The testosterone derivative 4,16-androstadien-3-one (AND) and the estrogen-like steroid estra-1,3,5(10),16-tetraen-3-ol (EST) are candidate compounds for human pheromones. AND is detected primarily in male sweat, whereas EST has been found in female urine. In a previous positron emission tomography study, we found that smelling AND and EST activated regions covering sexually dimorphic nuclei of the anterior hypothalamus, and that this activation was differentiated with respect to sex and compound. In the present study, the pattern of activation induced by AND and EST was compared among homosexual men, heterosexual men, and heterosexual women. In contrast to heterosexual men, and in congruence with heterosexual women, homosexual men displayed hypothalamic activation in response to AND. Maximal activation was observed in the medial preoptic area͞anterior hypothalamus, which, according to animal studies, is highly involved in sexual behavior. As opposed to putative pheromones, common odors were processed similarly in all three groups of subjects and engaged only the olfactory brain (amygdala, piriform, orbitofrontal, and insular cortex). These findings show that our brain reacts differently to the two putative pheromones compared with common odors, and suggest a link between sexual orientation and hypothalamic neuronal processes.olfaction ͉ positron emission tomography ͉ hypothalamus ͉ homosexual males A ccording to animal studies, the choice of sexual partner is highly influenced by sex-specific pheromone signals, which are processed by male and female mating centers located in the anterior hypothalamus (1-3). A lesion of the respective mating center, as well as impairment of pheromone transduction, may alter the coital approach in a sex-specific way (3, 4).In a majority of animals, pheromone signals are transferred to the hypothalamus from the vomeronasal organ via the accessory olfactory nerve (5). Because our vomeronasal pit lacks neuronal connections to the brain (5, 6), the occurrence of pheromone transduction has long been questioned in humans. Several recent observations, however, suggest that this type of chemical communication cannot be ruled out. Sex steroid-derived compounds such as 4,16-androstadien-3-one (AND) and, less consistently, estra-1,3,5(10),16-tetraen-3-ol (EST) have been reported to induce sexspecific effects on the autonomic nervous system, mood, and context-dependent sexual arousal (7-12). The exact effects of AND and EST vary with the administered dose and experimental design, but, nevertheless, they seem to be sex-differentiated (especially with respect to AND), and thus to differ from the effects of ordinary odors. Studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have shown that smelling both AND and of EST activates the human brain (13-15), even in nonodorous concentrations (14,15). AND is a derivative of testosterone and is primarily produced in male sweat (16), whereas EST is an estrogen-resembling steroid that has been detected in the ...