolysaccharide (LPS) that too infects the nonciliated cells of the mucosa. This LPS further upregulates the production of tumor necrosis factor alpha. The second mechanism described shows that the TNF-alpha released by the stimulus of gonococcal LPS, selectively targets the uninfected ciliated cells by a protective anti-apoptotic effect exerted on infected cells by this pathogen.[44],[45],[46]

  Gardnerella Vaginalis Top

Gardnerella vaginalis is a Gram-negative bacterium that often occurs on the vaginal mucosa of women. It is considered a conditionally pathogenic microorganism whose presence in the urogenital tract of women is primarily associated with bacterial vaginosis (BV).[8] BV is a disease that affects women of reproductive age more often. It is characterized by an alteration in the recipe of vaginal microflora in favor of G. vaginalis, Atopobium vaginae, urogenital mycoplasmas, and ureaplasmas. Majority are anaerobic bacteria, including the genus Mobiluncus, which are not commonly found on the vaginal mucosa. In males, the incidence of G. vaginalis is up to 44% however, their clinical manifestations are rare. Colonization of the genital tract mucosa and subsequent contamination of the ejaculate may adversely affect its quality that also affects the female partner by sexual intercourse.[47] Diagnostic options are the PCR method. In the therapy of G. vaginalis- induced infections, especially BV, metronidazole, and clindamycin are used.[48]

  Mycobacterium Tuberculosis Top

Mycobacteria TB of the urogenital tract of men and women is well known and contributes to the second-most common location of lung disease, with a prevalence of 1% in the US and up to 18% in developing countries. Infections affect various parts of the genital system. Women are most often affected by fallopian tubes, ovaries, uterine mucous membranes, and rarely scabies. TB of the genital tract in males mainly affects the testicles, superficial, or prostate. During the disease, granulomas are produced in the genital tracts that cause their obstruction and consequently impair the reproductive capacity of the affected person.[48] Detection methods include the gold standard Ziehl–Nielson staining along with PCR and radiography wherever needed.[49],[50],[51]

  Chlamydia Trachomatis Top

Chlamydia trachomatis, an obligate intracellular Gram-negative bacterium, is another most prevalent cause of bacterial STIs after Niesseria, that is recognized throughout the world.[52] It affects both the sexes with almost five times more incidence in females than males. Almost 80% of reported cases of C. trachomatis infection of urogenital tract of women occur asymptomatically. It particularly affects young women and sexually active adolescents.[53] Cervix is the major prone area, from where it spreads to other parts of the genital tract. Distinctive complications by this organism include salpingitis and endometritis. Chlamydia is also considered to be an etiological agent of PID as with Niesseria. Chlamydiosis is a major cause of tubal obstructions, lacerations, and ectopic peritonitis and formation of adhesions which may disrupt the passing of oocytes through the tubes; therefore, this female infection truly interferes with the reproduction. Approximately 20% of women with chlamydial-induced PIDs develop permanent infertility as a consequence of limiting the passage of the fallopian tubes. Occurrence of C. trachomatis in pregnant women is associated with birth and postpartum complications such as premature birth and low birth weight of neonates. During birth, there is a risk of transmission of the infection to the newborn.[53] In males, chlamydial infections commonly appear as nonNGU with dysuria. Similar to females, in males also, approximately 50% of the affected inflammation is asymptomatic.[52] From the urethra with C. trachomatis spreads to higher levels of the urogenital tract, where it can cause epididymitis, orchitis, and more rarely, prostatitis. Thus, C. trachomatis significantly affects reproductive ability in both the males and females. The diagnosis of C. trachomatis is a tedious and difficult task. It can be cultured on tissue culture cells (HeLa, McCoy). However, molecular diagnostic methods of PCR, DNA hybridization or ligase chain reaction along with, immunofluorescence and antibody detection are of great importance.

  Conclusion Top

Microorganisms damage different parts of the genital tract of men and women either directly or by their metabolic products. A recent systematic review addressing worldwide time-based declining trends in sperm counts has once again fuelled alarming reports in media with infections being a major contributory factor.[54] Despite the focus on sexually transmitted diseases (STDs), infertility may also follow blood borne infections such as tuberculosis, mixed aerobic and anaerobic infections of other pelvic sites. Many other microorganisms which have not been talked in detail in this review include Treponema pallidum, Herpes Simplex Virus, Human Immunodeficiency virus, and Human Papilloma Virus as they are widely studied cause of sexual transmitted diseases, reproductive anomalies and infertility. Reports on newer pathogens like Serratia marscecens having a role in impairing the sperms are pouring in,[55] but these studies are still in vitro and further validation is required to prove them as significant organisms responsible for infertility.

This tale on “Fecundity and Infections” thus briefly consolidates studies on various uropathogenic organisms, their interactions, patho-mechanisms, and impairment of various sperm parameters providing an insight into their impact on male and female fertility. Regardless, of the advancement in techniques, voids still persist which need to be addressed for understanding the exact mechanisms therefore the best hope for reducing the incidence of infertility related to infection lies in prevention and early detection. Health-care providers must stress upon the mandatory use of condoms, avoiding high-risk sexual behavior for the preservation of future fertility. Irrespective of whether a relationship between genital tract infection and infertility exists or not, understanding their early interactions and accurate identification would help in timely management options, thus giving hope to several infertile couples to have a successful pregnancy.


Sincere thanks are to Dr. Vijay Prabha, Professor, Dept of Microbiology, Panjab University, Chandigarh for her critical analysis and valuable suggestions during the structuring of this Review article.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

Ethical conduct of research

For writing this review, the authors utilized data from reputed organizations such as the World Health Organization, Centers of Disease Control and Prevention U.S. Department of Health and Human Services, Medline, and PubMed. Only highly relevant articles from manual and electronic databases were selected for the present review. Applicable EQUATOR network (https://www.equator-network.org/) guidelines were followed.

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