Paracoccidioidomycosis, a disease caused by Paracoccdioides brasilensis, which is endemic to Latin America, is much more common in men than women, suggesting a role for hormonal factors. We recently showed that two other yeasts possess steroid binding proteins and postulated that these receptorlike molecules represented a mechanism by which the hormonal milieu of the host might influence an infecting pathogen. Therefore, we examined P. bralensis for a sex steroid binding protein. Mr of =60,000. Competition experiments revealed that estrone, estriol, and progesterone had 25% of the affinity of estradiol, whereas diethylstilbestrol, androgens, and corticosteroids had low affinity. Investigation of steroid hormone actions in P. brasiienis indicated that estradiol inhibited the fungal transformation from mycelial form to yeast form, the initial step of infection. This suppressive effect was dose-dependent and not found with testosterone. We hypothesize that endogenous estrogens in the host, acting through the cytosol binding protein in the fungus, inhibit mycelialto-yeast transformation, thus explaining the resistance of women *to paracoccidioidomycosis.Paracoccidioides brasiliensis is a pathogenic fungus, the etiologic agent of paracoccidioidomycosis (South American blastomycosis). Although paracoccidioidomycosis is 13-87 times more common in men than women (1), contact with P. brasiliensis is essentially the same for the two sexes (2). The possibility has been considered that the hormonal milieu of the host might directly influence P. brasiliensis, affecting its pathogenicity (1, 3). Although this hypothesis is speculative, our recent findings (4-6) suggest a basis for a mechanism by which host hormones could affect an invading pathogen and alter its infectious properties. We have demonstrated the existence of intracellular proteins in two fungal genera that bind vertebrate steroid hormones with high affinity and specificity. Candida albicans possesses a protein that binds corticosterone and progesterone (4, 5), and Saccharomyces cerevisiae contains a different protein that selectively binds estrogens (6). We have postulated that these macromolecules may represent primitive hormone receptors in fungi. These proteins appear not only to bind endogenous fungal ligands but also to bind vertebrate steroid hormones, a fact we have exploited in selecting the radioprobes for these studies. Therefore, we considered the possibility that P. brasiliensis could possess either an androgen or an estrogen binding protein which, when occupied by the appropriate host sex steroid, might result in altered pathogenicity, thus explaining the predominance of infections in males. The data to be presented in this report demonstrate that P. brasiliensis does contain an estrogen binding protein. We also show that estradiol inhibits the fungal, transformation from mycelial form to yeast form (mycelial-to-yeast transformation), the initial step in the establishment of infection (7). Although the concordance of binding in vitro and bi...