In addition to the enhancement of growth by glucocorticoids, several species of Aspergillus respond to serotonin. In vitro, serotonin in concentrations ranging from 14 to 235 mM has antifungal properties for conidia and hyphae (Lass-Florl et al. 2002). Interestingly, serotonin receptor antagonists did not have any effect on growth (Lass-Florl et al. 2002). However, similar to data for C. albicans, sertaline inhibited the growth of Aspergillus, and the authors suggested the mechanism may be that of an interaction with a fungal transporter system (Lass-Florl et al. 2001).

Little is known about possible interactions of host hormones with species of Cryptococcus. C. neoformans var grubii and C. neoformans var. neoformans are primary etiologic agents of fungal meningitis in immunocompromised patients (e.g., AIDS), whereas C. gattii causes meningitis largely in immunocompetent individuals (Casadevall and Perfect 1998). Dopamine is a neuroendocrine hormone produced by the tinea nigra of the brain. Cryptococcus is able to utilize dopamine in the production of melanin, which is considered a virulence factor for this organism (Polacheck et al. 1990) and may also be related to the tropism of these fungi for the central nervous system. In recent work, the prevalence of cryptococcal meningitis in males was noted to be greater than in females. Men were more also prone to death despite having significantly higher CD4+ T lymphocyte counts. A laboratory strain and 28 clinical isolates were tested for release of capsular glucoronoxylomannan (a probable immunosuppressant and virulence factor); testosterone but not E₂ was associated with higher levels of glucoronoxylomannan release (McClelland et al. 2013).

Tamoxifen has been known to have antifungal activity (Wiseman et al. 1989). A recent study indicated that tamoxifen, which can act as an E₂ receptor antagonist, and some analogues, synergize with other antifungals against C. neoformans in vitro and in vivo, inhibit the fungus in macrophages, and appear to act by inhibition of the fungal protein, calmodulin, and related proteins (Butts et al. 2014).

We have previously discussed the interactions between hormones and drug-resistance genes in Candida and Saccharomyces. Early studies had shown ketoconazole was a competitive stereo-specific binder for the CBP in C. albicans, and acted as an antagonist against mammalian glucocorticoid receptors (Stover et al. 1983). This binding did not appear related to the antifungal activity of the drug, and there appeared no corticoid effect on the activity. Others have reported inhibitory (Hogl and Raab 1980, 1982) or stimulatory (Ramondenc et al. 1998, 2001) interactions of steroids on azoles. It has been speculated that the presence of an estrogen-like 1,2 diarylethane moiety in azoles may relate to their antifungal activity, and synthesis of azole derivatives emphasizing this moiety produced compounds with antifungal activity (Massa et al. 1992).

The observation of gynecomastia in some of our patients led to our discovery that azole drugs block steroidogenesis in mammalian cells and in man, due to interference with specific P450 steroidogenic enzymes (Stevens 1985). This has led to the utility of these agents in the therapy of hypercortisolemic states and in androgen blockade in prostatic cancer.

The direct effects of hormones on the fungi can influence the pathogenesis of the organism, such as those we described for paracoccidioidomycosis. However, there are alternative explanations for fungal pathogenesis that include hormonal effects on host mucosa, as is important in vaginal candidiasis, and possibly oral candidiasis (Junqueira et al. 2005), and hormonal effects on the host immune response (Marriott and Huet-Hudson 2006). There is an extensive literature on hormonal effects on the mucosa and on the immune response, which could profoundly affect the host-fungal pathogen interplay, and we have only cited some key articles here. Perhaps the most well-known effect of hormones on the immune response to fungi relates to the effect of glucocorticoids in promoting invasive mycoses, particularly aspergillosis and mucormycosis. The newest focus of hormone-related effects on host response to infection is on the effect of vitamin D, crucial for the development and maintenance of bones. The vitamin D precursor is created by the human skin through exposure to sunlight; more specifically, ultraviolet B rays convert stored 7-dehydrocholesterol into cholecalciferol (vitamin D₃). Vitamin D₃ is transferred via the bloodstream to the liver where it is converted to calcidiol. Vitamin D has also been shown to enhance a great variety of immune functions (Baeke et al. 2010). Of particular relevance to fungal infection, vitamin D deficiency increases Th2 responses to A. fumigatus, and vitamin D has been shown to down-regulate Aspergillus-induced Th-2 cytokines, such as IL-5 and IL-13, from cells of allergic bronchopulmonary aspergillosis (ABPA) patients; however, gliotoxin, produced by the fungus, has been shown to overcome the vitamin D/vitamin D receptor down-regulation of IL-5 and IL-13 (Kreindler et al. 2010). We were unable to show any effect of vitamin D on systemic aspergillosis in mice or its treatment (Sirivoranankul et al. 2014).

As is evident from the information presented in this chapter, the field of fungal endocrinology encompasses a number of different areas and shows that these simple eukaryotic organisms can indeed have true hormone receptor interactions. Additional studies are needed in the search for endogenous hormones that regulate mating of higher fungi, such as the dermatophytes, or Coccidioides. The influence and interactions of mammalian hormones on pathogenic fungi remains an area for study that has thus far given indications that host hormones can positively or negatively influence the pathogenesis of a fungal infection. For example, hormonal influences on C. albicans have been implicated in the pathogenesis of Candida vaginitis (Tarry et al. 2005). The question of whether these interactions occur through a fungal receptor-mediated process has begun to be addressed for C. albicans, where genomic expression studies have demonstrated up-regulation of genes in the organism related to drug resistance, for example. With the advent of genomics tools, such as microarrays and high throughput sequencing technologies, as well as improvements in proteomic technologies, additional studies are now possible to examine whether the hormonal influence on growth of a fungus is receptor-mediated and what cellular pathways are involved. That is to say, how does estrogen stimulate C. albicans or Coccidioides or how does progesterone inhibit the growth of Trichophyton?

Studies such as those we discussed will shed light on not only the hormonal interactions, but on the basic biology of the organism and the mechanisms by which morphologic change might be regulated. There remains a question of whether fungi like C. albicans or P. brasiliensis produce steroid ligands similar to mammalian estrogens. Thus, does an organism like P. brasiliensis make an endogenous hormone that acts as a regulator of morphology?

Lastly are the questions of what other pathogenic fungi show interactions with the host hormonal milieu and what are the responses of the organisms to the hormones? Thus, we believe that fungal endocrinology is still in its infancy as a field of research and that much remains to be done to gain a full understanding of these interactions.