**2. Infection and fertility alteration**

#### **2.1. Mumps virus infection and fertility**

Even though Hippocrates described mumps many years ago and its vaccine has been available for long time, the disease continues to spread in the world. Mumps, a disease of droplet contact,

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is transmitted to the population via the respiratory tract. The viruses multiply in upper respiratory tract mucosa and are carried to the affinity organs, such as the inner ear, pancreas and mammary glands, testis, and ovaries. [1]

Mumps virus is an RNA virus, which causes inflammatory reactions. Infections of mumps virus cause a variable clinical symptom. At the very beginning of infection, the virus attacks the testes, destroying the testicular parenchyma and reducing androgen production. [2] Most commonly they lead to fever and parotitis, and about 30% of male adolescents with mumps will develop orchitis. [3] Because orchitis is the most common complication in men, the disease sometimes develops in adult patients.

Previous studies consisting of about 300 patients with mumps orchitis were carried out between 1951 and 1970. Following mumps orchitis, cytogenic deterioration, with regard to sperm morphology, is a long-lasting effect. Spermiogenesis was greatly disrupted in half of the patients. In many patients whose testes were not atrophied, poor fertility was found persistently. According to the observations, sperm morphology was the most influenced, of the characteristics that were studied, and sperm count might be the least affected. [4] In conclusion, mumps virus infection is a risk factor for male infertility.

#### **2.2. Hepatitis B virus infection and infertility**

Hepatitis B virus (HBV) is a double-stranded DNA virus, which is one of the most common viruses threatening health of human beings. [5] HBV infection has been a very serious public health problem worldwide, especially in Asia. HBV infection was found to be related to decreased instability of sperm chromosome, sperm function, [5] and impaired sperm viability and normal morphology. [6] Recent work has confirmed that sperm is possibly a vector for vertical transmission of HBV. [7] However, little is known about the influence of HBV infection on sperm functions, which is vital for the fertility of those HBV carriers.

In 1985, it was discovered that HBV DNA was in spermatozoa and proposed that HBV may be a cause of male infertility by damaging spermatozoa. [8] But the mechanisms of the HBV impacting on human sperm remain unclear. Therefore, the studies of the influences of viral proteins on sperm function and the explanation of the pathways involved are critically important for male reproduction. HBs is the main component of HBV envelope proteins, so its effects on sperm functions, such as motility, fertilizing ability of sperm, and the according pathways require full studies. [5] Other studies indicate that HBV infection induces adverse influence on sperm chromosomes. Fluorescence in situ hybridization technique can visualize HBV DNA sequences that integrate into sperm chromosomes. Consequently, HBV enters germ line of male and integrates into the genome. [8]

Results of some studies indicated that HBs were able to reduce the human sperm fertilizing ability by inducing loss of sperm mitochondrial membrane, which potentially leads to the decrease of sperm fertilizing ability. [9] With increased concentrations of HBs, sperm were found to lose mitochondrial membrane potential and have decreased sperm motility and sperm fertilizing ability was affected. However, the molecular mechanism of HB-induced reproduction dysfunction needs to be explored in the future.

HBV can be transmitted vertically to the offspring through the male germ line because HBV may do harm to sperm function. [8] Some observations concerning the viral infection indicate that woman carriers of HBV may have reduced fertility potential, but further work is needed to explore the field and understand the effect of chronic viral infection on the reproduction. [10] So more attention should be immediately paid to the patients with HBV infection in the aspect of reproductive health.

#### **2.3.** *Chlamydia trachomatis* **infection and infertility**

is transmitted to the population via the respiratory tract. The viruses multiply in upper respiratory tract mucosa and are carried to the affinity organs, such as the inner ear, pancreas

Mumps virus is an RNA virus, which causes inflammatory reactions. Infections of mumps virus cause a variable clinical symptom. At the very beginning of infection, the virus attacks the testes, destroying the testicular parenchyma and reducing androgen production. [2] Most commonly they lead to fever and parotitis, and about 30% of male adolescents with mumps will develop orchitis. [3] Because orchitis is the most common complication in men, the disease

Previous studies consisting of about 300 patients with mumps orchitis were carried out between 1951 and 1970. Following mumps orchitis, cytogenic deterioration, with regard to sperm morphology, is a long-lasting effect. Spermiogenesis was greatly disrupted in half of the patients. In many patients whose testes were not atrophied, poor fertility was found persistently. According to the observations, sperm morphology was the most influenced, of the characteristics that were studied, and sperm count might be the least affected. [4] In

Hepatitis B virus (HBV) is a double-stranded DNA virus, which is one of the most common viruses threatening health of human beings. [5] HBV infection has been a very serious public health problem worldwide, especially in Asia. HBV infection was found to be related to decreased instability of sperm chromosome, sperm function, [5] and impaired sperm viability and normal morphology. [6] Recent work has confirmed that sperm is possibly a vector for vertical transmission of HBV. [7] However, little is known about the influence of HBV infection

In 1985, it was discovered that HBV DNA was in spermatozoa and proposed that HBV may be a cause of male infertility by damaging spermatozoa. [8] But the mechanisms of the HBV impacting on human sperm remain unclear. Therefore, the studies of the influences of viral proteins on sperm function and the explanation of the pathways involved are critically important for male reproduction. HBs is the main component of HBV envelope proteins, so its effects on sperm functions, such as motility, fertilizing ability of sperm, and the according pathways require full studies. [5] Other studies indicate that HBV infection induces adverse influence on sperm chromosomes. Fluorescence in situ hybridization technique can visualize HBV DNA sequences that integrate into sperm chromosomes. Consequently, HBV enters germ

Results of some studies indicated that HBs were able to reduce the human sperm fertilizing ability by inducing loss of sperm mitochondrial membrane, which potentially leads to the decrease of sperm fertilizing ability. [9] With increased concentrations of HBs, sperm were found to lose mitochondrial membrane potential and have decreased sperm motility and sperm fertilizing ability was affected. However, the molecular mechanism of HB-induced

conclusion, mumps virus infection is a risk factor for male infertility.

on sperm functions, which is vital for the fertility of those HBV carriers.

and mammary glands, testis, and ovaries. [1]

236 Genital Infections and Infertility

sometimes develops in adult patients.

**2.2. Hepatitis B virus infection and infertility**

line of male and integrates into the genome. [8]

reproduction dysfunction needs to be explored in the future.

*Chlamydia trachomatis* is an intracellular bacterium and needs living cells to multiply. Its chromosome includes about 1 million base pairs. Identified serotypes of *C. trachomatis* are eighteen. This kind of bacterium's cell cycle is quite different from that of others. [11]

*C. trachomatis* infections are considered to be the most common sexually transmitted bacterial infections allovertheworld.[12]The infectioncycle startswiththe entryof aninfectiousparticle into an epithelial cell. *Chlamydia* infections cause great medical, economic, and even social problems. To diagnose *C. trachomatis* infection, nucleic acid amplification tests are done. [13]

Many studies have studied the link between chlamydial infection and semen quality. Some *in vitro* and *in vivo* studies tried to study the relationship between chlamydial infection and markers in spermatozoa. The establishment of a causal relationship between chlamydia and male infertility would have important effects on public health. [12] However, *C. trachomatis* infections are more harmful to the reproductive health of women than to men.

*C. trachomatis* is one of the major causes of mucopurulent cervicitis, which leads to about three kinds of complications and pelvic inflammatory disease in female. [14] Chlamydial pelvic inflammatory disease (PID) is a significant preventable cause of infertility and bad pregnancy outcome. According to a study about chlamydial infection and women, significantly higher prevalences of IgA and IgG antibodies were found among individuals suffering from infertil‐ ity. The results of polymerase chain reaction (PCR) testing indicated that the women with positive IgA and IgG antibodies might possibly have been infected with *C. trachomatis* before. However, this study had some limitations, such as many bias and small sample size. [15]

Consequently, additional studies are necessary to get more epidemiologic data about *C. trachomatis* infection and to formulate useful prevention and intervention actions such as health education among adolescents. When talking about the treatment of this infection, the use of azithromycin should be considered during pregnancy. Treatment of sex partners is vital for reducing the risk of re-test after treatment.

#### **2.4.** *Toxoplasma gondii* **infection and infertility**

*Toxoplasma gondii* is a very common protozoan parasite infecting warm-blooded animals, including both mice and humans. About one-third of the human population has been ex‐ posed to it.[16] Approximately 50% ofthe humans are infected and developed a disease named toxoplasmosis, which is one of the most common parasitic zoonoses throughout the world. In different regions within any country and among different population groups based on various social,culturallifestyle,andenvironmentalfactors,theprevalenceof*T.gondii*alwaysvaries.[17] Some studies indicate that low socioeconomic status has contributed to *T. gondii* exposure. [18] Another risk factor of the exposure might be the consumption of raw fruits and vegetables that were contaminated with *T. gondii* oocysts. Globally, very limited amount of studies of the agricultural population about the prevalence of *T. gondii* infection are conducted by research‐ ers. The goal of a study was to investigate the prevalence and possible risk factors of toxo‐ plasmosis among female farmworkers in a region of Turkey. [17]

In adults, *T. gondii* does not cause serious diseases, but in women infected with *T.gondii*, lifethreatening complications such as congenital disease or even abortion occurs in the developing fetus. [19] However, there were some relations between infection of *Toxoplasma* and the sperm quality in human population. Zhou et al. [20] found that *Toxoplasma* infection in infertile human couples was higher than that in fertile ones. It may be related to the antisperm antibodies that were higher in infected human couples. A recent research of *T. gondii* infection in men with sterility indicated that among the cases of man's sterility, some of them were serologically *Toxoplasma*-IgG, IgM, and CAg positive. It was concluded that *T. gondii* infection may influence men's fertility. [21] Lu et al. concluded that acute infection of *T. gondii* can cause male infertility, and Sun et al. [22] concluded that acute *T. gondii* infection can devastate the reproductive function of infected male mice experimentally. Researchers used rats to study the effect of toxoplasmosis on male reproduction and found that in the *Toxoplasma*-infected group, sperm motility was decreased significantly. However, in median sperm concentration, they did not find any significant difference in infected animals and controls. Results indicate that there is possibly a correlation between toxoplasmosis and disturbed reproduction in male rats. [23]

Furthermore, a large-scale experiment with greater amount of animals and generations will be required to study the significant effect statistically. [24] Based on current researches, control programs of *Toxoplasma* infection in many countries should be implemented. Faster and reliable diagnostic tests should also be developed for male and female. [17]

#### **2.5. Human papillomavirus infection and infertility**

It was estimated that the prevalence of human papillomavirus was at about 12% globally in 2012, [25, 26] despite licensure of HPV vaccines in over 50% of the countries. Recent data indicate that in the United States more than 10 million people are newly infected every year and 79 million people are currently affected. [27] Inconsistent vaccination rates may contribute to continuing prevalence of this virus. [28, 29] Furthermore, in 2010, the whole cost of pre‐ venting and treating HPV-associated disease was said to be \$8.0 billion. [30] Consequently, more attention has to be paid to the HPV infection.

Over 100 HPV types could spread by skin-to-skin contact, including sex, oral sex, sexual intercourse, and other contacts, involving the skin surfaces and genitals. People are commonly susceptible to this virus distributing in the skin and mucous membranes. It has been estimated that more than 50% sexually active populations will acquire the HPV infection during their whole lifetime, [31] and the risk of infection increases with the lack of condom use, the number of sexual partners, and smoking. [32, 33] Majority of sexually active adults may possibly acquire HPV during their lifetime. Generally, with the increasing amount of lifetime sexual partners, the risk of developing illness caused by HPV increases. [30] The human papilloma‐

virus is considered to be one of the most common sexually transmitted viruses affecting fertility.

Some studies indicate that low socioeconomic status has contributed to *T. gondii* exposure. [18] Another risk factor of the exposure might be the consumption of raw fruits and vegetables that were contaminated with *T. gondii* oocysts. Globally, very limited amount of studies of the agricultural population about the prevalence of *T. gondii* infection are conducted by research‐ ers. The goal of a study was to investigate the prevalence and possible risk factors of toxo‐

In adults, *T. gondii* does not cause serious diseases, but in women infected with *T.gondii*, lifethreatening complications such as congenital disease or even abortion occurs in the developing fetus. [19] However, there were some relations between infection of *Toxoplasma* and the sperm quality in human population. Zhou et al. [20] found that *Toxoplasma* infection in infertile human couples was higher than that in fertile ones. It may be related to the antisperm antibodies that were higher in infected human couples. A recent research of *T. gondii* infection in men with sterility indicated that among the cases of man's sterility, some of them were serologically *Toxoplasma*-IgG, IgM, and CAg positive. It was concluded that *T. gondii* infection may influence men's fertility. [21] Lu et al. concluded that acute infection of *T. gondii* can cause male infertility, and Sun et al. [22] concluded that acute *T. gondii* infection can devastate the reproductive function of infected male mice experimentally. Researchers used rats to study the effect of toxoplasmosis on male reproduction and found that in the *Toxoplasma*-infected group, sperm motility was decreased significantly. However, in median sperm concentration, they did not find any significant difference in infected animals and controls. Results indicate that there is possibly a correlation between toxoplasmosis and disturbed reproduction in male rats. [23] Furthermore, a large-scale experiment with greater amount of animals and generations will be required to study the significant effect statistically. [24] Based on current researches, control programs of *Toxoplasma* infection in many countries should be implemented. Faster and

plasmosis among female farmworkers in a region of Turkey. [17]

238 Genital Infections and Infertility

reliable diagnostic tests should also be developed for male and female. [17]

It was estimated that the prevalence of human papillomavirus was at about 12% globally in 2012, [25, 26] despite licensure of HPV vaccines in over 50% of the countries. Recent data indicate that in the United States more than 10 million people are newly infected every year and 79 million people are currently affected. [27] Inconsistent vaccination rates may contribute to continuing prevalence of this virus. [28, 29] Furthermore, in 2010, the whole cost of pre‐ venting and treating HPV-associated disease was said to be \$8.0 billion. [30] Consequently,

Over 100 HPV types could spread by skin-to-skin contact, including sex, oral sex, sexual intercourse, and other contacts, involving the skin surfaces and genitals. People are commonly susceptible to this virus distributing in the skin and mucous membranes. It has been estimated that more than 50% sexually active populations will acquire the HPV infection during their whole lifetime, [31] and the risk of infection increases with the lack of condom use, the number of sexual partners, and smoking. [32, 33] Majority of sexually active adults may possibly acquire HPV during their lifetime. Generally, with the increasing amount of lifetime sexual partners, the risk of developing illness caused by HPV increases. [30] The human papilloma‐

**2.5. Human papillomavirus infection and infertility**

more attention has to be paid to the HPV infection.

HPV is a kind of pathogen that induces chronic infections without any specific symptoms. It is generally accepted that sexually transmitted viruses can cause some changes in infertility. According to a summary of findings, there are some effects of HPV on sperm parameters. For example, HPV infections can alter sperm motility. On the other hand, HPV may increase sperm DNA fragmentation and change semen pH. In general, studies indicate that HPV infection is a factor adversely affecting male fertility or even resulting in infertility.

The studies that report on the differences in sperm quality between uninfected and infected men are discordant. *In vitro* studies have demonstrated that after incubation with specific HR-HPV DNA, higher motility of normal spermatozoa was found. [34] Additionally, there have been quite different influences of seminal HPV infection on some sperm parameters; a few studies have demonstrated that in HPV-infected men, sperm motility decreased, but they do not provide significant information on which sperm parameter could indicate HPV infection.

However, there was no significant difference in sperm quality between HPV-infected men and the uninfected. A study suggests that the presence of HPV may not affect sperm quality. In another recent study, about 300 semen samples of male partners of couples treated by IVF were screened for the HR-HPV DNA infection. [34] Between infected and uninfected men, the HPV DNA infection did not differ significantly. That is to say, sperm quality does not be impaired by the presence of HPV.

It was interesting that HPV-infected couples with the help of assisted reproduction technique might have an increased risk of pregnancy loss compared with the controls, according to a study. [35] However, additional larger studies are necessary to demonstrate the findings before clinical application and support the possibility of reducing the risk of the infection by assisted reproductive technology (ART). [36] Surely, including HPV infection, there are a great amount of other factors that cause infertility. [37] Small sample sizes and limited range of HPV types tested may possibly explain the discrepancies. In conclusion, studies of diverse results will promote more discussions about the influences of HPV infection on infertility.

#### **2.6. Herpes simplex virus (HSV) infection and infertility**

The Herpesviridae family consists of over 200 species infecting birds, mammals, fish, and so on. [38] In accordance with the World Health Organization (WHO), about 90% of the Earth's population is infected by viruses of the Herpesviridae family. HSV can be categorized into two types: HSV-1 and HSV-2. Through direct contact with sites of viral shedding or with muco‐ cutaneous fluids carrying the virus, individuals can contract HSV-1. HSV-1, the most prevalent virus among herpes viruses, is transmitted through oral secretions or sores, causing ocular and oral manifestations. Diseases caused by the virus are pharyngitis, tonsillitis, and gingivosto‐ matitis, causing inflammation of the pharynx and tonsils and swelling of the gums. [39] During sexual contact with people having a genital HSV-2 infection, someone can get HSV-2 infection. Additionally, HSV-2 may possibly enhance the risk of acquiring HIV. Generally, someone infected with it does not know the infection is present in his/her body. When it induces symptoms, it is extremely painful.

Some studies have established the association between HSV infection and male infertility. By semen analysis, researchers compare mean sperm count and morphology of samples. Using real-time PCR method, researchers find a prevalence of HSV DNA in semen. [40] According to a study of 279 infertile women attending an *in vitro* fertilization and embryo transfer program, the positivity rate for HSV was about 6.30%. [41] In order to investigate the preva‐ lence of HSV in the infertile men, a study used serologic testing and PCR to test semen and blood samples. The PCR results indicated that the prevalence of HSV in semen was about 12%. [39] However, more researches should be conducted to correctly compare infertile individuals with and without HSV.

HSV targets the reproductive system, and the infection among males and females leads to infertility problems, but the mechanism seems different in the two populations. As shown in transgenic mice and in some experiments, it seems to affect the semen in males. [42] Interest‐ ingly, there have been no specific semen parameter associated with the HSV infection so far. [43] In women, HSV infection is a risk factor for infertility. The causal relationship between the infection and infertility in males and females would be established through further researches.

#### **2.7.** *Helicobacter pylori* **infection and infertility**

*Helicobacter pylori* is a spiral-shaped, microaerophilic organism, a member of the genus *Helicobacter*, and infects humans, especially at the gastroduodenal tract level. [44] Its genome is as small as 1667 kb, its niche is restricted, and the genome expresses a small amount of metabolic events. However, due to specific virulence determinants, *H. pylori* has been able to establish an adaptive evolutionary machinery. [45]

*H. pylori* infection is not limited in the gastroduodenal tract; *H.pylori* infection causes other digestive illness too. In the 1990s, some epidemiological studies indicated that *H. pylori* infection might be related to extra-digestive diseases affecting the heart and the blood vessels; then further studies showed that the disorders associated with this infection also affect the oropharynx, skin, and various other systems, such as the respiratory, endocrine, immune, hemopoietic, and central nervous systems. [46, 47]

Recently, more and more evidence in the literature indicates that *H. pylori* infection seems to negatively influence the reproductive function. Moretti et al. first investigated the association of *H. pylori* infection and female infertility. They reported an increased prevalence of *H. pylori* infection in female patients with fertility disorders compared to controls. [48] Several years later, a Japanese retrospective survey including almost 200 female patients supported the observation. [49] Figura et al. reported that the anti–*H. pylori* antibody levels in serum samples were higher in individuals with reproductive disorders than in controls and suggested that the risk of infertility may be increased by *H. pylori* infection. [48] Furthermore, Moretti et al. [50] found that the prevalence of *H. pylori* infection was higher in male patients with fertility problems than in controls.

Through various mechanisms, such as the release of molecular mimicry, inflammatory mediators, and systemic immune response, *H. pylori* infection can directly or indirectly impair reproductive functions. [51] Before considering reproductive disorders as another manifesta‐ tion of extra-digestive diseases related to *H. pylori* infection, it is significant to carry out further studies about the prevalence of *H. pylori* infection in patients and controls, and particularly to perform study evaluating reproductive potential after *H. pylori* infection. [50] Furthermore, biologic researches to explain the relationship between *H. pylori* infection and infertility are required.

#### **2.8. Bacterial semen infection and infertility**

infected with it does not know the infection is present in his/her body. When it induces

Some studies have established the association between HSV infection and male infertility. By semen analysis, researchers compare mean sperm count and morphology of samples. Using real-time PCR method, researchers find a prevalence of HSV DNA in semen. [40] According to a study of 279 infertile women attending an *in vitro* fertilization and embryo transfer program, the positivity rate for HSV was about 6.30%. [41] In order to investigate the preva‐ lence of HSV in the infertile men, a study used serologic testing and PCR to test semen and blood samples. The PCR results indicated that the prevalence of HSV in semen was about 12%. [39] However, more researches should be conducted to correctly compare infertile individuals

HSV targets the reproductive system, and the infection among males and females leads to infertility problems, but the mechanism seems different in the two populations. As shown in transgenic mice and in some experiments, it seems to affect the semen in males. [42] Interest‐ ingly, there have been no specific semen parameter associated with the HSV infection so far. [43] In women, HSV infection is a risk factor for infertility. The causal relationship between the infection and infertility in males and females would be established through further

*Helicobacter pylori* is a spiral-shaped, microaerophilic organism, a member of the genus *Helicobacter*, and infects humans, especially at the gastroduodenal tract level. [44] Its genome is as small as 1667 kb, its niche is restricted, and the genome expresses a small amount of metabolic events. However, due to specific virulence determinants, *H. pylori* has been able to

*H. pylori* infection is not limited in the gastroduodenal tract; *H.pylori* infection causes other digestive illness too. In the 1990s, some epidemiological studies indicated that *H. pylori* infection might be related to extra-digestive diseases affecting the heart and the blood vessels; then further studies showed that the disorders associated with this infection also affect the oropharynx, skin, and various other systems, such as the respiratory, endocrine, immune,

Recently, more and more evidence in the literature indicates that *H. pylori* infection seems to negatively influence the reproductive function. Moretti et al. first investigated the association of *H. pylori* infection and female infertility. They reported an increased prevalence of *H. pylori* infection in female patients with fertility disorders compared to controls. [48] Several years later, a Japanese retrospective survey including almost 200 female patients supported the observation. [49] Figura et al. reported that the anti–*H. pylori* antibody levels in serum samples were higher in individuals with reproductive disorders than in controls and suggested that the risk of infertility may be increased by *H. pylori* infection. [48] Furthermore, Moretti et al. [50] found that the prevalence of *H. pylori* infection was higher in male patients with fertility

symptoms, it is extremely painful.

240 Genital Infections and Infertility

with and without HSV.

**2.7.** *Helicobacter pylori* **infection and infertility**

establish an adaptive evolutionary machinery. [45]

hemopoietic, and central nervous systems. [46, 47]

problems than in controls.

researches.

Almost 15% of cases of male infertility can be explained by infections about genitourinary tract. [52] Both infections and inflammation in the male reproductive system may impair the sperm cell, function, and the overall spermatogenetic process, [53 – 55] altering qualitative and quantitative sperm.

The bacteria, viruses, and fungi that contribute to semen infection may be sexually transmitted or come from the urinary tract; their effect on impairing male fertility has already been discussed. [56]

The sperm bacterial contamination is very normal and might contribute to the impairment of semen quality in infertile patients. Some studies have investigated the effect of bacterial semen infection in male fertility, but the putative influence of bacteria on semen quality is still inconsistent. [57]

Bacteria can affect the male reproductive function directly, by reducing the acrosome reaction, causing the agglutination of motile sperm, and changing cell morphology, and indirectly, by producing reactive oxygen species caused by the inflammatory response to bacterial infection. [58] The negative effect of bacteria on sperm motility is known to all. [55, 59] The findings of Moretti et al. [60] show that in all groups except for in two, sperm motility was reduced significantly. Moretti et al. suggested that the existence of bacteria would possibly alter the sperm quality. In the positive group, the mean sperm concentration for bacteria was signifi‐ cantly less than that in controls, whereas the value was always considered normal for WHO. Findings reported by other researchers [53, 57] indicate that *Escherichia coli*, *Enterococcus faecalis*, and *Ureaplasma* urealyticum have negative influence on semen quality of infertile patients. Alterations frequently observed in spermatozoa attributed to bacteria in both *in vitro* and *in vivo* conditions are reduced sperm concentration, sperm morphological alterations, loss of motility, and impaired acrosome reactions.

However, there is no absolute agreement on the detrimental effect of bacteria in the semen. A research reported that the bacteria isolated from the genitourinary tracts of men do not have any influence on semen quality; however, bacteria always impaired the antioxidant ability of sperm in infertile patients with pathological semen parameters. [55]

The exact molecular mechanism that the male fertility is affected by bacteria infection is not only multifactorial but also complex, and it is still a puzzle. [60] More studies based on the molecular approach should be applied to this problem to provide new explanation to the microorganisms contacting with sperm and eventually monitoring the health of male genito‐ urinary organs. In fact, re-evaluating sperm characteristics of patients treated would help to confirm the role of bacterial presence of the observed sperm abnormalities.

#### **2.9. Human immunodeficiency virus infection and infertility**

Initially, in the 1980s, human immunodeficiency virus (HIV) was found in the mononuclear cell fraction of the semen of one HIV-1-seropositive man and two men developing acquired immunodeficiency syndrome. [61] In the early period of the epidemic, those individuals diagnosed as HIV positive were not estimated to live a long life. [62] Since the HIV and AIDS were identified, in the management and long-term prognosis for infected people, vital advances have been made.

According to the WHO, about 75 million people have been infected with the HIV and more than 30 million humans have died of it. During the past 20 years, it has been extensively researched on the field of HIV infection, which invades the human immune system. In Sub-Saharan Africa remaining severely influenced, about 1 in 20 adults is infected by HIV and the number accounts for 71% of the infected people globally. [63]

With the appearance and especially the development of the immunodeficiency syndrome pandemic, attention of the sexual transmission of viruses in human population and its health effects has peaked accordingly. [61] HIV that causes AIDS is the most enormously studied virus among the sexually transmitted viruses. Some studies assessed the influence of HIV infection on sperm parameters in HIV-positive men. Researchers analyzed the association between markers of HIV infection and characteristics of semen. For example, a significant correlation between sperm count and CD4 cell count was demonstrated. Compared with fertile men, HIV-positive men's semen volume, sperm motility, and total sperm count were impaired. Dulioust et al. [64] investigated almost 200 HIV-infected men free from AIDS symptoms on the semen characteristics. Standardized methodology was used to analyze the semen samples collected. However, they did not observe any relation between HIV infection and semen characteristics. In the study of HIV-infected men, the semen changes may be not remarkable enough to affect fecundity greatly. The perfect study design of larger patient size is a longitu‐ dinal cohort study, which describes semen parameters during the development of an HIV infection. [65]

Studies showed that fertility was lower in HIV-1–infected women than the controls in Sub-Saharan Africa. It was the first time to suggest that HIV/AIDS was related to the fertility defects. [66] Recently, more studies indicate that fertility rates in HIV-infected women have decreased in the United States. [67] Among HIV-1–infected women, subfertility may be explained by biological alterations in reproductive physiology. Based on a reproductive endocrinology, HIV-infected women are more likely to have amenorrhea and protracted anovulation com‐ pared to the uninfected women. [68, 69] Many studies have linked HIV infection with prema‐ ture ovarian failure. Additionally, pregnancy-related problems will continue after conception. In several clinical studies, it is more common that HIV-infected women may have pregnancy loss. [66] The correlation between HIV infection and infertility is a significant area for further research and investigation. The observations of those studies demonstrate that access to investigating infertility and treating HIV-positive individuals is very limited in many coun‐ tries. Healthcare professionals who care for these patients must pay more attention to conduct effective strategies to change the situation. [62] Researchers should design more treatments to minimize the risk of HIV transmission and to better understand the influences HIV and its treatments have on reproductive competence and fertility. [66]
