The anatomical pathways for processing of odorous stimuli include the olfactory nerve projection to the olfactory bulb, the trigeminal nerve projection to somatosensory and insular cortex, and the projection from the accessory olfactory bulb to the hypothalamus. In the majority of tetrapods, the sex-specific effects of pheromones on reproductive behavior is mediated via the hypothalamic projection. However, the existence of this projection in humans has been regarded as improbable because humans lack a discernable accessory olfactory bulb. Here, we show that women smelling an androgen-like compound activate the hypothalamus, with the center of gravity in the preoptic and ventromedial nuclei. Men, in contrast, activate the hypothalamus (center of gravity in paraventricular and dorsomedial nuclei) when smelling an estrogen-like substance. This sex-dissociated hypothalamic activation suggests a potential physiological substrate for a sex-differentiated behavioral response in humans.

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 ...

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...