Human Pheromones, Neuroscience, and Male Homosexual Orientation *
by James V. Kohl
Dedicated to William J. (Bill) Turner, whose early interest inspired this work.
It has been more than three decades since the first indication that human pheromones might be linked to sexual orientation. We now know that mammalian pheromones, including human pheromones, typically elicit a predictable neuroendocrine response that correlates well with affective reactions and with predictable sexual behavior. We also know that some mammalian males exhibit an atypical neuroendocrine response to pheromones, and that they respond to the pheromones of other males with behavior typically elicited by the pheromones of females. The neuroanatomical basis for the typical neuroendocrine response and for the atypical neuroendocrine response is discussed, as well as the most likely psychophysiological basis of the behavioral response. In this manner, converging lines of independent evidence help to advance a pheromonal explanation of male homosexual orientation. This evidence comes from a review of neuroanatomical data, which support a link from mammalian pheromones to a predictable neuroendocrine response that has repeatedly been linked to sexual behavior. This neuroanatomical data includes data from human studies. Human studies of the typical neuroendocrine response support extension of the mammalian model to human males by incorporating a learned sexuality paradigm in which sexually dimorphic pheromones from the social environment hormonally condition the visual response associated with attractive physical features. Thus, mammalian olfactory-genetic-neuronal-hormonal-behavioral reciprocity provides a psychophysiological basis for sexual orientation. Mammalian neuroanatomy, including human neuroanatomy, must be organized in a similar manner, or activation of this mammalian response by pheromones would not occur. In the absence of any other neuroanatomically organized and neuroendocrinologically activated model linking sensory input from the social environment directly to sex differences in hormones and to sex differences in behavior, the pheromonal explanation of male homosexual orientation is unparalleled.
"A homogeneity of sexual preferences inevitably masks a heterogeneity of desired emotional productions …. [E]ven the most conventional may find their sources of sexual excitement fueled by the slightest "whiff" of the unthinkable." - William Simon (1994)
A general rule in the endocrine relationships that underlie behavior is that neuroendocrine responses must first be elicited by sensory input from the social environment. Mammalian pheromones are one type of sensory (i.e., olfactory) input from the social environment that elicits a typical neuroendocrine response. A typical neuroendocrine response to mammalian pheromones correlates with affective reactions in the development of heterosexual preferences. Kohl et al. (2001) proposed that preferences for sexually attractive human physical features are influenced by gonadotropin releasing hormone (GnRH)-directed, gonadotropin-modulated, androgenic and estrogenic changes (i.e., affective reactions) that occur in the brain during conditioning of the human visual response to pheromones. For example, sex steroid hormone-dependent pheromone production and distribution from conspecifics conditions preferences for sex-steroid hormone-associated characteristics such as facial symmetry, facial attractiveness, waist-to-hip ratio, and other sexually dimorphic physical features. Conditioning of the human visual response to pheromones helps to explain how psychophysiological effects of sexually explicit visual stimuli elicit elevations in luteinizing hormone (LH) and/or testosterone (T) in men (Hellhammer et al. 1985; LaFerla, et al. 1978; Redoute et al. 2000; Stoleru, et al. 1993).
This conditioning of the visual response to pheromones also incorporates the "learned sexuality" motivational theory of behavior (see Woodson, 2002 for review). In this case, learned sexuality accounts for the species-specific stimulus involved—namely, human pheromones. Even in the absence of cognitive assessment, human pheromones could be important in mate choice for other non-cognitively based personal preferences associated with sensory input from the social environment. Succinctly stated, according to Kohl et al. (2001), pheromones cause affective reactions leading to neuroendocrine changes, and these neuroendocrine changes are associated with the development of heterosexual preferences and heterosexual orientation.
In a similar manner, affective reactions caused by pheromones might help to explain the development of homosexual preferences and homosexual orientation. Accordingly, GnRH-directed, gonadotropin-modulated, androgenic and estrogenic changes, which occur in the brain during conditioning of the human visual response to pheromonal input, may also extend to humans a biologically based mammalian pheromonal model for the development of sexual orientation.
Recent studies provide additional significant evidence of a link among olfaction, pheromones, and mammalian sexual orientation, including human sexual orientation. For example, there are differences in the production of human odor profiles, and differences in the preferences for human odor profiles that correlate with sexual orientation. In addition to the aforementioned finding, Martins et al. (2005) found that homosexual men distinguish between the odors of heterosexual men and homosexual men, and that homosexual men prefer the natural body odor from other homosexual men. Their report appears to link human pheromones to sexual orientation.
Savic, et al. (2001) found that the human male and female brain responds differently to the androgen-like compound 4,16-androstadien-3-one (AND) and the estrogen-like steroid estra-1,3,5(10),16-tetraen-3-ol (EST), as compared to common odors, which elicit responses in the olfactory cortex. However, in contrast to heterosexual men, and in congruence with heterosexual women, homosexual men displayed greater hypothalamic activation in response to AND (Savic, et al., 2005). Therefore, it may be timely to review research findings that support a pheromonal model for the development of male homosexual orientation.
PARAMETERS AND PITFALLS FOR THIS REVIEW
This review encompasses chemical communication via odors and olfaction, as well as a typical hormonal response that is linked to behavior. Standard definitions of odors and pheromones are constrictive and ambiguous, and are not used here. With regard to olfaction, odors are chemical stimuli, regardless of whether they are consciously perceived (i.e., smelled). These odors include mammalian pheromones, which are produced by one individual and are received via olfactory input by another individual of the same species. Typically, species-specific pheromones elicit both hormonal and behavioral changes. A well known hormonal change is the LH response to mammalian pheromones from opposite sex conspecifics (Meredith and Fernandez‑Fewell, 1994). The LH response to mammalian pheromones occurs throughout life; it is not restricted to any “critical period” of postnatal development. To avoid pitfalls inherent in the definitions of an odor or in the definition of a pheromone, pheromones are defined here simply as social-environmental chemical stimuli (e.g., odors) that effect a measurable change in levels of LH in conspecifics (personal communication, Robert Johnston).
Additional pitfalls are likely in any discussion of mammalian chemical communication via odors and olfaction because there are two mammalian olfactory systems: a main olfactory system (MOS) and an accessory olfactory system (AOS). Here, the AOS and the MOS are considered collectively as the mammalian olfactory system because features found in the AOS that are involved in the mammalian response to pheromones (e.g., the vomeronasal organ, or VNO) have been the subject of ongoing debate over their presence and function in humans (Meredith, 2001; Wysocki and Preti, 2004). To the degree that cross-species comparisons are valid, and whether or not an AOS or a human VNO is involved, the focus is on the unambiguous sexually dimorphic mammalian LH response to pheromones (personal communication, Michael Meredith).
Sexually dimorphic epigenetic phenomena that may influence behavior are not considered, nor is enzyme (e.g., aromatase) induction by prenatal hormone conditions that might result either in anatomical differences (e.g., estradiol receptor content in the amygdala) or in odor differences. Similarly, demonstrable sexual dimorphism in the auditory system of adults, which may reflect prenatal hormonal effects, is not addressed because no evidence yet demonstrates that the mammalian auditory system (or any other non-olfactory sensory system) is sexually dimorphic at birth with regard to perception of voices, or that auditory (or other non-olfactory sensory) input substantially impacts a neuroendocrine pathway to limbic system structures (see for review Loehlin and McFadden, 2003; personal communication Dennis McFadden).
For concision, this review does not attempt to address any objections (e.g., failure to replicate findings) to the interpretation and integration of selected supporting data, or to the extension of a mammalian model to humans. No attempt is made to prove the model. Furthermore, the model, which incorporates selected supporting data, does not explain all aspects of sexual orientation. However, a pheromonal model of sexual orientation is proposed in the absence of any other neuroanatomically organized and neuroendocrinologically activated biologically based model of human physical attraction, with the expectation that the model may be refined through further research and discussion, as well as through comparison with any other proposed mammalian model of human physical attraction. It seems obvious that, despite unsubstantiated opinions, there is no biologically based (e.g., neuroanatomically organized and neuroendocrinologically activated) mammalian developmental model linking visual or other non-olfactory sensory input from the social environment to human physical attraction.
PHEROMONES, NEUROENDOCRINOLOGY AND AFFECTIVE REACTIONS
Because the mammalian olfactory system is sexually dimorphic at birth, a pheromonal model for the development of male homosexual orientation can be expected to include sexually dimorphic neuroanatomical features that correlate with a sexually dimorphic neuroendocrine response to pheromones that begins at birth. Indeed, in all mammals that have been studied, the innate prenatal neuroanatomic sexual dimorphism of the mammalian olfactory system establishes sexual dimorphism in the postnatal neuroendocrine (i.e., the postnatal GnRH-directed LH) response to the pheromones of opposite sex conspecifics. As is detailed below, the specialized role that GnRH plays in prenatal and in postnatal sexual differentiation is central to the concept that is modeled here—namely, that by influencing GnRH pulsatility, mammalian pheromones can also play an important role in postnatal sexual differentiation. During postnatal sexual differentiation, the effect of pheromones on GnRH can be expected to correlate with affective reactions as proposed by Kohl et al., (2001).
“The ‘affective primacy hypothesis' asserts that positive and negative affective reactions can be evoked with minimal stimulus input and virtually no cognitive processing. Olfactory signals seem to induce emotional reactions whether or not a chemical stimulus is consciously perceived. We theorize that the importance of human non-verbal signals is based upon information processing, which occurs in the limbic system, and without any cognitive (cortical) assessment. Affect thus does not require conscious interpretation of signal content. Underlying this fact is that affect dominates social interaction and it is the major currency in social interactions. Affective reactions can occur without extensive perceptual and cognitive encoding. They are made with greater confidence than cognitive judgments, and can be made sooner. Olfactory input from the social environment is well adapted to fit such assertions. For example, chemical cues allow humans to select for, and to mate for, traits of reproductive fitness that cannot be assessed simply from visual cues (p. 310).”
An example of a postnatal “affective reaction” is the GnRH-directed LH response to pheromones.
Prenatal and Postnatal Sexual Dimorphism
Prenatal organization of the sexually dimorphic LH response to pheromones occurs when embryonic migration of GnRH neurosecretory neurons from the olfactory placode to the hypothalamus establishes the hypothalamic GnRH pulse. The hypothalamic GnRH pulse modulates the pre- and postnatal concurrent maturation of the neuroendocrine system, the reproductive system, and the central nervous system. In both animal and human studies, two things seem clear: 1) When hypothalamic GnRH pulse frequency decreases, levels of follicle stimulating hormone (FSH) increase, 2) When hypothalamic GnRH pulse frequency increases, levels of LH and of either T, or estradiol (E2) increase (see for review Grumbach and Styne, 1992; Everett, 1994; Silverman et al., 1994).
The GnRH-directed prenatal secretion of androgens, like T, and of estrogens, like E2, is primarily responsible for establishing traditionally conceived pre- and postnatal sexual dimorphism in the classical gonad to hormones to behavior (G-H-B) model. This G-H-B model includes sexual dimorphism both in the olfactory system and in many other neuronal pathways and neurohormonal systems of all terrestrial mammals (see for review Diamond et al., 1996).
Throughout postnatal development, the hypothalamic GnRH pulse continues to help develop the neural substrates that enable mammalian olfactory pathways to exhibit sexually dimorphic specificity to pheromones. The hypothalamic GnRH pulse also promotes the general ability of these neural substrates to transduce sexually dimorphic pheromones into a neuroendocrine response. In a reciprocal relationship, this neuroendocrine response to pheromones alters the hypothalamic GnRH pulse, the release of gonadotropins (i.e., LH and FSH), and levels of sex steroid hormones. Levels of sex steroid hormones correlate with sex-typical pheromone production during sexual maturation and sexual differentiation (Kloek, 1961; Preti and Huggins, 1975; Nixon et. al. 1988).
There is abundant evidence both that GnRH is secreted episodically and that LH is secreted in a pulsatile manner long before physical signs of puberty become apparent (Jakacki et al, 1982). Presumably, mammalian pheromones influence GnRH-directed LH secretion from birth until death.
The LH response to human pheromones from opposite sex conspecifics is linked to changes in LH/FSH ratios and in levels of sex steroid hormones like T and E2. This LH and T response has been repeatedly either indicated or reported in findings from human studies. Short-term exposure of males to females is linked to increased T in men as well as in rats, mice, rabbits, bulls, rams and monkeys. The T response is believed to be due to the effect of pheromonal conditioning of an LH response, which precedes the T response (Graham and Desjardins, 1980).
An aqueous mixture of five ovulatory fatty acids (i.e., copulins) evoke increased saliva T levels in men (Jütte,1995). Additional reports (cited below) show that hormone responses in mammalian males and females vary with exposure to the pheromones of either males or females. For example, exposure to sexually dimorphic pheromones that elicit an LH response is the most likely explanation for the recent finding that saliva T levels in men increase with exposure to a young woman, but do not increase with exposure to a young man (Roney et al. 2003).
Through recent reports, it has become clearer that human pheromones elicit an LH response in other humans as a reaction to social-environmental changes that are accompanied by olfactory input, as evidenced by several studies. Berliner et al. (1996) indicated that a progesteronic pheromone alters LH pulsatility (and T levels) in men. Stern and McClintock (1998) showed that the pheromones of women regulate ovulation in other women, presumably by affecting the LH/FSH ratio. Similarly, Shinohara et al. (2001) showed that axillary pheromones from women either in the follicular or in the ovulatory phase of the menstrual cycle differentially modulate pulsatile LH pulse frequency in other women. Preti et al. (2003) showed that male axillary extracts increase LH levels and they also elevate mood in female recipients. The putative human pheromone androstadione also has been shown to elicit hormonal and behavioral (i.e., mood) changes (Jacob and McClintock, 2000; Grosser et al. 2000). Androstenol elicits changes in LH pulse frequency in women (Shinohara et al. 2000)
The ability of mammalian pheromones, including putative human pheromones, to influence GnRH modulated levels of LH in conspecifics implies that pheromones elicit postnatal affective reactions, which alter levels of hormones, including sex steroids like T and E2 that influence behavior. Postnatal affective reactions that occur in response to pheromonal input can be powerful influences on behavior. For example, pheromones that male rats learn to visually associate with sexual activity can be used to condition LH release. After minimal association with the natural odor of a female, an arbitrary odor will elicit a male LH response, even in the absence of odor previously associated with a female. It follows that pheromones (i.e., natural body odor) may initially be responsible for the LH response, but that other odors associated with the pheromonally induced LH response may also play a role in the conditioning of either the visual responses or other sensory responses to olfactory cues.
According to Graham and Desjardins (1980), the functional significance of the conditioned change in LH secretion lies principally in the unequivocal demonstration that olfactory cues can activate the male hypothalamic-pituitary-gonadal (HPG) axis in a way that mimics, in every respect, the activation achieved by exposure to a female. Thus, it has become apparent that after the LH response has been conditioned to olfactory cues, associated visual or other associated sensory input can activate the HPG axis in the absence of olfactory cues. From an endocrine perspective, given the link between mammalian LH and levels of sex steroid hormones like T, the female odor cues that condition LH release presumably also condition T release. Therefore, it seems likely that human pheromones, via their influence on LH release, also have the ability to condition T responses to non-olfactory sensory (e.g., visual) input. Since change in levels of T have repeatedly been linked to sexual behavior, this biologically based affective reaction to pheromones links the postnatal social environment to the GnRH-directed neuroendocrinology of sexual behavior. However, this affective reaction to pheromones does not require the ongoing presence of olfactory/pheromonal sensory input, and it does not require cognition.
Mammalian Models That Link Pheromones, Neuroendocrinology, and Sexuality
Perhaps the best evidence that affective reactions to pheromones, which influence hormones and behavior, do not require cognition comes from non-human mammalian models, since only humans have cognition. Three mammalian models link pheromones to neural pathways and limbic system structures, which exert significant cumulative effects on the HPG axis and on behavior (effects on the HP-adrenal axis notwithstanding). These cumulative effects on the HPG axis include development of a sexually dimorphic LH response to the pheromones of conspecifics, effects on estradiol receptors (ERs), and effects on sexual behavior, which include sexual responses that might be linked to sexual orientation.
In the first mammalian model, neonatal treatment with 1,4,5-androstatriene-3,17-dione (ATD), which blocks the aromatization of T to E2, also affects the sexual differentiation of olfactory pathways. (Sex differences in odor preference are most likely related to functional T and E2-determined sex differences in the olfactory pathway of rats.) Male rats that are treated with ATD show a female‑like mammalian pheromone-processing system (i.e., the vomeronasal system) and exhibit lordosis (a female-like behavioral response) when exposed to the odors of sexually active males. However, ATD males also exhibit mounting behavior when exposed to the odors of estrus female rats. Apparently, ATD treatment causes male rats to respond with what may tentatively be called bisexual behavior in the presence of pheromones either from females or from other males (see for review Bakker et al., 1996a; Bakker et al., 1996b).
In this first mammalian model linking pheromones, hormones, and behavior, bisexual behavior cannot be linked to male sexual orientation. However, the addition of a second mammalian model suggests there is a neuroendocrinologically based pattern that links mammalian pheromones, hormones, and olfaction to sexual orientation, and that also includes sexual differentiation.
In the second mammalian model, pheromonal induction of GnRH release influences the HPG axis and levels of E2, resulting in higher levels and occupancy rates of ERs in the mediobasal hypothalamus of hormone-treated male rats that exhibit lordosis (see for review Samama and Aron, 1989). Lordosis in males has been challenged, along with either all or nearly all claims of demonstrable behaviors that have been linked either to males or to females, and therefore to sexual orientation in mammals.
A third mammalian model linking pheromones, hormones, and sexual behavior may help to persuade others to reconsider such challenges. In this model, the typical mammalian heterosexual male LH response, which estrus female pheromones elicit in heterosexual rams, does not occur in homosexual rams when they are exposed to estrus females (Perkins et al.1992). Absence of the LH response indicates that an atypical neuroendocrine response to pheromones might be involved in the homosexual behavior of rams. Therefore, in an attempt to help explain the existence of exclusive homosexual orientation in rams, Perkins et al. (1995) discuss correlates among perception of olfactory input from potential mates and levels of LH, T, and estrogens, as well as correlates with E2 receptor (ER) content in the amygdala (AMY). “Estradiol receptors present in the AMY could… translate information about peripheral concentration of testosterone, thereby integrating the AMY with other centers important for copulation ( p. 38).” It seems likely that androgenic pheromones translate information about peripheral concentrations of testosterone, and that the AMY is capable of integrating this information with other sensory input that is important for copulation.
Pheromonal induction of the sexually dimorphic LH response can be expected to influence levels of E2, which ultimately affect ER content in the AMY of rams. The LH response (or lack thereof) to the pheromones of estrus ewes, as well as ER content in the AMY, appear to be measurable factors that correlate with sexual orientation in rams. Rams that exhibit a full range of proceptive homosexual behaviors lack the LH response. These rams also have less ER content in the AMY. ER content in the AMY of homosexual rams and in ewes was similar, but less than the ER content in the AMY of heterosexual rams. The apparent link among pheromones, LH, T and E2, ER content in the AMY, and homosexual orientation in another mammal incorporates the first two models and provides a reason to look for additional clues that might link pheromones, hormones, and human male homosexual orientation.
Linking Mammalian Models to Human
The link from sexual dimorphism of the olfactory system to the sexually dimorphic LH response to pheromones, and to ER content in the AMY of homosexual rams, is important because it may also link pheromones to the development of adult cyclic hormone secretion, which may vary with human sexual orientation.
The adult cyclic hormone secretion that is characteristic of women includes an estrogen (i.e., E2) induced ovulatory LH surge. In homosexual men, an LH response to estrogen priming may be intermediate to the response of heterosexual males and females (Gladue et al. 1984; see for review Dörner, 1988). The equivocal LH response to estrogen priming appears to exemplify incomplete sexual differentiation of the homosexual male brain. It is believed by some that this intermediate response indicates that homosexual men have higher levels of E2 during development (see also Dörner et al. 1987).
Typically, higher T levels during male reproductive maturation neutralize the mechanism for adult cyclic hormone secretion in men. If homosexual men have higher levels of E2 during development, T levels may fail to neutralize the E2 induced LH surge during development, which indicates that a neuroendocrine predisposition may exist for human male homosexuality. This neuroendocrine predisposition could be manifest in E2 and T levels, which are modulated by the hypothalamic GnRH pulse.
The GnRH-directed human endocrine milieu is extremely likely to be influenced by pheromones during development. Thus, it seems likely that pheromones would also affect relationships among T levels, levels of estrogens, an E2 evoked LH surge, and ER’s in limbic system structures (e.g., the AMY). All of these are associated with sexual differentiation and with male sexual orientation. GnRH-directed perturbations that affect LH/FSH ratios; male levels of T and E2; or their "end-organ" effects during pre- and postnatal development, might fail to eliminate the estrogen-induced LH surge in homosexual males.
The aforementioned scenario offers a possible example of how incomplete sexual differentiation, which includes sexual differentiation of the olfactory system, could affect ER content in the AMY. The AMY is important to the processing of olfactory input (Zald and Pardo, 1997). During postnatal development, pheromones could influence sexual differentiation of ER content in the AMY via their influence on GnRH, LH secretion, and thus on steroid hormone secretion. And, as noted above, E2 induced patterns of steroid hormone secretion have been linked, albeit equivocally, to human male sexual orientation. Thus, pheromones could influence sexual differentiation and sexual orientation.
With regard to GnRH-directed LH secretion and its potential association with sexual orientation via classical conditioning, it is noteworthy that an atypical LH response to GnRH correlates with human sexual orientation in both male-to-female and female-to-male transsexuals. Sensitivity of LH secretion to GnRH in transsexual women is decreased, but increased in transsexual men. Kula et al. (1986) proposed that these correlates might reflect the effect of the environment on the down-regulation of the pituitary LH response. Thus, the LH response to social environmental sensory input (e.g., human pheromones) could be the best adult indicator of the endocrine milieu during postnatal development.
To reiterate, it appears that pheromones are likely to influence postnatal brain development via their GnRH-directed effect on the HPG axis, and thus their effect on LH, T, and E2. Neuroendocrine activation is manifest in these hormonal responses, and these responses parallel neuroendocrine responses seen in animal studies in which sex differences in hypothalamic activation, and in the LH response to pheromones, have been correlated with the influence of pheromones on reproductive sexual behavior. It is extremely likely that during the GnRH-directed concurrent maturation of the neuroendocrine system, the reproductive system, and the central nervous system, the influence of pheromones on GnRH-directed perturbations could allow pheromonal conditioning of the LH response.
NEUROANATOMICAL ASPECTS OF SEXUAL ORIENTATION
In this pheromonal model, the obvious neuroanatomical basis for mammalian neuroendocrine function predicts neuroanatomical links to sexual orientation. These neuroanatomical links may help to detail regulatory aspects of the aforementioned levels of sex steroids, as well as the involvement of sex steroids in the LH surge that is induced by E2, which regulates ER content in various tissues. Neuroanatomical (e.g., organizational) differences that vary both with genetic sex and with sexual orientation also suggest that there are genetically determined neuroanatomical aspects of sexual orientation.
Genetically determined neuroanatomical aspects of sexual orientation include the comparatively increased production both of LH and of androgens (e.g., testosterone) that tonically occurs in human males due to a more frequent GnRH pulse, and that cyclically occurs in females. Evidence of neonatal sexual dimorphism in the GnRH neuronal system of rats strongly (albeit speculatively) attests to the likelihood that more GnRH neurons (Tobet and Fox, 1992), or their sexually dimorphic connectivity, collectively allow for a more frequent GnRH pulse. Indeed, with regard to both neuronal number and sexually dimorphic connectivity, males have greater numbers of neurons at sites of synaptic transmission that are involved with the processing of olfactory input in the limbic system (see for review Segovia and Guillamon, 1993). Perhaps fewer GnRH neurons in the hypothalamic nuclei of females correlate with a less frequent GnRH pulse and with the normal occurrence of comparatively increased production of FSH and E2 in human females. In any case, consistent differences among the neuronal density of hypothalamic nuclei and heterosexual activity in non-human primates, and in homosexual and heterosexual men (Byne et al., 2001), suggest that neuroanatomical differences in hypothalamic nuclei might lead to alteration in GnRH pulse frequency and to a more female-type pattern of gonadotropin (i.e., LH and FSH) secretion in homosexual males. The importance of consistent neuroanatomical differences in the hypothalamus includes neuroanatomical differences in the medial preoptic area of the anterior hypothalamus (MPOA/AH).
The MPOA/AH of the anterior hypothalamus is critical for the expression of male sexual behavior in many mammals (Hull et al., 2002). The MPOA/AH also is essential for gonadotropin (e.g., LH) release, and thus, retrospectively, it is very likely to play a role in GnRH pulse frequency (see for review Meisel and Sachs, 1994). Within the MPOA/AH, sexually dimorphic cell groups that are larger in males than in females have been identified in several species, including humans.
Experiments in several species indicate that the development of these sexually dimorphic cell groups within the MPOA/AH are the direct result of exposure to testosterone or its metabolites during a critical period in prenatal or early neonatal life (Cooke et al., 1998). In addition, a sexually dimorphic nucleus (SDN) exists in the sheep MPOA/AH. It is three times larger in volume and contains more neurons in rams than in ewes (Roselli et al., 2003). Without specifying which sensory cues might be most relevant (e.g., odor cues), these authors note that SDN volume in sheep and the number of cells in the SDN could bias the processing of sexually relevant sensory cues. This dimorphism (i.e., the SDN) also correlates with ER content in the AMY of sheep and with sexual partner preference. Furthermore, an SDN in male rats treated with ATD correlates positively with male-typical behavior and with female-directed partner preferences (Houtsmuller et al., 1994). (For additional discussion of the importance of the SDN in the MPOA/AH, see Roselli et al., 2003.)
In the rat, males have greater numbers of neurons at sites of synaptic transmission that include the MPOA/AH and the AMY (Bressler and Baum, 1996). To the degree that cross-species comparisons are valid, a sexually dimorphic response to pheromones in hypothalamic nuclei (e.g., those in the MPOA/AH) that regulate GnRH-directed gonadotropin (e.g., LH and FSH) release could help to explain the development of sex differences in behaviors that include partner preference. These neuroanatomical sex differences can be expected to correlate with neuroendocrine (e.g., GnRH-directed) sex differences such as the sexually dimorphic LH response, which occurs with exposure to human pheromones.
Putative human pheromones and neuroanatomy
Genetically determined neuroanatomical aspects of sexual orientation also are the most likely reason that hypothalamic activation by the estrogenic compound oestra-1,3,5(10),16-tetraen-3-ol (EST) is greater in men, while hypothalamic activation with the androgenic compound 4,16-androstadien-3-one (AND) is significantly greater in women. The effect of the putative human pheromone EST on men was concentrated in the dorsomedial hypothalamic nucleus. However, the effect on women of the putative human pheromone AND was in the MPOA/AH, and this effect was concentrated in the preoptic nucleus (Savic et al., 2001).
Ishai et al. (1999) showed that pheromones are associated with neocortical aspects of facial recognition, via the comparative study of activation of these areas by presenting odors paired with pictures of houses, faces, and chairs. Oomura et al. (1988) suggested that MPOA/AH neurons integrate visual and/or olfactory cues from the receptive female leading to sexual arousal and initiation of mating by the male. Therefore, it is not surprising that AND and EST also elicited sexually dimorphic responses in neuroanatomical regions (i.e., the fusiform and lingual gyrus) that have been linked to the visual imagery of faces (Savic et al., 2001).
Savic et al. (2001) briefly touch on the possible reasons for sexually dimorphic activation of the hypothalamus by putative human pheromones—namely, that sex steroids modulate sexually dimorphic neuronal density. Sex steroids also modulate sex steroid receptor content in the hypothalamus or, more globally, in the limbic system as has been represented herein. Simply put, data from this human study appears to support extension to humans of the mammalian model for sexual orientation, which is presented herein.
While addressing sexually dimorphic neuroanatomy, Savic et al. (2001) specifically mention the third interstitial nucleus of the anterior hypothalamus (INAH3), which may help to link pheromones to male homosexual orientation in the following manner. Arguably, the size of the INAH3 is intermediate between human heterosexual males and females (LeVay, 1991). A sex difference in INAH3 volume has been attributed to a sex difference in neuronal number. A sexual orientation difference in volume was not. Instead, variation in INAH3 size with male sexual orientation appears to correlate best with neuronal density, which is likely to be influenced by environmental cues during postnatal brain development (Byne et al., 2001). The developmental effects of social-environmental cues, like human pheromones, on steroidogenesis might cause sex differences both in INAH3 size and in INAH3 neuronal density during postnatal brain development. Indeed, based upon animal (and primarily mammalian) models, Byne et al (2001) acknowledge that the most likely reason for a sex difference in the INAH3 is that it depends, in part, upon sex differences in developmental exposure to gonadal hormones.
Given this neuroanatomically based explanation for a correlation between sex steroids and sexual differentiation, the production of gonadal sex steroids like T and E2 might be expected to vary with male and female heterosexual orientation. However, neuroanatomical correlates of heterosexual male and of homosexual male orientation do not sufficiently explain why neuronal density in the INAH3 co-varies with male sexual orientation. Accordingly, it is important to address the most likely neuroendocrine substrate that could be involved in the development of this neuroanatomical (i.e., neuronal density) correlate—one that allows pheromones to alter postnatal T and E2—and thus to potentially alter neuronal density in the INAH3.
The INAH3 is located in the MPOA/AH. As noted above, this area is essential for gonadotropin release, which modulates sex steroid release and, thereby, the sexual behavior of other mammals. In contrast to heterosexual men, and in congruence with heterosexual women, homosexual men displayed greater hypothalamic activation in response to the androgenic compound AND. In congruence with heterosexual women, the MPOA/AH of homosexual men was activated by AND (Savic, et al. 2005).
The role of MPOA/AH activation in sexual orientation should not be underestimated. Neurotoxic or electrolytic MPOA/AH lesions in male ferrets (Kindon et al., 1996) and electrolytic MPOA/AH lesions in male rats (Paredes et al., 1998) change their preferred stimulus from estrous female to male, which suggests that the males’ preference for an estrus female depends on a functional MPOA/AH . Male rhesus monkeys stopped mating after MPOA/AH lesions. Lesions of the MPOA/AH also inhibit pursuit of females by male rats.
After its conversion by aromatase to estradiol, testosterone may facilitate male sexual behavior via estradiol receptors on neurons in the MPOA/AH. Lower aromatase activity in the MPOA/AH is present in rams that prefer mounting other males instead of estrus females. The presence of a female rat is sufficient to activate MPOA/AH neurons in sexually inactive males; sniffing and pursuing the female increase the firing rate of MPOA/AH neurons. The MPOA/AH is a fundamental part of the olfactory pathways which process pheromones. Mating induces MPOA/AH changes in c-fos activation (and neuronal Fos immunoreactivity) in males within 30 minutes of exposure to a female. The functional integrity of MPOA/AH neurons is crucial for the male’s ability to identify a female partner, determine partner preference and eventually mate with the female. (see for review, Paredes, 2003).
It seems likely that the unconscious effect of human pheromones on GnRH, the gonadotropins LH and FSH, and on T and E2 during postnatal development will help to explain environmentally affected co-variation in the neuronal density of the INAH3, and thus in the MPOA/AH. This environmentally affected co-variation could be related both to GnRH pulsatility and to genetically predisposed male sexual orientation.
With regard to environmentally affected co-variation, Byne et al (2001) note that the major expansion of the human brain occurs postnatally while the individual is in constant interaction with the environment. The social environment was not specified. However, it may be the effect of pheromones from the social environment on GnRH pulsatility and on other hormone levels (such as LH) that best explains how the influence of the social environment can affect sexually dimorphic postnatal expansion of the human brain during development.
COMBINING ASPECTS OF GENETICS, NEUROANATOMICAL DEVELOPMENT, AND NEUROENDOCRINE DEVELOPMENT
This pheromonal model suggests that in homosexual males the LH response to pheromones is incompletely sexually differentiated, and it follows that homosexual males might respond to the pheromones of other males as they otherwise would respond to the pheromones of females. This was indicated in homosexual rams that respond to the odors of other males, but do not respond with an LH response to the odors of estrus ewes. An atypical preference for the pheromones of other males might lead to neuroanatomical, and therefore, neuroendocrine differences that correlate with sexual preferences. During postnatal expansion of the human brain, these differences could be expected to correlate with the LH response to pheromones, with ER content in the AMY, and with neuronal size and density in the MPOA/AH.
A noteworthy proposal made by Hamer and Copeland (1994) concerning the genetics of sexual orientation may help to further extend mammalian models to humans. "Where might a "gay gene" fit into LeVay's analysis? The most simple hypothesis would be that Xq28 makes a protein that is directly involved in the growth or death of neurons in the INAH‑3. Alternatively, the gene could encode a protein that influences the regulation of this region by hormones (p. 163)." Given this speculation about the genetics of neuronal number (and perhaps in neuronal density) in the INAH3, about regulation of this structure by hormones, and about male sexual orientation, it is interesting to note that the presence of the Kalig 1 gene affects olfaction, GnRH secretion, and sexual behavior (see Kohl 2002a, 2002b). However, even before this proposal by Hamer and Copeland, William J. Turner (personal communication) had this to say about Xq28, olfaction, and homosexuality.
"As you may gather from our conversation I am only now beginning to study the literature on olfaction. I want to assure you that I shall not ever attempt to claim any primacy in the concept that the gene for Homosexuality Type 1 functions through olfaction, though I did come to the idea quite independently. No, I did not even come to it that way. In 1952 I was told by an aging Gay patient that he had never made a mistake in choosing a partner. He said, 'I smell them'. I would claim that the gene lies at Xq28."
It seems likely that other genes will be found that influence olfaction, GnRH secretion, and sexual orientation.
PSYCHOPHYSIOLOGICAL SUPPORT FOR THE PHEROMONAL MODEL
Another area of research that supports a pheromonal model of sexual orientation is psychophysiology—specifically studies of the effects of various types of visual stimuli. For example, it has been shown conclusively that odors are associated with the psychophysiological responses that are involved in the development of food preferences. Indeed, it would probably be difficult to find someone who believed that the visual appeal of food was more important than its olfactory appeal in ingestive behavior (i.e., food choice).
Gottfried et al (2003) showed that appetitive neural responses to a particular food can be generated by pairing odor with the sight of an abstract computer image. The ability to make neural connections between appetitive or aversive odors and visual stimuli is a part of learning that is probably common to all animals. This type of learning is the means by which picture advertisements play on the development of human food preferences. For example, a picture of a steak affects appetite. This is referred to as classical conditioning. In classical conditioning, a previously neutral item (the conditioned stimulus, CS) gains behavioral significance after being paired with a biologically active unconditioned stimulus (UCS). The efficacy of conditioning depends on establishing CS:UCS links. Typically, biologically based CS:UCS links are formed during multiple UCS representations that allow association of the CS with sensory features, a reward value, or a general effect. For example, olfactory input (the UCS) elicits a hormone response, and the hormone response is integrated with visual input (the CS) during olfactory-visual integration. Thus, olfactory input conditions and integrates the hormone response to visual input.
In demonstrations of the underlying neural mechanisms of olfactory-visual integration in the human brain, it may at first appear that olfactory information becomes more reliable when it is paired with visual input. However, it is more likely that visual input is reliable only in the presence of olfactory input. Obviously, no mammal chooses to eat food that lacks chemical/olfactory appeal, and humans do not eat pictures of food. On the other hand, even though the same visual stimulus is processed, a picture of a steak is unlikely to "look" good to a vegetarian. Therefore, it is reasonable to consider individual comments on how food looks as little more than a means to describe the food's chemical appeal. Others who have developed different personal preferences in accord with variations in ingestive behavior may not agree on chemical appeal; it might not look good to them. In a similar manner, personal preferences for erotic imagery could be expected to correlate with one's conditioned response to pheromones. Thus, erotic imagery of a female that is designed to elicit heterosexual arousal, and most likely the female herself, would lack any classically conditioned olfactory-hormonal association with chemical appeal in a homosexual male, and the erotic imagery of the female would probably not look good to a homosexual male.
Neural responses to chemical stimuli also demonstrate that olfactory classical conditioning can be used to differentiate appetitive and aversive conditioning to pleasant or unpleasant odors that have been paired with faces. Recent studies of neural responses that occur in the orbitofrontal cortex and AMY link conscious choice to emotions generated from the limbic system and help to establish the means by which consciously perceived olfactory input can influence how we respond to visual input from faces (Gottfried et al 2002). Personal preferences (e.g., emotional responses) seem likely to reflect olfactory classical conditioning of the visual appeal of either food or faces. Simply put, another person may or may not look like he or she would smell good.
Predictably, via olfactory conditioning, estrogenic pheromones would increase a female's visual appeal to a heterosexual male (make her look better). This would help to explain the reproductive function of a male preference for the scent of ovulatory phase women (Singh and Bronstad, 2001). Similarly, physically appealing testosterone-linked characteristics like height, darker complexion, and masculine facial features (including aspects of bilateral symmetry) might explain a preference for a tall, dark, and handsome man, because these characteristics are associated with androgenic pheromones (see Kohl and Francoeur, 2002 for review). It is not surprising that Cornwell et al. (2004) showed concordance between olfactory and visual signals during the partner preference judgments of men and women. They surmised that putative human pheromones and sexually dimorphic facial characteristics convey common information about the quality of potential mates. Kovacs et al. (2004) showed that gender specific chemical cues affect the judgment of female faces by men.
SEX DIFFERENCES IN PHEROMONE PRODUCTION
Sex differences in pheromone production lend further support to a pheromonal model of human male sexual orientation. Apart from the fact that some hormones, such as testosterone, metabolize to pheromones that are associated with physical characteristics, these hormones have no inherent value as social stimuli. The metabolism of steroid hormones (such as testosterone, estradiol, and progesterone) into pheromones involves several factors. One important factor is the initial production level of a particular hormone and how its production level compares to that of other hormones. Men produce more androgens than women, whereas women produce more estrogens and progesterone than men. This explains why men also produce different concentrations of androgenic, estrogenic, and progesteronic pheromones than women.
Although no human pheromone has been isolated, effects of human pheromones are readily apparent, as evidenced by the LH response. Clearly, these pheromones and their effects are sexually dimorphic. If, as Martins et al. (2005) indicates, homosexual males distinguish among different pheromones and establish a preference for the pheromones of other homosexuals, the question arises, How might they do this? An investigation of steroid hormone metabolism provides some clues.
An investigation of steroid hormone metabolism that could be important to human pheromone production might well start with adrenal hormone production. This is reasonable because primates are unique in having adrenals that secrete large amounts of the precursor steroid dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) into the bloodstream of males and females. In humans, DHEA AND DHEA-S are the major adrenal steroid secretory products. Depending on the relative enzymatic activities of aromatase and other enzymes, DHEA or its derivatives will be preferentially converted in peripheral tissues into androstenedione or androstenediol and then into potent androgens and estrogens.
Thereby, androstenedione and androstenediol maintain a close correlation between the concentration of androgens and estrogens in the blood (Adams, 1985). Androstenedione is the principle metabolite of DHEA. The C19 steroids, androsterone (A) and etiocholanolone (E) are the enzymatically reduced metabolites of androstenedione. Studies have noted that, in humans, various characteristics of A and E, such as blood concentration, metabolism, and localization, are sexually dimorphic. That is, the A/E ratio varies between males and females. For example, the urinary A/E ratio in men is usually greater than or equal to 1.5 (as opposed to 1 in women).
The sexually dimorphic A/E ration might help to explain how Massion-Verniory (1957) predicted that a byproduct of hormone metabolism found in urine would be found to differentiate homosexuals from heterosexuals. Indeed, more than three decades ago, Margolese (1970) reported that A/E ratios in urine samples could be used to determine whether a particular urine sample came from a heterosexual male or a homosexual male. His finding that homosexual males have decreased urinary A/E ratios was subsequently confirmed by Evans (1972), Margolese and Janiger (1973), and Friedman et al. (1977).
Though A/E ratios are very sensitive to other influences, Margolese and Janiger (1973) speculated that the decreased urinary A/E ratios in homosexual males indicate a shift in metabolic pathway, toward the female side, and they raised the possibility of possible enzyme induction by prenatal hormone conditions. They went on to propose "that the metabolic pathway which results in a relatively high androsterone value is associated with sexual preference for females by either sex, whereas a relatively low androsterone value is associated with sexual preference for males by either sex (p. 210)." Notably, this same study, along with replicate studies, may have provided the first evidence of a genetic basis for homosexuality. Of 24 heterosexuals, two reported homosexual relatives. Of 28 homosexuals, 17 reported homosexual relatives, five of whom had two each.
Typically, aromatic compounds found in urine can also be found in different concentrations in the peripheral blood, saliva, and axillary secretions of men and women. Accordingly the A/E ratio is likely to also contribute to components in salivary secretions and in axillary (or other bodily) secretions, and thus to pheromone production. Manifestation of the A/E ratio in pheromone production might best explain the ability of homosexual males to distinguish among pheromones that are representative of sexual orientation and to establish a preference for the pheromones of other homosexuals, as indicated by Martins et al., (2005).
Though a pheromonal model of heterosexual orientation (Kohl et al., 2001) appears to explain heterosexual orientation, a pheromonal model of homosexual orientation has not yet been fully considered. Perhaps this is because many people believe that in the development of sexual preferences, the influence of pheromones on human behavior is minimal compared to the influence of other sensory input from the social environment—particularly visual input. For example, Grammer et al., (2003) view attractive human physical features almost solely from the perspective of visual input. Aron et al., (2005) propose that romantic love is a developed form of a mammalian drive to pursue preferred mates. Their use of photographic stimuli and brain imagery seems counterintuitive given the fact that the mammalian drive to pursue a preferred mate is based on olfactory stimuli; there is no direct link from visual input to a neuroendocrine response, and no innate sexual dimorphism in visual pathways. Similarly, mass media reports on physically attractive features and heterosexual attraction, fail to even consider the puzzle of how some physically attractive features of males become attractive to other males. How then, might a man find the physical features of another man to be visually attractive? In this regard, it is important to note that the relative functional importance of visual, auditory, tactile, or chemosensory (e.g., gustatory and olfactory) cues, and the developmental effects of previous sexual experience on mammalian behavior are not completely known for any species. Furthermore, the influence of culture on human behavioral responses to sensory stimuli is a confounding factor in attempts to establish a causal relationship between either a particular sensory signal or a collection of sensory signals and any behavioral response that may be elicited.
Given our current lack of knowledge about how sensory input from the social environment influences sex differences in behavior, it is interesting to note that people typically think more about non-olfactory sensory input during an initial encounter (e.g., visual or auditory input). Most people do not think about pheromones despite the fact that pheromones, rather than either visual or auditory stimuli, appear to elicit the neuroendocrine response and the hormonal influence that drives mammalian sexual behavior.
Regardless of what anyone thinks about the relative value of sensory input, it is obvious that mammalian conditioning paradigms are typically based on olfactory conditioning of visual input, not on the visual conditioning of an olfactory response. For example, a male canine doesn't look for a good-looking mate; he sniffs out the odor of a bitch in heat (i.e., estrus female). Similarly, few people would challenge the claim that the visual appeal of food is based on its chemical/olfactory appeal. However, few people seem willing to accept the claim that the appeal of human faces (or of other sexually dimorphic, visually perceived, attractive human physical characteristics) is based on olfactory conditioning of the visual response. In the existing literature, the theme that humans are primarily visual creatures is ever-present, though there is no biological or behavioral evidence from the study of other mammals that suggests this. Simply put, there is no biologically based mammalian model that links sensory input from the social environment (i.e., nurture) to sex differences in hormones and behavior (i.e., nature). From a review of existing literature on mammalian sexual attraction, it would be difficult, if not impossible, to find any biologically based explanation of how visual appeal develops (if ever it does) in other mammals.
In contrast, if you examine the evidence reviewed here, it certainly appears that pheromones could, albeit unconsciously, affect the conscious processing of visual stimuli. If so, then pheromones could also affect human thinking about the relative value of visual input (e.g., a pretty or handsome face, or other attractive features) in sexual choice, while visual input is cognitively compared during periods of hormonal change and unconscious affect that are elicited by pheromones.
Minimally, this review serves as a reminder that pheromones and olfaction determine, without conscious thought, all (or nearly all) aspects of mating and other sexual behavior in mammals, and in most (if not all) non-mammalian species (see for review Kohl & Francoeur, 1995, 2002; Wyatt, 2003). The evidence presented here also strongly suggests that pheromone-affected mood, psychophysiological responses, and brain activity are as likely to be associated with homosexual preferences as they are to be associated with heterosexual preferences.
*This was a a presentation paper for the International Behavioral Development Symposium
August 3-6, 2005, Minot State University, Minot ND
The technical writing and editing skills of John R. Kohl were essential to the preparation of this article.
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James V. Kohl is considered by many to be the foremost internationally known authority on human pheromones. He continues to present to, and publish for, diverse scientific and lay audiences as new information becomes available. Kohl's 1995 book, Scent of Eros was released in 2002 as an updated paperback edition.
Kohl has worked as a clinical laboratory scientist since 1974, and he has devoted more than sixteen years to researching the relationship between odors and human sexual behavior. He is certified with the National Credentialing Agency for Laboratory Personnel, American Society for Clinical Laboratory Science, and the American Medical Technologists. He is a member of the Society for the Scientific Study of Sexuality, the Association for Chemoreception Sciences, Human Behavior and Evolution Society, Mensa, and the Society for Behavioral Neuroendocrinology and the Across-Species Comparisons and Psychopathology Society (a branch of the Psychotherapy Section of the World Psychiatric Association). Kohl developed his public speaking skills as a former member of Toastmasters International. He began presenting his findings to the scientific community in 1992 and continues to do so, while constantly monitoring the scientific presses for new information that is relevant to the concept of human pheromones. He was invited to participate during the prestigious International Behavioral Development Symposium: Biological Basis of Sexual Orientation and Sex-Typical Behavior (1995), which is reported here: "... 89 scientists participated... [T]he conference was... the first to assemble virtually all the top researchers in the field." Kohl returned to participate in the equally prestigious second International Behavioral Development Symposium held in 2000, and will return for the third symposium in 2005. His 2001 peer-reviewed journal publication (with distinguished colleagues from Vienna) detailed the role of pheromones in heterosexual attraction, and received The Zdenek Klein award (diploma and medal) for the best paper linking neuroendocrinology and ethology.
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