Brain response to putative pheromones in homosexual men

Abstract

According 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 sex-specific 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 urine of pregnant women (17). Male sweat has recently been reported to alter the pulsative hypothalamic release of luteinic hormone in females in an ovulation-promoting way (18). Thus, although it is premature to classify AND and EST as pheromones, the data suggest that they may function as chemosignals.

In a previous PET study of regional cerebral blood flow (rCBF) in heterosexual subjects (13), we found that smelling AND and EST caused a sex-differentiated activation of the anterior hypothalamus. In women, AND activated the preoptic area and ventromedial nuclei, whereas, in men, activation by EST involved an area covering the paraventricular and dorsomedial nuclei. In contrast, when men smelled AND and women EST, activations were found only in amygdala plus piriform cortex, anterior insular cortex, orbitofrontal cortex, and anterior cingulate cortex. These areas are reported to process the signals of common odors (19, 20, 21), and were possibly recruited by the odor components of AND and EST. Our interpretation of this sex-differentiated pattern of activation was that the two steroid compounds may act bimodally, both as pheromones and odors. We proposed the hypothesis that the anterior hypothalamus primarily processed signals from the pheromone-like component of AND and EST, whereas the olfactory brain primarily mediated the signals of their odor component. Depending on the sex of the responder in relation to the specific compound (AND or EST), one pathway dominated, whereas the other was suppressed. This hypothesis was based upon observations of a similar phenomenon in studies of other bimodal odorants (for example, acetone) (22).

In the present study, we investigated the question whether the pattern of activation induced by AND and EST could be related to sexual orientation rather than to the biological sex. We therefore compared the pattern of activation between homosexual men and heterosexual men and women. The activations were induced by smelling AND, EST, and ordinary odors (here denoted as OO). Smelling of odorless air served as the baseline condition. The following issues were addressed in particular: (i) In homosexual men (HoM), is the hypothalamus activated by AND, EST, or both? (ii) Is the pattern of activation in HoM similar to that in heterosexual men (HeM) and that in heterosexual women (HeW), or are entirely different regions involved in HoM? (iii) If there are group differences, are they confined to the pheromone-like compounds, or do they occur also with OO?

Activations calculated with one-random effect analysis (spm99). All the significant clusters, calculated with T-threshold at P = 0.001 (a corrected P<0.05), are included. Talairach coordinates indicate local maxima. The OO clusters also covered minor portions of anterior cingulate. R, right; L, left.

Activations calculated with conjunctional analysis (SPM99). T-threshold at P = 0.001 (corrected P < 0.05). R, right; L, left.

DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; LH, luteinizing hormone.

Acknowledgments

Notes

Author contributions: I.S. designed research; I.S., H.B., and P.L. performed research; I.S. analyzed data; P.L. recruited subjects; and I.S. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: HoM, homosexual men; HeM, heterosexual men; HeW, heterosexual women; AND, 4,16-androstadien-3-one; EST, estra-1,3,5(10),16-tetraen-3-ol; AIR, odorless air; OO, ordinary odors; PET, positron emission tomography; rCBF, regional cerebral blood flow; MRI, magnetic resonance imaging; ROI, region of interest.