**3. HIV effects on fertility**

pact of cART on fertility; and the management of reproductive issues among HIV-

There were approximately 37 million people living with human immunodeficiency virus (PLWHIV) globally at the end of 2014.[1] The course of HIV infection has changed from a deadly disease to a chronic and manageable disease since the introduction of combination antiretroviral therapy (cART) in the 1990s. The estimated life expectancy of a 20-year-old PLWHIV has increased from 30 years during 1996–1999 to 46 years during 2006–2008 accord‐ ing to the UK Collaborative HIV Cohort Study.[2] The increased life expectancy along with improved quality of life has led to increase in reproductive desire among this population.[3] Fertility of PLWHIV can be affected by HIV infection and associated infections. Infections can physically impact the anatomical structure and biological function of the reproductive system, whereas stress and psychiatric disorders related to HIV infection may lessen sexual drive and frequency of sexual intercourse. In addition, socioeconomic factors including limited financial means, difficulty accessing HIV care, and stigmatization can contribute to social withdrawal and reduced reproductive potential among PLWHIV. Management of reproductive health along with cART has become a necessary component of comprehensive HIV care in the post– cART era. The etiologies and epidemiology of HIV-related infertility, factors that may impact fertility, and management options and considerations for infertility among HIV-infected

The data on the magnitude and burden of HIV-related infertility derive mostly from studies conducted among HIV-infected women. A previous study using data from case–control studies and theoretical predictions from a model of the proximate determinants of fertility and HIV incidence in African countries demonstrated the 25–40% lower rate of fertility among HIV-infected women compared to HIV-negative women.[4] In a prospective cohort study from the United States during 1994–2002, women with HIV were less likely to conceive than uninfected women (pregnancy rates 7.4 vs.15.2 per 100 person-years, respectively).[5] Using demographic and health surveys between 2003 and 2007, the Joint United Nations Program on HIV/AIDS (UNAIDS) estimated that the global age-specific fertility ratio for HIV-infected women in the reproductive age group of 20–44 years is 0.53 to 0.76 compared to that of women without HIV.[6] A survey study conducted at HIV fertility clinics in the United Kingdom demonstrated a 40% prevalence of tubal factor infertility among HIV-infected women.[7] Despite the infertility in women living with HIV, pregnancy rates among this population have

infected individuals.

**1. Introduction**

178 Genital Infections and Infertility

**Keywords:** HIV, AIDS, Infection, Infertility

individuals are reviewed in this chapter.

**2. Epidemiology of HIV-related infertility**

There are several factors associated with HIV infection that can potentially affect fertility in PLWHIV. These factors can be categorized into biological factors, psychological factors, and social factors (Figure 1).


**Figure 1.** Factors associated with infertility among people living with human immunodeficiency virus

#### **3.1. Biological factors**

Demographic characteristics that have been reported to be associated with low rates of pregnancy among HIV-infected women include advanced age, white ethnicity (compared to black ethnicity), having CD4 cell count of less than 100 cells/mm3 , and poor adherence to cART. [8-10] Systemic illnesses from HIV and its related comorbidities, stress, and weight loss generally impact the reproductive potential of both sexes.[3] HIV-infected women are more likely than non-HIV-infected women to have protracted anovulation and amenorrhea.[11-14] The number of ovulatory cycles was found to correlate with the severity of immunosuppres‐ sion and having an AIDS diagnosis. Although there have been no reports of ovarian aging or failure,[15] HIV-infected women may have reduced ovarian reserve.[16] In HIV-infected men, impairment of sperm parameters affecting fertility has been described. The impairment includes lower ejaculation volume, sperm count, and progressive motility (defined as the percent of sperm with forward motility) despite normal morphology compared to non-HIVinfected men.[17-19] Sperm concentration levels, total count, and motility were found to positively correlate with the height of the CD4 cell count, indicating the adverse effect of worsening immunodeficiency on these sperm parameters.[19] Other studies demonstrated that the semen of HIV-infected men was more viscous and contained fewer motile sperm but more round cells.[20] In addition, a study of testicular specimens from autopsy samples (1981– 1998) revealed progressive loss of germ cells within the testes with prolonged survival with AIDS.[21] Although recent data indicate that cART significantly decreased total sperm count and progressive motility and increased the proportion of abnormal sperm forms,[22] these adverse effects are balanced by the overwhelming benefits of cART for immune reconstitution, morbidity and mortality reduction, and overall improvement of sperm characteristics associ‐ ated with higher CD4 cell counts.

#### *3.1.1. Hypogonadism and HIV/AIDS*

Hypogonadism was recognized as a relatively common condition early in the HIV epidemic and characterized by a low level of testosterone among HIV-infected men. Hypogonadism can be categorized into primary hypogonadism, which is a disorder of the testes, and secondary hypogonadism, which is a disorder of the pituitary or hypothalamus. Hypogonadism can be associated with various signs and symptoms, including muscle wasting, weight loss, low bone mineral density, and decreased libido.[23] During the early course of HIV disease, men tend to have normal serum testosterone levels. As the disease progresses to AIDS, low serum testosterone levels become more frequent, particularly in those with more advanced immu‐ nosuppression (e.g., CD4 cell count less than 100 cells/mm3 ). Early in the HIV epidemic, 30– 50% of symptomatic HIV-infected men had low total serum testosterone levels, which significantly correlated with weight loss and CD4 cell depletion.[24-26] The prevalence of hypogonadism in HIV-infected men has decreased with cART initiation occurring at earlier stages of HIV infection. Effective HIV therapy can normalize testosterone levels over time.[27] Most cases of decreased testosterone levels in HIV-infected men are related to secondary hypogonadism.[24, 28] Other characteristics that have been reported to be associated with low testosterone levels include older age, a detectable HIV RNA level of greater than 10,000 copies/ mL, injection drug use, hepatitis C coinfection, high body mass index, and insulin resistance. [28-31] In addition, several medications commonly used among HIV-infected individuals can affect testosterone levels through varied mechanisms. Systemic glucocorticoids and megestrol acetate can cause hypogonadism by suppressing the hypothalamic–pituitary–gonadal axis, whereas a high dose of ketoconazole (at least 400 mg per day) directly inhibits steroidogenesis. Psychotropic medications can cause hyperprolactinemia and testosterone deficiency, whereas chronic use of alcohol, opiates, and marijuana can impair testosterone production.[32, 33]


**Note:** FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

**Table 1.** Causes of hypogonadism in males

**3.1. Biological factors**

180 Genital Infections and Infertility

ated with higher CD4 cell counts.

*3.1.1. Hypogonadism and HIV/AIDS*

nosuppression (e.g., CD4 cell count less than 100 cells/mm3

Demographic characteristics that have been reported to be associated with low rates of pregnancy among HIV-infected women include advanced age, white ethnicity (compared to

[8-10] Systemic illnesses from HIV and its related comorbidities, stress, and weight loss generally impact the reproductive potential of both sexes.[3] HIV-infected women are more likely than non-HIV-infected women to have protracted anovulation and amenorrhea.[11-14] The number of ovulatory cycles was found to correlate with the severity of immunosuppres‐ sion and having an AIDS diagnosis. Although there have been no reports of ovarian aging or failure,[15] HIV-infected women may have reduced ovarian reserve.[16] In HIV-infected men, impairment of sperm parameters affecting fertility has been described. The impairment includes lower ejaculation volume, sperm count, and progressive motility (defined as the percent of sperm with forward motility) despite normal morphology compared to non-HIVinfected men.[17-19] Sperm concentration levels, total count, and motility were found to positively correlate with the height of the CD4 cell count, indicating the adverse effect of worsening immunodeficiency on these sperm parameters.[19] Other studies demonstrated that the semen of HIV-infected men was more viscous and contained fewer motile sperm but more round cells.[20] In addition, a study of testicular specimens from autopsy samples (1981– 1998) revealed progressive loss of germ cells within the testes with prolonged survival with AIDS.[21] Although recent data indicate that cART significantly decreased total sperm count and progressive motility and increased the proportion of abnormal sperm forms,[22] these adverse effects are balanced by the overwhelming benefits of cART for immune reconstitution, morbidity and mortality reduction, and overall improvement of sperm characteristics associ‐

Hypogonadism was recognized as a relatively common condition early in the HIV epidemic and characterized by a low level of testosterone among HIV-infected men. Hypogonadism can be categorized into primary hypogonadism, which is a disorder of the testes, and secondary hypogonadism, which is a disorder of the pituitary or hypothalamus. Hypogonadism can be associated with various signs and symptoms, including muscle wasting, weight loss, low bone mineral density, and decreased libido.[23] During the early course of HIV disease, men tend to have normal serum testosterone levels. As the disease progresses to AIDS, low serum testosterone levels become more frequent, particularly in those with more advanced immu‐

50% of symptomatic HIV-infected men had low total serum testosterone levels, which significantly correlated with weight loss and CD4 cell depletion.[24-26] The prevalence of hypogonadism in HIV-infected men has decreased with cART initiation occurring at earlier stages of HIV infection. Effective HIV therapy can normalize testosterone levels over time.[27] Most cases of decreased testosterone levels in HIV-infected men are related to secondary hypogonadism.[24, 28] Other characteristics that have been reported to be associated with low testosterone levels include older age, a detectable HIV RNA level of greater than 10,000 copies/

, and poor adherence to cART.

). Early in the HIV epidemic, 30–

black ethnicity), having CD4 cell count of less than 100 cells/mm3

HIV-infected men with symptomatic hypogonadism may present with loss of facial and body hair, decreased muscle mass and strength, diminished libido, impotence, testicular atrophy, gynecomastia, depression, low energy, and poor concentration.[34] Diagnosis of hypogonad‐ ism is made based on a clinical suspicion and low serum testosterone levels (generally less than 300 ng/dL). The screening test of choice is the serum total testosterone concentration (free plus protein-bound fractions). However, in some cases, the total testosterone levels may be normal, whereas the free levels may be low because of the higher sex hormone-binding globulin levels among HIV-infected persons. Thus, in a patient with suspected testosterone deficiency and serum total testosterone concentration in the lower half of the normal range (less than 500 ng/dL), the free testosterone levels should be assessed.[34] Testosterone levels should not be evaluated during an acute illness because of the transient decline of androgen levels related to the acute event. To distinguish between primary and secondary hypogonad‐ ism, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels need to be measured. The elevated FSH and LH levels suggest primary hypogonadism, whereas normal or low levels of FSH and LH are consistent with secondary hypogonadism. Further evaluation should be geared toward diagnosing the possible causes of primary and secondary hypogo‐ nadism in HIV-infected men as detailed in Table 1.

#### *3.1.2. Comorbid diseases and HIV/AIDS*

#### *3.1.2.1. Sexually Transmitted Infections (STIs)*

The impact of STIs on fertility among PLWHIV depends on the local prevalence of the STIs. Given the common route of transmission of causative agents and immunosuppressive status caused by HIV, STIs tend to be more prevalent, to be more severe, to take longer to resolve, and to be more prone to treatment failure in HIV-infected persons compared to the general population. Common causative pathogens for STIs among PLWHIV include bacteria, such as *Neisseria gonorrhoeae*, *Chlamydia trachomatis*, *Ureaplasma urealyticum*, *Mycoplasma hominis*, *Mycoplasma genitalium*, *Treponema pallidum*, *Haemophilus ducreyi*, and *Klebsiella granulomatis*; viruses, such as hepatitis B and C viruses, herpes simplex virus (HSV), and human papillo‐ mavirus (HPV); and protozoa, such as *Trichomonas vaginalis*. The underlying pathogenesis for STI-related infertility is direct damage and subsequent anatomical and functional abnormali‐ ties of the genital organs, including the testes and epididymis in men and cervix, uterus, fallopian tubes, and ovaries in women. A previous study demonstrated that the DNA of STI pathogens was detected in semen of 45 of 241 asymptomatic men seeking an infertility investigation (19%) and was associated with a decrease in sperm concentration, motile sperm concentration, total sperm count, and neutral alpha-glucosidase concentration.[35]

Gonorrhea is a STI caused by *N. gonorrhea* and commonly manifests as urethritis in both sexes and pelvic inflammatory disease in women. The reported complications related to fertility of gonorrhea include urethral strictures and subsequent impairment of testicular functions in men.[36] Similarly, *C. trachomatis* can cause urethritis in both sexes and pelvic inflammatory disease in females. Epidemiologic data suggest that *C. trachomatis* may be associated with tubal obstruction and subsequent infertility in women.[37] The impact of Mycoplasma, that is, *U.* *urealyticum*, *M. hominis*, and *M. genitalium*, on fertility is uncertain. *U. urealyticum* may cause infertility through its effects on sperm chromatin and DNA, whereas *M. genitalium* can attach to spermatozoa and can be transported to the female genital tract.[38, 39] Syphilis is caused by *T. pallidum* and is more prevalent among PLWHIV. Orchitis, epididymitis, and testicular mass have been reported as manifestations of syphilis in HIV-infected men.[40, 41] Although *H. ducreyi* and *K. granulomatis* do not directly affect the reproductive tract, they both cause ulcers and lymphadenopathy around the genital area, which may affect reproductive potential.

Chronic viral hepatitis B and C can cause impairment in sperm concentration, motility, morphology, and viability, whereas HPV primarily affects sperm motility.[42] The presence of HSV DNA in semen has been associated with decreased sperm concentration and reduced motility.[43] In HIV-infected women, chronic HPV infection increases the risk of cervical cancer development and possibly leads to infertility. An important protozoan *T. vaginalis* is the cause of vaginitis, endometritis, adnexitis, and pyosalpinx in women, which can lead to infertility and preterm birth and low birth weight of the newborn.[44] In men, it is associated with complications including urethritis, prostatitis, epididymitis, and infertility through inflammatory damage or interference with sperm function.[44]

#### *3.1.2.2. Opportunistic Infections (OIs)*

HIV-infected men with symptomatic hypogonadism may present with loss of facial and body hair, decreased muscle mass and strength, diminished libido, impotence, testicular atrophy, gynecomastia, depression, low energy, and poor concentration.[34] Diagnosis of hypogonad‐ ism is made based on a clinical suspicion and low serum testosterone levels (generally less than 300 ng/dL). The screening test of choice is the serum total testosterone concentration (free plus protein-bound fractions). However, in some cases, the total testosterone levels may be normal, whereas the free levels may be low because of the higher sex hormone-binding globulin levels among HIV-infected persons. Thus, in a patient with suspected testosterone deficiency and serum total testosterone concentration in the lower half of the normal range (less than 500 ng/dL), the free testosterone levels should be assessed.[34] Testosterone levels should not be evaluated during an acute illness because of the transient decline of androgen levels related to the acute event. To distinguish between primary and secondary hypogonad‐ ism, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels need to be measured. The elevated FSH and LH levels suggest primary hypogonadism, whereas normal or low levels of FSH and LH are consistent with secondary hypogonadism. Further evaluation should be geared toward diagnosing the possible causes of primary and secondary hypogo‐

The impact of STIs on fertility among PLWHIV depends on the local prevalence of the STIs. Given the common route of transmission of causative agents and immunosuppressive status caused by HIV, STIs tend to be more prevalent, to be more severe, to take longer to resolve, and to be more prone to treatment failure in HIV-infected persons compared to the general population. Common causative pathogens for STIs among PLWHIV include bacteria, such as *Neisseria gonorrhoeae*, *Chlamydia trachomatis*, *Ureaplasma urealyticum*, *Mycoplasma hominis*, *Mycoplasma genitalium*, *Treponema pallidum*, *Haemophilus ducreyi*, and *Klebsiella granulomatis*; viruses, such as hepatitis B and C viruses, herpes simplex virus (HSV), and human papillo‐ mavirus (HPV); and protozoa, such as *Trichomonas vaginalis*. The underlying pathogenesis for STI-related infertility is direct damage and subsequent anatomical and functional abnormali‐ ties of the genital organs, including the testes and epididymis in men and cervix, uterus, fallopian tubes, and ovaries in women. A previous study demonstrated that the DNA of STI pathogens was detected in semen of 45 of 241 asymptomatic men seeking an infertility investigation (19%) and was associated with a decrease in sperm concentration, motile sperm

concentration, total sperm count, and neutral alpha-glucosidase concentration.[35]

Gonorrhea is a STI caused by *N. gonorrhea* and commonly manifests as urethritis in both sexes and pelvic inflammatory disease in women. The reported complications related to fertility of gonorrhea include urethral strictures and subsequent impairment of testicular functions in men.[36] Similarly, *C. trachomatis* can cause urethritis in both sexes and pelvic inflammatory disease in females. Epidemiologic data suggest that *C. trachomatis* may be associated with tubal obstruction and subsequent infertility in women.[37] The impact of Mycoplasma, that is, *U.*

nadism in HIV-infected men as detailed in Table 1.

*3.1.2. Comorbid diseases and HIV/AIDS*

182 Genital Infections and Infertility

*3.1.2.1. Sexually Transmitted Infections (STIs)*

HIV-infected persons are at increased risk for opportunistic infections (OIs) depending on their degree of immunosuppression. Tuberculosis is a common OI in HIV-tuberculosis endemic locales and its prevalence is higher among PLWHIV compared to non-HIV-infected persons, regardless of the CD4 cell count. Genital tract infection caused by *Mycobacterium tuberculosis* contributes to infertility and poorer reproductive health outcomes in both sexes.3 Salmonello‐ sis, toxoplasmosis, and cryptococcosis can manifest as disseminated infections involving the genital organs. Although cytomegalovirus (CMV) can cause orchitis and epididymitis in HIVinfected men, there are no data on its effect on sperm characteristics.[42] Candidiasis is frequently reported among HIV-infected persons with CD4 cell counts less than 200 cells/ mm3 . It is the cause of balanitis in men and vaginitis and cervicitis in women, which may affect fertility.

#### *3.1.2.3. Other infections*

Other infectious causes of orchitis in both HIV-infected and non-HIV-infected men include bacteria, such as *Escherichia coli*, *Klebsiella pneumoniae*, *Pseudomonas aeruginosa*, *Staphylococcus* spp., and *Streptococcus* spp., and viruses, such as mumps, varicella, coxsackievirus, and echovirus.[45] These infections may also contribute to infertility.

#### *3.1.3. Antiretroviral agents*

Nucleoside reverse transcriptase inhibitors (NRTIs) remain key components of recommended cART regimens. They inhibit HIV-1 reverse transcriptase, which reduces viral replication and improves disease control. However, these medications also inhibit mitochondrial DNA (mtDNA) synthesis and cause a decrease in polypeptides involved in electron transport, which can result in cell injury.[46] The degree of mitochondrial toxicity is specific to each NRTI. Theoretically, an HIV-infected person's fertility may be affected by NRTI use via the damage to mitochondrial biogenesis of gametes.3 This is supported by the mtDNA depletion observed in sperm and oocytes of HIV-infected patients taking NRTIs and in low oocyte mtDNA in patients with ovarian insufficiency.[47-49] Data from epidemiologic studies are conflicting regarding the impact of cART on fertility. A prospective cohort from the United States reported the lower likelihood of conception associated with antiretroviral therapy among HIV-infected women,[5] whereas a more recent study from Africa demonstrated significantly higher pregnancy rates among HIV-infected women on cART compared to those not on cART.[50] However, these two studies were conducted in different settings and time, and specific behavioral and biological mechanisms were not explored. Zidovudine (azidothymidine, AZT) is the NRTI drug that has been studied the most. In animal studies, AZT has been shown to suppress cell division in the preimplantation mouse embryo, causing reduction in inner cell mass proliferation, greater number of resorptions, and fewer fetuses.[51, 52] A previous study demonstrated that exposure to NRTI transplacentally caused significant fetal mitochondrial damage in experimental monkeys.[53] Unfortunately, there have been no studies examining fertility effect of NRTIs in humans.

#### **3.2. Psychological factors**

Decrease in sexual activity after a new diagnosis of HIV infection is usually observed and may be accompanied by the feeling of guilt and shame and aggravated by the stigma related to HIV infection.[54] Individuals recently diagnosed with HIV infection reported to have decreased desire for or interest in sex relations. They also reported to use condom more consistently during sexual intercourse to avoid transmission of HIV to their partners.[55] Previous studies indicated that HIV-infected women often chose to avoid pregnancy.[56, 57] However, another study revealed that high-risk behaviors, unplanned pregnancies, and pregnancy termination remain prevalent among this population.[58] In the pre–cART era, there was a significant increase in the pregnancy termination rate from 3.5 to 6.3 per 100 women-years following a new HIV diagnosis in the United Kingdom and Ireland[56] and 47% of pregnancies were voluntarily terminated following a new HIV diagnosis in an Australian study.[57] The reasons for pregnancy termination may include challenges of pregnancy, birth and parenting in the context of HIV infection, concerns about increased risks of complications related to pregnancy and delivery, and risk of HIV transmission to the newborn. A previous study reported that unplanned pregnancy, lower CD4 cell count, and having an HIV-infected current partner were factors associated with the decision to terminate a pregnancy.[59] Following the introduction of cART with overall improvement in health and immune status of HIV-infected women, the rates of elective pregnancy termination after a HIV diagnosis were 22%-26% decreased from the pre–cART period.[60, 61] With the success of cART in preventing mother-to-child HIV transmission, HIV infection was reported to have no effect on desire for pregnancy among young urban African Americans aged 15–24 years.[62] Reproductive desire among PLWHIV may now be associated with personal health, cART, concern about HIV transmission, and social factors. Some HIV-infected persons have an increased desire for children as a way of concealing their HIV-infected status and improving their feelings of self-worth. Others stated that their HIV diagnosis increased their desire for children at an earlier age and some chose to have children following advances in HIV care.[63-65]
