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Mucignat-Caretta C, editor. Neurobiology of Chemical Communication. Boca Raton (FL): CRC Press/Taylor & Francis; 2014.

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Chapter 18Pheromone Processing in Relation to Sex and Sexual Orientation

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18.1. INTRODUCTION

Whether pheromone signaling exists in humans is still a matter of intense discussion. Emerging brain imaging studies suggest sexually dimorphic neuronal response to certain chemosignals, which, according to psychophysical data, possess pheromone-like properties. There are also indications that the neuronal response to these compounds depends on sexual orientation. Furthermore, our brain seems to be able to extract kin-specific signals, and processes body odors differently than other perceptually similar odors. Together, this data sheds new light on the chemosensory perception in humans and the implications thereof are discussed.

18.2. PHEROMONE PROCESSING IN MAMMALS

According to the original definition by Karlson and Luscher (1959), pheromones are “airborne chemical signals released by an individual into the environment, and affecting the physiology and behavior of other members of the same species.” Pheromones have traditionally been defined as either releasers, compounds triggering immediate short-term behavioral responses, or primers, compounds triggering medium- to long-term changes in behavior or physiology. Such clear categories are, however, not always easy to attribute to the phenomena being studied, which has led the new generation of chemosensory biologists to add so-called modulator pheromones to the classification. A modulator pheromone modifies “ongoing behavior or a psychological reaction to a particular context without triggering specific behaviors or thoughts” (McClintock et al. 2001). Pheromones are produced in sweat, blood, saliva, and vaginal secrete. Both volatile and nonvolatile compounds (proteins, steroids, cholesterols) can act as pheromones (Karlson and Luscher 1959). Pheromone signals provide information about gender and reproductive status and mediate social and sexual behaviors as well as neuroendocrine changes (Brennan and Keverne 2004). Animal experiments show that both pheromone perception and response is dependent of the hormone status and the genetic makeup of the animal (Dulac and Torello 2003).

Most mammals have two olfactory systems: the main olfactory system with the olfactory epithelium and the olfactory bulb (MOB), and the vomeronasal system with the vomeronasal organ (VNO). The MOB and VNO have their own distinct primary projection targets in the brain. There is increasing evidence that both systems may be involved in pheromone detection, and that they both project to the medial amygdala (Kang et al. 2009). In a majority of animals the VNO is still regarded to be the primary sensory organ for the detection of pheromone signals. The VNO expresses specific classes of vomeronasal receptors (VR), VR type 1 and 2, which detect pheromone signals. The VR type 2 receptors interact with a nonclassical major histocompatibility complex (MHC) class 1b molecule to form a functional receptor complex (Keverne 2008). This interaction implies that perception of a particular pheromone may be related to the genetic composite of the receiver. From the VNO the pheromone signals are transduced via the accessory olfactory nerve directly to the specific mating centers of the anterior hypothalamus (Dulac and Torello 2003). This direct access to the hypothalamus allows pheromones to play a major role in the sexual behavior and the choice of sexual partner in animals. A lesion of the respective mating center, as well as impairment of pheromone transduction, may alter the coital approach in a sex-specific way. 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 (Kindon et al. 1996). 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 (Kindon et al. 1996; Paredes et al. 1998). Female rats, however, increased the proportion of approaches to females after kindling of the preoptic area (Dominguez-Salazar et al. 2003).

18.3. DOES VNO EXIST IN HUMANS?

Although vomeronasal pits are detectable in many persons, the VNO seems to be vestigial in humans (Trotier et al. 2000). Several observations support this view. First, the human VNO epithelium resembles more strongly the respiratory epithelium than the VNO neuroepithelium found in species with functional VNOs (Witt et al. 2002). Second, the olfactory marker protein (OMP), which is a reliable marker for mature VNO neurons in many animals, is not expressed in human VNO (Dennis et al. 2004). Third, genes coding for the TrpC2 ion channels necessary for pheromone signal transduction are pseudogenes in humans, as are most of the genes identified to code for receptor proteins in the mouse VNO (Zufall et al. 2002). As a consequence, pheromone signaling has long been questioned in humans. This view is, however, contradicted by growing arguments for an influence by pheromone-like compounds on human physiology and behavior, and it is also possible that pheromone signals in humans, like in several other mammals (pigs, ferrets) may be transduced via the olfactory mucosa (Dorries et al. 1995); see further in this text. One argument is that the well-known synchronization of menstrual cycles among female roommates seems to be relayed by sweat, which contains such compounds (Stern and McClintock 1998). Another is that women smelling male sweat shift their luteinic hormone pulsatility to promote ovulation (Preti et al. 2003). Furthermore, smelling of two steroids, the 4,16-androstadien-3-one (AND), and estra-1,3,5(10),16-tetraen-3-ol (EST), have in several consecutive experiments shown to affect mood and arousal (Bensafi et al. 2003; Jacob et al. 2001; Lundstrom and Olsson 2005). AND is a derivative of gonadal progesterone and has been identified in urine, plasma, apocrine sweat, as well as semen and axillary hair (Brooksbank et al. 1972; Fukushima et al. 1991; Gower et al. 1994; Kwan et al. 1992; Nixon et al. 1988) in higher concentrations in men than in women. EST, which has been investigated much less than AND, is an estrogen-like derivative detected in the urine of pregnant women (Thysen and Katzman 1968). Both AND and EST have been used in several brain imaging studies and at least AND may be regarded as a candidate pheromone, though the precise modulation of psychological states by the compound has yet to be definitively determined.

18.4. IMAGING STUDIES OF HUMANS EXPOSED TO CHEMOSIGNALING COMPOUNDS WITH PHEROMONE-LIKE PROPERTIES

18.4.1. Synthetic Compounds

Several groups have employed brain imaging tools to study pheromone-like signals in humans. In a series of positron emission tomography (PET) studies of heterosexual healthy men and women during exposure to AND and EST, we found that smelling of these compounds activated regions covering sexually dimorphic nuclei of the anterior hypothalamus, and that this activation was differentiated with respect to sex and the specific compound (Savic et al. 2001). In women, AND activated the preoptic area and the ventromedial nuclei, whereas in men a hypothalamic activation was detected with EST and involved an area covering the paraventricular and dorsomedial nuclei. In contrast, when men smelled AND and women EST, activations were found in the classical odor processing regions—the amygdala and piriform cortex, the anterior insular cortex, the orbitofrontal cortex, and the anterior cingulate cortex. This sex difference in brain regions processing the signals of AND and EST was not related to the perceived intensity or quality of the odor of the respective compound, which was rated similarly by all participating subjects. Our interpretation of the sex-differentiated pattern of activation was that the two steroids might act bimodally as pheromones and odors. We proposed the hypothesis that the anterior hypothalamus primarily processes signals from the pheromone-like component of AND and EST, whereas the olfactory brain primarily mediates the signals of their odor component. Depending on the sex of the responder in relation to the specific compound (AND or EST), one pathway dominates, whereas the other is suppressed. This hypothesis was based on observations of a similar mutual competition in studies of bimodal odorants (e.g., acetone) (Lundstrom and Hummel 2006; Savic et al. 2002).

The observed sex differentiated pattern is congruent with results from other imaging experiments in which AND, AND-like compounds, or EST has been applied. In a functional MR study of healthy women, Zhou and Chen found, for example, that AND activated only the anterior hypothalamus and not the olfactory cortex (Zhou and Chen 2008). Accordingly, when women smelled androstenol, a derivative of AND, significant activation was found only in the hypothalamus and to a minor extent in the medial amygdala (Savic and Berglund 2010). Conversely, in male subjects Sobel et al. found that EST activated the thalamus and the hypothalamus; interestingly, the EST-related activations were detected even when the compound was presented in extremely low concentrations, which were not possible to detect consciously (Sobel et al. 1999).

The described activations by AND and EST seem to be mediated by the olfactory mucosa. This is indicated by several recent imaging studies, as well as the observation that human olfactory mucosa expresses a functional VR1 gene (Frasnelli et al. 2010; Rodriguez et al. 2000; Savic et al. 2009). Using PET we found that men whose olfactory mucosa was occluded due to nasal polyps were unable to activate the brain with EST, whereas strong hypothalamic activation was observed in healthy male controls (Savic et al. 2009). Accordingly, Frasnelli et al. detected clear hypothalamic activations in females smelling AND both when their VNO was occluded and when it was open (Frasnelli et al. 2010).

The concentrations of AND, androstenol, and EST in the aforementioned studies were variable (10 ml of a 25% and 100% solution in Frasnelli’s study, 1 ml of 916-µM AND diluted in propylene glycol, in Zhou’s study, and 200 mg of pure crystalline compounds in our experiments). Consequently, while brain imaging data convinces us that our brain detects signals of AND, androstenol, and EST, and that this detection is likely to relate to sex of the smeller in relation to the compound, it is important to express uncertainty regarding the relevance of concentrations used in the experiments for the physiological conditions, something that needs to be investigated in the near future.

18.4.2. Body Odors

The natural human body odor consists of about 120 individual chemicals (Labows et al. 1979), of which some have pheromone properties. In general, body odors carry informational cues of great importance for individuals across a wide range of species, and signals hidden within the body odor cocktail are known to regulate several key behaviors in animals. For a long time, the notion that humans may be among these species has been dismissed. Psychophysical studies suggest, however, that humans, like many other animals, may be able to identify the emotional state of an individual belonging to the same species based solely on the body odor. A recent study collected body odor samples from individuals who watched either funny or scary movie sequences. Participants were later asked, in a forced-choice detection task, to identify the emotional state of the donors. Remarkably, participants were able to accurately identify both happy and fearful emotional odors at levels above chance value, though they performed much better with body odor samples from fearful donors.

It is possible that each human has a unique odor signature that carries information related to his or her genetic makeup. Brain imaging investigations of the central processing of body odors have demonstrated that the human brain responds to fear signals hidden within the body odor mixture, is able to extract kin-specific signals, and processes body odors differently than other perceptually similar odors. Lundström and Gottman-Jones found that smelling a friend’s body odor activated regions previously seen for familiar stimuli, whereas smelling a stranger activated the amygdala and insular regions akin to what has previously been demonstrated for fearful stimuli (Lundstrom et al. 2008). In addition, when the cerebral activity was compared between situations when subjects identified the body odor of their siblings (kin) and the body odor of a friend (nonkin), it was found that a neuronal network generally consistent with the neuronal substrates of self-referential mental tasks was activated (Lundstrom et al. 2008). This interesting finding suggests that salient body odor signals may recruit additional neuronal circuits.

One unexpected observation in the aforementioned studies is that body odor perception seems to recruit primarily the areas located outside rather than within the main olfactory system. Possibly, the processes involved are too transient to be detected by the olfactory cortex, which has a documented high susceptibility to habitation effects. Alternatively, there might exist separate functional subsystems for common odors and endogenous odors. Whether these systems are entirely separated or overlapping with the dominance of one or the other, depending of the stimulus, is currently uncertain. When endogenous odors contain pheromone-like compounds of the opposite sex the hypothalamus should also be recruited, provided that the aforementioned hypothesis about processing of AND and EST stimuli is correct. However, the majority of hitherto published PET and fMRI studies of body odors did not show significant hypothalamic activations. One possible reason is that the majority of these studies were carried out in the same-sex setting—the body odor (sweat) was collected from females and the subjects exposed to this odor were also females. Notably, when sweat was collected from male subjects and the test persons were females, as in the study of Zhou and Chen, pronounced hypothalamic clusters were present (Zhou and Chen 2008). This issue needs to be more specifically addressed in future studies.

18.5. ACTIVATION WITH PHEROMONE-LIKE COMPOUNDS IN RELATION TO SEXUAL ORIENTATION

The reproductive functions in humans, like in animals, are mediated by neuronal circuits in the anterior hypothalamus. These circuits 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 (Kindon et al. 1996). The preoptic area of the hypothalamus harbors cells releasing luteinic hormone-releasing hormone and mediating estrogen feedback. The estrogen feedback differs between males and females (Dorner et al. 1968) and is also reported to differ between homosexual men (HoM) and heterosexual men (HeM). The anterior hypothalamus also contains neuronal conglomerates (interstitial hypothalamic nuclei), of which two are reported to differ in volume between men and women, and one was found to differ between HoM and HeM (LeVay 1991; Swaab et al. 1990). A difference between HoM and HeM has also been detected in the volume of the suprachiasmatic nucleus (Swaab et al. 1990). The finding of sex differentiated AND and EST activations of the hypothalamus, therefore, directly raised the question as to whether the corresponding processes are mediated in a similar manner in homosexual subjects.

Subsequent studies with identical design showed that in HoM, like in heterosexual women (HeW) but unlike HeM, the signals from AND were processed by the anterior hypothalamus. Maximal cerebral activation was detected in an area corresponding to the preoptic, ventromedial, and tuberomamillary nuclei (Figure 18.1a). To the contrary, signals from EST were in HoM mediated by the olfactory brain (the left amygdala and piriform cortex) (Savic et al. 2005). Interestingly, and at variance to the other three study groups in, lesbian women the classical odor-processing circuits (the amygdala, the piriform and insular cortex) were engaged during the presentation of AND as well as EST (Figure 18.1a). Significant activations appeared only when restricting the analysis to the hypothalamus, and only with EST, not AND. Direct group comparisons showed that lesbian women differed only from HeW and that the difference was constituted by the absence of the preoptic activation with AND in lesbian women and the presence of this activation in HeW. In contrast to the two steroids, common odors were in all four groups of subjects processed by the classical olfactory regions without any group differences (Berglund et al. 2006).

FIGURE 18.1. FIGURE 18.

FIGURE 18.1

FIGURE 18.1 (a) Activation with AND and EST. Significant activations illustration of group-specific activations with putative pheromones during smelling of AND and EST in relation to smelling of air (which was the so-called baseline condition). Clusters (more...)

The less-prominent sex-atypical pattern of activation in the lesbian group was difficult to explain, given that their Kinsey ratings were, like in the HoM group, at the extreme end of the scale. One possibility discussed by the authors is that female homosexuality differs from male homosexuality. As opposed to HoM who are reported to have a later birth order relative to HeM, no significant birth order has been reported in lesbian women. The genetic influence is found to be higher in male compared with female homosexuals (Lyons et al. 2004).

18.6. UNDERLYING MECHANISMS

The mechanisms behind the observed differences of brain activation with AND and EST can only be speculated. One possibility is that the core network mediating AND and EST stimuli is rather similar in all subjects but that this network is responding differently depending of sex and sexual orientation, just as the core network for sexual arousal seems to be shared by homosexual and heterosexual subjects, but the triggering stimulus is reciprocal. Viewing erotic videos of heterosexual or homosexual content produces activation in the hypothalamus, but only when subjects are viewing videos of their respective sexual orientation (Karama et al. 2002). Furthermore, the neuronal response of the ventral striatum and the centromedian thalamus is reported to be stronger to stimuli from the preferred relative to nonpreferred sex (Ponseti et al. 2006). The perception of faces also seems to be modulated by sexual preference. Looking at a female face led to a stronger reaction of the thalamus and medial prefrontal cortex in heterosexual men and homosexual women, whereas in homosexual men and heterosexual women the reaction in these structures was stronger when looking at a male face (Kranz and Ishai 2006).

Another, and equally likely, interpretation, is that signals from AND and EST are processed differently in the nasal mucosa, and/or by the downstream forebrain structures, depending of the sex and sexual orientation. Such a scenario is supported by a recent study suggesting that certain sexually dimorphic features in the brain, which are unrelated to reproduction, also vary with sexual orientation.

We investigated hemispheric asymmetry, using volumetric MRI and functional connectivity of the amygdala, using PET measurements of cerebral blood flow in 90 homosexual and heterosexual men and women (Savic and Lindstrom 2008). Volumetric measurements in HeM and lesbian women showed a rightward cerebral asymmetry, whereas the volumes of the cerebral hemispheres were symmetrical in HoM and HeW. The homosexual subjects also showed sex-atypical amygdala connections (Figure 18.1b). In HoM, as in HeW, the connections were more widespread from the left amygdala. In lesbian women and HeM, on the other hand, the connections from the right amygdala were more widespread. Furthermore, in HoM and HeW the connections displayed were primarily with the contralateral amygdala and the anterior cingulate, while in HeM and lesbian women the connections displayed were primarily with the caudate, putamen, and the prefrontal cortex (Savic and Lindstrom 2008). Whether these latter sexual-orientation-related features of cerebral morphology and function may relate to processes laid down during the fetal or postnatal development is an open question.

18.6.1. Testosterone Organizational and Activational Theory

Mechanisms behind homosexuality are often discussed in terms of an underexposure to prenatal androgens. In rats, male cerebral asymmetry is established, in part, by early androgen exposure (or, more precisely, by the estrogen produced by testosterone aromatization). Castration at birth is shown to block the normal rightward brain asymmetry, whereas hemispheric symmetry in females can be reversed to the male pattern by neonatal ovariectomy. It has, therefore, been advocated that exposure to androgens during the fetal development could have major organizational effects on cerebral structures also in humans (Negri-Cesi et al. 2004), although the active compound ought to be testosterone in both sexes, considering that XY subjects with full androgen receptor insensitivity show complete female features despite high testosterone levels (Hughes et al. 2012). The theory about testosterone-mediated masculinization can be tested in humans by application of so-called experiments of nature. Ciumas et al. tested this hypothesis with respect to pheromone processing and amygdala connectivity in a 15O-H2O PET study of women with congenital adrenal hyperplasia (CAH), a condition with high fetal testosterone (Ciumas et al. 2009). Contrary to the hypothesis, the amygdala connectivity in CAH women, as well as the activation with AND and EST, was found to be similar to that of control women (HeW), and reciprocal to control men (HeM). Thus, with regard to both functional organization and activation of the limbic circuits, CAH women showed a pattern congruent with their biological sex and different from the opposite sex. This data illustrates that intrauterine virilization of genitalia is not necessarily paralleled by a masculinization of the limbic brain. Although being unfavorable toward the testostosterone-organizational theory, this data does not exclude such a possibility. Various sex dimorphic features in the brain could, in theory, be affected by fetal testosterone in a dose-dependent manner. They could also have multiple etiological factors (some could be primarily hormonal, other primarily genetic), as recently proposed by Arnold, who pointed out the existence of early and testosterone-independent chromosomal effects on the brain (Arnold et al. 2004). It is fully possible that several different etiological factors contribute to a same sexually dimorphic cerebral feature, for example, psychosexual outcome.

18.7. CONCLUDING REMARKS

Accumulating neuroimaging and behavioral data show that the human brain processes signals from pheromone-like compounds, and that this processing may be mediated via the olfactory mucosa. A recently published study of human tears provides a compelling indication that humans produce volatile compounds that can be detected by smelling, and that such detection may induce an altered physiological response—thus fulfilling the classical criteria for pheromone communication (Gelstein et al. 2011). It is, however, unreasonable to believe that human behavior could be altered in an automated fashion as in animals, and the described chemical communication seems to have modulating effects.

Emerging studies suggest that signals from some synthetic pheromone-like compounds are processed in a manner related to the sex and sexual orientation. This does, however, not imply that pheromone processing drives the sexual orientation. The observed pattern of hemispheric asymmetry and amygdala connectivity suggests that homosexual and heterosexual individuals of the same sex may differ in neurophysiological/neuroanatomical aspects, which, in turn, may related to behavior. Preliminary investigations do not provide support for a major influence of fetal testosterone, and the underlying mechanisms remain unclear.

ACKNOWLEDGMENTS

VINNOVA, Swedish Research Council, AFA, and FAS are acknowledged for financial support.

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© 2014 by Taylor & Francis Group, LLC.
Bookshelf ID: NBK200984PMID: 24830042
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