On the Existence of Human Pheromones

            A fictionalized version of Hank Walter, the former chairman of International Flavors & Fragrances, Inc. (IFF), is portrayed by actor Josh Charles on Season 2 of the Showtime series Masters of Sex. IFF was (and continues to be) a massive global conglomerate that provided the chocolate flavor in Cocoa Puffs, as well as scents for the foremost perfume makers of the time. IFF and other private food and fragrance companies provided grant money to Masters and Johnson’s clinic to develop a pheromonal perfume and this collaboration served as a major plotline in Season 2 of the dramatic series. The fictional Walter character, ‘Dan Logan,’ conducts research on the show (See Figure above, left panel) aimed at marketing a natural aphrodisiac-infused scent to the general public. This led me to wonder: What is the deal with human pheromones? Have we actually identified smells (volatile molecules) that affect human behavior or is this junk pseudoscience propagated by the perfume industry? It turns out that the answer is: Yes, we have certainly identified olfactory signaling molecules that seem to influence our behavior. And the putative pheromone structures are steroids.

            Pheromones were first described in 1959 as airborne chemosignal molecules that convey information and produce behavioral, neuroendocrine or developmental changes in members of the same species. Olfactory chemical communication is ubiquitous in the animal kingdom but, until recently, was not believed to extend to human behavior and social interaction. However, contemporary studies describing the gender-specific psychological and physiological effects of two human steroids contradict this notion. The two specific putative pheromones are androsta-4,16-dien-3-one and estratetraenol (structures displayed below), from the general steroid class referred to as 16-androstenes. These are steroidal molecules that lack an oxygen atom at C17, which is required for androgenic or estrogenic activity.

            A 2014 study led by Wen Zhou at the Chinese Academy of Sciences (Beijing) aimed to determine whether or not the above-mentioned steroids communicate gender in a sex-specific manner. The authors showed that smelling androstadienone biases heterosexual females, but not males, toward perceiving images of walkers as more masculine. Moreover, exposure to estratetraenol odor was found to bias heterosexual males toward perceiving the walkers as more feminine. The results provide direct evidence that the two steroids communicate opposite gender information with the larger implication of the work being that human visual gender perception draws on chemosensory biological cues. Those chemosensory cues can be considered pheromones based on the definition that is referenced above. The intriguing results reported by Zhou and co-workers are consistent with previous findings that androstadienone increases cortisol levels and activates brain areas linked to social cognition. In addition to documented effects on human gender perception and physiology, there is also psychological evidence regarding androstadienone’s direct impact on male behavior. In a 2013 investigation conducted in Finland, androstadienone was found to increase cooperative behavior in decision-making tasks. Indeed, as a chemical signal of mate quality and dominance, the steroid elicited observable psychological effects on male subjects that seemed to place them in a socially subordinate position. Notably, this was the first study to show that androstadienone directly influences behavior in human males, acting in this instance as ‘the chemical equivalent of a peacock’s tail.’

            The 16-androstenes that have been identified in humans are biosynthesized from naturally occurring pregnenolone (see Scheme above). The biogenesis of the putative steroidal pheromones androstadienone and estratetraenol relies on the 16-ene-synthase activity of cytochrome P450 17A1 (CYP17A1), which excises the side chain subtituent from the enzymatic substrate and simultaneously installs the D^16,17 double bond within the steroidal D-ring.

            It’s interesting to compare the structure of 5a-androst-16-en-3-one to the odorous macrocyclic ketone, civetone. Civetone is a known pheromone derived from African civet musk that is used in perfumery. When drawn in a somewhat biased fashion, key features of the two-dimensional structure of civetone are cleanly superimposed over the corresponding groups found in the A and D-rings of androstenone. The structural features responsible for a given odor have been referred to as ‘olfactophores’ or ‘odotypes.’ Androstenone happens to be the active ingredient in a commercial product called Boarmate^TM, which, as one might gather from its name, was developed to assist farmers with swine breeding.

            In vertebrates, odors are sensed by members of a family of seven-transmembrane G-protein-coupled receptors called odorant or olfactory receptors (ORs) that are localized on the terminal knobs of olfactory sensory neurons (see Diagram below). The human receptor OR7D4 responds specifically to 16-androstenes including androstadienone and androstenone. Upon odorant binding, the OR undergoes a conformational change that activates an olfactory-specific subtype of G-protein. This triggers a downstream signaling cascade that ultimately leads to the nerve cell signal. Interestingly, perceptual variation in the intensity and pleasantness of certain odors has been shown to be dependent on the OR7D4 gene variant that an individual carries. The OR7D4 genotype also predicts the sensory perception of meat containing androstenone, which is consistent with the idea that genetic variation in this important OR can alter food preferences. Whether one chooses to believe in the existence of human pheromones or not, steroids clearly serve an essential olfactory signaling function that impacts broadly ranging aspects of the human condition from gender perception to social behavior to dietary choices.