The progesterone 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. In previous positron emission tomography studies, we found that smelling AND and EST activated regions primarily incorporating the sexually dimorphic nuclei of the anterior hypothalamus, that this activation was differentiated with respect to sex and compound, and that homosexual men processed AND congruently with heterosexual women rather than heterosexual men. These observations indicate involvement of the anterior hypothalamus in physiological processes related to sexual orientation in humans. We expand the information on this issue in the present study by performing identical positron emission tomography experiments on 12 lesbian women. In contrast to heterosexual women, lesbian women processed AND stimuli by the olfactory networks and not the anterior hypothalamus. Furthermore, when smelling EST, they partly shared activation of the anterior hypothalamus with heterosexual men. These data support our previous results about differentiated processing of pheromone-like stimuli in humans and further strengthen the notion of a coupling between hypothalamic neuronal circuits and sexual preferences.hypothalamus ͉ olfaction ͉ positron emission tomography ͉ sexual orientation I n animals, the choice of sexual partner is highly influenced by signals from sex-specific pheromones. These signals are processed by specific nuclei located in the anterior hypothalamus, identified as male and female mating centers (1-5). A lesion of the respective mating center as well as impairment of pheromone transduction may alter the coital approach in a sex-specific way (3-5). For example, electrolytic lesion of the preoptic area is reported to shift the mean preference of male ferrets away from the estrous females to the stud males (3, 5). Male rats are found to reduce their coital behavior after destruction of the preoptic area and show more interest in stimulus males than receptive females (1). Female ferrets, however, preferred females after destruction of the ventromedial hypothalamic nucleus (2) and did not allow males to intromit (4), whereas female rats increased the proportion of female approaches after kindling of the preoptic area (6).In humans, reproductive functions are mediated by neuronal circuits of the anterior hypothalamus. There is reason to believe that these circuits also participate in the integration of the hormonal and sensory cues that are necessary for our sexual behavior and may also be involved in our sexual preferences (7). The preoptic area of the hypothalamus harbors cells releasing luteinic hormone-releasing hormone (8). These cells develop from the migrating neuroblasts of the olfactory mucosa (9) and mediate estrogen feedback. The estrogen feedback differs between males and females and also is reported to differ between homosexual men (HoM) and heterosexual men (HeM) (10). In addition, the anterior hypothalamus contains neuronal congl...