Increased prevalence of sexually transmitted viral infections in women: the role of female sex hormones in regulating susceptibility and immune responses

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Abstract

Sexually transmitted infections (STIs) caused by viruses, including HSV-2, HIV-1, HPV, are among the most prevalent infectious diseases worldwide and a major cause of morbidity and mortality. Despite decades of effort, the attempts to develop efficacious vaccines against viral STIs have failed repeatedly, with the exception of the recent HPV vaccine. Given the higher prevalence rates of STIs in women, it is becoming clear that a better understanding of gender-specific differences in STIs may be critical for the development of preventative strategies for these diseases. In order to gain this insight, it is important to examine the distinct microenvironment of the female reproductive tract, the site of primary infection, since it can significantly influence the outcome of infection. An important biological factor in the female reproductive tract is the presence of female sex hormones, estrogen and progesterone, which are produced endogenously primarily by the ovaries and commonly provided exogenously via the use of hormonal contraceptives. Here we review our current knowledge of the role played by the female sex hormones in regulating susceptibility and immune responses to viral sexually transmitted infections and whether this could contribute to higher prevalence of STIs in women. Manipulating the microenvironment of the female genital tract with sex hormones may contribute to the development of improved immunization strategies against sexually transmitted infections.

Introduction

Sexually transmitted infections (STIs) are among the most prevalent infectious diseases worldwide and are a major cause of morbidity and mortality (Tang and Rosenthal, 2010). While bacterial STIs such as Chlamydia and gonorrhoea are curable, viral STIs such as genital herpes, HIV and HPV cause incurable lifelong infections. In 2008, a bulletin from the World Health Organization estimated that 536 million people aged 15–49 are infected with HSV-2, the virus that causes genital herpes (Looker et al., 2008). In addition, 23.6 million people in this age group become newly infected with HSV-2 every year. The prevalence rates of HSV-2 infection are higher in women than men, with the lowest prevalence rates being 13% among West European men and the highest prevalence rates being 70% among sub-Saharan African women (Looker et al., 2008). Similar to HSV-2 infections, women are also more likely to become infected with HIV. Since the 1980s, HIV has shifted from a disease caused predominantly by use of shared hypodermic needles and male–male contact to a disease caused by heterosexual transmission. In fact, recent estimates have found that 30–40% of annual worldwide HIV infections occur through heterosexual transmission in the female reproductive tract (Unaids, 2008, Hladik and Mcelrath, 2008). Currently, in sub-Saharan Africa, 57% of all people infected with HIV are women and girls, and 76% of young people (aged 15–24) living with HIV are female (Unaids, 2006). In these and other epidemiological studies on bacterial STIs such as chlamydia and gonorrhoea, women are consistently found to have higher prevalence rates compared to men (Center for Disease Control and Prevention, 2009).

Despite decades of effort, the attempts to develop efficacious vaccines against viral STIs have failed repeatedly, with the exception of the HPV vaccine (Corey et al., 1999, Koutsky et al., 2002, Koelle, 2006, Joura et al., 2007, Buchbinder et al., 2008, Fauci et al., 2008). However, some trends have emerged that provide learning opportunities for improved future strategies. While social, behavioural and economic factors can contribute to the increased prevalence of STIs in women, it is also important to examine biological factors. Given the higher prevalence rates of STIs in women, it is becoming increasingly clear that a better understanding of these gender-specific differences in the acquisition of STIs may be critical for the development of preventative strategies for these diseases. Understanding the distinct microenvironment of the female reproductive tract, the site of primary infection, is crucial since it can significantly influence the outcome of infection. An important biological factor in the female reproductive tract is the presence of female sex hormones, estrogen and progesterone, which are produced endogenously via the ovaries and commonly provided exogenously via the use of hormonal contraceptives. Sex hormones can have profound effects on the susceptibility to a number of STIs as well as the immune responses in the genital tract. This review will focus on the role that sex hormones play in regulating the acquisition of and immune responses to viral STIs.

Section snippets

Impact of hormonal contraception on STI acquisition and disease progression

The female sex hormones, estrogen and progesterone, influence susceptibility and disease predisposition for many genital tract infections (Sonnex, 1998). Not only are these hormones produced in a cyclic fashion by the ovaries over the course of the menstrual cycle, but large numbers of women use hormonal contraceptives as well. In fact globally, at least 150 million women currently use hormonal contraceptive methods, with ≥100 million women using combined oral contraceptive pills and ≥50

Animal models: progesterone increases susceptibility whereas estrogen protects against viral STIs

Given the clinical observations that the use of hormonal contraceptives can increase susceptibility to STIs in humans, several studies have examined directly the role that sex hormones play in the acquisition of STIs in animal models. Rhesus macaques were found to be more susceptible to intravaginal SIV infection during the luteal phase (high progesterone) compared to the follicular ovarian phase (high estrogen) (Sodora et al., 1998). In addition, the administration of DMPA to rhesus macaques

Innate defence mechanisms regulated by sex hormones

In order to develop effective preventative therapies against STIs, it is essential to understand the underlying mechanisms by which sex hormones regulate susceptibility to these diseases. One possible mechanism is the effects that sex hormones have on the epithelial lining of the reproductive tract, since epithelial cells are the first to come in contact with sexually transmitted pathogens. In particular, the effects of sex hormones on vaginal epithelium have been studied in details in macaque

Regulation of adaptive immune responses by the menstrual cycle

In addition to the physical differences observed in the vaginal morphology and innate factors in both humans and animals, the changes in susceptibility to STIs may also be the result of hormone-induced changes in the host adaptive immune response following infection. The female menstrual cycle can have dramatic effects on adaptive immunity generated in the female reproductive tract, other mucosal tissues, and systemically (Paavonen, 1994, Beagley and Gockel, 2003). Antigen presenting cells and

Regulation of host immune responses by progesterone-based contraceptives

Treatment of animals and humans with progesterone-based contraceptives can have significant effects on the host immune response to STIs. We have previously reported that mice treated with Depo-Provera have decreased levels of HSV-2 specific mucosal immune responses after intravaginal immunization with the attenuated strain of HSV-2 (TK-HSV-2). Consequently, these mice fail to develop protective immune responses against subsequent WT HSV-2 challenge (Gillgrass et al., 2003, Kaushic et al., 2003

Regulation of host immune responses by estrogen

The effects of estrogen on the immune system of women are well documented. Depending on the concentration, estrogen can have either pro-inflammatory or anti-inflammatory effects (Straub, 2007). At low concentrations, estrogen induces TNFα, IL-6 and IL-1β expression, inhibits Th2-type cytokines, and increases migration of leukocytes to the site of inflammation (Straub, 2007). Other studies have shown that estrogen can also inhibit the production of TNFα, IL-1β and IL-6 by T cells, macrophages

Conclusion

There is significant evidence suggesting that female sex hormones could contribute to increased prevalence of sexually transmitted infections in women. With the increase in heterosexual transmission of sexually transmitted infections in women, it is important to fully understand the microenvironment of the female reproductive tract since this is the site for both initiation of infection and the generation of immune responses that clear the infection. Both susceptibility and immune responses to

Acknowledgement

The authors would like to acknowledge the funding support from Canadian Institutes of Health Research (CIHR), Ontario HIV Treatment Network (OHTN) and Canadian Foundation of AIDS Research (CANFAR). CK was supported by a Scholarship Award from OHTN, a New Investigators Award from CIHR and an Early Researchers Award (ERA) from Ontario Ministry of Research and Innovation.

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