Sex Hormones and HCV

An Unresolved Mystery

Radwa Y Mekky; Ahmed I Abdelaziz

Disclosures

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

In This Article

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]

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