Vomeronasal Organ and Human Pheromones

European Annals of Otorhinolaryngology, Head and Neck diseases (2011) 128, 184—190

UPDATE Vomeronasal organ and human pheromones

D. Trotier ∗

CNRS, INRA, FRE 3295, Neurobiologie Sensorielle, domaine de Vilvert, bâtiment 325, 78350 Jouy-en-Josas, France

Available online 5 March 2011

KEYWORDS Summary For many organisms, pheromonal communication is of particular importance in Olfaction; managing various aspects of reproduction. In tetrapods, the vomeronasal (Jacobson’s) organ Vomeronasal; specializes in detecting pheromones in biological substrates of congeners. This information trig- Pheromones; gers behavioral changes associated, in the case of certain pheromones, with neuroendocrine Human correlates. In human embryos, the organ develops and the nerve fibers constitute a substrate for the migration of GnRH-secreting cells from the olfactory placode toward the hypothalamus. After this essential step for subsequent secretion of sex hormones by the anterior hypophysis, the organ regresses and the neural connections disappear. The vomeronasal cavities can still be observed by endoscopy in some adults, but they lack sensory neurons and nerve fibers. The genes which code for vomeronasal receptor proteins and the specific ionic channels involved in the transduction process are mutated and nonfunctional in humans. In addition, no accessory olfactory bulbs, which receive information from the vomeronasal receptor cells, are found. The vomeronasal sensory function is thus nonoperational in humans. Nevertheless, several steroids are considered to be putative human pheromones; some activate the anterior hypothalamus, but the effects observed are not comparable to those in other mammals. The signaling process (by neuronal detection and transmission to the brain or by systemic effect) remains to be clearly elucidated. © 2011 Published by Elsevier Masson SAS.

Introduction strate activation of a sense organ capable of transmitting such information to the brain and to identify relevant beha- A variety of products containing ‘‘pheromones’’ are on vioral and/or physiological effects. Is the vomeronasal offer here and there, especially on the Internet: erotic organ, involved in detecting pheromones in other mammals, ‘‘pheromone-based’’ perfumes keep appearing on the functional in humans? Can certain steroids be considered market, promising enhanced attractiveness and personal as genuine human pheromones, able to induce appropriate performance. What do the scientists say? Apart from the effects? methodological issues involved in such studies [1], the claim that human pheromones exist implies being able to demon- The concept of pheromones

Establishing a hierarchy, encountering members of the oppo- ∗ Corresponding author. Tel.: +33 01 34 65 29 55. site sex and estimating their reproductive potential while E-mail address: [email protected] maintaining genetic diversity, or again signaling a threat are

1879-7296/$ – see front matter © 2011 Published by Elsevier Masson SAS. doi:10.1016/j.anorl.2010.11.008 Vomeronasal organ and human pheromones 185 essential tasks for any animal species. To these ends, individuals deploy a range of sensory signals, in which chemical signals play an important role. When a chemical message triggers specific effects in the receiver, the substance is said to be a pheromone. Two main types are generally distinguished. Releaser pheromones act on the receiver’s behavior: e.g., an alarm releaser pheromone is perceived and quickly interpreted so as to elicit flight or alert behavior. Primer pheromones have a deeper and more endur- ing action on the receiver’s physiology: e.g., a dominant male’s pheromones alter the endocrine function of subordi- nate males so as to reduce their sexual aptitude; likewise, a sexually mature male mouse is able to trigger puberty in young females. This concept of ‘‘pheromone’’ thus cov- ers different effects, some eliciting a rapid characteristic response while others produce deep and sustained changes in the target’s hormonal biology and corresponding behavior. The molecular nature of animal pheromones is not known in most cases. Studies of rodents, however, showed that small airborne molecules are involved [2] along with nonvolatile substances such as steroids [3], peptides [4,5] and Figure 1 A: Location of a vomeronasal organ (V) in the nasal proteins [6]. Air-transport enables volatile pheromones to cavity of a deer, after the original drawing by Ludvig Jacob- reach the olfactory system; nonvolatile substances, how- son. The opening of the organ is near the nasopalatine duct ever, accompanied by volatile substances in solution, can (1). The vomeronasal neuron axons (2) transmit information be detected only by the vomeronasal organ. to the accessory olfactory bulbs behind the main olfactory The role played by proteins and peptides in pheromonal bulbs. The organ is vascularized (3) and innervated by sym- communication is surprising. One example is aphrodisin [7], pathetic/parasympathetic fibers (4). B: Cross-section of a rat a protein found in the vaginal secretions of the hamster vomeronasal organ, showing the internal canal (5) covered on and which triggers reproductive behavior in young males one side by sensory epithelium (6) containing the neurons and by activating the vomeronasal organ. Likewise, major uri- on the other by erectile tissue and a blood vessel (7). Variation nary proteins (MUPs) are proteins emitted in abundance in tissue turgescence actively pumps stimuli into the internal in mouse urine (several milligrams per day!). The MUPs canal. C: Cross-section of sensory epithelium, showing the two set produced by a given individual acts as an authentic types of sensory neuron carrying distinct receptor proteins. signature [8]. Detection of such molecules involves the The short-dendrite neurons (8) expressing V1R proteins trans- vomeronasal organ. Aphrodisin and MUPs are lipocalins: i.e., mit information to the posterior part of the accessory olfactory water-soluble proteins but equipped with an internal sac bulbs, whereas the long-dendrite neurons (9) expressing V2R in which small hydrophobic molecules can lodge [9]. Apart proteins transmit information to the anterior part of the acces- from their role as pheromone carriers, these proteins, or sory olfactory bulbs. peptide derivatives, also seem to play a signaling role them- selves. In invertebrates, the specificity of the pheromonal mes- viding direct contact with biological substrates emitted by sage often derives from some particular molecule: e.g., congeners. Information is transmitted via the accessory bombykol, which enables males to attract females over olfactory bulbs, which lie behind the main olfactory bulbs, long distances. In vertebrates, message specificity, par- toward the amygdala and the anterior hypothalamus, which ticularly as regards primer pheromones, seems rather to is directly involved in gonadoliberin (GnRH) secretion and derive from a combination of several molecular entities thus in sex hormone activity via the anterior hypophysis associating small molecules and macromolecules [10]. This [12]. During the evolution of species, the vomeronasal organ molecular diversity greatly hinders precise description of appears with the advent of amphibians and adaptation to the substances at work in any given pheromonal effect. life on land. Fish do not have it: pheromones are detected Our knowledge of pheromonal effects mainly concerns by specialized neurons in the olfactory epithelium, and the rodents, which live mainly in darkness, making chemical information is processed in cerebral pathways distinct from communication essential. As far as other mammals are con- those of the general olfactory neurons. cerned, it must be admitted that the molecular nature of The vomeronasal organ was discovered by Ludvig Jacob- pheromones and their physiological effects remain largely son in the 1810s [13]. Jacobson showed that it was to be obscure. found in mammals, but also pointed out that in humans it appeared to be vestigial. The organ comprises two tubu- lar structures in a low and forward position on either side The animal vomeronasal organ of the nasal septum, near the vomer bone (Fig. 1A). Its internal duct is closed at the back and communicates for- The location of the animal vomeronasal organ [11],ina ward via a small aperture which, depending on the species, forward position on the base of the septum near to the opens either onto the nasopalatine ducts which connect the nasopalatine duct (Fig. 1A), allows a pumping action pro- oral cavity to the nose, or onto the nasal cavities. The 186 D. Trotier medial side of the lumen is covered by sensory epithe- information deriving from different sensory inputs appears lium containing detector neurons; the lateral side contains increasingly well founded. richly vascularized erectile tissue, innervated by sympathetic/parasympathetic fibers: the distension/contraction of this tissue induces active pumping of substrates into the The human vomeronasal organ vomeronasal lumen (Fig. 1B). Stimulus molecules reach the opening either via the nostrils or by the nasopalatine duct, The vomeronasal organ develops in utero. Nerve fibers depending on the species. emerge from the developing organ and travel towards the The vomeronasal detector neuron receptor proteins are brain. This is a crucial step in the development of the repro- distinct from those of the olfactory neurodetectors. Two ductive system: as of puberty, gonad functioning depends families of protein have been studied (Fig. 1C) [14]: short on hormonal secretion by the anterior hypophysis, and this extracellular chain proteins (V1R), carried by short-dendrite is governed by peptide GnRH secreting cells in the arcu- sensory neurons synapsing at the posterior part of the acces- ate nucleus of the hypothalamus. Embryologically, these sory olfactory bulbs; and long extracellular chain proteins GnRH secreting cells derive from the olfactory placode, from (V2R), carried by neurons deep in the epithelium synapsing which the olfactory and vomeronasal organs develop, and at the anterior part of the accessory olfactory bulbs. The lat- migrate along the vomeronasal axons toward the brain [23]. ter neurons also express a gene family involved in the major In humans, defective GnRH cell migration induces hypo- histocompatibility complex [15], which is thought to govern gonadotropic hypogonadism syndrome (LH and FSH pituitary individual recognition. In mice, the short-dendrite neu- hormone secretion defect), which is associated with absence rons, carrying V1R, are highly and very selectively sensitive or aplasia of the olfactory bulbs, orbitofrontal cortex alter- to small pheromonal molecules, at picomolar concentra- ation in the olfactory sulcus and reduction in or absence tions. V2R neuron sensitivity is less clearly established, of olfactory sensitivity. After this initial development, how- but may select vector proteins or peptide derivatives. ever, the vomeronasal organ regresses, leaving only a few Recently, another contingent of vomeronasal neurons has vestiges in adults [24,25]. Following Jacobson in the 19th been identified, expressing olfactory receptor proteins and century, Kölliker [26] and then Potiquet detailed the posi- transmitting information to the accessory olfactory bulbs tion of the vomeronasal cavities in adults: on base of the [16]. Receptor protein activation activates the vomeronasal nasal partition above the foot, near the vomer bone. The ca- neurons by opening particular ion channels (trpc2) [17] vity openings are now clearly visible on endoscopy (Fig. 2A) which initiate cell depolarization and action potential in some but not all individuals [25]. Histologic examination emission. All the vomeronasal neurons use these trans- finds an internal canal of variable length, extending back and duction channels: experimental deactivation of the genes covered with ciliary epithelium with numerous underlying involved in their synthesis totally and specifically abolishes glands (Fig. 2B). Compared to in other mammals, the general vomeronasal function. Mice in which the trpc2 channels structure shows many signs of regression: notably, absence have been deactivated are unable to distinguish the sex of any veins or turgescent tissue able to produce active of partners [18,19]. The vomeronasal organ thus provides pumping. Immunohistochemistry confirms the absence of information on congeners’ sex and social and reproductive epithelial receptor neurons and even of underlying nerve status. fibers that might allow neural information to be transported to the brain [25]. With contrast medium injection, the cavities can be visualized on CT (Fig. 2C and D), at the base of Contribution of other sensory systems the septum, above the foot of the partition. The vomeronasal organ is thus nonfunctional in adults Other organs in the nasal cavities are also involved in [25]. Other decisive arguments back up this conclusion. pheromone detection [20]. The vomeronasal organ was long The genes coding for V1R-type receptor proteins are mostly thought to be the sole pheromone detection organ, the deactivated by mutation: only five sequences remain in the olfactory organ being dedicated to general olfaction; in human genome (whereas mice have more than 180!) [27]; fact, however, the olfactory organ does indeed seem to the same is true for those coding for V2R-type receptor contribute to detecting certain pheromones [21], with a proteins [28]. Moreover, the genes coding for the trpc2 chan- cerebral connection between the principal olfactory bulbs nels, essential to vomeronasal neuron activation, are again and the amygdalar region which receives vomeronasal input. pseudogenes unable to give rise to functional ion chan- The nasal cavities of many mammal species also contain nels [29]. These features are shared by New World monkeys the Grüneberg ganglion, which in rodents is located in a van- and marine mammals. Finally, on histologic examination of guard position in the nasal vestibule and is connected to the the olfactory bulbs in humans and New World monkeys, olfactory bulbs. Via its ciliary detector neurons, in mice it the accessory olfactory bulbs are found to be absent [30], is involved in detecting alarm pheromones emitted by con- whereas they are precisely the target of the vomeronasal geners under stress; experimental destruction abolishes the axons in those species in which the vomeronasal organ is stereotyped freezing response to alarm pheromones [22]. functional. Taken together, these arguments lead to the Finally, there is also the septal organ of Masera, compri- conclusion that the vomeronasal function is inoperative in sing two little islands of detector neurons on either side of humans. As nothing is known as to the existence of the and below the rodent nasal septum, but which has not yet Grüneberg ganglion or organ of Masera in humans, the been sufficiently well studied for it to be known whether only sensory channel that might possibly allow detection it contributes to detecting certain pheromones. The idea of pheromones in the nasal cavities would be the olfactory that pheromonal messages result from combined analysis of system itself. Vomeronasal organ and human pheromones 187

Figure 2 Vestigial human vomeronasal organ [25]. A: Endoscopic observation of a cavity opening; p: posterior edge; a: anterior edge. B: Histologic cross-section of a human vomeronasal cavity (see text). C and D: Location, on contrast-enhanced CT scan, of a vomeronasal cavity at the base of the septum, above the foot of the nasal partition.

Human pheromones? activation patterns are specific [36]. Obviously, these find- ings are of interest only if the idea of individual sexual Various studies point to the possible existence of chemical orientation is considered well founded and stable. communication in humans, although the molecules involved Since the anterior hypothalamus is activated, the remain to be identified. Thus, men sniffing T-shirts worn by question arises as to whether there is a demonstrable neu- ovulating women show higher testosterone levels than men roendocrine and physiological correlate lending weight to sniffing nonovulating women’s T-shirts [31]. Likewise, Stern the idea of a pheromonal effect. In the present state of and McClintock [32] showed that compounds taken from the knowledge, the answer has to be ‘‘no’’. Rather, the effects armpits of women in the terminal follicular phase of the observed are psychological. Lundström et al. [37], for exam- menstrual cycle and applied to the upper lip of recipient ple, reported that androstadienone presented at a level women accelerated the luteotropic hormone peak and short- below the olfactory perception threshold positively mo- ened their menstrual cycle, whereas axillary compounds dulated mood and psychophysiological alertness in women, sampled during the ovulation phase conversely prolonged but only in the presence of a male experimenter. In this the cycle. The limitation inherent to such studies lies in the difficulty of distinguishing between sensory and systemic effects. Other studies have focused on the effects of steroids (Fig. 3) isolated in secretions such as sweat. Possible action is explored by investigating variation in brain activity on functional imaging or evoked potential recording, or cognitive and psychological changes, or again sympathetic/parasympathetic system effects. One such steroid is androstadienone (delta 4,16- androstadien-3-one), a testosterone derivative found in axillary secretions at levels up to 20 times as high in men as in women. Inhalation of crystal androstadienone by heterosexual women activates the ventroanterior hypothalamus [33], an effect not observed in heterosexual men, in whom the same region is activated by estra-1,3,5(10),16-tetraen- 3-ol, a substance similar to natural estrogen [33]. According to the authors, the effect as seen on PET scan is too rapid to be due to nasal vessel absorption; eliminating a possible systemic route, the observed activation thus sug- gests an olfactory contribution. Chronic anosmia due to polyposis abolishes the response to estratetraenol (estra- 1,3,5(10),16-tetraen-3-ol). In homosexual women, the cerebral activation pattern Figure 3 Some molecules currently under study as candidate resembles that of heterosexual men [34] and, in homosexual pheromones. A: androstadienone (delta 4,16-androstadien-3- men, that of heterosexual women [35]; in transsexuals, the one); B: androstenol (5 alpha-16-androsten-3 alpha-ol); C: estratetraenol (estra-1,3,5(10),16-tetraen-3-ol). 188 D. Trotier regard, it should be borne in mind that improved mood Conclusion is also observed in both men and women in response to a pleasant odor [38]. Bensafi et al. [39] also reported In rodents, pheromones show great molecular diversity, from that high-concentration androstadienone enhanced positive small volatile molecules to peptides and proteins. Three mood in women, with observable sympathetic correlates, sense organs contribute to detection: the vomeronasal whereas in men parasympathetic effects were observed. organ, the olfactory organ, and the Grüneberg ganglion. Lundström et al. [40] describe this effect on women’s In humans, the vomeronasal organ develops in utero but mood as ‘‘a positive change of women’s feeling of being subsequently regresses; all studies agree on its nonfunc- focused’’. tional status. Nothing is known as to the presence of the Jacob et al. [41] reported that androstadienone added Grüneberg ganglion in human nasal cavities. to an odor of cloves activated brain regions thought to Steroids, whether odorant or not, have, on the other be involved in emotional state and attention processes. hand been studied as putative human pheromone proto- Hummer and McClintock [42] reported that androsta- types in adults. Some, but not others, activate the anterior dienone applied at a non-painful concentration on the hypothalamus. Effects observed after sniffing or upper- upper lip improved attention to certain emotionally charged lip application strongly depend on experimental context; visual stimuli: there was thus investment of psychological they are more psychological (mood shift, increased atten- resources; in the experimental setting used in this study tion) than physiological and are context-dependent. Such (subject alone), no mood change was to be observed. effects are very far from the pheromonal effects observed A study by Saxton et al. [43] suggested that women in animals (stereotypic behavioral effects, neuroendocrine exposed to androstadienone judged men who were physi- changes). They can at most be considered to be possible cally present to be more attractive. modulators of certain psychological variables [55]. One problem with androstadienone is the wide associ- In menstrual cycle synchronization, the sole index of ated intersubject variation in sensitivity [44]. Jacob et al. a neuroendocrine effect, the substances at work and the [45] furthermore showed that repeated sniffing of androsta- action mechanism (systemic or sensory) remain unknown. dienone strongly increased sensitivity in certain subjects and Human sexuality involves such a diversity of psychologi- was accompanied by a qualitative change in perception of cal, physiological and cognitive processes that susceptibility the odor. The mechanisms underlying such potentiation of to pheromone-analog chemical messengers seems slight sensitivity remain unknown. indeed. Human sexuality detached from reproduction Evoked potential kinetics during androstadienone stim- escapes the pheromonal necessities to which animals are ulation indicated accelerated brain response compared to bound in recognizing and encountering the opposite sex to other odorous compounds [46]. The detection threshold, ensure the survival of the species. hedonic valence and induced brain response (evoked potentials) also evolved over repeated stimulation, suggesting Conflict of interest statement differential perceptual learning between men and women [47]. The effects of inhaling androstadienone are more psychological than physiological [48], although neurovege- None. tative system effects have been reported. Androstadienone blended with odor of cloves, applied below the nose, References increased skin temperature on men’s hands and decreased it on women’s; it increased skin conductance more strongly [1] Winman A. Do perfume additives termed human pheromones in women than in men, but only in the presence of a male warrant being termed pheromones? Physiol Behav experimenter [49]. 2004;82:697—701. Another steroid, androstenol (5 alpha-16-androsten-3 [2] Zhang JX, Liu YJ, Zhang JH, et al. Dual role of preputial gland alpha-ol), is also a putative human pheromone. 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