During the nineteenth century in western countries, especially in the United States and Britain, male circumcision has been largely medically adopted like a method to discourage masturbation and became the most common surgical intervention against masturbation.

#### **2.2.  It is located above and in front of the scrotum, below and in front of the pubic symphysis. Its root is in the perineum, attached to the ischio-pubic branches and the suspensor ligament of the penis. The body of the penis has a flattened cylindrical shape, formed by the two corpora cavernosa and corpus spongiosum of the urethra. The corona separates the base of the glans from the shaft of the penis. The glans is formed by the swelling of the corpus spongiosum of the urethra in the shape of a cone.

 Its blood supply is independent of the erectile bodies and is derived from the external pudendal branches of the femoral vessels. The skin that covers the glans like a hood is called prepuce or foreskin. The prepuce is a fold, half skin and half mucosa that continues in the mucosa of the glans at the balanopreputial sulcus. So the outer surface is continuous with the skin of the penis, while the inner surface is modeled on the glans adhering only at the level of the balanopreputial sulcus and the frenulum. The frenulum is a triangular mucosal fold that tends from the inner surface of the foreskin to the underside of the glans 8–10 mm behind the external urethral meatus. A short frenulum can prevent complete retraction of the foreskin and can make painful erection and tear.

The virtual cavity of the prepuce is lubricated by the smegma secreted from Tyson's glands. In case of poor hygiene, the smegma can accumulate and become infected generating balanoposthitis. Repeated balanoposthitis may form adhesions between the inner surface of the foreskin and the mucosa of the glans. In most cases, the preputial orifice is quite wide and weak to be freely retracted over the glans, and allows the glans discovering during erection. The restriction of the preputial ring, preventing the glans to escape from the preputial cavity either at rest or during erection, is called phimosis. Phimosis can be congenital or acquired, and can cause disturbances to urination and erection, and facilitate the appearance of inflammation and infection. In the newborn boy in the first months of life, the prepuce is contracted around the glans. The retraction of the foreskin is possible in the 50% of cases after 1 year of life, and in the 89% at 3 years of age [1]. Phimosis is then present in the 8% of 6–7-year-old children and in only 1% of 16–18-year-old males [2]. In some cases, the glans can go out the foreskin but then cannot be able to reenter generating a swelling accompanied by pain or ulceration; this process is called paraphimosis and requires an immediate manual reduction maneuver.

#### **2.3. Surgical techniques**

immunodeficiency virus (HIV) testing with immediate initiation of antiretroviral therapy. Many controversies exist around male circumcision. In fact, if the procedure can bring benefits in relation to the prevention of several STDs, short-term surgical complications and suspected long-term harms, in relation to sexual dysfunction, have been also advocated by those oppo-

Circumcision is practiced for three main reasons. First, it can be performed for ritual or religious meanings (e.g., Jews circumcise children after 8 days of life, while Muslims between 4 and 13 years of age). Second, it can be done for a prophylactic purpose to guarantee a correct hygiene. Third, especially in western countries, it has also a therapeutic indication to treat

The technique of circumcision is very old and the first documented evidences of this practice are dated as early as the third millennium BC. In the ancient Egypt, circumcision was made for hygienic reasons and documented evidences have been found to date to sixth dynasty tomb (2345–2181 BC). The reasons for circumcision between the different cultural people were different: religious, hygienic, rites of passage, and a way to differentiate cultural groups.

According to Jewish religion (Genesis 17:10-14), God commanded Abraham to be circumcised, an act to be followed by his descendants. Male circumcision is performed by a circumciser (mohel) during a ceremony (covenant of circumcision called "brit milah") on the eighth

"Khitan" is the term for male circumcision carried out by Muslims as an Islamic rite. Although the Quran itself does not mention circumcision (and in fact some Quranists are against circumcision adducing that Quran forbids to alter one's body), male circumcision is widely practiced among Muslims like a rite to symbolize their inclusion into the Islamic community. It is considered obligatory in Shia tradition and not obligatory but highly recommended among the Sunni Islam. There is no fixed time for circumcision. The parents should circumcise their children before the age of 10. The preferred age is seven although some Muslims are circumcised as early as on the seventh day after birth (like Jewish people) and as late as at the puberty.

During the nineteenth century in western countries, especially in the United States and Britain, male circumcision has been largely medically adopted like a method to discourage masturbation and became the most common surgical intervention against masturbation.

 It is located above and in front of the scrotum, below and in front of the pubic symphysis. Its root is in the perineum, attached to the ischio-pubic branches and the suspensor ligament of the penis. The body of the penis has a flattened cylindrical shape,

many diseases of the foreskin, the most common of which is phimosis.

nents to the procedure.

**2. Circumcision**

day of a male infant life.

**2.2. Anatomy and functions of the prepuce**

**2.1. Circumcision in the history**

162 Fundamentals of Sexually Transmitted Infections

Literally from Latin, circumcision means "to cut around." The procedure aims to expose the glans sufficiently to prevent phimosis or paraphimosis (**Figure 1**). It is one of the oldest surgical procedures, performed since the age of the Egyptians. It is surely the most common surgical procedure performed on males. Over the world, it is estimated that 30% of males are circumcised. In the US, an average of a million newborn males is circumcised yearly. Circumcision rate in US is as high as 70%, while in Britain it is 6%.

Absolute indications for medical circumcision are secondary phimosis at any age, primary phimosis with recurrent balanoposthitis and urinary tract infection, and sexual discomfort. The European Association of Urology (EAU) does not recommend routine neonatal circumcision to prevent penile cancer as a recent meta-analysis could not find any risk in uncircumcised patients without a history of phimosis [1]. On the other hand, contraindications for

**Figure 1.** Short-term aesthetic result after circumcision in an adult patient.

circumcision are acute local infection and congenital anomalies of the penis (e.g., hypospadias or buried penis, in which the foreskin may be required for a reconstructive procedure). Asepsis, adequate excision of the outer and inner preputial skin layers, hemostasis, protection of the glans and urethra, and cosmetics are the principles of circumcision.

Circumcision is generally performed under local anesthesia (topical anesthetic cream or anesthetic infiltration at the base of the penis). Different techniques were described depending on the age of the patient and the surgeon's experience. There are device methods and free-hand techniques.

In pediatric settings, the device methods are favored. In this case, the Gomco clamp and its variations, like the Plastibell, are suture-less techniques that use devices that protect the glans, resect the prepuce, and provide hemostasis. The Gomco clamp uses a metal bell placed over the glans after the prepuce is fully retracted. The prepuce is then replaced over it. This is sometimes facilitated by a dorsal slit. A metal plate is placed over the bell and thus the prepuce lies between the two parts. The device is then tensioned to trap the foreskin in position to be adequately removed after a scalpel incision. The Plastibell is a plastic device with a groove on its back that has to be slipped between the glans and the prepuce. In this case, suture material is looped around in the groove and tied tightly. The foreskin withers and drops off in 7–10 days as the suture cuts off the blood supply distally to the groove.

In adulthood, the Sleeve technique or the dorsal slit technique is preferred.  The prepuce is returned to cover the glans and another circumferential incision is made around the shaft at the same position as the first one. The strip of the skin is then removed and the free edges are sutured. When the foreskin cannot be retracted over the glans, a dorsal slit may be suggested. The prepuce is freed from the glans of adhesions and with the aid of forceps, and then a longitudinal incision of both layers of the prepuce is done to some millimeter of the corona. It is cosmetically unacceptable to carry out a dorsal slit alone without excising the prepuce.

Male circumcision has low complication rates when properly performed. The most common complications are bleeding, incomplete removal of the foreskin, infection, urethral meatitis, inclusion cyst, excessive removal of the skin that can lead to severe cosmetic consequences, and functional problems. Injury of the glans, severe scarring, and urethra-cutaneous fistula are major although rare complications of the procedure.

## **3. Circumcision and HIV infection**

circumcision are acute local infection and congenital anomalies of the penis (e.g., hypospadias or buried penis, in which the foreskin may be required for a reconstructive procedure). Asepsis, adequate excision of the outer and inner preputial skin layers, hemostasis, protection

Circumcision is generally performed under local anesthesia (topical anesthetic cream or anesthetic infiltration at the base of the penis). Different techniques were described depending on the age of the patient and the surgeon's experience. There are device methods and free-hand

In pediatric settings, the device methods are favored. In this case, the Gomco clamp and its variations, like the Plastibell, are suture-less techniques that use devices that protect the glans, resect the prepuce, and provide hemostasis. The Gomco clamp uses a metal bell placed over the glans after the prepuce is fully retracted. The prepuce is then replaced over it. This is sometimes facilitated by a dorsal slit. A metal plate is placed over the bell and thus the prepuce lies between the two parts. The device is then tensioned to trap the foreskin in position to

of the glans and urethra, and cosmetics are the principles of circumcision.

**Figure 1.** Short-term aesthetic result after circumcision in an adult patient.

164 Fundamentals of Sexually Transmitted Infections

techniques.

### **3.1. Biological evidence of reduced HIV transmission in circumcised men**

Between 75 and 85% of cases of HIV infection worldwide have probably occurred during sexual activity. Two main biological mechanisms are thought to be responsible of the lower HIV infection rate in heterosexual circumcised men [3].

The first is the protective effect of keratinization of the glans and the sulcus following the procedure. Thereafter, male circumcision removes the inner part of the prepuce that is more susceptible to HIV infection. In fact, the inner surface of the foreskin contains Langerhans' cells (LCs) exposing HIV receptors.

HIV binds to the CD4 and CCR5 receptors on antigen-presenting cells—which include Langerhans' cells and dendritic cells—in the genital and rectal mucosa [5].

A keratinized, squamous epithelium covers the penile shaft and outer surface of the foreskin providing a protective barrier against HIV infection. By contrast, the inner mucosal surface of the foreskin is not keratinized and is rich in LCs making it particularly susceptible to the virus.

A widely accepted model for the sexual transmission of HIV is based on infection of the genital tract of rhesus macaques with Simian immunodeficiency virus (SIV). The same sequence of cellular events involving the infection of LCs has been sperimentally shown in male macaques following the SIV inoculation into the penile urethra or onto the foreskin [6]. Once infected, LCs fuse with adjacent CD4 lymphocytes and migrate to deeper tissues. Within 2 days of infection, the virus can be detected in the internal iliac lymph nodes and shortly thereafter in systemic lymph nodes.

Other mechanisms of increased incidence of HIV infection in uncircumcised men are the ulcerative and inflammatory lesions of the foreskin, and frenulum or glans caused by other STDs. In uncircumcised males, the highly vascular frenulum is particularly susceptible to trauma during intercourse, and ulcerative lesions produced by other STDs increase the ability of HIV to enter in the submucosal layer and link to APCs and CD4 cells. So that circumcision further reduces the risk of infection by lowering the synergy that normally exists between HIV and other STDs.

#### **3.2. Male circumcision and HIV infection**

Several observational studies showed a protective effect of male circumcision regarding the human immunodeficiency virus acquisition in heterosexual men (**Table 1**).

In 2000s, three large randomized trials specifically designed to evaluate the effect of male circumcision on the risk of HIV infections were performed in South Africa, in Uganda, and in Kenya [7–9] for a total of more than 11,000 subjects enrolled. Male circumcision showed a

**Table 1.** HIV-1 seroprevalence in relation to circumcision status in some high-incidence areas (A) and low-risk areas (B): June 1998 UNAIDS/WHO percentage estimates.

protective effect with a relative risk (RR) reduction of acquiring HIV infection of 50% after 12 months and 54% after 24 months. All the studies were stopped early due to these significant findings. The results have also been confirmed by a meta-analysis of the studies [10]. The number needed to treat was 56; it means that circumcision prevented 17 HIV infections per 1000 men at 2 years.

According to some mathematical models, the full coverage of male circumcision in those countries at high rate of HIV incidence, like sub-Saharan Africa, could avert 0.3 million deaths in the first 10 years and a further 2.7 million in the next 10 years [11].

The evidences of male circumcision benefits have also been shown from observational studies conducted in the USA and Israel [12], where the HIV burden is lower than Africa, and in lowincidence countries like India [13].

A consultation in Montreux (Switzerland) held on 28 March 2007 and sponsored by the World Health Organization (WHO) and the Joint United Nations Program on HIV/AIDS (UNAIDS) resulted in the recommendation of circumcision as a strategy for the prevention of heterosexually acquired HIV infection in men.

#### **3.3. Effect of male circumcision on the risk of women HIV acquisition**

cellular events involving the infection of LCs has been sperimentally shown in male macaques following the SIV inoculation into the penile urethra or onto the foreskin [6]. Once infected, LCs fuse with adjacent CD4 lymphocytes and migrate to deeper tissues. Within 2 days of infection, the virus can be detected in the internal iliac lymph nodes and shortly thereafter in

Other mechanisms of increased incidence of HIV infection in uncircumcised men are the ulcerative and inflammatory lesions of the foreskin, and frenulum or glans caused by other STDs. In uncircumcised males, the highly vascular frenulum is particularly susceptible to trauma during intercourse, and ulcerative lesions produced by other STDs increase the ability of HIV to enter in the submucosal layer and link to APCs and CD4 cells. So that circumcision further reduces the risk of infection by lowering the synergy that normally exists between

Several observational studies showed a protective effect of male circumcision regarding the

In 2000s, three large randomized trials specifically designed to evaluate the effect of male circumcision on the risk of HIV infections were performed in South Africa, in Uganda, and in Kenya [7–9] for a total of more than 11,000 subjects enrolled. Male circumcision showed a

**<20% circumcised Seroprevalence >80% circumcised Seroprevalence**

Zimbabwe 25.84 Kenya 11.64 Botswana 25.10 Congo 7.64 Namibia 19.94 Cameroon 4.89 Zambia 19.07 Nigeria 4.12 Swaziland 18.50 Gabon 4.25 Malawi 14.92 Liberia 3.65 Mozambique 14.17 Sierra Leone 3.17 Rwanda 12.75 Ghana 2.38

Cambodia 2.40 Pakistan 0.09 Thailand 2.23 Philippines 0.06 Myanmar 1.79 Indonesia 0.05 India 0.82 Bangladesh 0.03

**Table 1.** HIV-1 seroprevalence in relation to circumcision status in some high-incidence areas (A) and low-risk areas (B):

human immunodeficiency virus acquisition in heterosexual men (**Table 1**).

systemic lymph nodes.

166 Fundamentals of Sexually Transmitted Infections

HIV and other STDs.

**(A) Sub-Saharan Africa**

**(B) South/southeast Asia**

June 1998 UNAIDS/WHO percentage estimates.

**3.2. Male circumcision and HIV infection**

An earlier observational study in Rakai, Uganda, found a relative male-to-female HIV transmission rate ratio of 0.41 (confidence interval (CI): 0.10–1.14) in couples with circumcised versus uncircumcised HIV-infected men. In the same study, for all HIV-positive male partners with viral loads of less than 50,000 copies/ml, no transmissions were observed in circumcised men, compared with a transmission rate of 9.6 per 100 patients (CI: 6.1–13.1, *p* = 0.02) in uncircumcised men [14].

In particular, it was estimated that circumcision may confer a 46% reduction in the rate of HIV transmission from circumcised men to their female partners [15].

Assuming a reduction in male-to-female transmission, the projected impact of circumcision on HIV spread is substantially enhanced, especially for women. Although male circumcision is an intervention applied to men, it brings substantial benefits for women as well.

An increase in the risk of acquisition and transmission of HIV during circumcision woundhealing period is an admitted possibility [16], but it is unlikely to have a major effect on the population. Premature resumption of sexual activity before the wound is healed or "compensatory" increase in risk following circumcision are both unlikely to substantively undermine the benefits of male circumcision on HIV incidence among women or men.

#### **3.4. Infection of men who have sex with men**

A Cochrane systematic review and meta-analysis including more than 65,000 participants showed that circumcision may reduce HIV acquisition among men who have sex with men having an insertive anal role but probably have no role among those having a receptive role [17].

## **4. Male circumcision and other sexually transmitted infections**

#### **4.1. Human papillomavirus**

Circumcision was shown to decrease human papillomavirus (HPV) infection rates among both HIV-negative and HIV-positive heterosexual men included in a randomized controlled trial (RCT) performed in Uganda (RR 0.40, 95% CI: 0.19–0.84), control event rate 24.7% [18]. Male circumcision decreases also HPV infection rates in female partners especially of circumcised HIV-negative males [19, 20]. It is important to note that female partners of circumcised males have a lower risk of cervical cancer [21].

### **4.2. Mycoplasma**

Circumcision was found to nearly halve the odds of Mycoplasma infection of the genitalia in circumcised men (odds ratio (OR) 0.54; 95% CI: 0.29–0.99) [22]. On the contrary, genital Mycoplasma is not reduced in female partners of circumcised men [23].

#### **4.3. Genital ulcer disease**

Two large RCTs showed that male circumcision reduce genital ulcer disease (GUD) incidence with a risk ratio of 0.51 and 0.52 [24]. The risk for GUD is also decreased in female partners of circumcised males as for Chlamydia trachomatis infection [25], bacterial vaginosis, and trichomonas infection [26].

### **4.4. Syphilis**

The relation between male circumcision and new acquisition of syphilis is not clear. In fact, one large RCT showed no significant difference between circumcised and uncircumcised men (adjusted hazard ratio 1.10, 95% CI: 0.75–1.65, *p* = 0.44) [27]. However, another large RCT showed that circumcision was associated with a 42% reduction in the incidence of syphilis (adjusted hazard ratio 0.58, 95% CI: 0.37–0.91). In particular, a 62% reduction of syphilis among HIV-infected men was noted, whereas a nonsignificant reduction in the incidence of syphilis was observed among men without HIV [28].

#### **4.5. Herpes simplex virus**

A discrepancy of results exists between the trials conducted in order to evaluate the association of male circumcision and herpes simplex virus (HSV) prevalence. The reason for such a discrepancy is due to the nonunivocal use of the test employed for HSV detection and because of nonhomogeneous characteristics of the subjects and their sexual life.

In fact, two RCTs from Uganda [27] and South Africa [29] showed a significant reduction in HSV infection rates after circumcision. Two other trials conducted in Kenya failed to show such a reduction [24, 30].

#### **4.6. Gonorrhea and Chlamydia**

**4. Male circumcision and other sexually transmitted infections**

Circumcision was shown to decrease human papillomavirus (HPV) infection rates among both HIV-negative and HIV-positive heterosexual men included in a randomized controlled trial (RCT) performed in Uganda (RR 0.40, 95% CI: 0.19–0.84), control event rate 24.7% [18]. Male circumcision decreases also HPV infection rates in female partners especially of circumcised HIV-negative males [19, 20]. It is important to note that female partners of circumcised

Circumcision was found to nearly halve the odds of Mycoplasma infection of the genitalia in circumcised men (odds ratio (OR) 0.54; 95% CI: 0.29–0.99) [22]. On the contrary, genital

Two large RCTs showed that male circumcision reduce genital ulcer disease (GUD) incidence with a risk ratio of 0.51 and 0.52 [24]. The risk for GUD is also decreased in female partners of circumcised males as for Chlamydia trachomatis infection [25], bacterial vaginosis, and

The relation between male circumcision and new acquisition of syphilis is not clear. In fact, one large RCT showed no significant difference between circumcised and uncircumcised men (adjusted hazard ratio 1.10, 95% CI: 0.75–1.65, *p* = 0.44) [27]. However, another large RCT showed that circumcision was associated with a 42% reduction in the incidence of syphilis (adjusted hazard ratio 0.58, 95% CI: 0.37–0.91). In particular, a 62% reduction of syphilis among HIV-infected men was noted, whereas a nonsignificant reduction in the incidence of

A discrepancy of results exists between the trials conducted in order to evaluate the association of male circumcision and herpes simplex virus (HSV) prevalence. The reason for such a discrepancy is due to the nonunivocal use of the test employed for HSV detection and because

In fact, two RCTs from Uganda [27] and South Africa [29] showed a significant reduction in HSV infection rates after circumcision. Two other trials conducted in Kenya failed to show

of nonhomogeneous characteristics of the subjects and their sexual life.

Mycoplasma is not reduced in female partners of circumcised men [23].

**4.1. Human papillomavirus**

168 Fundamentals of Sexually Transmitted Infections

**4.2. Mycoplasma**

**4.3. Genital ulcer disease**

trichomonas infection [26].

**4.5. Herpes simplex virus**

such a reduction [24, 30].

**4.4. Syphilis**

males have a lower risk of cervical cancer [21].

syphilis was observed among men without HIV [28].

Male circumcision probably does not interfere with gonorrhea incidence. In fact, both observational [31] and randomized [32] did not show a risk reduction of gonococcus infection after circumcision.

Similarly, there is no association between Chlamydia infection and circumcision status [32].

## **5. Circumcision and sexual function**

The possible implication of circumcision on sex needs more thorough discussion. The dorsal nerves provide sensory innervation to the penis. These nerves follow the course of the dorsal arteries and richly supply the glans. The prepuce is also a primary sensory part of the penis. In fact, it contains a high concentration of Meissner's corpuscles and sensory cells, which make it a specialized sensory mucosa. The effect of circumcision on sexual sensation is widely discussed and contradictory results have been shown. Some authors reported that the foreskin is important for normal sexual activity and affirm that circumcision removes the most sensitive parts of the penis. In addition to this, the glans of circumcised penis was found to be less sensitive compared to the glans of uncircumcised men, probably due to the subsequent thickening of the glans epithelia. Conversely, other authors showed that there is no substantial difference in sexual pleasure in circumcised and uncircumcised males, but an increased penile sensitivity. The same contradictory results were reported for women partners. In fact, the gliding mechanism, which makes the penis shaft to glide in its own skin covering during intercourse, was thought to add to the comfort of both partners in theory.

However, although one trial conducted in Denmark [33] reported a reduction in sexual satisfaction, more orgasm difficulties, and higher rate of dyspareunia among women partners of circumcised men, the most part of the studies supported the thesis that circumcision does not change or even improve sexual pleasure of women partners.

 Moreover, using the Brief Male Sexual Function Inventory (BMFSI) and the Intravaginal Ejaculation Latency Time (IELT), after an observational 12-week study, Senkul et al. [35] noted a prolonged mean ejaculatory latency time, which may be considered an advantage, and no substantial differences in the mean BMSFI (**Table 2**).

To analogous conclusions arrived, the studies of Kigozi et al. [36] and Collins et al. [37] use, respectively, the International Index of Erectile Function (IIEF) and the Brief Male Sexual Function Inventory (BMFSI).

On the contrary, the World Health Organization in 2007 [38] stated that there was little evidence to support a negative effect of male circumcision on sexual pleasure.

**Table 2.** Effects of male circumcision on sexual function.

## **6. Ethical and legal arguments of male circumcision**

#### **6.1. Adults**

An ethical argumentation regarding male circumcision should focus on four bioethical principles: autonomy, dignity, integrity, and vulnerability, which are to be understood without giving priority to one principle over another, but according to their mutual connections [40]. Bodily integrity is not a value worthy of respect in his own meaning (per se), unless related to dignity and values of a human person under all circumstances concerning health. Integrity, as mentioned in the Barcelona Declaration (1998), is not limited to the body, conversely it concerns the whole life of every person, in its physical, mental, and narrative dimension [41]. Dignity is considered a property of every human being who has dignity if it is the expression of his/her autonomy, at a given moment of his/her life. Strongly related to the notion of autonomy is the obligation of informed consent during the course of health care, with the focus on self-determination [40]. By applying the principle of autonomy in medical ethics, one could even justify the refusal of medical and surgical treatment deemed necessary or, on the contrary, admit the possibility that a competent adult person consent to medical treatment, in spite of the possibility of unwanted negative effects and outcomes. In fact, since last century, patient's informed consent was considered the expression of a wiliness permitting to attempt patient physical integrity and, if it had been missed, any medical act could be understood as "violence."

Some authors opposing to male medical circumcision, skeptical about the Center for Disease Control and Prevention (CDC) guidelines, argued about supposed health benefits of female "circumcision," some forms of which may be even considered as less invasive than male circumcision, trying to balance similarities [42]. This argument is strongly denied by medical classification of the WHO that named "mutilation" as all forms of female circumcision and consequently no far similarities must be drawn between two practices. Thus, the practices banned by the WHO, as female genital mutilations, even with patient consent, could not be considered lawful [43].

On the point of view of health professionals and physicians duties, by applying the "beneficence" ethical principle, benefits must "simply" exceed predictable risks and complications, all evaluated in the light of scientific evidence principles. Values of integrity and honesty of health professionals are moral aptitudes worldwide mentioned, which must contribute to reach a convinced opinion of the patient [44], with a proper illustration of pros and cons attributable to each medical practice, taking into account all aspects worthy of consideration in patient's perspective [45–48]. The ratio between risks and benefits, in the case of adult patient, may justify the proposal and adoption of male circumcision, within updated medical guidelines evidence, provided it does not impose to anyone an also minimal genital surgery, even in consideration of absolutely rare frequency of risks and complications related to this practice.

#### **6.2. Children**

However, a recent systematic review analyzing the highest quality studies, conducted by Morris and Krieger [39], concluded that male circumcision has no negative effects on sexual

questionnaire

**Author Study Sexual assessment Outcome**

Collins et al. [37] Observational BMFSI No change

Senkul et al. [35] Observational BMFI Increase IELT and no

Kigozi et al. [36] Randomized IIEF No difference between

Frisch et al. [33] Case-control Survey More orgasm difficulties

change

groups

satisfied)

No difference (very

An ethical argumentation regarding male circumcision should focus on four bioethical principles: autonomy, dignity, integrity, and vulnerability, which are to be understood without giving priority to one principle over another, but according to their mutual connections [40]. Bodily integrity is not a value worthy of respect in his own meaning (per se), unless related to dignity and values of a human person under all circumstances concerning health. Integrity, as mentioned in the Barcelona Declaration (1998), is not limited to the body, conversely it concerns the whole life of every person, in its physical, mental, and narrative dimension [41]. Dignity is considered a property of every human being who has dignity if it is the expression of his/her autonomy, at a given moment of his/her life. Strongly related to the notion of autonomy is the obligation of informed consent during the course of health care, with the focus on self-determination [40]. By applying the principle of autonomy in medical ethics, one could even justify the refusal of medical and surgical treatment deemed necessary or, on the contrary, admit the possibility that a competent adult person consent to medical treatment, in spite of the possibility of unwanted negative effects and outcomes. In fact, since last century, patient's informed consent was considered the expression of a wiliness permitting to attempt patient physical integrity and, if it had been missed, any medical act could be understood as

Some authors opposing to male medical circumcision, skeptical about the Center for Disease Control and Prevention (CDC) guidelines, argued about supposed health benefits of female "circumcision," some forms of which may be even considered as less invasive than male circumcision, trying to balance similarities [42]. This argument is strongly denied by medical classification of the WHO that named "mutilation" as all forms of female circumcision and

function, sensitivity, sexual sensation, or satisfaction.

**Table 2.** Effects of male circumcision on sexual function.

170 Fundamentals of Sexually Transmitted Infections

Krieger et al. [34] Observational Non-validated

**6.1. Adults**

"violence."

**6. Ethical and legal arguments of male circumcision**

With regard to health-care decisions for young children, it is generally assumed that their parents should make these. Only when parents make decisions that are very clearly against the interest of their children, an external imposition could be assumed. It is also worthy of consideration for the family that have to live with the results of health decision, and every family has its own set of values; the basis for decision making is related to the model of "surrogate decision-making standard" or, alternatively, the "best interest" standard. Disagreement between the parents' decision and the health-care professionals involved in the care and the treatment sometime should require legal evaluation in Court.

Criticism related to the Guidelines of the American Academy of Pediatrics (AAP) 2012 policy statement and technical report is yet reported and debated in scientific literature [41]. Basically, this matter regards prophylactic infant male circumcision and parents' consent, in the view of the best child's interest and future consequences related to circumcision. One position concludes that, before an age of consent, circumcision is not a desirable health-promotion strategy, given more effective and less ethically problematic alternatives [42]. On the contrary, from a scientific point of view, like infant vaccinations, the benefits of male circumcision exceed risks by a large margin; following these clinical and epidemiological indications, the pro-male circumcision arguments include also legal arguments [49]. Within this favorable approach, parents must make many decisions on behalf of their children. The decision whether to circumcise or not, as for some not obligatory vaccination, is one of those pertaining to parents.

### **7. Conclusions and key messages on male circumcision**

## **Author details**

Marco Vella<sup>1</sup> \*, Alberto Abrate1 , Antonina Argo<sup>2</sup> and Alchiede Simonato<sup>1</sup>

\*Address all correspondence to<EMAIL_ADDRESS>
1 Urological Section, Department of Surgical, Oncological and Stomatological Science, University of Palermo, Palermo, Italy

2 Medico-Legal Section, Department for Health Promotion, Maternal and Child Care, University of Palermo, Palermo, Italy

## **References**

• Male circumcision is an addition to, not a substitute for, other proven methods for prevent-

• Sex should be resumed at least 6 weeks after circumcision and after a medical examination

• Male circumcision seems to confer protection against HIV infection also in women assum-

• Male circumcision reduces HIV acquisition among men who have sex with men having an

• Male circumcision reduces the incidence of HPV infection in males and of cervical cancer

• Male circumcision has a protective effect regarding Mycoplasma genitalia infection and

• Conflicting data are available about the benefits of circumcision over the transmission of

• There is no substantial difference in sexual pleasure between circumcised and uncircum-

• Several surgical techniques are available, but none has demonstrated superiority over the

• When performed freely after informed consent, male circumcision is a lawful practice in adult. • In children, the lack of an informed consent is overcome by the favorable risk/benefit ratio

1 Urological Section, Department of Surgical, Oncological and Stomatological Science, University

2 Medico-Legal Section, Department for Health Promotion, Maternal and Child Care, University

and Alchiede Simonato<sup>1</sup>

• Male circumcision is generally well accepted by female partners.

and the decision whether to circumcise or not pertains to the parents. • Male circumcision and female genital mutilation are very different things.

, Antonina Argo<sup>2</sup>

• Surgical complications are rare in hospital settings.

\*, Alberto Abrate1

\*Address all correspondence to<EMAIL_ADDRESS>
• Male circumcision is a preventive measure with an optimal cost/benefit ratio.

ing that sexual intercourses are avoided during the wound-healing period.

ing HIV infection, as it provides only partial protection.

confirming that the healing process is complete.

insertive anal role.

172 Fundamentals of Sexually Transmitted Infections

genital ulcer disease.

other sexually transmitted diseases.

in women.

cised men.

others.

**Author details**

of Palermo, Palermo, Italy

of Palermo, Palermo, Italy

Marco Vella<sup>1</sup>

[23] Tobian AA, Gaydos C, Gray RH, Kigozi G, Serwadda D, Quinn N, Grabowski MK, Musoke R, Ndyanabo A, Nalugoda F, Wawer MJ, Quinn TC. Male circumcision and Mycoplasma genitalium infection in female partners: A randomised trial in Rakai, Uganda. Sexually Transmitted Infections. 2014;**90**:150-154. DOI: 10.1136/sextrans-2013-051293

[13] Arora P, Nagelkerke NJ, Jha P. A systematic review and meta-analysis of risk factors for sexual transmission of HIV in India. PLoS One. 2012;**7**:e44094. DOI: 10.1371/journal.

[14] Gray RH, Kiwanuka N, Quinn TC, Sewankambo NK, Serwadda D, Mangen FW, Lutalo T, Nalugoda F, Kelly R, Meehan M, Chen MZ, Li C, Wawer MJ. Male circumcision and HIV acquisition and transmission: Cohort studies in Rakai, Uganda. Rakai Project Team.

[15] Hallett TB, Alsallaq RA, Baeten JM, Weiss H, Celum C, Gray R, Abu-Raddad L. Will circumcision provide even more protection from HIV to women and men? New estimates of the population impact of circumcision interventions. Sexually Transmitted Infections.

[16] Wawer MJ, Makumbi F, Kigozi G, Serwadda D, Watya S, Nalugoda F, Buwembo D, Ssempijja V, Kiwanuka N, Moulton LH, Sewankambo NK, Reynolds SJ, Quinn TC, Opendi P, Iga B, Ridzon R, Laeyendecker O, Gray RH. Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: A randomised controlled trial. Lancet. 2009;**374**:229-237. DOI: 10.1016/S0140-6736(09)60998-3

[17] Wiysonge CS, Kongnyuy EJ, Shey M, Muula AS, Navti OB, Akl EA, Lo YR. Male circumcision for prevention of homosexual acquisition of HIV in men. Cochrane Database Systemic Revision. 2011; Issue 6: CD007496. DOI: 10.1002/14651858.CD007496.pub2 [18] Serwadda D, Wawer MJ, Makumbi F, Kong X, Kigozi G, Gravitt P, Watya S, Nalugoda F, Ssempijja V, Tobian AA, Kiwanuka N, Moulton LH, Sewankambo NK, Reynolds SJ, Quinn TC, Oliver AE, Iga B, Laeyendecker O, Gray RH. Circumcision of HIV-infected men: Effects on high-risk human papillomavirus infections in a randomized trial in Rakai, Uganda. Journal of Infectious Disease. 2010;**201**:1463-1469. DOI: 10.1086/652185 [19] Wawer MJ, Tobian AA, Kigozi G, Kong X, Gravitt PE, Serwadda D, Nalugoda F, Makumbi F, Ssempiija V, Sewankambo N, Watya S, Eaton KP, Oliver AE, Chen MZ, Reynolds SJ, Quinn TC, Gray RH. Effect of circumcision of HIV-negative men on transmission of human papillomavirus to HIV-negative women: A randomised trial in Rakai,

Uganda. Lancet. 2011;**377**:209-218. DOI: 10.1016/S0140-6736(10)61967-8

[20] Davis MA, Gray RH, Grabowski MK, Serwadda D, Kigozi G, Gravitt PE, Nalugoda F, Watya S, Wawer MJ, Quinn TC, Tobian AA. Male circumcision decreases high-risk human papillomavirus viral load in female partners: A randomized trial in Rakai, Uganda. International Journal of Cancer. 2013;**133**:1247-1252. DOI: 10.1002/ijc.28100 [21] Castellsague X, Bosch FX, Munoz N, Meijer CJ, Shah KV, de Sanjose S, Eluf-Neto J, Ngelangel CA, Chichareon S, Smith JS, Herrero R, Moreno V, Franceschi S. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. New England Journal of Medicine. 2002;**346**:1105-1112. DOI: 10.1056/NEJMoa011688 [22] Mehta SD, Gaydos C, Maclean I, Odoyo-June E, Moses S, Agunda L, Quinn N, Bailey RC. The effect of medical male circumcision on urogenital Mycoplasma genitalium among men in Kisumu, Kenya. Sexually Transmitted Disease. 2012;**39**:276-280. DOI: 10.1097/

pone.0044094

AIDS. 2000;**14**:2371-2381

174 Fundamentals of Sexually Transmitted Infections

OLQ.0b013e318240189c

2011;**87**:88-93. DOI: 10.1136/sti.2010.043372

[46] Homfray V, Tanton C, Miller RF, Beddows S, Field N, Sonnenberg P, Wellings K, Panwar K, Johnson AM, Mercer CH. Male circumcision and STI acquisition in Britain: Evidence from a national probability sample survey. PLoS One. 2015;**10**:e0130396. DOI: 10.1371/journal. pone.0130396

[33] Frisch M, Lindholm M, Gronbaek M. Male circumcision and sexual function in men and women: A survey-based, cross-sectional study in Denmark.  Journal of Sexual Medicine. 2008;**5**:2610-2622. DOI: 10.1111/j.1743-6109.2008.00979.x [35] Senkul T, Iser IC, Sen B, Karademir K, Saracoglu F, Erden D. Circumcision in adults:

[36] Kigozi G, Watya S, Polis CB, Buwembo D, Kiggundu V, Wawer MJ, Serwadda D, Nalugoda F, Kiwanuka N, Bacon MC, Ssempijja V, Makumbi F, Gray RH.  BJU

[37] Collins S, Upshaw J, Rutchik S, Ohannessian C, Ortenberg J, Albertsen P. Effects of circumcision on male sexual function: Debunking a myth? Journal of Urology. 2002;**167**:

[38] World Health Organization. Male Circumcision: Global Trends and Determinants of Prevalence, Safety and Acceptability. 2007. Available from: http://whqlibdoc.who.int/

[39] Morris BJ, Krieger JN. Does male circumcision affect sexual function, sensitivity, or satisfaction?--A systematic review. Journal of Sexual Medicine. 2013;**10**:2644-2657. DOI:

[40] Pegoraro R, Putoto G, Wray E, editors. Hospital Based Bioethics. A European Perspective.

[41] Kemp P, Rendtorff JD. The Barcelona Declaration. Towards an integrated approach to

[42] Earp BD. Do the benefits of male circumcision outweigh the risks? A critique of the proposed CDC guidelines. Frontiers in Pediatrics. 2015;**3**:18. DOI: 10.3389/fped.2015.00018

[43] Vella M, Argo A, Costanzo A, Tarantino L, Milone L, Pavone C. Female genital mutilations: Genito-urinary complications and ethical-legal aspects. Urologia. 2015;**82**:151-159.

[44] Argo A, Zerbo S, Triolo V, Averna L, D'Anna T, Nicosia A, Procaccianti P. Legal aspects of sexually transmitted diseases: Abuse, partner notification and prosecution. Giornale

[45] Friedman B, Khoury J, Petersiel N, Yahalomi T, Paul M, Neuberger A. Pros and cons of circumcision: An evidence-based overview. Clinical Microbiology and Infection.

basic ethical principles. Synthesis Philosophica. 2008;**46**:239-251

Italiano di Dermatologia e Venereologia. 2012;**147**:357-371

2016;**22**:768-774. DOI: 10.1016/j.cmi.2016.07.030

International. 2008;**101**:65-70. DOI: 10.1111/j.1464-410X.2007.07369.x

Epidemiology. 2011;**40**:1367-1381. DOI: 10.1093/ije/dyr104

Effect on sexual function. Urology. 2004;**63**:155-158

publications/2007/9789241596169\_eng.pdf

2111-2112

176 Fundamentals of Sexually Transmitted Infections

10.1111/jsm.12293

Padova: Piccin; 2007. p. 198

DOI: 10.5301/uro.5000115

**Section 5**

## **Complications**

## **Infection by Human Papillomavirus (HPV), Chlamydia trachomatis and Ureaplasma urealyticum, in Relation with Reproductive Failure**

Adriana Ancer‐Arellano, Jesus Ancer‐Rodríguez,

David Hardisson, Alberto Niderhauser-Garcia,

Jose Sanchez‐Hernández,

Alvarez‐Cuevas Salomón and

Guadalupe Gallegos‐Avila

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68696

#### **Abstract**

Recent studies suggest that besides oncogenic capacity, HPV could have etiological role on infertility, but more evidence is necessary to confirm these results. We pres‐ ent in this chapter the microbiological and clinical outcome of 104 infertile women aleatory selected, from northeast of Mexico: 84.6%, with genital infection (GI) by mul‐ tiple germs: *Chlamydia trachomatis* (*Ct*) [86.5%], HPV [49%], *Ureaplasma urealyticum* (*Uu*) [47.11%] and *Mycoplasma hominis* [35.57%]. Significant association (P ≤ 0, 05) was observed between the HPV presence and *Uu* diagnosis, assisted‐reproduction unsuc‐ cessful like previous treatment, cervical cytology with inflammatory process, multiple sexual partners, white‐dense‐mucous, secretion into the vagina, and HPV diagnosed in early years. The more frequent genotypes of HPV present in the infertile women studied were 6/18/16/58/11 and 68. In 60% of them, more than two genotypes were founded. The most frequent associations of high‐risk HPV (HPVhr) were 16/18, 16/58, 16/33, 16/52 and 18/58. Considering the isolate or combined presentation of HPVhr, 79.5% of these women would have a potential to develop cervix carcinoma. GI by HPV/*Uu*/*Ct* affects the fertility. Infertile women with GI that include these microor‐ ganisms with probed (HPV/*Ct*) or suspicious carcinogenic effect (*Uu*) would be con‐ sidered a group of high risk for cervical cancer.

**Keywords:** genital infection, HPV, *Chlamydia trachomatis*, *Ureaplasma urealyticum*, Infertility, risk for cervical cancer

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **1. Introduction**

At present, reproductive failure affects to a great population. Human infertility is defined by World Health Organization, like the absent of conception and outcome of healthy baby borne, after 1 year of unprotected intercourse. Infertility is a health complex problem with low qual‐ ity life for the couples. Estimations on 2010 referred 1.9 and 10.5% of primary and secondary infertility, respectively, on women at reproductive age (20–40 years old). A high prevalence of fertility health is documented in South of Asia, Medium East, Central Europe, East Europe, and Central Asia [1].

Genitourinary unspecific infection is associated with unexplained infertility, subfertility, obstet‐ ric and gynecologic complications that not have known clear etiology for several decades like recurrent abortion, premature delivery, placenta dysfunction and preeclampsia [2, 3]. As well, assisted reproduction treatment for infertility had been associated with genital infection [4–7]. Specific treatment for genital infection is recommended to improve the successful of *in vitro* fer‐ tilization an embryo implantation [8, 9]. The low age of sexual activity initiation and with mul‐ tiple sexual partners is a recognized risk factor for sexually transmitted genitourinary infection, but the absent or subtle clinical manifestations prevent the opportune treatment and persisting infection for long time and thus may exert detriment on the reproductive function [10].

Besides the still controversial participation of HPV on fertility and obstetric complications, the major bacteria implicated for a long time are *C. trachomatis,* and other atypical bacteria treated in next section: *U. urealyticum*, *M. hominis,* that were considered for a long time an improbable cause of female internal genital infection, were isolated from endometrial tissue and material obtained by hysteroscopy and laparoscopy procedures, in women with tubary obstruction, hidrosalpinx, and adherence syndrome [11–15]. In recent years, another species of Mycoplasmataceae, *M. genitalium*, has been considered an emerging sexually transmitted infec‐ tion that exerts damage in female genital tract and is implicated in fertility problems [16–18].

## **2. Human papillomavirus**

### **2.1. Classification**

HPV belongs to *Papoviridae* family microorganism and comprises a group of approximately 200 small DNA viruses. According to its tissue tropism, HPV has been classified like *Alpha* HPV that affects epithelial mucosae and is subclassified into high risk and low risk of carcino‐ genic potential *Beta, gamma, nu* and *mu.* HPV has more potential to affect cutaneous epithelia and more associated with papilloma and external warts and had been associated with no melanocytic skin carcinoma [19, 20].

### **2.2. Epidemiology**

The HPV infection has an epidemiologic importance. Registered prevalence is influenced by diagnostic test applied, the number and age of individuals of studied population, the geographic region studied [21]. Nevertheless, actually are considered the most common sexu‐ ally transmitted viral infection worldwide, present in 11–12% of population and are 14 mil‐ lion people infected by first time each year. The incidence of HPV infection in the United States is one of higher, as 44.8%, and is present principally in women 20–24 years old [22]. In Mexico from 2005 to 2010, urogenital candidiasis and HPV infection present an incidence of 12.3/100,000 habitant between 15 and 24 years old and were higher between 20 and 24 years old. In this country had been estimated that toward 2050, there are not a clear tendency to diminish of the HPV infection. This situation is very worrying due to the potential malig‐ nancy of the lesions [23]. On the records of National Institute of Statistic and Geography of Mexico, were informed that 4417 women died by cervical cancer, in 2013 [24].

#### **2.3. Biomedical importance**

**1. Introduction**

182 Fundamentals of Sexually Transmitted Infections

and Central Asia [1].

**2. Human papillomavirus**

melanocytic skin carcinoma [19, 20].

**2.1. Classification**

**2.2. Epidemiology**

At present, reproductive failure affects to a great population. Human infertility is defined by World Health Organization, like the absent of conception and outcome of healthy baby borne, after 1 year of unprotected intercourse. Infertility is a health complex problem with low qual‐ ity life for the couples. Estimations on 2010 referred 1.9 and 10.5% of primary and secondary infertility, respectively, on women at reproductive age (20–40 years old). A high prevalence of fertility health is documented in South of Asia, Medium East, Central Europe, East Europe,

Genitourinary unspecific infection is associated with unexplained infertility, subfertility, obstet‐ ric and gynecologic complications that not have known clear etiology for several decades like recurrent abortion, premature delivery, placenta dysfunction and preeclampsia [2, 3]. As well, assisted reproduction treatment for infertility had been associated with genital infection [4–7]. Specific treatment for genital infection is recommended to improve the successful of *in vitro* fer‐ tilization an embryo implantation [8, 9]. The low age of sexual activity initiation and with mul‐ tiple sexual partners is a recognized risk factor for sexually transmitted genitourinary infection, but the absent or subtle clinical manifestations prevent the opportune treatment and persisting

infection for long time and thus may exert detriment on the reproductive function [10].

Besides the still controversial participation of HPV on fertility and obstetric complications, the major bacteria implicated for a long time are *C. trachomatis,* and other atypical bacteria treated in next section: *U. urealyticum*, *M. hominis,* that were considered for a long time an improbable cause of female internal genital infection, were isolated from endometrial tissue and material obtained by hysteroscopy and laparoscopy procedures, in women with tubary obstruction, hidrosalpinx, and adherence syndrome [11–15]. In recent years, another species of Mycoplasmataceae, *M. genitalium*, has been considered an emerging sexually transmitted infec‐ tion that exerts damage in female genital tract and is implicated in fertility problems [16–18].

HPV belongs to *Papoviridae* family microorganism and comprises a group of approximately 200 small DNA viruses. According to its tissue tropism, HPV has been classified like *Alpha* HPV that affects epithelial mucosae and is subclassified into high risk and low risk of carcino‐ genic potential *Beta, gamma, nu* and *mu.* HPV has more potential to affect cutaneous epithelia and more associated with papilloma and external warts and had been associated with no

The HPV infection has an epidemiologic importance. Registered prevalence is influenced by diagnostic test applied, the number and age of individuals of studied population, the HPV infect principally undifferentiated keratinocytes into de basal level of stratified squa‐ mous epithelia, from mucous genital and oropharyngeal epithelia cutaneous and, as well as glandular cells of endocérvix [25–27]. HPV had been recognized as definitive anogenital carcinogen for male and female, mainly in uterine cervix cancer [28], alone or in combina‐ tion with other germs [29]. Some estimations show that the presence of HPV represents 12 more opportunities to develop cervical cancer than general population [30] and the HPV infection the most important between the factor risk for cervical cancer [21]. Recently, HPV was associated, lung cancer [31–34] to larynx and pharynx carcinoma that their incidence are increasing in the last years [35, 36].  All of these observations were referred as argue to carry out comparative epide‐ miologic study of HPV infection and associated with carcinoma of head and neck and cervical cancer [37].

#### **2.4. Their role in reproductive failure**

Although is well known than many authors are interested to search carcinogenic roll of HPV, there are only a few studies about the effect of HPV infection on human reproduction [38–41]. There is evidence showing the adherence of HPV to the equatorial segment of sperm cell [42]. Epidemiologic data about the infection by HPV in infertile men associated high levels of semi‐ nal leukocytes, with altered movement and morphology of head sperm, with the HPV infec‐ tion [43–45]. Previously, experimental studies had been demonstrated chromosomic damage in HPV infected sperm, depending of genotypes 16 and 3 [46, 47]. An association has been found between cervical HPV of high risk and premature membrane rupture and preterm new borne [48–50]. The genital infection by more than one genotype of HPV was higher in recurrent early lost pregnancy, and HPV was identified in placenta tissue of preterm delivery by preeclampsia [41]. The frequency of cervical HPV infection and high‐grade lesion was higher in women that have indicated assisted reproduction than general population [6] and successful of assisted reproduction were affected by the presence of HPV [5, 7]. The HPV transmission from mother to child *in utero* was informed in several investigations [51–54]. These authors remark the risk to appear papillary lesions in oropharynx and larynx of new born from mothers infected by HPV.

## **3. Chlamydia trachomatis**

### **3.1. Biology and classification**

The family Chlamydiaceae consists of two clinically important genera, *Chlamydia* and *Chlamydophila*, with three species responsible for human disease: *Chlamydia trachomatis*, *Chlamydophila psittaci*, and *Chlamydophila pneumoniae* [55]. *C. trachomatis*, as all the members of the family Chlamydiaceae, is an obligate intracellular parasite whose developmental cycle occurs within a eukaryotic host. Infection of eukaryotic host cells is initiated by the metaboli‐ cally inactive and the infectious elementary bodies (EBs). Through largely unknown mecha‐ nisms, EBs attach to and induce their internalization by host cells. Within the first few hours post infection, EBs differentiate to the larger and more pleomorphic reticulate bodies (RBs), which are metabolically active, noninfectious, and replicative. At the end of a successful developmental cycle, the cell lyses, releasing the EBs [56, 57].

#### **3.2. Medical relevance**

*Chlamydia trachomatis* is the most prevalent sexually transmitted bacterial infection, recog‐ nized worldwide, which causes a wide spectrum of diseases, including salpingitis, endo‐ metritis, and uterine, cervical lesions with scarring process, which often causes infertility in women [58]. Serotypes D‐K of *C. trachomatis* has an etiologic relation to pelvic inflammatory disease; it has been isolated from superior genital tract in a quarter of women with pelvic inflammation and is possible that chronic process would be in relation to ovarian cancer [59]. The role of *C. trachomatis* with regard to inducing male factor infertility is a matter of debate. Chlamydial infection could potentially exert a strong influence on male infertility, as it is the main cause of urethritis and accessory gland inflammation in men. Sequelae of ascending infections might be occlusions in the canaliculi system of the genital tract, damage of the epi‐ thelial cells involved in spermatogenesis, and immunoreaction with the production of anti‐ sperm antibodies [60, 11]. Also, the relationship of *C. trachomatis* infection with semen quality and sperm morphology is still controversial [61, 62]. In men, are documented that *Chlamydia trachomatis* is responsible of epididymitis, orchitis, prostatitis and urethritis [63–66]. Then more, there are many evidence of that this infection cause sperm damage with low motility, altered morphology, and diminish of sperm concentration, with detriment of male fertility [67–71]. Sexually transmitted infections are hypothesized to play a role in the development of prostate cancer, perhaps due to inflammation‐induced oncogenesis [71]. Eventually, more evidence supports this affirmation. An investigation to evaluate the possible role of *Chlamydia trachomatis* in the pathogenesis of prostate cancer assessed the presence of this bacterium in prostate biopsies of patients with prostate cancer, patients with benign prostatic hyperplasia (BPH) and control subjects. Tissue sections were analyzed using a direct fluorescent‐anti‐ body (DFA) assay. When proliferative areas were compared, *C. trachomatis* was most fre‐ quently detected in prostate cancer group that in BPH patients (*p* = 0.006). In inflammation areas, *C. trachomatis* was most frequently detected in prostate cancer patients that in control subjects (*p* = 0.008). These data suggest an association between the presence of *C. trachomatis* and prostate cancer [72].

### **4. Mycoplasmataceae Genus**

#### **4.1. Biology and classification**

transmission from mother to child *in utero* was informed in several investigations [51–54]. These authors remark the risk to appear papillary lesions in oropharynx and larynx of new

The family Chlamydiaceae consists of two clinically important genera, *Chlamydia* and *Chlamydophila*, with three species responsible for human disease: *Chlamydia trachomatis*, *Chlamydophila psittaci*, and *Chlamydophila pneumoniae* [55]. *C. trachomatis*, as all the members of the family Chlamydiaceae, is an obligate intracellular parasite whose developmental cycle occurs within a eukaryotic host. Infection of eukaryotic host cells is initiated by the metaboli‐ cally inactive and the infectious elementary bodies (EBs). Through largely unknown mecha‐ nisms, EBs attach to and induce their internalization by host cells. Within the first few hours post infection, EBs differentiate to the larger and more pleomorphic reticulate bodies (RBs), which are metabolically active, noninfectious, and replicative. At the end of a successful

*Chlamydia trachomatis* is the most prevalent sexually transmitted bacterial infection, recog‐ nized worldwide, which causes a wide spectrum of diseases, including salpingitis, endo‐ metritis, and uterine, cervical lesions with scarring process, which often causes infertility in women [58]. Serotypes D‐K of *C. trachomatis* has an etiologic relation to pelvic inflammatory disease; it has been isolated from superior genital tract in a quarter of women with pelvic inflammation and is possible that chronic process would be in relation to ovarian cancer [59]. The role of *C. trachomatis* with regard to inducing male factor infertility is a matter of debate. Chlamydial infection could potentially exert a strong influence on male infertility, as it is the main cause of urethritis and accessory gland inflammation in men. Sequelae of ascending infections might be occlusions in the canaliculi system of the genital tract, damage of the epi‐ thelial cells involved in spermatogenesis, and immunoreaction with the production of anti‐ sperm antibodies [60, 11]. Also, the relationship of *C. trachomatis* infection with semen quality and sperm morphology is still controversial [61, 62]. In men, are documented that *Chlamydia trachomatis* is responsible of epididymitis, orchitis, prostatitis and urethritis [63–66]. Then more, there are many evidence of that this infection cause sperm damage with low motility, altered morphology, and diminish of sperm concentration, with detriment of male fertility [67–71]. Sexually transmitted infections are hypothesized to play a role in the development of prostate cancer, perhaps due to inflammation‐induced oncogenesis [71]. Eventually, more evidence supports this affirmation. An investigation to evaluate the possible role of *Chlamydia trachomatis* in the pathogenesis of prostate cancer assessed the presence of this bacterium in prostate biopsies of patients with prostate cancer, patients with benign prostatic hyperplasia

developmental cycle, the cell lyses, releasing the EBs [56, 57].

born from mothers infected by HPV.

184 Fundamentals of Sexually Transmitted Infections

**3. Chlamydia trachomatis**

**3.1. Biology and classification**

**3.2. Medical relevance**

Mycoplasma are microorganisms derived from Gram‐positive bacteria characterized by: streamlined and very small genome, the absence of a cell wall, requiring cholesterol for mem‐ brane function and growth, and displaying genetic economy that determine a strict depen‐ dence of the host for nutrients and refuge [73, 74]. They have a parasitic lifestyle, invading target cells and existing and replicating for extended periods intracellularly [75]. From 200 species established into class Mollicutes, six of them: *Ureaplasma urealyticum*, *Mycoplasma homi‐ nis*, *Mycoplasma genitalium*, *Mycoplasma primatum*, *Mycoplasma spermatophilum* and *Mycoplasma penetrans* have like their main site of colonization, the genital tract [76]. These microorganisms can be commensal in low genitourinary tract of sexually active men and women and can live in close relationship to mammalian cells. Nevertheless, they may cause disorders and pathologies associated with infertility: non‐gonococcal and non‐chlamydial, epididymitis, urolitiasis, as well with reproductive problems and infertility [77–84].

#### **4.2. Medical relevance**

Gnarpe and Friberg in early seventies informed for the first time a high percentage (85%) of infertile patients with *Ureaplasma urealyticum* isolated from semen by specific culture, com‐ pared to low percentage (22%) in fertile men. Then, these authors showed by scanning elec‐ tron microscopy, Mycoplasma adhered to sperm tail [85]. Similar observation was done in the following years by different authors [86–90]. The use of PCR techniques confirmed the presence of *Ureaplasma urealyticum* in seminal samples of subfertile men with sperm altera‐ tions [62, 91, 92]. Since two before decade, had been affirm that Mycoplasma have carcino‐ genic potential due to the long latency an infection chronicity that may induce malignant cellular transformation [93]. Recently, experimental studies demonstrated induction of genic expression altered in prostatic and cervical cells and progression to malignant transforma‐ tion [94, 95]. *Mycoplasma hominis* and *Mycoplasma hyorhinis*, a mycoplasma frequently present in patients with AIDS, induce malignant transformation with increased karyotypic entropy, chromosomal aberrations and polysomy, in BPH‐1 cells, after 9 months that were infected with these germs [96]. These observation had been supported a relationship between prosta‐ titis and cancer, in etiologic association referred in 2002 [97].

## **5. Mechanism of genital coinfection by HPV,** *chlamydia trachomatis* **and**  *mycoplasmas*

The cervical overlaying columnar epithelia can be invaded by *Ureaplasma urealyticum* and *Chlamydia trachomatis* that produce severe inflammatory response, with discharge of exuda‐ tive secretions and clinical signs and symptoms [98, 99]. Nevertheless, usually the appro‐ priated diagnostic test will not be applied, and the treatment generally is unspecific. The presence of inflammatory cells in the genital ducts enhances the adherence of virus [100, 101], and *Chlamydia trachomatis* has been considered an enhancer to the entry of human immuno‐ deficiency virus and HPV, the only one germ directly associated with the etiology of cervi‐ cal cancer [101–104]. Several studies have demonstrated an association between *Chlamydia trachomatis* and a high risk HPV persistence [105, 106]. A study realized by Paba et al., (2008), in patients with intraepithelial neoplasia or cervical cancer, confirmed the association of *Chlamydia trachomatis* and multiple high risk HPV persistence, and like a consequence of viral integration, inhibition of cell apoptosis, overexpression of E6/E7 oncogenes and cellular trans‐ formation [107].

## **6. Our experience**

#### **6.1. Studies on male infectious factor of infertility**

Our group has reported different studies in couples with infertility of unknown etiology, from northeast Mexico. In that patients with spontaneous and recurrent abortion and failure in assisted reproduction treatments, was frequently detected the presence in seminal fluid, urethral swab and cervix and vagina secretions, of *Chlamydia trachomatis* and *Ureaplasma urealyticum,* and *Mycoplasma hominis*. The diagnosis of *Chlamydia trachomatis* was made by direct immunofluores‐ cence, the gold standard for this microorganism for a long of time. For detection of *Ureaplasma urealyticum* and *Mycoplasma sp.,* we practiced specific media culture, considered too, the gold standard. In morphologic seminal analysis, we described the presence of elementary bodies and inclusion vacuoles of Chlamydia and bacterial particles similar to Mycoplasmas, inside the cytoplasm, adhered to the principal piece and into the middle piece of the sperm [108].

A pattern of structural sperm alteration and inflammatory reaction with sperm phagocyto‐ sis, by leucocytes and macrophages, were described by semi thin section at light microscopy and thin section by transmission electron microscopy [109–113]. Beside this the infectious process result a diminish motility, vitality, linear movement and sperm concentration. These seminal parameters were associated with high levels of sperm chromatin fragmentation (SCD test), and high levels of reactive oxygen species (ROS) detected by NBT test. The antibiotic, antioxidant and drugs against the inflammation treatment determine the reduction of bacte‐ riospermia, increase percentage of normal sperm, especially from acrosome damage, middle piece flagellum and nuclear defects. After 6 weeks of treatment, the probability of outcome of pregnancy with healthy newborn increased, and seminal parameters of predictive value were chromatin fragmentation, bacteriospermia and head sperm anomalies [114–117].

#### **6.2. Studies on female infectious factor of infertility**

**5. Mechanism of genital coinfection by HPV,** *chlamydia trachomatis* **and**

The cervical overlaying columnar epithelia can be invaded by *Ureaplasma urealyticum* and *Chlamydia trachomatis* that produce severe inflammatory response, with discharge of exuda‐ tive secretions and clinical signs and symptoms [98, 99]. Nevertheless, usually the appro‐ priated diagnostic test will not be applied, and the treatment generally is unspecific. The presence of inflammatory cells in the genital ducts enhances the adherence of virus [100, 101], and *Chlamydia trachomatis* has been considered an enhancer to the entry of human immuno‐ deficiency virus and HPV, the only one germ directly associated with the etiology of cervi‐ cal cancer [101–104]. Several studies have demonstrated an association between *Chlamydia trachomatis* and a high risk HPV persistence [105, 106]. A study realized by Paba et al., (2008), in patients with intraepithelial neoplasia or cervical cancer, confirmed the association of *Chlamydia trachomatis* and multiple high risk HPV persistence, and like a consequence of viral integration, inhibition of cell apoptosis, overexpression of E6/E7 oncogenes and cellular trans‐

Our group has reported different studies in couples with infertility of unknown etiology, from northeast Mexico. In that patients with spontaneous and recurrent abortion and failure in assisted reproduction treatments, was frequently detected the presence in seminal fluid, urethral swab and cervix and vagina secretions, of *Chlamydia trachomatis* and *Ureaplasma urealyticum,* and *Mycoplasma hominis*. The diagnosis of *Chlamydia trachomatis* was made by direct immunofluores‐ cence, the gold standard for this microorganism for a long of time. For detection of *Ureaplasma urealyticum* and *Mycoplasma sp.,* we practiced specific media culture, considered too, the gold standard. In morphologic seminal analysis, we described the presence of elementary bodies and inclusion vacuoles of Chlamydia and bacterial particles similar to Mycoplasmas, inside the

cytoplasm, adhered to the principal piece and into the middle piece of the sperm [108].

chromatin fragmentation, bacteriospermia and head sperm anomalies [114–117].

A pattern of structural sperm alteration and inflammatory reaction with sperm phagocyto‐ sis, by leucocytes and macrophages, were described by semi thin section at light microscopy and thin section by transmission electron microscopy [109–113]. Beside this the infectious process result a diminish motility, vitality, linear movement and sperm concentration. These seminal parameters were associated with high levels of sperm chromatin fragmentation (SCD test), and high levels of reactive oxygen species (ROS) detected by NBT test. The antibiotic, antioxidant and drugs against the inflammation treatment determine the reduction of bacte‐ riospermia, increase percentage of normal sperm, especially from acrosome damage, middle piece flagellum and nuclear defects. After 6 weeks of treatment, the probability of outcome of pregnancy with healthy newborn increased, and seminal parameters of predictive value were

*mycoplasmas*

186 Fundamentals of Sexually Transmitted Infections

formation [107].

**6. Our experience**

**6.1. Studies on male infectious factor of infertility**

After confirming that a very high percentage of couples in northern Mexico with incapacity to procreate, have *Chlamydia trachomatis* and *Ureaplasma urealyticum* infections in the ducts and organs of the seminal tract, associated with detrimental damage of fertilization capacity of the sperm, we studied the endometrium histopathology and *endometrialis bacteria.* Although endometritis is included into the internal genital infection, present in a high percentage of infertile couples, the study of endometrial biopsy is out of the diagnostic routine evaluation of infertility female factor. Microscopic analysis was performed on paraffin embedded and H&E stained tissue sections, observed at 1000X. In all the cases, it was possible to recognize, the presence of bacterial particles, identified according to their morphology, such as Chlamydia or Ureaplasma, which were previously diagnosed in genital secretions. The most frequent histopathologic findings at the endometrial tissue were interstitial edema (93%), lymphocytic and polymorphonuclear subepithelial infiltrate (72%) and in 48%, plasmocytic subepithelial infiltrate. The cell denudation of the lining epithelia was observed in 69% of biopsies, and in 62% of them, intracytoplasmic vacuole of epithelial cells, known as spongiosis, was observed. In a low percentage of cases, intraepithelial inflammatory cells (lymphocytes and polymor‐ phonuclears) were found at the endometrium, both lining and glandular epithelia. Germinal center of inflammatory cells in the connective stroma also was observed. The concluding results of this study showed the invading endometrium with *Chlamydia trachomatis* and *Ureaplasma urealyticum* that were present too, into the mucus of uterine cavity and cervical duct. In view of glandular and stromal changes, inflammatory reaction and presence of bac‐ teria into the stromal tissue and glandular and lining epithelia, endometritis due to *Chlamydia trachomatis* and *Ureaplasma urealyticum*, should be considered like an adverse condition to the female fertility as well implantation and normal embryo development. The clinician must consider the study of endometrial biopsy in all patients that need evaluation for infertility, even more if signs and symptoms of internal genital infection or chronic inflammatory pro‐ cess are present. Early diagnosis of genital infection and laboratory test performance looking for *Chlamydia trachomatis* and *Ureaplasma urealyticum* and its corresponding treatment could be prevent reproductive failure and scarring injuries and maybe can improve the results of reproduction treatments [118, 119]. While male genital infection by *Chlamydia trachomatis and Ureaplasma urealyticum* is generally asymptomatic, the women have a variable signs and symptoms of the sick, and clinical improvement is easier to appreciate; in male, their low and subtle clinical signs of infection and the treatment results can be see only by the study of seminal parameters in relation to the infection. For some years, we have focused on the investigation of the clinical and pathogenic aspects of the internal genital infections as well as the integral therapeutic management of male and female reproductive pathologies named as treatment of "binomials gineco‐andrologic" of the infectious factor of Infertility [120, 121].

#### **6.3. Study of HPV in infertile couples**

In addition of sexually transmission of *Chlamydia trachomatis and Ureaplasma urealyticum*, along the clinical evaluation, is necessary to be in alert to another sexually transmitted germ. This chapter focuses on the results of the first work that we carried out about the importance of the presence of HPV in the population with infectious factor of infertility. The aim of this analysis was to establish the HPV and genotype prevalence, the relationship of HPV presence with other microorganism, and to describe clinical findings of the studied group of patients.

#### *6.3.1. Patients, material and methods*

#### *<IP_ADDRESS>. Study population*

For the present analysis, samples of mucous secretion from cervix and vagina and endocervi‐ cal scrapes of 104 women randomly selected women, from patients attended at private clinic in Monterrey, México, for infertility and genitourinary infection since 2003–2014. Patients were recruited by verbal invitation at the time of consultation. They gave voluntary authori‐ zation, by Informed consent, to use the clinical data and results of the laboratory test for sta‐ tistical analysis. Ethical issues were in accordance with the Helsinki Declaration and endorsed by the Ethics Committee of our institution (PA15‐001). All selected patients had polymerase chain reaction (PCR) test for HPV in genital secretions and were tested by direct specimen test Kit for *Chlamydia trachomatis* detection (MicroTrak; Trinity Biotech, Wicklow, Ireland); the isolation of *Ureaplasma urealyticum* and *Mycoplasma hominis* was done using the Mycoplasma IST kit (BioMerieux, Marcy L' Etoile, France). For any other microorganism, we applied gen‐ eral culture.

#### *<IP_ADDRESS>. Clinical assessment*

An infertility medical history was taken and recorded on a standardized form by a single experienced clinician, who also performed external genital, vaginal exploration, pelvic examinations and realized the sampling of genital secretions. The data obtained from medi‐ cal file were: demographic parameters, history of fertility and infertility, gestational losses and obstetric complications, treatment of infertility problems, history of cervical lesions, and surgical procedures, result of previous cervical‐vaginal cytology Pap smears, signs and symp‐ toms of genitourinary infections and pathological data of the cervix and vagina examina‐ tion. At subjective appreciation, the clinical parameters were considered for semiquantitative record: low, medium, and high or abundant.

#### *<IP_ADDRESS>. HPV DNA extraction and genotyping*

For the extraction and purification of DNA from cervical samples, 100 μL of the cell suspen‐ sion previously prepared was used. Silica extraction columns (Nucleospin® Blood, Machery‐ Nagel GmBH & Co., Germany) were used under the manufacturer's instructions. During the 12 years covered by this study, the technology for HPV diagnosis was changing. For this reason, different techniques were applied depending on the time when the patient arrives for medical treatment. In 34 patients, molecular detection of HPV‐AND was carried out by PCR‐Multiplex that detect 4–12 genotypes; for 36 patients, secretions from the cervix and vagina were tested for HPV capillary electrophoresis using "Applied Biosystems 3130 series genetic analyzer systems" and the software GeneMapper, which diagnostic 14–19 genotypes high and low risk. Molecular detection of ADN from HPV was done in the 36 patients by Dual Priming Oligonucleotide, more specific and that detect 14–19 genotypes of HPV and in the 34 last patients *in situ* Hybridization with oligo specific probes to identified 20–28 HPV genotypes.

#### *<IP_ADDRESS>. Statistical analysis*

of the presence of HPV in the population with infectious factor of infertility. The aim of this analysis was to establish the HPV and genotype prevalence, the relationship of HPV presence with other microorganism, and to describe clinical findings of the studied group of patients.

For the present analysis, samples of mucous secretion from cervix and vagina and endocervi‐ cal scrapes of 104 women randomly selected women, from patients attended at private clinic in Monterrey, México, for infertility and genitourinary infection since 2003–2014. Patients were recruited by verbal invitation at the time of consultation. They gave voluntary authori‐ zation, by Informed consent, to use the clinical data and results of the laboratory test for sta‐ tistical analysis. Ethical issues were in accordance with the Helsinki Declaration and endorsed by the Ethics Committee of our institution (PA15‐001). All selected patients had polymerase chain reaction (PCR) test for HPV in genital secretions and were tested by direct specimen test Kit for *Chlamydia trachomatis* detection (MicroTrak; Trinity Biotech, Wicklow, Ireland); the isolation of *Ureaplasma urealyticum* and *Mycoplasma hominis* was done using the Mycoplasma IST kit (BioMerieux, Marcy L' Etoile, France). For any other microorganism, we applied gen‐

An infertility medical history was taken and recorded on a standardized form by a single experienced clinician, who also performed external genital, vaginal exploration, pelvic examinations and realized the sampling of genital secretions. The data obtained from medi‐ cal file were: demographic parameters, history of fertility and infertility, gestational losses and obstetric complications, treatment of infertility problems, history of cervical lesions, and surgical procedures, result of previous cervical‐vaginal cytology Pap smears, signs and symp‐ toms of genitourinary infections and pathological data of the cervix and vagina examina‐ tion. At subjective appreciation, the clinical parameters were considered for semiquantitative

For the extraction and purification of DNA from cervical samples, 100 μL of the cell suspen‐ sion previously prepared was used. Silica extraction columns (Nucleospin® Blood, Machery‐ Nagel GmBH & Co., Germany) were used under the manufacturer's instructions. During the 12 years covered by this study, the technology for HPV diagnosis was changing. For this reason, different techniques were applied depending on the time when the patient arrives for medical treatment. In 34 patients, molecular detection of HPV‐AND was carried out by PCR‐Multiplex that detect 4–12 genotypes; for 36 patients, secretions from the cervix and vagina were tested for HPV capillary electrophoresis using "Applied Biosystems 3130 series genetic analyzer systems" and the software GeneMapper, which diagnostic 14–19 genotypes high and low risk. Molecular detection of ADN from HPV was done in the 36 patients by

*6.3.1. Patients, material and methods*

188 Fundamentals of Sexually Transmitted Infections

*<IP_ADDRESS>. Study population*

eral culture.

*<IP_ADDRESS>. Clinical assessment*

record: low, medium, and high or abundant.

*<IP_ADDRESS>. HPV DNA extraction and genotyping*

Absolute frequency of qualitative parameters is expressed in percentages. For quantitative variable was calculated media and, or median as well standard deviation. Sensitivity, specific‐ ity, positive and negative predictive values were calculated using (2 × 2) contingency tables. The association between clinical results and HPV and the association between other micro‐ organisms present were calculated with Fisher's exact test. For all tests, the significance level was P ≤ 0.05 and power of (1‐β) = 80% for two‐tail. The statistical software used was SPSS version 17 for Windows (SPSS Inc.)

#### *6.3.2. Results*

From 690 infertile couples attended from 2003 to 2012, the aleatory selected sample of 104 female partners was representative, according to medium probability ponderation of 48% for the different genotypess, that was estimated based in some reports [122]. A total of 104 female partners from couples with genitourinary infection were included in this study. Primary infertility was present in 65 couples and secondary infertility in 13 couples. The median age of the patients was 34 years (range, 22–55 years). The microorganisms identified on the group studied are *C. trachomatis* (86.5%), HPV (49%), *U. urealyticum* (47.11%), *M. Hominis* (35.57%), *E. coli* (20.2%), *C. Albicans* (17.3%) and *S. faecalis* (10.6%). In a high proportion of the vaginal samples, microbiota vaginal was reduced or absent in a (76.9%) and 86% have more than one pathogen germs. *C albicans* was present like solitary microorganism in 17.3% as well HPV was the only identified germ in one patient. Statistical analysis established positive correlation between HPV and *U. urealyticum* (p = 0.05) and decreased microbiota (p = 0.001).

The distribution of *C. trachomatis* was similar in the positive and negative to HPV group (**Figure 1**).

Between the clinical parameters taken into account for this investigation, some of them pre‐ sented statistics correlation to the presence of HPV: the presence of more than one sexual part‐ ner (p = 0.05), genitourinary infection symptoms (p = 0.01), white mucous vaginal secretion fluxing from the uterine duct (p = 0.05), failure in assisted reproduction previously carried out (p ≤ 0.0001), and previous HPV infection diagnosed by suspicious lesion or cytological exam (p ≤ 0.0001) was in association to HPV (**Table 1**). For *Microbiota vaginalis*, the relationship to the presence of HPV was proportionally inversed.

Prevalent genotypes of HPV detected in the infertile patients studied group were; HPVar 6 (19.2%), HPVhr 18 (12.5%), HPVhr 16 (11.6%), HPVhr 58 (11.1%), HPVhr 52 (7.1%), HPVlr 11 (6.7%) and HPVhr 68 (7.5%). Thirteen different genotypes of PVH were detected in low fre‐ quency. These data are concentrated on **Table 2**. To consider the percentage of this frequency, it is necessary to remember that the results depend on the number of HPV search in each one of the three different tests applied that was not equal for all patients.

**Figure 1.** Microorganism identified into the cervix and vagina secretions of 104 female partners from couples with genitourinary infection. The most frequent bacteria in the genital sample of infertile women studied were *Chlamydia trachomatis*. However, if we considered that *Ureaplasma urealyticum* and *Mycoplasma hominis* belong to the same genus: Mycoplasmataceae, the presence of these bacteria, result of major importance in this group.

Combinations of more than one HPV genotypes were detected in 60% on the studied samples. From them 46.3% were the following associations between high risk for cancer HPV: 16/18, 18/58, 16/33, 16/52 and 18/52. In a similar percentage (44.8%) of women, low risk for cancer, principally HPV 6, was detected in combination with high risk HPV: 18, 52, 16 and 39. As well, we observed that three to five different HPV genotypes were present in 23.5% of the positive group infertile patients (**Figure 2**).

According to the results of this study, a total of 79.5% of positive HPV group of patients, pre‐ sented one or more high‐risk genotypes, and considering the statistical association between the positivity to HPV and the clinical history of previous HPV infections, this condition may represent a persistent infection or a reinfection. Consequently, we consider convenient a rec‐ ommendation to take in account women with reproductive failure, like a group of risk of cervical cancer. There was statistical association between the positivity to HPV to clinical his‐ tory of previous HPV infections. Would be very important, the simultaneously presence with *Ureaplasma urealyticum*, and *Chlamydia trachomatis*, sexually transmitted germs with suspi‐ cious carcinogenic potential, in a population in reproductive age, as we observed in this study.

With the results obtained from this study, it was not possible to establish an association between the abortions presented in 28 of the studied women, and the positivity to HPV. Nevertheless for future studies that include a high number of patients, is may be important to observe that low risk to cancer genotypes 6 and 11, were present in a high prevalence in this investigation, and their importance on the results of inseminations, in vitro fertilization and gestational loss, and are not defined now a days. Finally, our data confirm the recommendation to investigate HPV before to carry out *in vitro* fertilization, in view of the high frequency of failure of this treatment of infertility, when HPV is present.

Infection by Human Papillomavirus (HPV), Chlamydia trachomatis and Ureaplasma urealyticum, in Relation... http://dx.doi.org/10.5772/intechopen.68696 191

The most frequent bacteria in the genital sample of infertile women studied were *Chlamydia trachomatis*. However, if we considered that *Ureaplasma urealyticum* and *Mycoplasma hominis* belong to the same genus: Mycoplasmataceae, the presence of these bacteria, result of major importance in this group.

**Table 1.** Microbiological and clinical data associated with HPV.

Combinations of more than one HPV genotypes were detected in 60% on the studied samples. From them 46.3% were the following associations between high risk for cancer HPV: 16/18, 18/58, 16/33, 16/52 and 18/52. In a similar percentage (44.8%) of women, low risk for cancer, principally HPV 6, was detected in combination with high risk HPV: 18, 52, 16 and 39. As well, we observed that three to five different HPV genotypes were present in 23.5% of the positive

**Figure 1.** Microorganism identified into the cervix and vagina secretions of 104 female partners from couples with genitourinary infection. The most frequent bacteria in the genital sample of infertile women studied were *Chlamydia trachomatis*. However, if we considered that *Ureaplasma urealyticum* and *Mycoplasma hominis* belong to the same genus:

Mycoplasmataceae, the presence of these bacteria, result of major importance in this group.

According to the results of this study, a total of 79.5% of positive HPV group of patients, pre‐ sented one or more high‐risk genotypes, and considering the statistical association between the positivity to HPV and the clinical history of previous HPV infections, this condition may represent a persistent infection or a reinfection. Consequently, we consider convenient a rec‐ ommendation to take in account women with reproductive failure, like a group of risk of cervical cancer. There was statistical association between the positivity to HPV to clinical his‐ tory of previous HPV infections. Would be very important, the simultaneously presence with *Ureaplasma urealyticum*, and *Chlamydia trachomatis*, sexually transmitted germs with suspi‐ cious carcinogenic potential, in a population in reproductive age, as we observed in this study. With the results obtained from this study, it was not possible to establish an association between the abortions presented in 28 of the studied women, and the positivity to HPV. Nevertheless for future studies that include a high number of patients, is may be important to observe that low risk to cancer genotypes 6 and 11, were present in a high prevalence in this investigation, and their importance on the results of inseminations, in vitro fertilization and gestational loss, and are not defined now a days. Finally, our data confirm the recommendation to investigate HPV before to carry out *in vitro* fertilization, in view of the high frequency of failure of this

group infertile patients (**Figure 2**).

190 Fundamentals of Sexually Transmitted Infections

treatment of infertility, when HPV is present.

**Table 2.** Prevalent genotypes of HPV detected by PCR in secretions of cervix and vagina of infertile women studied group.

The following description will give an illustration of some of cases included in this study resume of microbiologic and gineco obstetric data are included at the **Figures 3**–**5**.

**Case 2.** Women 34 years, previously treated with five intrauterine inseminations and three *in vitro* fertilization (IVF) with intracytoplasmic sperm injection (ICSI). This patient had been treated repeatedly too, for genitourinary infection, unsuccessfully. After abnormal findings in a colposcopy, and histopathologic diagnosis of koilocyte in a cervix biopsy the clinician decide to practice hysterectomy, principally to solve the recurrent infections. One year later, these women required medical assistance due to severe signs and symptoms of genitouri‐ nary infection. In the vaginal sample were presented HPV 18, 35, 39, 51, 56, 66 y 74 (**Figure 3**). **Case 3.** Woman of 29 years old attended by primary infertility of unknown etiology and had been treated two times by assisted reproduction, with negative results. At the time of her arrive to the specially clinic, she referred previous result of ASCUS in PAP and signs and symptoms of genitourinary infection: dysuria, pelvic pain, abnormal menstrual bleeding, and a fluxing of white secretion from the vagina. At genital exploration, hypertrophy and erythema of cervix and papillary lesion at vaginal wall were found. The secretion of cervix and vagina was positive to *C. trachomatis*, *U. urealyticum* and *C. albicans*. PCR detected geno‐ types 16, 31, 33, 52, and 54 (**Figure 4**).

**Case 3.** Female 31 years, with two pregnancy loss of the first trimester, in both were diagnosed by ultrasound a chorionic vesicle without embryo. This patient did not have any fertility treat‐ ment previously. She had some PAP inform with inflammation but in one of them was diag‐ nosed metaplastic changes. Genital infection was clinically diagnosed, and multi‐microbial infection was detected in samples of secretions. (**Figure 4**). **Case 4.** A 37‐year‐old woman, who had a child without fertility treatment and did not have a second pregnancy, despite having no contraceptive treatment. This patient required medical assistance for chronic infection that was resistant to many treatments implemented previously. In this case were found HPV 44

The following description will give an illustration of some of cases included in this study

**Table 2.** Prevalent genotypes of HPV detected by PCR in secretions of cervix and vagina of infertile women studied

**Risk for cancer Patients studied for genotype Positive result**

 Low 66 63.5 2 3 High 69 66.3 3 4.3 High 69 66.3 1 1.4 High 73 69.2 1 1.4 High 73 69.2 1 1.4 Low 70 67.3 1 1.4 Low 69 66.3 1 1.4 Low 63 60.6 1 1.6 Low 1 1 1 –

**N % N %**

**Case 2.** Women 34 years, previously treated with five intrauterine inseminations and three *in vitro* fertilization (IVF) with intracytoplasmic sperm injection (ICSI). This patient had been treated repeatedly too, for genitourinary infection, unsuccessfully. After abnormal findings in a colposcopy, and histopathologic diagnosis of koilocyte in a cervix biopsy the clinician decide to practice hysterectomy, principally to solve the recurrent infections. One year later, these women required medical assistance due to severe signs and symptoms of genitouri‐ nary infection. In the vaginal sample were presented HPV 18, 35, 39, 51, 56, 66 y 74 (**Figure 3**). **Case 3.** Woman of 29 years old attended by primary infertility of unknown etiology and had been treated two times by assisted reproduction, with negative results. At the time of her arrive to the specially clinic, she referred previous result of ASCUS in PAP and signs and symptoms of genitourinary infection: dysuria, pelvic pain, abnormal menstrual bleeding, and a fluxing of white secretion from the vagina. At genital exploration, hypertrophy and erythema of cervix and papillary lesion at vaginal wall were found. The secretion of cervix and vagina was positive to *C. trachomatis*, *U. urealyticum* and *C. albicans*. PCR detected geno‐

**Case 3.** Female 31 years, with two pregnancy loss of the first trimester, in both were diagnosed by ultrasound a chorionic vesicle without embryo. This patient did not have any fertility treat‐ ment previously. She had some PAP inform with inflammation but in one of them was diag‐ nosed metaplastic changes. Genital infection was clinically diagnosed, and multi‐microbial infection was detected in samples of secretions. (**Figure 4**). **Case 4.** A 37‐year‐old woman, who had a child without fertility treatment and did not have a second pregnancy, despite having no contraceptive treatment. This patient required medical assistance for chronic infection that was resistant to many treatments implemented previously. In this case were found HPV 44

resume of microbiologic and gineco obstetric data are included at the **Figures 3**–**5**.

types 16, 31, 33, 52, and 54 (**Figure 4**).

**HPV genotype identified**

192 Fundamentals of Sexually Transmitted Infections

group.

**Figure 2.** HPV genotyping results: Combinations of HPV. The number inside the square represents the patients with at least two different genotypes HPV detected in cervical and vaginal secretions of the women studied. Inside the square is the number of cases identified with the combined presence in the sample of cervical secretion of different Genotype HPV. For example: 4 cases have a combination of 16 and 18 genotypes of HPVhr; another 4 cases have simultaneously HPVhr 16 and 58.

and HPV 52 in association to *C. trachomatis*, *U. urealyticum* that eventually may be an etiologic association to secondary infertility of this case. Then more, *S. faecalis* and *E.coli* were present as part of the microorganism found in genital secretions. *Lactobacillus acidophilus* was absent (**Figure 5**). **Case 5**. Another patient that not received infertility treatment, but do not have a baby, even to be active sexually and do not have protection contraceptive. This woman suffers urinary symptoms since 2 years ago, and clinical signs and symptoms of vaginal recurrent infection, resistant to previous treatments. The diagnostic test applied to vaginal and cervical fluids was positive to one of the most common HPV associations: 16 and 18, but HPV 39, *C. trachomatis*, *U. urealyticum* and *C*. *albicans* were part of the multiple germs infection (**Figure 5**).

**Figure 3.** Infertile women with chronic genitourinary infection, and failure in assisted reproduction. Case 1. The patient was treated by hysterectomy due to persistent infection, after several fruitless treatment of assisted reproduction for primary infertility. The images illustrate clinical, histopathological and HPV test in vaginal secretions. (A) Abnormal colposcopy; (B) koilocyte was found in the cervix biopsy; (C) arrow shows lesion on vaginal fundus; (D) results of PCR and HPV genotyping of vaginal secretions. Multiple HPV were present, except the 74 of unknown significance, all correspond a high risk for cancer genotype.

**Figure 4.** HPV genotypes combinations associated with genitourinary infection by multiple microorganisms.

**Figure 5.** HPV genotypes combinations associated with genitourinary infection by multiple microorganisms in infertile patients.

## **7. Concluding remarks**

**Figure 3.** Infertile women with chronic genitourinary infection, and failure in assisted reproduction. Case 1. The patient was treated by hysterectomy due to persistent infection, after several fruitless treatment of assisted reproduction for primary infertility. The images illustrate clinical, histopathological and HPV test in vaginal secretions. (A) Abnormal colposcopy; (B) koilocyte was found in the cervix biopsy; (C) arrow shows lesion on vaginal fundus; (D) results of PCR and HPV genotyping of vaginal secretions. Multiple HPV were present, except the 74 of unknown significance, all

**Figure 4.** HPV genotypes combinations associated with genitourinary infection by multiple microorganisms.

correspond a high risk for cancer genotype.

194 Fundamentals of Sexually Transmitted Infections

This is a study carried out by aleatory selection of 104 infertile women attended by repro‐ ductive failure and genital infection; the main objective was to establish the relationship of HPV presence, with other microorganism and the genotype of HPV detected in this group of infertile women. All patients authorized the use of clinic and laboratory analysis data from her cervical and vaginal samples, to realize statistical analysis and sign an informed consent. The clinical parameters considered were: signs and symptoms of infection disease, results of previous assisted reproduction treatments, and the presence of previous abortions. These data were compared to genotype HPV present, and the diagnosis of others germs by labora‐ tory test included direct investigation with immunofluorescence monoclonal antibodies to *Chlamydia trachomatis,* and bacterial cultures, included selective media to *U. urealyticum*, *M. hominis*. The microorganisms identified on the group studied are *C. trachomatis* (86.5%), HPV (49%), *U. urealyticum* (47.11%), *M. Hominis* (35.57%), *E. coli* (20.2%), *C. Albicans* (17.3%) and *S. faecalis* (10.6%). In a high proportion of the vaginal samples, microbiota vaginal was reduced or absent in a (76.9%) and 86% have more than one pathogen germs. *C albicans* was present like solitary microorganism in 17.3% as well HPV was the only identified germ in one patient. Statistical analysis established positive correlation between HPV and *U. urealyticum* (p = 0.05), and decreased microbiota (p = 0.001). The distribution of *C. trachomatis* was similar in the posi‐ tive and negative to HPV group.

In this study, more than one sexual partner (p = 0.05), genitourinary infection symptoms (p = 0.01), white mucous vaginal secretion fluxing from the uterine duct (p = 0.05), failure in assisted reproduction before carry out, and previous HPV infection diagnosed by suspi‐ cious lesion or cytological exam (p ≤ 0.0001) were in association to HPV. Prevalent geno‐ types of HPV detected in the infertile patients studied group were HPV six (19.2%), HPV 18 (12.5%), HPV 16 (11.5%), HPV 58 (7.2%), HPV 52 (6.7%), HPV 11 (6.7%) and HPV 68 (7.5%). Combinations of more than one HPV genotypes were detected in 60% on the studied samples. From them, 46.3% were the following associations between high risk for cancer HPV: 16/18, 18/58, 16/33, 16/52 and 18/52. In a similar percentage (44.8%) of women, low risk for cancer, principally HPV 6, was detected in combination with high risk HPV: 18, 52, 16 and 39. As well, we observed that three to five different HPV genotypes were present in 23.5% of the positive group infertile patients. According to the results of this study, a total of 79.5% of positive HPV group of patients, presented one or more high risk genotypes, and considering the statistical association between the positivity to HPV and the clinical history of previous HPV infections, this condition may represent a persistent infection or a reinfection. Consequently, we consider convenient a recommendation to take in account women with reproductive failure, like a group of risk of cervical cancer. With the results obtained from this study, was not possible to establish an association between the abortions presented on 28 of the studied women, and the positivity to HPV. Nevertheless for future studies that include a high number of patients, is may be important to observe that low risk to cancer genotypes 6 and 11, were present in a high prevalence in this investigation, and their importance on the results of inseminations, *in vitro* fertilization and gestational loss, still not defined now a days.

## **Acknowledgements**

Authors acknowledge to"Center for Research and Development in Health Sciences (CIDICS) of Autonomous University of Nuevo León", for their assessment in molecular test for HPV, C. trachomatis and U. urealyticum, and for the financial support to this publication.

### **Author details**

Adriana Ancer‐Arellano1 , Jesus Ancer‐Rodríguez<sup>1</sup> , David Hardisson2 , Alberto Niderhauser‐ Garcia<sup>1</sup> , Jose Sanchez‐Hernández3 , Alvarez‐Cuevas Salomón<sup>1</sup> and Guadalupe Gallegos‐Avila3 \*

\*Address all correspondence to<EMAIL_ADDRESS>
1 Faculty of Medicine, Department of Pathology, Autonomous University of Nuevo León, México

2 Department of Pathology, Hospital Universitario La Paz, Faculty of Medicine, Universidad Autonoma de Madrid, Madrid, Spain

3 Sertoli Lab Asociados, Civil Association, Monterrey, Nuevo León, México

## **References**

In this study, more than one sexual partner (p = 0.05), genitourinary infection symptoms (p = 0.01), white mucous vaginal secretion fluxing from the uterine duct (p = 0.05), failure in assisted reproduction before carry out, and previous HPV infection diagnosed by suspi‐ cious lesion or cytological exam (p ≤ 0.0001) were in association to HPV. Prevalent geno‐ types of HPV detected in the infertile patients studied group were HPV six (19.2%), HPV 18 (12.5%), HPV 16 (11.5%), HPV 58 (7.2%), HPV 52 (6.7%), HPV 11 (6.7%) and HPV 68 (7.5%). Combinations of more than one HPV genotypes were detected in 60% on the studied samples. From them, 46.3% were the following associations between high risk for cancer HPV: 16/18, 18/58, 16/33, 16/52 and 18/52. In a similar percentage (44.8%) of women, low risk for cancer, principally HPV 6, was detected in combination with high risk HPV: 18, 52, 16 and 39. As well, we observed that three to five different HPV genotypes were present in 23.5% of the positive group infertile patients. According to the results of this study, a total of 79.5% of positive HPV group of patients, presented one or more high risk genotypes, and considering the statistical association between the positivity to HPV and the clinical history of previous HPV infections, this condition may represent a persistent infection or a reinfection. Consequently, we consider convenient a recommendation to take in account women with reproductive failure, like a group of risk of cervical cancer. With the results obtained from this study, was not possible to establish an association between the abortions presented on 28 of the studied women, and the positivity to HPV. Nevertheless for future studies that include a high number of patients, is may be important to observe that low risk to cancer genotypes 6 and 11, were present in a high prevalence in this investigation, and their importance on the results of inseminations, *in*

Authors acknowledge to"Center for Research and Development in Health Sciences (CIDICS) of Autonomous University of Nuevo León", for their assessment in molecular test for HPV, C.

, Alvarez‐Cuevas Salomón<sup>1</sup>

1 Faculty of Medicine, Department of Pathology, Autonomous University of Nuevo León,

2 Department of Pathology, Hospital Universitario La Paz, Faculty of Medicine, Universidad

, David Hardisson2

, Alberto Niderhauser‐

\*

and Guadalupe Gallegos‐Avila3

trachomatis and U. urealyticum, and for the financial support to this publication.

, Jesus Ancer‐Rodríguez<sup>1</sup>

3 Sertoli Lab Asociados, Civil Association, Monterrey, Nuevo León, México

\*Address all correspondence to<EMAIL_ADDRESS>
*vitro* fertilization and gestational loss, still not defined now a days.

**Acknowledgements**

196 Fundamentals of Sexually Transmitted Infections

**Author details**

Garcia<sup>1</sup>

México

Adriana Ancer‐Arellano1

, Jose Sanchez‐Hernández3

Autonoma de Madrid, Madrid, Spain

[31] Syrjänen K. 2013: Detection of human papillomavirus in lung cancer: Systematic review and meta‐analysis. Anticancer Research. 2012;**32**:3235‐3250

[15] Anagrius C, Loré B, Jensen JS. *Mycoplasma genitalium*: Prevalence, clinical significance,

[16] Ross JD, Jensen JS. *Mycoplasma genitalium* as a sexually transmitted infection: Implications for screening, testing, and treatment. Sexually Transmitted Infections. 2006;**82**:269‐271

[17] Baczynska A, Funch P, Fedder J, Knudsen HJ, Birkelund S, Christiansen G. Morphology of human fallopian tubes after infection with *Mycoplasma genitalium* and *Mycoplasma*

[18] Manhart LE, Holmes KK, Hughes JP, Houston LS, Totten PA. *Mycoplasma genitalium* among young adults in the United States: An emerging sexually transmitted infection.

[19] Haedicke J, Iftner T. Human papillomaviruses and cancer. Radiotherapy and Oncology.

[20] Ghittoni R, Accardi R, Chiocca S, Tommasino M. Role of human papillomaviruses in

[21] Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet‐Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012;**30** (Suppl

[22] Steben M, Duarte‐Franco E. Human papillomavirus infection: Epidemiology and patho‐

[23] Secretaría de Salubridad y Asistencia (SSA‐México). CENEVACE. Anuarios de Morbilidad 1984‐2010; CONAPO. Proyecciones de población en México 2005‐2050 [24] National Institute of Statistic and Geography of Mexico (*Consulte of 2 June, 2015* http://

[25] Longworth M, Laimins L. Pathogenesis of human papillomaviruses in differentiating

[26] Handisurya A, Day PM, Thompson CD, Buck CB, Kwak K, Roden RB, Lowy DR, Schiller JT. Murine skin and vaginal mucosa are similarly susceptible to infection by pseudovi‐ rions of different papillomavirus classifications and species. Virology. 2012;**433**:385‐394

[27] Dunne EF, Park IU. HPV and HPV‐associated diseases. Infectious Disease Clinics of

[28] zur‐Hausen H. Papillomaviruses and cancer: From basic studies to clinical application.

[29] Bhatla N, Puri K, Joseph E, Kriplani A, Iyer VK, Sreenivas V. Association of *Chlamydia trachomatis* infection with Human Papilloma Virus (HPV) and cervical intraepithelial

[30] Serman F. Cáncer cervicouterino: epidemio‐logía, historia natural y rol del virus del papiloma humano, perspectivas en prevencion y tratamiento. Rev Chil Obstet Ginecol.

neoplasia—A pilot study. Indian Journal of Medical Research. 2013;**137**:533‐539

epithelia. Microbiology and Molecular Biology Reviews. 2004;**68**:362‐372

*hominis in vitro*—Organ culture study. Human Reproduction. 2007;**22**:968‐979

and transmission. Sexually Transmitted Infections. 2005;**81**:458‐462

American Journal of Public Health. 2007;**97**:1118‐1125

carcinogenesis. Ecancer Medical Science. 2015;**9**:526

physiology. Gynecologic Oncology. 2007;**107** (Suppl 1):S2–S5

2013;**108**:397‐402

198 Fundamentals of Sexually Transmitted Infections

5):F12‐F23

www.inegi.org.mx)

2002;**67**:318‐323

North America. 2013;**27**:765‐778

Nature Reviews Cancer. 2002;**2**:342‐350

[56] Al‐Younes HM, Brinkmann V, Meyer TF. Interaction of Chlamydia trachomatis serovar L2 with the host autophagic pathway. Infection and Immunity. 2004;**72**:4751‐4762

[44] **Garolla** A, Pizzol D, Bertoldo A, De Toni L, Barzon L, Foresta C.: Association, prev‐ alence, and clearance of human papillomavirus and antisperm antibodies in infected

[45] Yang Y, Jia CW, Ma YM, Zhou LY, Wang SY.: Correlation between HPV sperm infection

[46] Connelly DA, Chan PJ, Patton WC, King A.: Human sperm deoxyribonucleic acid fragmentation by specific types of papilloma‐virus. American Journal of Obstetrics &

[47] Lee CA, Huang CT, King A, Chan PJ.: Differential effects of human papillomavirus DNA types on p53 tumor‐suppressor gene apoptosis in sperm. Gynecologic Oncology.

[48] Gomez LM, Ma Y, Ho C, McGrath CM, Nelson DB, Parry S.: Placental infection with human papillomavirus is associated with spontaneous preterm delivery. Human

[49] Skoczyński M, Gozdzicka‐Józefiak A, Kwaśniewska A.: Prevalence of human papilloma‐ virus in spontaneously aborted products of conception. Acta Obstetricia et Gynecologica

[50] Cho G, Min KJ, Hong HR, Kim S, Hong JH, Lee JK, Oh MJ, Kim H.: High‐risk human papillomavirus infection is associated with premature rupture of membranes. BMC

[51] Rintala MA, Grénman SE, Puranen MH, Isolauri E, Ekblad U, Kero PO, Syrjänen SM. Transmission of high‐risk human papilloma‐virus (HPV) between parents and infant?: A prospective study of HPV in families in Finland. Journal of Clinical Microbiology.

[52] Castellsagué X, Drudis T, Cañadas MP, Goncé A, Ros R, Pérez JM, et al. Human Papillomavirus (HPV) infection in pregnant women and mother‐to‐child transmis‐ sion of genital HPV genotypes: A prospective study in Spain. BMC Infectious Diseases.

[53] Freitas A, Mariz F, Silva A, Jesus A. Human papillomavirus vertical transmission:

[54] Koskimaa HM, Paaso AE, Welters MJ, Grénman SE, Syrjänen KJ, van der Burg SH, Syrjänen SM. Human papillomavirus 16 E2‐, E6‐ and E7‐specific T‐cell responses in children and their mothers who developed incident cervical intraepithelial neoplasia during a 14‐year follow‐up of the Finnish Family HPV cohort. Journal of Translational

[55] Murray PR, Rosenthal KS, Pfaller MA. Chlamydia and chlamydophila. Medical

Review of current data. Clinical Infectious Diseases. 2013;**56**:1451‐1456

Microbiology. 6th ed. Philadelphia, PA: Mosby Elsevier; 2009. p. 441

semen samples from infertile patients. Fertility and Sterility. 2013;**99**: 125‐131

and male infertility. Asian Journal of Andrology. 2013;**15**: 529‐532

Gynecology. 2001;**184**: 1068‐1070

200 Fundamentals of Sexually Transmitted Infections

Reproduction. 2008;**23**: 709‐715

Scandinavica. 2011;**90**: 1402‐1045

Pregnancy Childbirth. 2013;**13**: 173

2002;**85**: 511‐516

2005;**43**:376‐381

Medicine. 2014;**12**:44

2009;**9**: 74

[83] Volgmann T, Ohlinger R, Panzig B. *Ureaplasma urealyticum*‐harmless commensal or underestimated enemy of human reproduction? A review. Archives of Gynecology and Obstetrics. 2005;**273**:133‐139

[70] Bezold G, Politch JA, Kiviat NB, Kuypers JM, Wolff H, Anderson DJ. Prevalence of sexu‐ ally transmissible pathogens in semen from asymptomatic male infertility patients with

[71] De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG. Inflammation in prostate carcinogenesis. Nature Reviews Cancer.

[72] Gallegos‐Avila G, Sánchez JJ, Chávez‐Briones ML, Ramos‐González B, Niderhauser‐ García A, Ancer‐Rodríguez J, Ortega‐Martínez M, Jaramillo‐Rangel G. A role of *Chlamydia trachomatis* in prostate cancer: A prostate biopsies study. In: Berhardt LV, edi‐ tor. Advances in Medicine and Biology. Vol. 37. NY, USA: Nova Science Publishers, Inc.;

[73] Razin S. The genus Mycoplasma and related genera (class Mollicutes). In: Dworkin M, Falkow S, Rosenberg E, Schleifer KH, Stackebrandt E, editors. The Prokaryotes. A Handbook on the Biology of Bacteria. Volume 4: Bacteria: Firmicutes, Cyanobacteria.

[74] Baseman JB, Tully JG. Mycoplasmas: Sophisticated, reemerging, and burdened by their

[75] Dallo SF, Baseman JB. Intracellular DNA replication and long‐term survival of patho‐

[76] Uusküla A, Kohl PK. Genital mycoplasmas, including *Mycoplasma genitalium*, as sexu‐ ally transmitted agents. International Journal of STD & AIDS. 2002;**13**:79‐85

[77] Kilic D, Basar MM, Kaygusuz S, Yilmaz E, Basar H, Batislam E. Prevalence and treatment of *Chlamydia trachomatis, Ureaplasma urealyticum*, and *Mycoplasma hominis* in patients with non‐gonococcal urethritis. Japanese Journal of Infectious Diseases. 2004;**57**:17‐20

[78] Jensen JS. *Mycoplasma genitalium*: The etiological agent of urethritis and other sexu‐ ally transmitted diseases. Journal of the European Academy of Dermatology and

[79] Yoon BH, Chang JW, Romero R. Isolation of *Ureaplasma urealyticum* from the amniotic cavity and adverse outcome in preterm labor. Obstetrics & Gynecology. 1998;92:77‐82

[80] Denks K, Spaeth EL, Jõers K, Randoja R, Talpsep T, Ustav M, Kurg R. Coinfection of *Chlamydia trachomatis*, *Ureaplasma urea‐lyticum* and human papillomavirus among patients attending STD clinics in Estonia. Scandinavian Journal of Infectious Diseases.

[81] Dieterle S. Urogenital infections in reproductive medicine. Andrologia. 2008;**40**:117‐119

[82] Zeighami H, Peerayeh SN, Yazdi RS, Sorouri R. Prevalence of *Ureaplasma urealyticum* and *Ureaplasma parvum* in semen of infertile and healthy men. International Journal of STD

3rd ed. New York, NY: Springer Science+Business Media, LLC; 2006. p. 836

and without leukocytospermia. Fertility and Sterility. 2007;**87**:1087‐1097

2007;**7**:256‐269

202 Fundamentals of Sexually Transmitted Infections

2011. pp. 1‐13. ISBN: 978‐1‐62100‐102‐7

Venereology. 2004;**18**:1‐11

2007;**39**:714‐718

& AIDS. 2009;**20**:387‐390

notoriety. Emerging Infectious Diseases. 1997;**3**:21‐32

genic mycoplasmas. Microbial Pathogenesis. 2000;**29**:301‐309

[109] Gallegos‐Avila G, Ancer‐Rodriguez J, Alvarez‐Cuevas S, Ramos‐González B, Sanchez‐ Hernández J, Nistal M, Regadera J. Relevancy of semithin section on the analysis of seminal damage, due to infection by Chlamydia and Mycoplasma, in couples with unsuccessful assisted reproduction. In: Ballesca Lagarda JL, Oliva Virgili R, edi‐ tors. Papers contributed to 9th International Congress of Andrology. MEDIMOND International Proceedings. Barcelona, Spain; 2009, pp. 123‐128

[97] Dennis LK, Lynch CF, Turner JC. Epidemiologic association between prostatitis and

[98] Smith JS, Muñoz N, Herrero R, Eluf‐Neto J, Ngelangel C, Franceschi S, et al. Evidence for *Chlamydia trachomatis* as a human papilloma‐virus cofactor in the etiology of inva‐ sive cervical cancer in Brazil and the Philippines. The Journal of Infectious Diseases.

[99] Agrawal T, Vats V, Salhan S, Mittal A. Determination of chlamydial load and immune parameters in asymptomatic, symptomatic and infertile women. FEMS Immunology

[100] de Lucena‐Oliveira M, de Amorim MM, de Souza AS, de Albuquerque LC, da Costa AA. Chlamydia infection in patients with and without cervical intraepithelial lesions.

[101] Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: The contribution of other sexually transmitted diseases to sexual transmission

[102] Luostarinen T, Lehtinen M, Bjørge T, Abeler V, Hakama M, Hallmans G, et al. Joint effects of different human papillomaviruses and *Chlamydia trachomatis* infections on risk of squamous cell carcinoma of the cervix uteri. European Journal of Cancer.

[103] de Luca G, Marin M, Schelover E, Chamorro E, Vicente L, Albhom M, Alonso JM. Infeccion por Chlamydia trachomatis y Papilomavirus en mujeres con alteraciones cito‐

[104] European Centre for Disease Prevention and Control. Annual Epidemiological Report on Communicable Diseases in Europe. 2008. http://ecdc.europa.eu/en/publications/

[105] Samoff E, Koumans EH, Markowitz LE, Sternberg M, Sawyer MK, Swan D, Papp JR, Black CM, Unger ER. Association of *Chlamydia trachomatis* with persistence of high‐risk types of human papillomavirus in a cohort of female adolescents. American Journal of

[106] Silins I, Ryd W, Strand A, Wadell G, Törnberg S, Hansson BG, et al. *Chlamydia trachoma‐ tis* infection and persistence of human papilloma‐virus. International Journal of Cancer.

[107] Paba P, Bonifacio D, Di Bonito L, Ombres D, Favalli C, Syrjänen K, Ciotti M. Co‐expres‐ sion of HSV2 and *Chlamydia trachomatis* in HPV‐positive cervical cancer and cervical intraepithelial neoplasia lesions is associated with aberrations in key intracellular path‐

[108] Gallegos‐Ávila G. Estudio citológico del semen de hombres infértiles con infección genital por Chlamydia y Mycoplasma. Observaciones en cortes semifinos y ultrafinos

of HIV infection. Journal Sexually Transmitted Infections. 1999;**75**:3‐17

histologicas de cuello uterino. Medicina (B Aires). 2006;**66**:303‐306

Publications/0812\_SUR\_Annual\_Epidemiological\_Report\_2008.pdf

prostate cancer. Urology. 2002;**60**:315‐319

and Medical Microbiology. 2009:**55**:250‐257

Revista Da Associacao Medica Brasileira. 2008;**54**:506‐512

2002;**185**:324‐331

204 Fundamentals of Sexually Transmitted Infections

2004;**40**:1058‐1065

Epidemiology. 2005;**162**:668‐675

ways. Intervirology. 2008;**51**:230‐234

[thesis]. Universidad Autónoma de Madrid; 2005

2005;**116**:110‐115

**Section 6**

## **Refugee**

[119] Chávez‐Briones ML, Alvarez‐Cuevas S, Ramos‐González B, Casillas‐Vega N, Niderhauser‐García A, Ancer‐Rodríguez J, Hardisson‐Hernáez D, Gallegos‐Ávila MG. Endometritis por Chlamydia trachomatis y Ureaplasma urealyticum en mujeres con

[120] Gallegos Ávila MG, Ramos González B, Sánchez Hernández JJ, Niderhauser García A, Ancer Rodríguez J. Disminución de la teratozoospermia secundaria a tratamiento antibiótico en pacientes infértiles con infección urogenital ocasionada por *Chlamydia*

[121] Gallegos‐Ávila MG, Álvarez‐Cuevas S, Sánchez‐Hernández JJ, Niderhauser‐García A, Casillas‐Vega N, Ramos‐González B. Resultado del tratamiento del binomio Andro‐ Ginecológico en la infertilidad conyugal por infección genital interna. Andrology.

[122] Alberts CJ, Schim van der Loeff MF, Papenfuss MR, da Silva RJ, Villa LL, et al. Association of Chlamydia trachomatis infection and herpes simplex virus type 2 serostatus with genital human papillomavirus infection in men: the HPV in men study.

*trachomatis* y *Mycoplasma sp.* International Review of Andrology. 2011;

**5**(Suppl 1):1‐124

**9**:90

infertilidad y aborto. Medicina Universitaria. 2013;

Sexually Transmitted Diseases. 2013;**40**:508‐515

2013;**11**:1‐14

206 Fundamentals of Sexually Transmitted Infections

## **Communicable Diseases Among Refugees with a Focus on the Middle East**

Inaya Hajj Hussein, Ibrahim Mortada, Alice Gerges Geagea and Abdo Jurjus

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68901

#### **Abstract**

During the past few years, millions of refugees from the Middle East and North Africa fled their countries to almost everywhere in the globe. Civil wars and acts of violence are the main reasons behind the exodus of populations seeking a better life and more secure living conditions. In fact, the current conflict in Syria and Iraq led to massive influx of refugees worldwide and in particular to neighboring countries of the Middle East. This refugee situation is unparalleled since the end of World War II. Besides the individual tragedies of refugees, a public health disaster is being witnessed in the countries of origin which, in many instances, affect the hosting countries as well. Many of these hosting countries witnessed a re-emergence of numerous communicable diseases as a result of the influx of refugees; they were unprepared, and their health sectors did not deliver the adequate response. In this chapter, we review major sexually transmitted diseases in refugees, with a focus on the Middle East. We also discuss the major actions taken in response to the ongoing displacement of refugees by the Government of Lebanon and suggest solutions and recommendations to the Lebanese public health system which is facing new urgent challenges.

**Keywords:** STIs, refugees' health, communicable diseases, Middle East, Lebanon, Syrian refugees

## **1. Introduction**

During the past decade, millions of refugees worldwide, in particular from the Middle East, fled their home country. The United Nations reported that at the end of 2010, there were over 43 million people in the world displaced because of conflict or persecution [1]. The latest

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

counts conducted by the United Nations High Commissioner for Refugees (UNHCR) revealed that there have been 16,121,427 refugees by the end of 2015 [2]. Over half of the refugees worldwide came from Syria, Iraq, Afghanistan and Somalia and the top hosting countries were Turkey (2.5 millions), Pakistan (1.6 million), Lebanon (1.1 million) and Jordan (0.5 million) [3]. Refugees face multiple barriers in accessing healthcare and maintaining proper follow-ups, including lack of resources needed to cover expenses, cultural differences and lack of health care facilities in the regions of residence.

The purpose of this chapter is to shed light on the reproductive health of displaced people in the Middle East, including sexually transmitted diseases.

## **2. Health of refugees at the international level**

In the United States of America, 18,007 Syrian refugees were resettled between October 1, 2011 and December 31, 2016. Despite the huge resources in the United States of America, the establishment of Medicaid was not sufficient to assure that all refugees have been adequately screened for diseases and have access to proper medical care. In many states, it was difficult to find health clinics that were willing to provide regular appointments to refugees on Medicaid, especially since the services needed to encompass primary care and include specialty clinics and surgery [4].

Europe is experiencing one of the most significant influxes of migrants and refugees in its history. European countries received over 2 million asylum applications in 2015, which represent around a three-fold increase to the number of applications received in 2014 (709,757). Most applications were from Syria (675,668), Afghanistan (406,300) and Iraq (253,558). Around 60% of these applications (1.2 million) were received by European Union member states with Germany and Sweden receiving almost half of the total applications. The number of refugees entering Europe passed the 1 million mark in 2015, a long expected and symbolically significant capstone to a year in which displaced persons flocked to the continent in historic proportions [5].

History is rife with examples of infectious diseases that have been linked to human mobility and migration. Diseases and epidemics often accompanied commercial traders, sailors, pilgrims and other migrants to thrive in new and foreign environments [6]. One particularly famous example is the re-emergence of tuberculosis (TB) in Europe. While once considered a disease of the past, new cases of TB in Europe and the West are frequently attributed to the migration of people from endemic countries, such as Africa and India [7]. In some refugee settings, women and children are believed to comprise about 80% of the population, and they are the most vulnerable to the consequences of displacement, including rape, infectious diseases, and, in particular, sexually transmitted infections (STIs) [8]. In addition, sexual violence and poverty were highlighted as leading to an increase in the transmission of STIs, HIV/AIDS and unwanted and/or high-risk pregnancies. Many become disconnected from their relatives and from their traditional cultural and legal supports. Such issues also impact their reproductive health status. If the hosting countries do not provide adequate reproductive health care services, this could aggravate the situation through unwanted pregnancy and unsafe abortion. In addition, such refugees carry an important disease burden due to disease prevalence in their country of origin, disruption of immunization programs, or even exposure during migration [9].

## **3. Health of refugees at the regional and national levels**

counts conducted by the United Nations High Commissioner for Refugees (UNHCR) revealed that there have been 16,121,427 refugees by the end of 2015 [2]. Over half of the refugees worldwide came from Syria, Iraq, Afghanistan and Somalia and the top hosting countries were Turkey (2.5 millions), Pakistan (1.6 million), Lebanon (1.1 million) and Jordan (0.5 million) [3]. Refugees face multiple barriers in accessing healthcare and maintaining proper follow-ups, including lack of resources needed to cover expenses, cultural differences and lack of health

The purpose of this chapter is to shed light on the reproductive health of displaced people in

In the United States of America, 18,007 Syrian refugees were resettled between October 1, 2011 and December 31, 2016. Despite the huge resources in the United States of America, the establishment of Medicaid was not sufficient to assure that all refugees have been adequately screened for diseases and have access to proper medical care. In many states, it was difficult to find health clinics that were willing to provide regular appointments to refugees on Medicaid, especially since the services needed to encompass primary care and include specialty clinics

Europe is experiencing one of the most significant influxes of migrants and refugees in its history. European countries received over 2 million asylum applications in 2015, which represent around a three-fold increase to the number of applications received in 2014 (709,757). Most applications were from Syria (675,668), Afghanistan (406,300) and Iraq (253,558). Around 60% of these applications (1.2 million) were received by European Union member states with Germany and Sweden receiving almost half of the total applications. The number of refugees entering Europe passed the 1 million mark in 2015, a long expected and symbolically significant capstone to a year in which displaced persons flocked to the continent in