Psychophysiological manifestations related to AND exposure in female subjects have been reported, based on AND detected in salivary cortisol levels (Wyart et al., 2007) and autonomic physiology levels showed a significant reduction in respiratory and cardiac frequency, as well as skin conductance and increased body temperature (Grosser et al., 2000). Beyond that, Lundström and colleagues suggested that AND enhanced women's feeling of being focused (Lundström et al., 2003) and induced an increased attentiveness, even outside the conscious detection of AND (Lundström and Olsson, 2005). In addition, analyses of chemosensory event-related potential (ERP) recordings revealed AND to be processed between 13 and 20 percent faster than odorants similar in hedonic and intensity ratings (Lundström et al., 2006b). With special regard to AND's generally proposed role in reproductive behavior, two studies (Thorne et al., 2002; Saxton et al., 2008) indicate that men's ratings of female attractiveness are modulated by this special chemosignal with higher evaluations of women in the AND condition, while another experiment (Lundström and Olsson, 2005) was not able to confirm this effect.

Saxton et al. (2008), who assessed the effect of AND in a speed-dating-event, argued that the suggested context-dependency of AND may occur only in the presence of a male person (Jacob et al., 2001; Lundström and Olsson, 2005). Furthermore, recent literature suggests that AND strenghtens intrasexual competition strategies in women (Parma et al., 2012).

The role of AND as modulator-chemosignal has also been discussed in the context of serving as a link between hormonal status and this special steroid: While women taking oral contraceptives are more sensitive to environmental odors, fertile women showed a higher sensitivity to chemosignals with reproductive relevance, like androstadienone (Lundström et al., 2006a). With regard to AND's influence on mood, AND was found to enhance a positive mood in women, with feelings of being more relaxed, calm, and free of negative feelings (Grosser et al., 2000; Preti et al., 2003). Another study reported that the setting, the manner, and by whom the experiment was conducted play a role in perception. Lundström and Olsson (2005) emphasized the impact of socioexperimental conditions in women who showed changes in self- reported mood only when experimental interactions were completed by a male experimenter, thus, again, proposing a context-dependent effect for AND.

Studies using male samples are rare. The only study investigating the effect of AND in men came out recently, and demonstrated that AND directly affected mens' cooperative behavior by increasing such behavior (Huoviala and Rantala, 2013).

We defined studies with mixed samples as those in which the study design included men and women.

With regard to the activational effects in the sympathetic nervous system, a study by Jacob et al. (2001) was able to confirm the suggested calming effects of AND on women's physiology, as already suggested by a study using the female sample presented in the above section (see Section “Studies Investigating AND in a Female Sample”; Grosser et al., 2000). While AND administration led to raised skin temparature in men and lowered temperature in women, AND increased skin conductance in both sexes, with a significantly higher effect observed in women, indicating that the arousing effect was more prevalent in women than in men (Jacob et al., 2001). Interestingly, the activational effects of AND were dependent on the socioexperimental context, since women's reactions were observed only in sessions administered by a male investigator. Some other findings emphasized the context-dependency of AND in a similar fashion. While AND administered in a neutral context, or in a context with little social interaction, did not influence autonomic nervous system functions, it enabled increased sexual arousal in a sexually arousing context in a sex-independent manner (Bensafi et al., 2004; Hummer and McClintock, 2009). During the same sexually arousing context, respiration rates, especially in men, decreased, while skin temperature in both sexes rose (Bensafi et al., 2004).

Concerning psychological variables, AND was reported to have divergent effects in men and women, as shown for psychophysiological states; while AND administration led to increased negative emotions in men (Jacob and McClintock, 2000), especially in unpleasant settings (Bensafi et al., 2004), no negative effect was evoked in women. Focusing on the context-dependency of AND, positive feelings in women were found to be sustained during a sad time (Bensafi et al., 2004) and were increased in a neutral context (Jacob and McClintock, 2000).

Further, another study that analyzed the effect of AND on mood and pain perception concluded that exposure to this steroid led to an amelioration of mood state only in women (Villemure and Bushnell, 2007). Based on this finding, the authors further hypothesized that women would show lower pain sensation when exposed to AND. However, this assumption was not confirmed, as women, interestingly, showed increased percieved pain (Villemure and Bushnell, 2007).

An effect of the experimenters sex on the baseline response in an AND experiment has recently also been observed in rodents (Sorge et al., 2014). Regarding future research, preliminary findings about the sex-divergent effects of AND on psychophysiological as well as psychological variables should be considered, especially the context-dependency of AND. This context-dependency should implicitly be noted when planning experiments, as well as interpreting results to prevent an interpretation bias.

Early positron emisson tomography (PET) studies exploring the neural correlates of AND perception suggested the presence of gender-specific neural activation in which the hypothalamic pathway was significantly activated in heterosexual women, but heterosexual men lacked this hypothalamic activation, and areas of the olfactory cortex were activated instead (Savic et al., 2001, 2005, 2009; Berglund et al., 2006, 2008; Hillert et al., 2007; Ciumas et al., 2009). However, contrary to these PET studies, a recent fMRI study found non-sex-specific hypothalamic activation (Burke et al., 2012). When the authors applied various concentrations of AND, significantly higher hypothalamic activation was demonstrated in women than in men when a higher concentration was used (10 mM). This corresponds with previous studies. However, when participants were exposed to medium concentrations (0.1 mM), men demonstrated a significantly stronger hypothalamic response than the participating women (Burke et al., 2012). These results led the authors to conclude that AND evokes hypothalamic responses in both sexes in a stimulus concentration-dependent manner. However, when comparing these results to the series of studies by Savic and co-workers (Savic et al., 2001, 2005, 2009; Berglund et al., 2006, 2008; Hillert et al., 2007; Ciumas et al., 2009), it should be noted that Burke et al. (2012) used other odor delivery methods, compound concentrations, as well as another imaging technique, all of which together affected our ability to directly compare results.

The last decade of brain imaging research has revealed that AND stimulation produces significant and localized group effects that are seemingly sexual orientation-dependent. There are several functional neuroimaging studies, which address cortical responses to pheromones that seem to be dependent on sexual orientation; homosexual men and male-to-female transsexuals were found to display the same activation pathway as heterosexual women, i.e., demonstrating hypothalamic responses upon exposure to AND (Savic et al., 2005; Berglund et al., 2008).

In contrast, Berglund and colleagues concluded that homosexual women process AND similar to heterosexual men, namely, by parts of the olfactory cortex (Berglund et al., 2006). Those findings (Savic et al., 2005; Berglund et al., 2006, 2008), are of great importance in order to underline existing evidence of sexual-orientation effects on neural processing in other research areas as well. Recently, behavioral and neuroimaging results from Perry et al. (2013) showed empathy to be related to gender, as well as sexual preference. Further, a study aiming to characterize regional homogeneity and functional connectivity during rest found significant differences between homo- and heterosexual men (Hu et al., 2013). Hence, it would be presumptuous not to consider the ability to use this variable as a modulating factor to achieve homogeneous subject groups.

As noted above, AND is processed in a gender-specific manner; however, thus far, few studies have dealt with the functional aspects beyond neural activity. Most published studies investigating the effect of AND on neural processes also included another potential human pheromone, namely estra-1,3,5(10),16-tetraen-3-ol (EST) (Savic et al., 2001, 2005, 2009; Berglund et al., 2006, 2008; Hillert et al., 2007; Ciumas et al., 2009). EST has, among others, been detected as a natural component of the urine in pregnant women (Thysen et al., 1968). Interestingly, the administration of this estrogen-like steroid causes an effect complementary to AND. Whereas AND application caused a hypothalamic activation in women and the activation of common olfactory areas in men, EST is processed in a diametrically opposite fashion, namely, via the hypothalamic pathway in heterosexual men and parts of the olfactory cortex in heterosexual women (Savic et al., 2001, 2005, 2009; Berglund et al., 2006, 2008; Hillert et al., 2007; Ciumas et al., 2009). This complementary relationship seems to be of great physiological relevance.

Compared to AND, specific psychophysiological measures of EST are largely unknown. However, while the results of Bensafi et al. (2003) revealed no effect of EST on physiological arousal, the same authors found EST to affect physiological arousal in a content-dependent way (Bensafi et al., 2004). Exploring the conscious odor perception of AND and EST in an animal model, a gender-specific effect was obtained by Laska et al. (2006), who detected olfactory sensitivity to AND in female, but not male, spider monkeys, while responses to the highest concentrations of EST were found in males, but not in female, monkeys. These data also highlight the gender-specific processing of these two pheromone-like compounds in non-human animal models. Finally, these results indicate that there is a considerable need for research on the psychophysiological effects of EST.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.