April 14, 2013

Sex Hormones and HCV

Expert Review of Gastroenterology and Hepatology

An Unresolved Mystery

Radwa Y Mekky, Ahmed I Abdelaziz

Expert Rev Gastroenterol Hepatol. 2013;7(1):69-75.

Abstract and Introduction
Abstract

The biological differences between males and females advocate the ultimate need for gender-specific medicine. The variation in response to viral infection as well as therapy among different genders makes it very intriguing to reveal the responsible factors for causing this discrepancy. HCV is one of the most noxious infectious diseases, however the impact of gender on the response to HCV has received negligible attention in the literature. The controversial studies concerning the effect of gender on the outcome of interferon-based therapy urge a need to judge the gender discrepancy in host factors responsible for both interferon release and action. The main aim of this review is to disentangle the interplay between sex hormones and several viral and host factors responsible for viral clearance in an attempt to clarify the role of gender in modulating the response to HCV as well as interferon-based therapy.

Introduction

The numerous diversities among males and females make them respond variably to disease and therapy. This variation has stimulated an interest in the implementation of gender-specific medicine, wherein the genetic diversity between different genders is taken into consideration. Accordingly, the therapeutic dosage given to either males or females is adjusted in an attempt to reach the optimal therapeutic outcome with minimal adverse events.

Chronic hepatitis C infection is considered a major healthcare burden worldwide, with high prevalence in Africa and the Middle East, especially in Egypt.[1] The fact that HCV is characterized by high mutation rates makes it capable of escaping the host immunological response.[2] Consequently most HCV-infected patients suffer a chronic form of infection. Recently gender has emerged as a major factor affecting the innate response to HCV; the rate of spontaneous clearance of HCV was found to be higher among HCV-infected females when compared with male patients.[3–5] The exact factors responsible for this variability in the natural history of the disease are still not well known.

Gender has also been suspected to contribute to the variable response to standard HCV therapy (pegylated interferon (IFN) and ribavirin).[6] The goal of standard therapy of HCV infection is to achieve a sustained virologic response (SVR), which is defined as the absence of HCV RNA in the serum, 6 months after the end of treatment.[7] Unfortunately, the possible effects of gender on treatment response are still contested. On one hand, some recent studies have revealed that an SVR is more prominent among male patients.[8,9] On the other hand, female gender has been widely reported to be a good prognostic factor to IFN based therapy.[10–12] Alternatively, various studies have denied the association between gender and the outcome of therapy.[13–16] To help unravel the ambiguity surrounding this issue an important question should be investigated: could the actions of sex hormones on viral and host factors explain the disparate rates of viral clearance and response to therapy between males and females? Thus this review aims at analyzing the sex hormones' impact on viral and host factors that are important in viral clearance in an attempt to demystify the gender variation in self-limited infection to HCV and therapeutic response to IFN-based therapy.

Viral Behavior Among Different Genders

Although HCV infection is characterized by persistence, it is documented that 15–30% of individuals show spontaneous clearance of the virus.[17] Gender is one of the main factors that has been widely reported to influence the HCV clearance rate, where HCV-infected females have shown higher clearance rates when compared with their male counterparts.[3,4]

The disparity in self resolution of HCV infection among males and females suggests a role for sex hormones in influencing viral behavior. However, the impact of female sex hormones on HCV remains enigmatic; it is not known whether they hold a beneficial or detrimental role towards virological clearance. For example, 17β-estradiol was found to act directly on the virus itself by possessing an inhibitory effect on mature virion production in cultured Huh-7.5 cells transfected with viral replicon (Figure 1).[18] However, in the same study this inhibitory effect was not observed upon treatment with progesterone.[18] Moreover, the coumestans family of phytoestrogens, naturally occurring estrogen-like compounds derived from some plants and belonging to the flavonoids category of phytoestrogens, was reported as novel candidates for targeting viral replication by acting on HCV NS5B, a nonstructural viral protein essential for replication.[19] Pregnancy, a state of elevated estrogen and progesterone, was found to decrease the activity of chronic HCV. This effect was abolished after delivery.[20] In contrast to the aforementioned studies, Watashi et al. reported that estrogen receptor-α is functionally associated with HCV replication and its blockage with tamoxifen, a selective estrogen receptor modulator, may be a novel approach for targeting HCV infection (Figure 1).[21] The conflicting data concerning the influence of female sex hormones on HCV necessitate an in-depth look into their effects at various stages of the viral life cycle.

778968-fig1

Figure 1.

Sex hormone impact on the HCV life cycle. 1. HCV enters the host cells through cell surface receptors CD81, SR-B and LDLR. Tight junction proteins OCLN and CLDN are co-receptor molecules important for viral entry. 2. After viral entry, uncoating of the virus and cytoplasmic release takes place. 3. Translation occurs on the rough endoplamic reticulum. 4. Association of produced viral proteins with the ER results in production of a membranous web upon which replication takes place. 5. Assembly of the viral proteins occurs. 6. Mature virions exit host cell via exocytosis. Testosterone was found to enhance HCV entry by positively (+) regulating both SR-B as well as CLDN. Oppositely, estrogen decreased (-) the expression of SR-B. Estrogen receptor a was found to be a crucial host factor used by the virus to promote its own replication. However, estrogen was reported to inhibit (-) the release of mature virions from infected Huh-7 cell lines.

CLDN: Claudin; ER: Endoplasmic reticulum; LDLR: Low-density lipoprotein receptors; OCLN: Occludin; SR-B: Scavenger receptors class B.

The impact of testosterone on HCV behavior represents another piece of the puzzle. Surprisingly, to date, the effect of testosterone on HCV replication has not been studied. However, it was reported that testosterone enhanced the expression of scavenger receptors, which are critical for viral entry, on both HepG2 cell lines and human monocyte-derived macrophages in a dose-dependent manner.[22,23] Interestingly, estrogen suppressed the expression of hepatic scavenger receptors (Figure 1).[24] In the same context, testosterone enhanced the expression of the tight junction protein claudin, which also plays a central role in HCV cellular entry (Figure 1).[25,26] These aforementioned studies might elucidate the role of testosterone in enhancing viral entry to host cells thus highlighting a gender bias toward HCV response.

Discrepancy in IFN Release Among Different Genders

Variation in IFN induction among males and females may help to explain the differences in immune response to HCV. Toll-like receptor (TLR) 7 is a receptor which recognizes HCV RNA. The activation of this receptor leads to IFN-α induction, which consequently activates interferon-stimulated genes (ISGs) that allow viral clearance (Figure 2).[27,28] TLR7 showed a higher sensitivity to TLR7 agonists in healthy females when compared with healthy males, which consequently led to enhanced production of IFN-α.[29]

778968-fig2

Figure 2.

Impact of sex hormones on pre- and post-IFN release. (A) HCV attaches to cell surface receptors, and after uncoating the virus, binds to endosomal TLR7 which consequently leads to induction of IFN-α, -β, -λ and -γ via activation of several transcription factors. Among these transcription factors are IRF7 and NF-κB. Sex hormones regulate IFN release in several ways. For example, estrogen and progesterone were found to enhance expression of TLR7. However, progesterone was found to abrogate the expression of IRF7. Estrogen was also found to downregulate the expression of NF-κB. (B) After IFN is released they bind to their receptors, which activate the JAK/STAT pathway leading to production of ISGs. The JAK/STAT pathway is negatively regulated by certain transcription factors such as SOCs. Estrogen was found to attenuate the JAK/STAT pathway by enhancing the expression of SOCs and downregulating ISG expression.

+: increasing the expression; -: decreasing the expression; IFNAR: Interferon receptor; IRF7: Interferon regulatory factor 7; ISG: Interferon-stimulated gene; SOCS: Suppressors of cytokine release; TLR: Toll-like receptor.

Female sex hormones were reported to affect certain host factors that are important for IFN release. For example, estrogen was reported to suppress the maturation of dendritic cells, which are the main producers of IFN.[30] Estrogen was also found to negatively regulate NFκB, a transcription factor that is fundamental for production of IFN (Figure 2).[31] Progesterone was also reported to impair the antiviral immune response by decreasing the response of plasmacytoid dendritic cells through abrogating the activation of interferon regulatory factor 7, an important transcription factor for IFN production (Figure 2A).[32] However conflicting data by Meier et al. found a significant correlation between an increased production of IFN-α in healthy female plasmacytoid dendritic cells after being triggered with TLR7/8 ligands and plasma levels of progesterone (Figure 2A).[33]

The impact of testosterone on IFN release has received negligible attention in the literature. However, the discrepant rates of self-limited infection in males and females may be explained by the contrasting effects of estrogen and testosterone on the expression of the TLR family; where testosterone did not alter the expression of TLR on the surface of peripheral blood mononuclear cells (PBMCs) from healthy volunteers, while estrogen enhanced its expression (Figure 2A).[34]

Regulation of IFN Response Among Different Genders

Gender variation in response to endogenous and exogenous IFN might help decode the differences between the sexes with respect to response to standard IFN therapy. After IFN is released it binds to its receptor, which consequently activates the JAK/STAT pathway (Figure 2B). A line of evidence exists that posits that genetic variation among different genders may be responsible for the variability in IFN activity. Polymorphism in the promoter region of IL-10 was shown to induce high amounts of IL-10 in HCV-infected females.[35] This cytokine was reported to be associated with IFN resistance through inhibition of the expression of IFN-α inducible genes by prevention of tyrosine phosphorylation of STAT and upregulation of suppressor of cytokine 3 (Figure 2B).[36] It was also recently reported that females carrying the minor allele of single nucleotide polymorphism (rs8099917) in IL-28B, one of the strong predictors of response to IFN-based therapy, have the highest probability of null response to IFN therapy when compared with males. The same study found that males carrying the major allele have the lowest probability of null response.[37] Another recent study reported that females carrying the favorable genotype of IL-28B polymorphism showed higher chances of IFN response when compared with males carrying either the favorable or unfavorable genotype of IL-28B.[38] Another explanation for the enhanced IFN action in HCV-infected females is the higher rate of ISGs induction in PBMCs after IFN stimulation compared with their male counterparts.[39]

Young age and low BMI are two factors rendering premenopausal women better responders to IFN therapy.[40,41] Nevertheless, it is considered inevitable that female sex hormones play a major role in enhancing IFN action.[42,43] The exact mechanisms by which female sex hormones affect IFN response are not well characterized, however suppression of hepatic iron load by estrogen could offer an explanation for the decreased rate of IFN resistance among female HCV patients.[44,45] It was also found that estrogen represses the elevated levels of IL-6,[46] a cytokine found to be elevated during menopause and to play a major role in IFN resistance.[43,47] Among the beneficial effects of estrogen is the attenuation of IL-8 release by monocytes, which has been reported to inhibit IFN-induced antiviral response.[48,49] Recently, a cohort study suggested a potential synergism between female sex hormone and IL-28B polymorphism; where women carrying favorable CC genotype for rs12979860 have the greatest likelihood to resolve HCV infection.[38] Although several studies have underlined the beneficial role of estrogen in promoting SVR among females, others have still reached opposing results. For example, estrogen was also proven to attenuate the JAK/STAT pathway by downregulating ISGs in HCV-infected PBMCs and upregulating SOCS expression, a negative regulator of the JAK/STAT pathway, in hepatic cells both in vivo and in vitro (Figure 2B).[39,50] This effect was reversed by progesterone in ovariectomized hormonal treated mice.[51] This latter study highlights the role of estrogen–progesterone interaction on immune modulation. These contradicting studies urge the need to study the cross talk between estrogen and progesterone in modulating the response to HCV infection.

To underscore the sexual dimorphism in IFN action, it's worth mentioning the impact of testosterone on various factors affecting IFN resistance. In vitro stimulation of female monocytes with testosterone enhanced the production of IL-1b, a cytokine negatively associated with IFN outcome.[52,53] Additionally, a recent correlation was drawn between an undesired outcome of IFN treatment and a low baseline of adiponectin.[54] It was suggested that testosterone plays a role in decreasing adiponectin levels in males after puberty, which may propose an indirect role for male sex hormones in modulating the response to IFN-based therapy.[55]

Conclusion

The disparate rates of viral clearance and response to therapy between HCV-infected males and females is still considered an unresolved mystery. Thus in an attempt to unravel this ambiguity, the authors highlight a plausible impact of sex hormones on viral behavior and on host factors affecting both IFN release and action. The scarce scientific studies addressing this issue hampered the comprehensive understanding of gender bias to this noxious viral infection. Consequently, the implementation of gender-specific medicine on HCV-infected patients is challenged. Thus it is considered particularly important to deeply investigate the precise role sex hormones on each specific step of the HCV life cycle.

Expert Commentary

From our point of view, though female sex hormones are downregulators of endogenous release of IFN, they indirectly inhibit various host factors that cause IFN resistance, therefore indirectly render females better responders to interferon therapy. The exact role of sex hormones in the natural course of infection and treatment has not been critically investigated. This raises the question: 'can HCV-infected males and females undergo hormone replacement therapy either alone or during IFN treatment?' More investigation is needed to clarify this issue.

It is noteworthy that 20–25% of HCV patients progress to chronic liver cirrhosis, wherein sex hormone levels are altered.[56] Female sex hormone levels are elevated while testosterone levels are decreased in patients who exhibit liver cirrhosis.[57–59] This makes it crucially important to study the impact of hormonal imbalance after HCV liver disease progression on viral behavior.

Five-year View

In the upcoming 5 years, hopefully comprehensive understanding of genetic disparities between HCV-infected males and females will unravel the ambiguity concerning this issue. Moreover, after the emergence of a HCV cell-culture system it might be easy to study the role of sex hormones on each step of the HCV life cycle. This might open the gates toward novel investigation in HCV pathogenesis. To date, the impact of sex hormones on direct acting antiviral agents, such as the protease inhibitors telaprevir and boceprevir, has never been investigated except from a pharmacokinetic point of view. Co-administration of hormonal contraceptives such as ethinyl estradiol with these antiviral drugs lead to a decrease in the therapeutic concentration of oral contraceptive and treatment failure.[60] This mandates that in the next 5 years, extensive investigation of the role of gender and sex hormones on direct acting antiviral agents should take place.

Sidebar
Key Issues
  • Recently, gender has emerged as a major factor affecting the innate response to HCV; the rate of spontaneous clearance of HCV was found to be higher among HCV-infected females when compared with male patients. The exact factors responsible for this variability in the natural history of the disease are still not well known.

  • Sex hormones influence viral behavior. However, the impact of female sex hormones on HCV remains enigmatic; it is not known whether they hold a beneficial or detrimental role towards virological clearance. However, to date, nothing is known concerning the effect of testosterone on HCV replication.

  • Female sex hormones were reported to be downregulators of many host factors that are important for interferon (IFN) release while the role of testosterone on IFN release has received negligible attention in the literature.

  • A line of evidence exists that proposes that genetic variation among different genders may be responsible for the variability to IFN therapy. In particular, females carrying the favorable genotype of the IL-28Bpolymorphism showed higher chances of IFN response when compared with males carrying either the favorable or unfavorable genotype of IL-28B [38]. Moreover, peripheral blood mononuclear cells derived from HCV-infected females showed higher rates of interferon-stimulated gene induction after IFN stimulation compared with their male counterparts [39].

  • The higher chance of premenopausal women achieving sustained virologic response when compared with postmenopausal HCV patients suggests a key role for female sex hormones in enhancing IFN action. Female sex hormones indirectly promote IFN action by decreasing various factors that causes IFN resistance. On the other hand, testosterone enhances the production of various cytokines involved in IFN resistance.

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** A recent study highlighting a possible pharmacokinetic interaction between telaprevir and hormonal contraceptives advises that females should use nonhormonal contraceptives when administering telaprevir.

Papers of special note have been highlighted as:
* of interest
** of considerable interest

Expert Rev Gastroenterol Hepatol. 2013;7(1):69-75. © 2013 Expert Reviews Ltd.

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