*4.1.2. PID and HIV*

A population-based study of fertility in women with human immunodeficiency virus type 1 (HIV-1) infection in Uganda demonstrated that fertility is greatly reduced in HIV-1-infected women because of a lower rate of conception and increased rates of miscarriage and stillbirth. Numerous epidemiologic studies have demonstrated that there is a synergy among bacterial and viral STDs. Bacterial STDs have been implicated in the enhancement of HIV transmission. Conversely, the immunosuppression caused by HIV worsens the clinical course of other STDs. The low prevalence and incidence of pregnancy among HIV-infected women could reflect preexisting tubal factor infertility and higher clinical and subclinical fetal losses resulting from HIV-1 infection.[21]

Pelvic inflammatory disease that is non-tubercular in origin can be divided into gonococcal, chlamydial, and nongonococcal-nonchlamydial disease based on the results of endocervical or peritoneal fluid cultures.

### **4.2. Gonococcal infection**

Gonococcal PID still a major cause of infertility in women in developing Asian and African countries.[22] The bacterium N. Gonorrhea (Figure 1) elicits a pyogenic, inflammatory reaction characterised by purulent exudates. As the organisms replicate, the ensuing local tissue damage diminishes the oxidation-reduction potential of the environment – this explains why it is common to discover co-existing pathogens.The recovery of *N. gonorrhoeae* from tubal or peritoneal fluid in acute salpingitis patients with endocervical gonorrhea ranges from 6% to 70%. Approximately one third of patients have *N. gonorrhoeae* as a sole isolate, one third have *N. gonorrhoeae* plus a mixture of aerobic and anaerobic bacteria, and one third have a mixture of aerobic and anaerobic bacteria in the cul-de-sac only.[23]

**Figure 1.** Neisseria Gonorrhea bacteria

*N. gonorrhoeae* secretes a toxin that can destroy cilia of adjacent cells in the tubal epithelium. Not only is the organism difficult to isolate from pus, but the recovery of *N. gonorrhoeae*depends on the stage of infection. The gonococcus is most frequently isolated within 2 days of the onset of symptoms and is rarely isolated if symptoms are present for 7 or more days.[24] Most symptomatic gonococcal PID cases have their onset during or just after the menses. These observations are consistent with the view that the gonococcus initiates the infection and, if the infection is not promptly treated, sets the stage for a mixed aerobic-anaerobic infection, involving pathogens that originate in the cervix and vagina.

#### **4.3. Chlamydial infection**

*4.1.2. PID and HIV*

8 Genital Infections and Infertility

HIV-1 infection.[21]

or peritoneal fluid cultures.

**4.2. Gonococcal infection**

**Figure 1.** Neisseria Gonorrhea bacteria

A population-based study of fertility in women with human immunodeficiency virus type 1 (HIV-1) infection in Uganda demonstrated that fertility is greatly reduced in HIV-1-infected women because of a lower rate of conception and increased rates of miscarriage and stillbirth. Numerous epidemiologic studies have demonstrated that there is a synergy among bacterial and viral STDs. Bacterial STDs have been implicated in the enhancement of HIV transmission. Conversely, the immunosuppression caused by HIV worsens the clinical course of other STDs. The low prevalence and incidence of pregnancy among HIV-infected women could reflect preexisting tubal factor infertility and higher clinical and subclinical fetal losses resulting from

Pelvic inflammatory disease that is non-tubercular in origin can be divided into gonococcal, chlamydial, and nongonococcal-nonchlamydial disease based on the results of endocervical

Gonococcal PID still a major cause of infertility in women in developing Asian and African countries.[22] The bacterium N. Gonorrhea (Figure 1) elicits a pyogenic, inflammatory reaction characterised by purulent exudates. As the organisms replicate, the ensuing local tissue damage diminishes the oxidation-reduction potential of the environment – this explains why it is common to discover co-existing pathogens.The recovery of *N. gonorrhoeae* from tubal or peritoneal fluid in acute salpingitis patients with endocervical gonorrhea ranges from 6% to 70%. Approximately one third of patients have *N. gonorrhoeae* as a sole isolate, one third have *N. gonorrhoeae* plus a mixture of aerobic and anaerobic bacteria, and one third have a mixture

of aerobic and anaerobic bacteria in the cul-de-sac only.[23]

*C. trachomatis*is an intracellular bacterium that proliferates in columnar epithelial cells, where it remains protected from host immune defences by a cell membrane. It takes a longer time for *C. trachomatis* to divide (24 to 48 hours) than for classic bacteria (1 to 4 hours). There is a characteristically long time between infection and the onset of symptoms among women with *C. trachomatis*, and only mild symptoms usually occur. Widespread or systemic symptoms are unusual, although infection of the endosalpinx can produce generalized peritonitis by contiguous spread, including perihepatitis (Fitz-Hugh-Curtis syndrome).

*Chlamydia* appears to be a particularly important organism in infertility. There are multiple published reports in which women with tubal infertility have a 25% to 70% higher incidence of *C. trachomatis* antibody than do infertile women with normal tubes.[25] In many developed countries, *C. trachomatis* infections are now clearly the leading cause of tubal infertility. *C. trachomatis* causes the same spectrum of disease (*e.g.* urethritis, cervicitis, endometritis, salpingitis) as the gonococcus. *C. trachomatis* causes salpingitis more frequently than the gonococcus. Also, the degree of acute tubal damage among women with chlamydial infection equals or exceeds that observed with gonococcal infection. Women with chlamydial infection may have gonorrhea and *vice versa.*

*C. trachomatis* is inhibited *in vitro* by doxycycline and azithromycin but not by cephalosporins. Women with salpingitis should be treated with tetracyclines or other antibiotics that inhibit *C. trachomatis*, because cephalosporin therapy alone does not eradicate *C. trachomatis*.[26] Lack of symptoms ensures that the undetected *C. trachomatis* are able to ascend from the lower to the upper genital tract, evade the host's immune response and persist for long periods of time.

Figure 2 shows the life cycle of Chlamydia infection. Extracellular *C. trachomatis* elementary bodies (EB) infect epithelial cells. Within the cell, the EBs convert to reticulate bodies (RB), which replicate by binary fission. The RBs then convert back to EBs that are released from the cell and infect other epithelial cells. The presence of extracellular EBs activates the host's immune response, and interferon-γ is released. The interferon blocks RB replication, resulting in the formation of large, aberrant RBs. However, the RBs remain viable, and when the extracellular infection is cleared and interferon-γ is no longer present, normal RB replication resumes. These repeated cycles of replication and immune activation followed by chlamydial persistence in epithelial cells of the fallopian tube eventually lead to scar formation and tubal occlusion.[27] As has been already discussed, Witkin and co-workers found that women

**Figure 2.** Effect of interferon-γ on the life cycle of *Chlamydia trachomatis*.

previously infected with chlamydia – detected by circulating systemic humoral immunity to HSP 60 had unfavourable outcomes with IVF.[18]

#### **4.4. Nongonococcal-nonchlamydial infection**

Approximately 1/4th of women with PID have a nongonococcal-nonchlamydial cause.[28] Patients with nongonococcal PID have the onset of pain distributed evenly throughout the cycle and less frequently associated with menses. There is less fever, vaginal discharge, and liver tenderness than with gonococcal PID. Despite these differences, the clinical presentation does not adequately distinguish between the two, and reliance on culture is necessary. There may be a critical number of organisms needed to breach the normally present protective host defence mechanisms and lead to infection. There is probably a continuum from bacterial vaginosis to endometritis and salpingitis, because women with bacterial vaginosis are significantly more likely to be diagnosed with PID.[29] The substantial isolation rate of bacteria other than gonococci or *C. trachomatis* from tubal fluid of these PID patients has shown that bacterial vaginosis organisms can cause acute salpingitis without antecedent chlamydial or gonococcal infection. Peritoneal or tubal cultures have yielded a mixed aerobic and anaerobic flora in 35% to 50% of patients, anaerobes alone in 15%, and aerobes alone in approximately 30% to 40% of patients. Between 4% and 17% of women with PID have had *M. hominis*, and 2% to 20%, have had *U. urealyticum* recovered from the fallopian tubes.[30]

#### **4.5. Genital mycoplasmas and unexplained infertility**

Mycoplasmas share characteristics of bacteria (they reproduce on cell-free media) and viruses (they have no cell wall and are 100 to 300 μm in diameter). Two species of mycoplasmas have been commonly isolated from the female and male reproductive tracts: *M. hominis* and the heterogeneous group known collectively as T mycoplasma (so named for their characteristic "tiny" colonies). A distinctive property of the T strains is their ability to hydrolyze urea, and they have been named *U. urealyticum*. A third species, *Mycoplasma genitalium* has been isolated from the urethra of men and is believed to be a cause of urethritis.

Genital mycoplasmas may be of etiologic importance in nonspecific urethritis, cervicitis, and vaginitis; some cases of acute salpingitis; fever after abortions; chorioamnionitis; and puerperal infections. However, the causal role of genital mycoplasmas in infertility is still unresolved.

#### **4.6. Genital tuberculosis**

previously infected with chlamydia – detected by circulating systemic humoral immunity to

Approximately 1/4th of women with PID have a nongonococcal-nonchlamydial cause.[28] Patients with nongonococcal PID have the onset of pain distributed evenly throughout the cycle and less frequently associated with menses. There is less fever, vaginal discharge, and liver tenderness than with gonococcal PID. Despite these differences, the clinical presentation does not adequately distinguish between the two, and reliance on culture is necessary. There may be a critical number of organisms needed to breach the normally present protective host defence mechanisms and lead to infection. There is probably a continuum from bacterial vaginosis to endometritis and salpingitis, because women with bacterial vaginosis are significantly more likely to be diagnosed with PID.[29] The substantial isolation rate of bacteria other than gonococci or *C. trachomatis* from tubal fluid of these PID patients has shown that bacterial vaginosis organisms can cause acute salpingitis without antecedent chlamydial or gonococcal infection. Peritoneal or tubal cultures have yielded a mixed aerobic and anaerobic flora in 35% to 50% of patients, anaerobes alone in 15%, and aerobes alone in approximately 30% to 40% of patients. Between 4% and 17% of women with PID have had *M. hominis*, and

Mycoplasmas share characteristics of bacteria (they reproduce on cell-free media) and viruses (they have no cell wall and are 100 to 300 μm in diameter). Two species of mycoplasmas have

2% to 20%, have had *U. urealyticum* recovered from the fallopian tubes.[30]

**4.5. Genital mycoplasmas and unexplained infertility**

HSP 60 had unfavourable outcomes with IVF.[18]

**Figure 2.** Effect of interferon-γ on the life cycle of *Chlamydia trachomatis*.

**4.4. Nongonococcal-nonchlamydial infection**

10 Genital Infections and Infertility

Tuberculosis continues to be endemic in many poor parts of the world like Latin America and Asia. The incidence of pelvic tuberculosis is difficult to assess as many patients are asympto‐ matic, therefore the disease often comes to light only incidentally during the course of investigation for a gynecological complaint. Schaefer[31] as early as in 1976 reported that 4-12% of women dying from pulmonary tuberculosis manifest evidence of genital involvement. He further mentioned that 5-10% of infertile women suffer from tuberculosis. The incidence of tuberculosis amongst women with infertility is believed to be higher in the third world countries.

The causative agent is *Mycobacterium tuberculosis* (95%) but in 5% cases it is *Mycobacterium bovis*. Genital tuberculosis almost always occurs secondary to a primary focus elsewhere, the commonest site being the lungs, but rarely from the kidneys, joints, GIT or as a part of a generalized military infection. The mode of spread is hematogenous or lymphatic and rarely from direct contiguity with an intra-abdominal organ or affected peritoneum. The fallopian tubes are affected first followed by subsequent dissemination to other genital organs – this explains the bilateral tendency of the disease. Primary genital tuberculosis is rare and possibly originates from the semen or saliva of a positive sexual partner. Tuberculosis of the cervix is present in about 5% of cases.

The leading presenting complaints in women suffering from genital tuberculosis include infertility, menstrual problems, abdominal pain, vaginal discharge and rarely genital fistulas or mass per abdomen. Sometimes general symptoms of low grade temperature, weight loss and fatigue may raise the suspicion of hitherto unsuspected tuberculosis. Classis feature is failure of fever to subside in spite of broad spectrum antibiotics. Therefore, a clinical course that is refractory to antibiotic therapy for the usual pelvic inflammatory disease should alert the physician to the possibility of tuberculosis. Pelvic examination may reveal findings like thickened adnexa which may be tender. However it may be completely normal.

Infertility is an important presenting symptom. In fact in 35-60% cases it is the only complaint. About 75% present with primary infertility and 25% give history of previous conception. These patients may or may not give a history of contact with a person suffering from pulmonary tuberculosis.

Diagnosing tuberculosis still remains a challenge. This is due to a wide variety of clinical presentation and lack of diagnostic tests with a good positive predictive and negative predic‐ tive value. A single, reliable, convenient, economical test that has a good degree of sensitivity and specificity is yet to be discovered. Diagnosis still remains subjective, and is done usually at the time of laparoscopy done for evaluating infertility or chronic pelvic pain. Pathognomic sign of appearance of small tubercles all over the peritoneum that represent caseating granu‐ lomas is seen only rarely. Other findings include appearance of tubo-ovarian masses with varying degree of intra-pelvic adhesions, bead like growths or rigid lead-pipe appearance of fallopian tubes, hydrosalpingx and military white tubercles on the serosa of the uterus. Samples can be taken for acid-fast bacilli staining (Figure 3) or culture. However both methods have low sensitivity. Polymerase chain reaction is highly sensitive, but may yield false positives due to contamination of sample from air or water contaminants. Mantoux test has limited utility now.

**Figure 3.** Typical tubercular lesion in histo-pathology

#### *4.6.1. Treatment of tuberculosis*

Extra pulmonary tuberculosis usually requires 8 to 10 months of continuous treatment particularly in developing countries to prevent emergence of multi-drug resistant tuberculosis, which is very common if treatment is given for a short period and stopped. Also, premature discontinuation of treatment may render the organisms resistant and lead to re-emergence of infection with much more severity. The therapeutic phase is divided into an intensive phase of about 2 to 4 months and continuation phase of 4 to 6 months. The two drugs used throughout the treatment period are usually rifampicin (10 mg/kg/day, not exceeding 600 mg/d) and isoniazid (5 mg/kg/day not exceeding 300 mg). In the past the third drug used during the initial 2-4 months was Ethambutol (5-25 mg/kg/day not to exceed 2.5 gm/day) but now pyrazinamide (15-30 mg/kg/day, not to exceed 2.5 gm/day) is preferred because it does not have the ocular toxicity which is seen with ethambutol. Rifampicin is safe in pregnancy.[32] Most of these drugs are hepatotoxic and have various side effects, these have to be watched for. Surgery for the management of tuberculosis is not preferred, and reserved for special situations like persistence of an adnexal mass in spite of anti-tubercular treatment or irresponsiveness of the infection to anti-tubercular therapy.
