**7. Concluding remarks**

282 Sex Steroids

reproduction and increasing its mortality (Vargas-Villavicencio et al., 2007). Another steroid that was recently tested and found to be implicated in the regulation of the parasite loads during murine cysticercosis is progesterone (P4). P4 treatment has a dichotomic effect: if mice of both sexes are non-gonadectomized (intact), P4 treatment increased parasite loads, possibly through manipulation of the specific cellular immune response, besides the steroid's promotion of parasite reproduction (Vargas-Villavicencio et al., 2005). However, if mice are gonadectomized, P4 completely decreases parasite loads, an impressive and unprecedented cysticidal effect, the likes of which are absent from other preventive or therapeutic measures (Vargas-Villavicencio et al., 2006). These two experiments suggests that, in intact hosts, progesterone is metabolized to estradiol, that is permissive for parasite reproduction, while in castrated animals, there is an active metabolism of progesterone in the adrenal glands to androgens, resulting in a toxic effect in the parasite growth (Vargas-Villavicencio et al., 2005, 2006). The major steroid produced by the adrenal gland is the androgen dehydroepiandrosterone (DHEA). So, another set of experiments showed DHEA effect on male and female infected mice. DHEA treatment reduced parasite loads by 70 and 80% respectively. In contrast with the common assumption of DHEA as an immunostimulatory hormone, the immune responses of our mice was not affected by DHEA treatment (Vargas-Villavicencio et al., 2008). *In vitro*, treatment of *T. crassiceps* cysticerci with DHEA induced an 80% reduction in parasite reproduction, which may partially explain the reduction of parasite loads observed *in vivo* a partial effect suggesting the involvement of other unknown factors in the *in vivo* regulation of parasite loads (Vargas-Villavicencio et al.,

Not only do sex steroids regulate parasite loads through the immune response modulation of the host, but also they directly act upon cysticerci reproduction. For instance, it has been shown that E2 and P4 *in vitro* treatment stimulates *T. crassiceps* reproduction, while *in vitro* treatment with T or DHT inhibit and even exert a slight toxic effect on the parasite (Escobedo et al., 2004). The possible molecular mechanisms by which sex-steroids affect *Taenia crassiceps* reproduction, imply the presence of estrogen receptors (both α and β isoforms) and androgen receptors, but no progesterone receptors. In addition, once host's E2 has bound to its parasite estrogen receptor, the active, ligand bound complex would activate the transcription of several *Taenia crassiceps* proliferative genes, such as *c-fos, c-jun* and cyclin D1, and in that way up-regulate parasite growth and reproduction. All this hypothetical molecular mechanism could be interrupted *in vitro* by means of using tamoxifen that is well known for its anti-estrogenic effects (Vargas-Villavicencio et al., 2007), which strongly suggests a genomic action mechanism for 17-β estradiol on the parasite. On the other hand, action mechanism of the androgen is likely different from the found for estrogens and progesterone. Testosterone and DHT likely directly affect parasitic DNA integrity by activating apoptotic mechanism in the cysticercus cells. This experimental finding is not dependent of a nuclear receptor, because flutamide (a well studied and used anti-androgen) did not have effects upon parasite reproduction *in vitro* (Escobedo et al., 2004). These results demonstrate that sex steroids act directly upon parasite reproduction perhaps by binding to receptors closely resembling classic and specific sex-steroid vertebrate receptors (Escobedo

**6. Sexual steroids directly act upon** *Taenia crassiceps*

2008).

et al., 2004) (64).

The evidence presented above illustrates the complexity and importance of neuroimmunoendocrine interactions during helminth infections, and provides clues to the many other possible mechanisms of parasite establishment, growth and reproduction in an immunocompetent host. Further, strong neuroimmunoendocrine interactions may have implications in the control of transmission and treatment of several parasitic diseases, but particularly in those produced by helminth parasites, in animals and humans. In practical importance, the complexity of the helminth-host relationship suggests that all physiological factors (i.e., sex, age) should be taken into account in the design of vaccines and new drugs. The differential response of helminthes to sex steroids may also be involved in their ability to grow faster in female or male hosts. Host and parasite sex-associated biases may be combined to favour their evolution towards a mutually acceptable relationship. Also, the strong immune-endocrine interactions observed during *Taenia crassiceps* and *Taenia solium* cysticercosis, could give ways to possible new mechanisms of parasite establishment, growth and reproduction in an immunocompetent host.
