Molecular Psychiatry (2002) 7, 335–336  2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp SCIENTIFIC CORRESPONDENCE Sex differentiated hypothalamic activation by putative pheromones Molecular Psychiatry (2002) 7, 335–336. DOI: 10.1038/ sj/mp/4001094 Sir – Recent positron emission tomography (PET) stud- ies suggest sexually dimorphic neuronal response to two putative pheromones. The specific regions acti- vated, combined with the sex difference depict a pher- omoneal-type of brain response in humans. The impli- cations of these observations are discussed. Pheromones are volatile compounds secreted into the environment (in sweat, urine, saliva) by one indi- vidual of a species and perceived by another individual of the same species, in whom they trigger a behavioural response or physiological change. 1 In the majority of mammals pheromones elicit signals which are trans- duced in the vomeronasal organ (VNO) situated in the nasal cavity, to the accessory olfactory bulb, the medial amygdala, and stria terminalis to finally reach the anterior hypothalamus. 2 Via the hypothalamus and its connections the pheromones influence sexual behavior and reproductive functions in a sex-specific way. 2 One of the most intriguing issues in the field of olfaction is whether pheromone transduction exists also in humans. Many researchers are skeptical because it is uncertain whether the pheromone signals can be con- veyed to the brain, as the accessory olfactory nerve in humans is vestigial, disappearing before birth. Although the vomeronasal organ can be identified in the nasal cavity below the olfactory mucosa in a majority of humans, it does not harbour functional neu- ronal elements, 3 and with one exception all putative members of the vomeronasal receptor family in the human genome are pseudogenes. 4 Other scientists are more positive, taking support from several behavioural studies implicating an involvement of putative phero- mones in regulating endocrine-dependent behaviours such as menstruation. For example, female axillary extract applied to the upper lip it shown to alter the timing of ovulation and menstruation of the recipient. 5 This phenomenon is suggested to underlie the men- strual synchrony among roommates and is presumably mediated by the hypothalamus. Furthermore, it has recently been reported that a putative pheromone receptor gene is expressed in human olfactory mucosa. 4 Consequently, there is a theoretical possi- bility that putative pheromones in humans, like for example in ferrets and pigs, could have an effect on the hypothalamus via the nasal mucosa. The controversy about pheromone transduction in humans was recently addressed in a PET study of cer- ebral activation with compounds suggested to be puta- tive pheromones. 6 This was done in 24 heterosexual, healthy subjects (12 females) by calculation of regional changes in cerebral blood flow (rCBF) during passive smelling of putative pheromones in relation to passive smelling of odorless air. The rCBF was measured with positron emission tomography (PET) and 15 -O H 2 O. Two compounds, resembling male and female sex hor- mones were used: 4,16-androstadien-3-one (AND), a derivative of testosterone, produced in human axillary secretions in higher concentrations in men than in women; and oestra-1,3,5(10),16-tetraen-3-ol (EST), a substance resembling naturally occurring oestrogenes. 7 In the concentrations used, both AND and EST were odorous. Three central issues were specifically addressed: (1) Do AND and EST activate the human brain? (2) Are these activations sex specific? (3) Are they are located in regions mediating reproductive behavior? Smelling of AND and EST was assumed to cause cerebral acti- vation if the measured rCBF was significantly higher compared to smelling odorless air. Women smelling AND activated only one cerebral area, the anterior hypothalamus. Men, in contrast, acti- vated exclusively the hypothalamus when smelling an estrogen-like substance. Notably, the respective centers of gravity for the hypothalamic activations were slightly different: in women, the maximum activation was located in the preoptic and ventromedial nuclei, whereas in men the center of gravity was in the para- ventricular and dorsomedial nuclei (Table 1). When men smelled AND and women EST, no hypothalamic activation was observed. Instead, the classical olfactory regions (amygdala, piriform cortex) were engaged. One possible explanation for this discrepancy may be that the administered compounds act bimodally, as odors and as pheromones. 6 The findings are of interest, because neither the sex dissociation nor the hypothal- amic involvement has previously been observed with more ordinary odorants (vanillin, butanol, cedar oil, lavender oil and eugenol), when used as stimulants in the same individuals. 8 The specific pattern of acti- vation with respect to AND and EST resembles the effects of pheromones in animals. Pheromone stimuli from male ferrets are shown to augment Fos-imunore- activity (IR) in the main olfactory bulb, preoptic, and ventromedial nuclei of female ferrets. Likewise, soiled bedding from female mice is found to induce IR in the ventral premamillary nucleus in their male conspe- cifics. 9 Interestingly, electric stimulation of the ven- tromedial nucleus in the female monkey elicits the copulatory act, whereas the stimulation of the dorso- medial hypothalamic nucleus in the male monkey elic- ited penile erection and yawning. 10 Not withstanding the impact of the complexity of the human brain, the similarity between results from animal studies and the referred PET data provides additional argument for a possible existence of pheromone transduction in humans. The imaging data do, however, not offer the