**8. Alternative approaches and their effect on immunity in post menopausal women**

Alternative approaches for dealing with menopausal symptoms have gained significant interest in recent years. One of the most popular interventions is nutritional supplementation with estrogen-like substances that might not have the undesirable side effects of hormones. Dietary phyto-estrogens are organic compounds found in soy products, fruits and legumes (Huntley and Ernst 2004). It has been proposed that the beneficial effects of soybean compounds are mediated by isoflavones such as genistein since they show structural similarities to estradiol (Bingham, Atkinson et al. 1998).

Some rodent studies support a beneficial effect of isoflavones on immune function in postmenopausal animals. In mature ovariectomized female rats, nutritional supplementation with soybean or soybean and green tea improved chemotaxis, phagocytic index as well as the production of reactive oxygen species by peritoneal macrophages (Baeza, De Castro et al. 2010). This nutritional supplementation also improved T and B cell proliferative potential and NK cell killing (Baeza, De Castro et al. 2010). Similar results were reported for human (Zhang, Song et al. 1999) and murine (Guo, McCay et al. 2001) NK cells after exposure to another isoflavone, genistein. Genistein treatment of murine splenocytes in vitro increased IL-10 production thereby tilting the cytokine balance towards a Th2 response (Rachon, Rimoldi et al. 2006).

Post-menopausal women receiving a daily dose of 70mg of isoflavones either in the form of soy milk (700ml) or oral supplements for 16 weeks experienced an increase in the frequency of circulating B cells as well as a reduction in plasma concentrations of 8-hydroxy-2-deoxyguanosine (8-OHdg), an oxidative damage marker (Ryan-Borchers, Park et al. 2006). No changes in the plasma levels of IL-2, IFN or TNF were observed in this and a second study where women consumed comparable amount of soymilk (Beavers, Serra et al. 2009). However in an earlier study where women consumed 1064 ml of soymilk for 16 weeks, a decrease in plasma levels of TNF and IL-1, but not IL-6, were detected (Huang, Cao et al. 2005). These data suggest that additional studies with a bigger range of doses in different populations of post-menopausal women need to be conducted in order to define dynamic ranges and individuals who stand to benefit the most from such nutritional interventions (Genazzani and Pluchino 2011).

Dehydroepiandrosterone (DHEA) is produced by the adrenal cortex and is the most abundant steroid in humans. Serum levels of DHEA and its sulfated conjugation product, DHEA sulfate (DHEAS), peak in men and women in the third decade and decrease progressively and profoundly with age. In the longitudinal Baltimore study, plasma levels of DHEAS emerged at the most consistent aging biomarker and correlated with longevity. In addition to its role as a precursor for androgens and estrogens, DHEA can exert a direct, physiologically relevant, agonistic effect on ERβ, a lesser antagonistic effect on androgen receptor, and a modest effect on ERα (Chen, Knecht et al. 2005). Therefore, DHEA supplementation has been explored as an alternative to classical hormone therapy. Early studies in aged mice, showed that age-related upregulation of IL-6 production could be effectively prevented and/or reversed by supplementing aging animals with DHEA (Daynes, Araneo et al. 1993). More importantly, either DHEA or DHEA sulfate supplementation promoted enhanced antibody responses against recombinant hepatitis B surface antigen by aged mice when incorporated directly into the vaccine (Araneo, Woods et al. 1993). In contrast to the rodent data, the effect of DHEA on the immune response to

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## **9. Conclusions and perspectives**

A considerable body of data strongly suggests that sex hormones modulate immune function with estrogen having an immune stimulatory effect whereas progesterone an immune inhibitory effect. Aging results in several changes in both the immune and the endocrine systems. However the interplay between these two organ systems remains poorly understood. While it is clear that some changes (such as increased IL-6 levels) can be strongly attributed to loss of ovarian steroids, other changes such as lymphocyte function are not easily attributable to menopause. Moreover, the effects of hormone therapy on the post-menopausal immune system are controversial. The discrepancies between studies are in large part due to the variety of hormone replacement regimens available (conjugated equine estrogens, 17 estradiol, progestin), but also reflect the lack of consensus over which immune parameters are analyzed. As new safer hormone replacement therapies become available such as transdermal low levels of estradiol, the immune modulatory capacities of these treatments should be characterized. Future studies should also examine how changes in additional sex hormones such as FSH, LH and increased androgen production by the senescent ovary affect the immune system.

#### **10. Acknowledgments**

This work was supported by American Heart Association career development grant 0930234N, NIH R01AG037042, NIH P51 RR00163-51, the Center for Gender Based Medicine and the Brookdale Foundation. We would like to thank Kristen Haberthur and Dr. Delphine Malherbe for reviewing and editing this chapter.

### **11. References**


influenza vaccine in older humans is controversial. Earlier studies showed one oral dose of DHEAS before influenza vaccination was associated with a demonstrable increase in the number of individuals with a fourfold increase in hemagglutinin inhibition (HI) titers following vaccination (Araneo, Dowell et al. 1995). Similarly, one dose of DHEAS administered at the time of influenza vaccination appeared to enhance the HI titer in a small group of older adults with lower prevaccination titers and lower DHEAS concentrations (Degelau, Guay et al. 1997). In contrast, a 6-day course of DHEA treatment that began 2 days before vaccination did not improve the age-related declined response to immunization against influenza in human subjects (Danenberg, Ben-Yehuda et al. 1997). These results suggest additional detailed immunologic investigations on the role of DHEAS in the aging

A considerable body of data strongly suggests that sex hormones modulate immune function with estrogen having an immune stimulatory effect whereas progesterone an immune inhibitory effect. Aging results in several changes in both the immune and the endocrine systems. However the interplay between these two organ systems remains poorly understood. While it is clear that some changes (such as increased IL-6 levels) can be strongly attributed to loss of ovarian steroids, other changes such as lymphocyte function are not easily attributable to menopause. Moreover, the effects of hormone therapy on the post-menopausal immune system are controversial. The discrepancies between studies are in large part due to the variety of hormone replacement regimens available (conjugated equine estrogens, 17 estradiol, progestin), but also reflect the lack of consensus over which immune parameters are analyzed. As new safer hormone replacement therapies become available such as transdermal low levels of estradiol, the immune modulatory capacities of these treatments should be characterized. Future studies should also examine how changes in additional sex hormones such as FSH, LH and increased androgen production by the

This work was supported by American Heart Association career development grant 0930234N, NIH R01AG037042, NIH P51 RR00163-51, the Center for Gender Based Medicine and the Brookdale Foundation. We would like to thank Kristen Haberthur and Dr. Delphine

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**13** 

*México* 

**The Role of Sex Steroids** 

*1Departamento de Infectología e Inmunología,* 

*Universidad Nacional Autónoma de México 3Subdirección de Investigación Básica,* 

**in the Host-Parasite Interaction** 

Karen Nava-Castro1, Romel Hernández-Bello2, Saé Muñiz-Hernández3 and Jorge Morales-Montor2

*Instituto Nacional de Perinatología, Secretaria de Salud* 

*Instituto Nacional de Cancerología, Secretaria de Salud* 

*2Departamento de Inmunología, Instituto de Investigaciones Biomédicas,* 

In this Chapter, we intend to review and discuss the current literature, and the state of the art related to the role that sex steroids play in the complex host-parasite relationship, particularly during *Taenia crassiceps* and *Taenia solium* cysticercosis. It is well known that sexsteroids regulate a variety of cellular and physiological functions of organisms such as growth, reproduction and differentiation. More recently the ability of sex steroids to affect the immunological response directed against pathogenic agents, and importantly the direct effect of these molecules on these organisms, have gained attention. These effects are clearly evident during various parasitic diseases including malaria, schistosomiasis, toxoplasmosis, cysticercosis, trypanosomiasis and leishmaniasis, where strong steroid hormone regulation of the immune response, has been described (Remoué et al., 2001; do Prado et al., 1998; Satoskar & Alexander, 1995; Vargas-Villavicencio et al., 2006; Libonati et al., 2006; Liesenfield et al., 2001). For instance, sex steroids play a significant role in regulating the parasite load in experimental intraperitoneal *Taenia crassiceps* cysticercosis of male and female Balbc/anN mice. Briefly, estrogens increase parasite loads and androgens decrease them (1) by acting directly on the parasite, favoring or hindering its reproduction, respectively, and (2) by biasing the hosts' immune response towards a parasite-permissive Th2 or a parasite-restrictive Th1 response. Recent experimental evidence, suggests that either steroids hormones may exert their effects directly upon the parasite, which may be able to exploit the host hormonal microenvironment for its exclusive benefit. The fact that steroids can directly influence parasites has been described in at least 17 different species of helminths and protozoan with medical and veterinary relevance. Briefly, we detail some of the most important experimental evidence about direct effects of steroid upon parasites. In fact, the hormonal microenvironment inside an immunocompetent host is so important, that experimental evidence suggests that an inadequate hormonal environment may lead to apoptosis of crucial parasite cells, as has been proposed in some parasites (e.g., retinoic acid

**1. Introduction** 

