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W2059449393 abstract "Introduction The same populations of women at risk for sexual acquisition of HIV are also at risk for pregnancy; many of these women use contraception. Combating the spread of HIV is a major global goal [1] ideally achievable with development of highly effective dual protection methods that prevent both sexual acquisition of HIV and unwanted pregnancy. Currently, emerging evidence [2] suggests that some commonly used contraceptives may increase risk of sexual HIV acquisition and transmission. There are several biologically plausible mechanisms by which hormonal contraceptives could increase HIV risk including disrupting epithelial barriers (thinning of the epithelium or altering epithelial integrity), causing changes in inflammatory responses that could in turn enhance HIV replication locally [3], or altering the vaginal microbiota which itself effects local immunity and genital inflammation. The objective of this manuscript is to review the evidence linking contraceptives to genital tract changes and to identify research gaps to be addressed with future studies. The anatomic, immune, and microbiological milieu of the female genital tract may be important determinants of both HIV acquisition and sexual transmission [4]. The likelihood of HIV acquisition when a susceptible individual is sexually exposed is driven by several factors, including viral load of the transmitting sexual partner [5], however, host factors are also important in acquisition risk. One potentially important host factor in HIV acquisition risk is the number of accessible cellular targets available for viral entry, a necessary step prior to systemic dissemination [3]. Genital tract immune cells are common portals of entry for HIV [3,6] yet little is known about the effects of hormonal contraceptives on genital architecture, immune cell populations, and microbiotain the genital mucosa, all of which may relate to susceptibility. Given mounting data [7] suggesting women using systemic hormonal contraceptives may have increased susceptibility to HIV, this is a significant knowledge gap. There are strong data supporting significant changes in epithelial thickness in animals exposed to depot medroxyprogesterone acetate (DMPA) and, in fact, DMPA dosing is required in several animal models to induce susceptibility to HIV/SIV infection. Interestingly, multiple investigators have examined genital tract tissues in women who use DMPA and have not confirmed a similar epithelial thinning in women [8–11]. Other architectural features, such as epithelial tight junctions or adherens proteins, may be important barriers to HIV transmission and if altered with use of hormonal contraceptives, may contribute to HIV risk. One study has reported that these epithelial architectural features are not altered with hormonal contraceptives use [11]. Other possible mechanisms by which hormonal contraceptives could increase HIV acquisition risk include: altering HIV target immune cells resident within the local tissues; interfering with innate or adaptive immunity within the genital tracttipping transmission probability towards establishing infection; or creating inflammation that promotes transmission by disrupting tight junctions between epithelial cells and increasing the number and activation state of target immune cells. Additionally, hormonal contraceptives could alter co-receptor expression on target immune cells required for HIV cell entry thus making exposed cells more permissive to infection. Finally, genital tract infection and endogenous microbiotacomposition may confound the relationship between sex hormones and immune cellular populations within the genital tract since hormonal contraceptive use alters vaginal microflora [12–17], but it is not known if these microbiota alterations result in changes to HIV susceptibility (Fig. 1).Fig. 1: Model relationships: contraceptives, microbiota and genital tract immune cells.To date, little research has been specifically designed to elucidate if hormonal contraceptives use causes cellular and/or microbiological changes in the genital tract that could increase the efficiency of HIV transmission. Although regulatory approval of these contraceptives required rigorous data supporting contraceptive efficacy and safety, there are limited data on the noncontraceptive effects that these drugs have on the genital tract. Do hormonal contraceptives differ in the types and concentrations of progestins present? Progestogens are compounds that induce a secretory endometrium in order to support pregnancy. The term progestogen is inclusive of the only naturally occurring progestogen, progesterone, as well as the wide array of synthetic progestogens, collectively called progestins. Some progestins are highly related to progesterone, such as medroxyprogesterone acetate (MPA), and other progestins are more closely related to testosterone, such as norethindrone, levonorgestrel, desogestrel and gestodene (Fig. 2). Progesterone-related progestins in particular induce profound suppression of estradiol levels via negative feedback on hypothalamic-pituitary-ovarian axis and bind more tightly to the glucocorticoid receptors compared with other progestins [18,19]. With MPA use, estradiol levels may become as low as those measured in menopausal women. A major determinant of progestogen action is the binding affinity of each progestogen for the progesterone receptor and for other steroid receptors, including the glucocorticoid receptor [19,20].Fig. 2: Systemic progestin concentration varies with contraceptive method.There are a wide variety of progestins used in modern hormonal contraceptivesand they belong to three main chemical families: progesterone derivatives (pregnanes), 19-nortestosterone derivatives (estranges and gonanes), and spironolactone derivatives (Table 1). Progestins impact many aspects of human physiology and so biological potency varies based on the end-point measured. Clinically, progestins are largely used for contraception with ovulation inhibition and endometrial transformation being the most typical endpoint evaluated. Gonane derivatives are the most active with respect to these contraceptive endpoints generally with potencies more than 100x that of progesterone. Little to nothing is known regarding whether the type of progestin, or the delivery route, or both influence the hormonal contraceptives effect on genital tract tissues, cells, and microbiota.Table 1: Common contraceptive progestins.The glucocorticoid receptor is a protein present in the cytosol of almost all cells that regulates genes controlling development, metabolism, and immune response. The glucocorticoid receptor is activated when bound by cortisol or synthetic glucocorticoids, including progestogens. Activation of glucocorticoid receptors generally results in immune suppression as is seen with cortisol use, andMPA can have similar immunosuppressive effects [21]. Interestingly, progestins that are classified together often have significantly different noncontraceptive biological effects. For instance, apart from progesterone and the related pregnanes (MPA), the progestin that has the highest relative binding affinity for glucocorticoid receptors is gestodene, a gonane, but the other gonanes, such as levonorgestrel, have very low relative binding affinities for glucocorticoid receptors [19]. Understanding the relative binding affinities of the various progestins for glucocorticoid receptors, mineralocorticoid receptors and androgen receptors and the subsequent immune and genital tract biological effects of these bound receptors is critical in evaluating the biological plausibility of HIV risk and hormonal contraceptives. Given the paucity of data into understanding these noncontraceptive effects of hormonal contraceptives use, this is a significant knowledge gap. Are HIV target cells in the genital tract impacted by hormonal contraceptives use? Genital tract lymphocytes and antigen presenting cells expressing surface receptors compatible with HIV entry are targets for the establishment of HIV infection and fluctuate with hormonal change, including pregnancy [22–26]. These critical immune cellular populations in the female genital tract have not yet been carefully assessed in the setting of contraceptive use, many of which contain hormones. CD4 T lymphocytes are thought to be the primary targets for initial HIV infection in the female genital tract [27–33]. HIV infects discrete subsets of CD4 T cells all of which express phenotypic receptors and co-receptors necessary for HIV to gain intracellular access [9,34–36]. CCR5 is the predominant target co-receptor for initial infection and CXCR4 appears to play a more prominent role in continuation of an already established infection [9]. CCR5 expression on CD4 T cells in the human female genital tract [22–24,37] may be increased in women who use combined oral contraceptive pills (COCs) [25] offering a potential biological link between HIV susceptibility and hormonal status. CCR5 expression on immune cells is influenced by sex hormones and may account for the observed increased risk of HIV acquisition during pregnancy [26,38–40]. Progesterone both activates and suppresses mucosal immune cells [41,42] since it increases recruitment of inflammatory cells [29,30,43] and decreases the cellular functions of natural killer cells and cytotoxic T-cells [31,44,45]. Ex-vivo studies have demonstrated that incubation of cervical tissue in media containing progesterone stimulates CCR5 expression [23]. However, data describing genital tract immune cell populations, including CCR5 receptor expression, in women who use various hormonal contraceptives are lacking. Several investigators have sought to characterize and quantify immune cells within the female reproductive tract. However, a comparison of the various methods and populations studied to date [25,46–51] highlights the heterogeneity in participants, tissues, and collection methods, making it difficult to directly compare data. Many of the published studies collected tissues from gynecologic surgery specimens that are more likely to come from older women with a variety of pathologic conditions, including malignancies that may not be relevant to the genital tract immune cell populations in women at the highest risk of HIV. Consensus data from healthy women remains elusive, and data from African women of reproductive age are particularly lacking. Endogenous and exogenous sex hormones may modulate the expression of HIV co-receptors on the surface of mucosal immune cells, and the expression of surface co-receptors may be critical to the cellular permissiveness to HIV entry and replication. Modulation by sex hormones may or may not be tissue dependent, and as the tissues permissive to HIV infection are not well delineated, it remains important to obtain data on cells from all of the relevant mucosal surfaces that may be sexually exposed: the lower genital tract, the upper genital tract, and the distal GI tract. Women are at risk of HIV acquisition from anal receptive intercourse [52]. The impact of hormonal contraceptives on immune cells in the distal GI tract is an important research gap that should be addressed but which will not be discussed further in this review. What is the evidence that vaginal microflora can alter immune cell populations? Hormonal contraceptive usage can alter genital tract microflora [8,13,17,53–55] (Fig. 1) and abnormal vaginal flora can impact susceptibility to HIV and other sexually transmitted infections including Herpes Simplex Virus (HSV) and Human Papilloma Virus (HPV) [56–58]. HSV and HPV are also associated with increased risk of HIV acquisition [59–61]. HSV is an example of a genital infection that significantly alters local immune cell composition [49,62]. HSV modifies the relationship between risk of HIV acquisition and hormonal contraceptive use, with HSV negative women having a greater increase in risk of HIV acquisition [63]. Bacterial vaginosis is a common condition in which the predominant lactobacilli, which comprise the microflora of healthy women, are replaced by a heterogeneous group of microbiota. Women with bacterial vaginosis have bacterial communities with species richness and diversity. Although no single bacterial species is present in all women with bacterial vaginosis, G. vaginalis is present in most women (97%) [64]. Other bacteria present in significant numbers in women with bacterial vaginosis include A. vaginae (92%), L. iners (86%) and Eggerthella species (85%), in addition to other anaerobic Gram-positive bacteria [64]. Bacterial vaginosis has been linked to increased risk of HIV acquisition [65,66], increased shedding of HIV [67] and increased transmission of HIV from HIV-infected women to their uninfected partners [68,69]. Treatment of bacterial vaginosis has been shown to decrease HIV target immune cells within the cervix [70]. Rebbapragada et al.[70] reported that when 15 HIV-infected women with bacterial vaginosis were successfully treated with oral metronidazole, there was a significant decrease in activated CD4 T cells in cervical cytobrush samples obtained before and after treatment. They also reported an increase in DC-SIGN+ immature dendritic cells among HIV+ women following treatment of bacterial vaginosis. These data are some of the only available that directly link changes in vaginal microflora with changes in immune cell populations in the genital tract [8,13,17,53–55]. Additional research exploring how changes in the vaginal microbiota impact the numbers, distribution, activation status and co-receptor expression of genital immune cell populations are needed in order to establish the biological basis of how flora changes alter risk of HIV. What is the evidence that contraceptive hormones cause changes in vaginal microbiota, including bacterial vaginosis and yeast vaginitis? An important and understudied mechanism by which contraceptives could alter HIV risk is by impacting the vaginal microflora and vaginal infections, which can in turn cause changes in the vaginal ecosystem and enhance HIV risk. Both bacterial vaginosis and yeast vaginitis cause changes that could enhance susceptibility to HIV, although the data linking bacterial vaginosis to enhanced HIV risk is more consistent than that of yeast vaginitis. In addition, women with bacterial vaginosis are more susceptible to HSV-2 [71,72], and women with HSV-2 are significantly more likely to acquire HIV [73]. Similarly, women with bacterial vaginosis are more susceptible to HPV [74]. Most studies that have reported associations between bacterial vaginosis and HIV risk or changes in immune cells, have not controlled for these viral infections that may also have synergy with bacterial vaginosis. In addition to changes in genital tract immune cells associated with bacterial vaginosis described above, women with bacterial vaginosis are known to have changes in the levels of pro-inflammatory and anti-inflammatory cytokines and secretory leukocyte protease inhibitor (SLPI) in cervical and vaginal fluid [75–80]. Although interleukin-1β (IL-1β) is consistently increased in bacterial vaginosis, other cytokines have been less consistently linked with alterations in vaginal flora. Among 81 women, increases in IL-1β, tumor necrosis factor, IL-γ, IL-2, IL-4, IL-10, and GM-CSF were present among women with bacterial vaginosis and declined with treatment and restoration of a Lactobacillus-dominant flora [77]. The absence of IL-8 elevation in bacterial vaginosis is consistent with the lack of increased neutrophils in this condition [78], but why it is low when IL-1β and TNF are elevated is unclear [78]. Most of the data linking contraceptive use with changes in the microbiota and vaginal infections are derived from cross-sectional studies of women presenting to clinics with symptoms or are secondary analyses derived from clinical trials of other interventions or longitudinal cohort data. Thus, the studies to date reporting changes in the vaginal flora and/or incident infections are usually very small observational cohort studies following women for 2–6 months after initiation of a new contraceptive method, or they are large secondary analyses of larger studies. The smaller cohort studies are generally of insufficient size or length of follow up to detect large or clinically significant changes in flora. A major deficiency of the larger secondary analyses is that the researchers group contraceptives together out of necessity as some contraceptive types are not used by many of the study participants. For example, IUD users are often grouped together even though the IUD types many be significantly different. As noted above, the exposure to progestin differs substantially among hormonal contraceptive methods, so grouping of methods may obscure real biological differences between contraceptive groups (Table 2).Table 2: Hormonal content, delivery route and progestin concentrations with various contraceptives.Women who enroll in cross-sectional studies may be using no contraception, may be using condoms alone for contraception or may be using hormonal methods or IUDs along with condoms. Therefore, in these studies it is methodologically unclear which group of women should be used as the comparator group when assessing the effects of contraceptives on vaginal infections. Women of reproductive age who do not use contraceptives and women who rely on condoms alone are likely behaviorally and demographically different from those women who are using a highly effective contraceptive method. In some studies, the authors have compared those women using oral contraceptives to everyone else [13], creating a binary variable, while in other studies women using condoms or those using nonhormonal methods have served as the comparator group [14]. The association between contraceptive use and prevalent bacterial vaginosis has been evaluated in a large number of cross-sectional studies [13,81–84], and selected studies published over the past 15 years are summarized in Table 3. As shown, women in these studies using oral contraceptives and those reporting consistent condom use have generally had a decreased risk of bacterial vaginosis, while those reporting IUD use have had inconsistent associations with prevalent bacterial vaginosis [81,82]. One of the largest and most recent studies evaluating the impact of contraceptive methods on bacterial vaginosis was performed by Riggs [13]. These authors recruited 3077 women of reproductive age from gynecologic and family planning clinics in Birmingham, AL for a 1-year prospective longitudinal study. Gram stains were used to quantify vaginal flora. In this study, there was decreased bacterial vaginosis prevalence among oral contraceptive users (odds ratio, OR 0.76; confidence interval, CI 0.63–0.90) and among those using hormonal injections/implants (OR 0.64; CI 0.53–0.76). An increased risk for bacterial vaginosis (OR 1.38; CI 1.11–1.71) was observed among those women who had tubal ligation, and condom users had no change in their bacterial vaginosis risk (Table 3). As noted in Tables 3 and 4[12–17], Riggs et al.[13] grouped those women using DMPA and those having implantable contraceptives together, even though the type, concentration and delivery route of progestins delivered in these hormonal contraceptives differs significantly [13].Table 3: Cross-sectional studies linking contraceptive use with prevalent bacterial vaginosis.Table 4: Longitudinal studies of contraceptives and acquisition of bacterial vaginosis.Six longitudinal studies that assessed bacterial vaginosis incidence or recurrence are summarized in Table 4. These authors reported that women using oral contraceptives had a reduced incidence of trichomoniasis when compared with the comparator group of women using either an IUD or having had a tubal ligation (RR 0.56, 95% CI 0.39–0.81) [12]. In this same study, there was a trend toward decreased incident bacterial vaginosis among women using oral contraceptives (Table 4). Rifkin et al.[14] enrolled 330 women recruited from a sexually transmitted clinic and evaluated incident bacterial vaginosis among women using progestin only oral contraceptives or combined oral contraceptives compared with women who reported no exogenous hormones. As summarized in Table 4, women using either type of oral contraceptives had significantly reduced rates of bacterial vaginosis. In a study of 948 Kenyan sex workers, Baeten et al.[17] reported a decreased incidence of bacterial vaginosis among women using oral contraceptives. Bradshaw et al.[16] performed a secondary analysis of a randomized trial evaluating a probiotic treatment for bacterial vaginosis and found that both consistent condom use and use of an estrogen-containing contraceptive reduced recurrent bacterial vaginosis. The least-well studied contraceptive method with respect to incident bacterial vaginosis is the IUD. As summarized in Tables 3 and 4, IUD usage was not reported to be associated with prevalent bacterial vaginosis by Shoubnikova [81], but was linked with a nearly threefold increased prevalence of bacterial vaginosis by Calzolari et al.[82]. The first study of both copper and levonorgestrol IUD users and incident bacterial vaginosis diagnosed by Gram stain Nugent criteria was reported by Madden et al. in 2012 [15]. In this study, women using IUDs were less likely to report condom usage than were women who reported using oral contraceptives, vaginal rings or patches. They were also more likely to report irregular bleeding, which was also associated with an increased incidence of bacterial vaginosis. By univariate analysis, IUD users were significantly more likely to acquire bacterial vaginosis. However, after adjustment for irregular bleeding, IUD usage was no longer associated with an increased risk of bacterial vaginosis. Even though this study had too few cases of incident bacterial vaginosis to clearly assess the impact of the hormonal vs. the nonhormonal IUD, the analysis demonstrated that factors such as bleeding and condom usage could confound the associations between contraceptive method and bacterial vaginosis. A number of prospective-cohort studies have evaluated vaginal microflora over 2–6 months of contraceptive use. For example, Gupta et al.[85] and Eschenbach et al.[86] reported that the vaginal microflora was unchanged 1–2 months after initiating COC use. Miller et al.[8] reported that among 38 women initiating DMPA use, there was a statistically significant decline in colonization by lactobacilli producing hydrogen peroxide, although bacterial vaginosis did not increase in these women over 6 months of follow-up. There is little published data available on the impact of vaginal rings on the vaginal ecosystem. In one crossover study of 64 women randomized to receive either the hormonal contraceptive ring or oral contraceptives, and who were then crossed over to the other method, participants were more than twice as likely to be colonized by more than 100 000 colony forming units of hydrogen peroxide producing lactobacilli while using the ring [87]. However, in this study and a subsequent randomized trial of 500 women comparing vaginal microflora among women using hormonal contraceptive rings or hormonal contraceptive patches, there was no statistically significant change in vaginal microflora over time as assessed by Nugent score [88]. Thus, there is no evidence suggesting the vaginal ring has any clinically significant impact on vaginal microflora and/or acquisition of vaginal infections. The data gathered to date are clearly insufficient to draw any conclusions about the impact of many contraceptives on vaginal infections. Although, the strongest data suggest a consistent association between oral contraceptives and reduced bacterial vaginosis, the mechanism for this protective benefit is unclear. The well controlled studies in which women are followed after initiating their contraceptive method are very small, and the measures of the microbiota rely on clinical signs of bacterial vaginosis, the Nugent criteria or very selected evaluation of individual constituents of the microbiota. There is almost no data that assess the impact of the hormonal vs. the nonhormonal IUD on the microbiota, and most studies have grouped different hormonal methods together for convenience. There are extremely limited data on the impact of the copper IUD on the vaginal microbiota even though it is the only nonhormonal long acting reversible contraceptive available at this time. It is therefore difficult to assess the independent role of progestins, or to ascertain from the existing studies whether there is any dose relationship between changes in the bacterial flora and contraceptive hormones. Is there an association between contraceptive use and yeast colonization or yeast vaginitis? Yeast vaginitis has been linked with an increased risk of HIV among Zimbabwean and Ugandan women who had vaginal yeast at the visit prior to and at the visit during which HIV was detected (hazard ratio 2.97, 95% CI 1.67–5.28) [89]. As summarized in Table 4, there has been an inconsistent association between oral contraceptive use and yeast vaginitis. Women using COCs have been reported to have an increase in yeast vaginitis [12,17], a decrease in yeast colonization [85] or no effect on yeast colonization [16] depending on the study size and design. There is a similar inconsistent relationship between DMPA usage and yeast with some studies reporting decreased colonization [8] and decreased yeast vaginitis [17], and other authorsreporting increased yeast colonization in women using DMPA [90]. The association between yeast colonization and yeast vaginitis and contraceptive deserves further study given the lack of adequate data on hormonal and nonhormonal IUDs, implants, and vaginal rings (Table 5) [8,12,17,85,86,90].Table 5: Association between contraceptive use and vaginal colonization by yeast or yeast vaginitis in longitudinal cohort studies.Summary and identification of key knowledge gaps Although there is a large body of published literature on the impact of contraceptive methods on genital immunity and vaginal microflora, these studies have several important limitations. The study of noncontraceptive effects of hormonal contraceptive use has been complicated by the sheer diversity of available contraceptive hormones, the unaccounted for differences in local tissue and systemic hormone exposure associated with different methods, and the differing routes of delivery, all of which may impact HIV risk. Few studies have accounted for how changes in bleeding patterns associated with some types of contraceptives and decreased condom usage, both of which can impact the genital microflora, altered the relationship between contraceptives and flora changes. Importantly, most studies evaluating the impact of contraception on genital immune cells or changes in the vaginal flora have been secondary analyses of randomized trials or small, well controlled prospective studies that have been too small to detect clinically significant changes. With concern that effective contraceptives such as DMPA could increase the risk of HIV for women living in high HIV-prevalence areas, some experts have advised that reliance on DMPA should be decreased. However, there are a number of research gaps that should be addressed to inform decisions about DMPA and about alternative contraceptives, which have been less studied, may be less effective, and may not have a better safety profile with respect to HIV risk. Although diversifying the contraceptive mix for women is a laudable goal, women and contraceptive providers need access to better research to guide these recommendations. Some of the most critical research gaps identified in this review include the following: The relative binding affinities of the various progestins used in hormonal contraceptives for glucocorticoid receptors, mineralocorticoid receptors and androgen receptors and the subsequent immune and genital tract biological effects of these bound receptors. The changes in genital tract immune cell populations, including CCR5 receptor expression, in women initiating use of a new contraceptive. The full range of available contraceptives should be evaluated. How changes in vaginal microflora impact the number, distribution, activation status, and co-receptor expression of immune cells in the reproductive tract. How bleeding patterns associated with contraceptive methods such as the IUD alter vaginal flora, and whether these changes lead to vaginal flora patterns that enhance HIV risk. The impact of hormonal vs. nonhormonal IUDs, and implantable contraceptives, on the microflora and immune cell populations, especially as these are highly effective contraceptive methods that are most likely to be recommended instead of DMPA. Acknowledgements Conflicts of interest S.L.H. is a consultant for Merck. S.L.A. has no conflicts of interest. Sources of support: US National Institutes of Health/National Institute of Allergy and Infectious Diseases grant support (NIH R01-AI102835)." @default.
W2059449393 created "2016-06-24" @default.
W2059449393 creator A5017547539 @default.
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W2059449393 date "2013-10-01" @default.
W2059449393 modified "2023-10-02" @default.
W2059449393 title "The complexity of contraceptives" @default.
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