**3. Host hormones influences in metabolism, development, and viability of platyhelminths**

The interaction between host and parasite depends on the ability of the parasite to successfully adapt to the host's microenvironment, allowing for a complete life cycle and parasite development [46]. That relationship suffers interference from age, sex, and reproductive status of the host and influences the hormonal profile [47]. Hormones, especially sex steroids, are fundamental for many biological processes such as reproduction, growth, development, and immunity. Parasites can evade the immune system. They can also exploit the host's hormones to improve their growth and reproduction, demonstrating that these organisms have mechanisms to interact with the host's molecules [48, 49].

Female supremacy is an older concept that assumes that female mammals suffer less parasitism than males. The statement that supports this paradigm implies that sexual dimorphism to parasite infections is based, principally, on the host immune system and has less interference of direct effects of hormones on parasites. Analysis of literature contests this paradigm, showing that publications represent few host-parasite systems, most of which have a medical bias, exploring, in general, human infections. Furthermore, there is no definition of infection and the immune parameters that contribute to host resistance or susceptibility to parasitism, casting doubt on the protective effect of those immune indicators. There are several exceptions to female supremacy: in malaria, toxoplasmosis, and cysticercosis, females are more affected by parasite infections than males [50].

Another line of discussion focuses on the influence of host sex in the genetic diversity of parasites. In this study of 2006, the researchers showed that independent of sex, schistosomes have more genetic diversity in male hosts. The authors postulated three hypotheses that explain the genetic variability of schistosomes: the relationship between rat-sex and duration of infection by cercaria; a combination of rat sex and specific habitat on host males that can contribute to more genetic diversity in parasites; a host sex bias in immunocompetence that select more diverse clones in male rats [51].

Together, these pieces of evidence raise new questions about the participation of host hormones in the host-parasite relationship. Do differences in concentrations of sex hormones between males and females have a significant role in the susceptibility to parasite infections? Can host hormones directly affect parasite biology? Do the parasites exploit the host hormones for their growth? Here in this topic, we aim to review the interaction between host hormones and platyhelminths, especially in *S. mansoni*, *T. crassiceps*, and *T. solium.*

As previously mentioned, hormones are important for the modulation of immune responses. The influence of host sex on resistance and susceptibility to parasitism in CBAJ/mice infected with *S. mansoni* showed the following results: females and castrated males had the worst survival rates, with 80% dead after 16 weeks of infection, compared to under 40% of infected males that died. In another experiment, investigators revealed that schistosomula grow better in the low testosterone level group, as noticed by the higher recovery rates of adult worms per cercaria. A possible explanation is the differences promoted by testosterone in the decline of infection effects, represented by a more pronounced organomegaly in the liver and spleen in females and castrated males, which are early pre-mortality indicators. These results start a discussion about the relationship between the host sex and differences in the parasite infection [52, 53].

When it comes to cestodes, we also see the effects of hormones on immunity. To test the influence of androgens in the parasite loads, the researchers investigated the effect of testosterone, dihydrotestosterone (DHT), and 17β-estradiol in castrated female and male mice infected with *T. crassiceps.* The castration triplicated the parasite burden in males and had the opposite effect in females, decreasing the number of parasites by 45%. The treatment with testosterone and DHT reduces de parasite loads in both genders, respectively, 60% and 70%. However, estradiol treatment increases the parasite number in female and male mice three times. Another experiment shows that parasite infection in male mice results in a high level of estradiol, a lower 90% testosterone, and a 95% decrease in DHT [54].

The antibodies' and cytokines' production is also affected by the sex steroids levels. In general, testosterone and DHT have no effect on the production of IgG, IL-6, and IL-10 in both sexes. On the other hand, the production of IL-2 and IFN-γ increases significantly in both sexes, and DHT promotes 70% recovery of the cytokines in males. Estradiol increases levels of anti-parasite IgG by 60% and duplicates IL-6 and IL-10 production in males and females. Those results demonstrated that androgens increase the cellular response in *T. crassiceps* infection with a specifically TH1 pattern. Oppositely, estrogens produce a TH2 immune response, which has no value in stopping the parasite's growth [54].

The effect of progesterone is also investigated in *T. crassiceps* and *T. solium* cysticercosis. In *T. crassiceps* treatment with progesterone, the number of parasites increases by three folds in male and two folds in female mice. Estradiol is increased two times in both genders, suggesting that progesterone is metabolized in the gonad. The cytokines, IL-4, IL-6, and IL-10 levels increase under the infection, with no change after progesterone treatment. In addition, IL-2, TNF-α, and IFN-γ concentration in the spleen is not modified with infection and treatment, but IL-2 is undetected in both sexes infected, and IFN-γ and TNF-α are increasing in progesterone-treated mice. Moving to *T. solium*, progesterone treatment decreases tapeworm length and increases IL-4, IL-6, and TNF-α in the duodenum, combined with a polymorphonuclear leukocytes infiltration. Once again, these results show that progesterone modulates TH1 immune response in *T. crassiceps* and improves intestinal mucosal immunity [55, 56].

Host hormones also directly affect the biology of parasites. Previous experiments showed that dehydroepiandrosterone (DHEA) and DHEA-S have a protected effect on mice infected with *S. mansoni* [57]. Another study demonstrated a negative correlation between DHEAS and intensity of parasitism, and this decline of *S. mansoni* infection also correlated to age [58]. Researchers investigated the effects of hypothalamic-pituitary-adrenal axis (HPA) hormones on *S. mansoni*, including DHEA. Cercariae are more affected than schistosomula and adults, with 100% dead after 48 h of culture, showing a concentration- and time-dependence.

Interestingly, males and paired worms are more resistant to the harmful effects of DHEA than females and separated worms. This fact suggests a beneficial effect of the

#### *Perspective Chapter: Molecular Crosstalk and Signal Transduction between Platyhelminths… DOI: http://dx.doi.org/10.5772/intechopen.103776*

relationship between female and male worms [59]. *T. crassiceps* is negatively affected by DHEA treatment with lower reproduction, motility, and viability [60].

17β-estradiol (E2), progesterone (P4), testosterone (T4), and dihydrotestosterone (DHT) also modulate the parasite physiology. Estrogens stimulated the reproduction and viability of *T. crassiceps*, with E2 being more effective than P4. These hormones are also involved in a high expression of genes c-fos and c-jun of the parasite, correlated to differentiation, reproduction, and apoptosis, showing a relative impact on viability changes. Since this parasite expressed estrogen and androgen receptors (excluding P4), sex steroids can bind these specific receptors and directly affect reproduction [61]. E2 and P4 also increase the expression of actin, tubulin, and myosin, major components of flame cells of the excretory system, benefiting the growth of *T. crassiceps* [62]. Progesterone also affects the development of *T. solium* by promoting evagination, maintaining motility, and inducing growth of the worms by two times [63].

In contrast to the positive effects of estrogens, T4 and DHT have deleterious actions, inhibiting the reproduction and reducing the viability of parasites. Additionally, they reduce the expression of c-fos and c-jun, explaining the changes in reproduction and growth of *T. crassiceps.* This data also agrees that cysticerci grow better in female and castrated males, proposing that the differences in sex steroids' concentrations in males and females are involved [61]. Moreover, T4 and DHT reduce the viability of the parasite by almost 90%, disrupting tegument and changing the structure of flame cells, with direct interaction with actin, tubulin, and myosin, without changes in their expression. This interaction results in the intoxication of the parasite, which explains the significant reduction in viability [64].

These findings improve the critical role of host sex hormones on the host-parasite relationship. Those sex hormones can determine the course of infection by direct effects like modulation in growth, reproduction, and viability or indirect effects such

#### **Figure 4.**

*Effects of sex steroids in parasites S. mansoni, T. crassiceps, and T. solium. Estrogens like E2 and P4 have positive effects on parasites and also modulate the immune response to the Th2 pattern. In contrast, testosterone, dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA) decrease parasite growth and reproduction and increase Th1 cytokines, which protect the host.*

as changes in gene expression and immune system of the host, which sometimes benefit the host and other, permitting the parasite to exploit the microenvironment (**Figure 4**). The knowledge that estrogens and progesterone are related to positive effects on parasites and androgens protecting the host can urge the investigation of the beneficial use of sex steroids as new therapeutic targets to the parasitic infections. It is currently known that taximofen, an antiestrogen, and RU486, a progesterone antagonist, can negatively affect the reproduction and growth of *T. crassiceps* and *T. solium*, respectively [50, 63]. In this way, more discovery of the crosstalk between parasites and sex hormones can change the scenario about antiparasitic drugs, permitting a faster development process with high efficacy and low toxicity [65].

**Figure 4** summarizes the effect of host hormones in the platyhelminths.
