James Vaughn Kohl

Clinical Laboratory Scientist

Las Vegas, NV

(email) jkohl@vegas.infi.net

(web site) http://www.pheromones.com

May 16, 1996

To reference this article, use this format: Kohl, J. (1996). Human pheromones: Mammalian olfactory, genetic, neuronal, hormonal and behavioral reciprocity, and human sexuality. Advances in Human Behavior and Evolution. http://psych.lmu.edu/ahbe.htm

Key words: pheromones, olfaction, gonadotropin, releasing hormone, human sexuality

Abstract 

Pheromonally induced alterations in gonadotropin releasing hormone (GnRH) pulsatility allow for a life­long causal linkage among olfaction, neurotransmission, autonomic responses, luteinizing hormone/follicle stimulating hormone ratios, steroidogenesis, neurotransmission, and hormonally induced behavioral changes. This integrative multidisciplinary literature review supports the following neuroendocrine sequence: The early prenatal migration of GnRH neurosecretory neurons establishes neural substrates. These substrates appear to enable human olfactory pathways to exhibit sexually dimorphic specificity to social environmental chemical stimuli and to exhibit the ability to transduce these chemical signals or pheromones. Human pheromones thereby appear to activate genes in GnRH neurons and to influence GnRH pulsatility and gonadotropin secretion. [para 1]

This article details a neuroendocrine model that links the "nature" and the "nurture" of human sexuality. It may assist evolutionary theorists by providing experimental data from animal and human studies. Since chemical communication is common among animals, these studies lend support to correlational research methods. [para 2]

Introduction

Pheromones are social-environmental chemical stimuli (e.g., odors). They are produced by one individual and detected by another individual of the same species. Typically, pheromonal communication elicits physiological and behavioral changes. These changes are expected to benefit both individuals. Pheromones exert their influence whether or not an animal is conscious of pheromone detection; the animal may not be aware that it is responding to an odor. [para 3]

Mammalian pheromones appear to influence a pulsatile intracerebral gonadotropin-releasing hormone (GnRH) response (Meredith & Fernandez-Fewell, 1994). This pheromonally induced GnRH response appears to be genetically directed (Guthrie, et al. 1993, p. 3333). It also correlates well with cellular activity in the central nervous system that has been linked to behavioral change (Sagar, Sharp, & Curran, 1988). [para4]

GnRH plays an integral role in sexual development and behavior. The link among mammalian pheromones, their effect on a genetically directed GnRH response, and on behavior involves the neuroendocrine sequence of events that follows: (1) cells in the preoptic­septal area of the brain secrete GnRH (in pulses) directly into the hypothalamic­hypophyseal portal system to the anterior pituitary; (2) pulses of GnRH trigger cells in the anterior pituitary to secrete the gonadotropins, which enter the systemic circulation; (3) the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), stimulate the secretion of steroid hormones. [para 5]

GnRH pulsatility is associated with changes in LH and in FSH pulsatility. LH/FSH ratios influence gonadal and adrenal steroidogenesis (see Knobil, 1990; Grumbach & Styne, 1992, p. 1153-4). The primary sex steroid hormones (e.g., testosterone (T), the predominant androgen in the male, and estradiol (E), the predominant estrogen in the female) are among the steroids that maintain secondary sexual characteristics and downregulate the gonadotropins. T and E also modulate mammalian neuronal apoptosis (Nordeen, et al. 1985), synaptogenesis, and synaptolysis (Arai, Matusumoto, & Nishizuka, 1986). Steroid hormone-induced neuronal modulation is associated with neurotransmission, which is manifest in behavior. Thus, there appears to be an olfactory-genetic-neuronal-hormonal link among pheromones, GnRH pulsatility, steroidogenesis, and mammalian behavior. [para 6]

This pheromonal link to steroidogenesis and to behavior exemplifies a five step pathway: gene--> cell--> tissue--> organ--> organ system. This pathway is common both to terrestrial mammals and to many other vertebrates. Furthermore, though the mechanism by which pheromones appear to influence mammalian GnRH pulsatility, steroidogenesis, and behavior is not completely defined, there appears to be sufficient evidence of transynaptic stimulus-transcription coupling (e.g., Curran & Morgan, 1995) in mouse olfactory bulb neurons (e.g., Ehrlich, et al. 1990) to propose that mammalian pheromones indirectly activate genes in GnRH neurosecretory neurons, which in turn influences GnRH production and its pulsatile secretion throughout life's continuum (see also, Rubin, et al., 1995). Simply put, mammalian pheromones appear to activate genes in GnRH neurosecretory cells of tissue in the brain--the most important organ involved in any organ system associated with behavior. [para 7]

Accordingly, reproductively relevant social-environmental odor cues may interact with the genetic substrates of mammalian behavior. Furthermore, via their influence on steroidogenesis, mammalian pheromones may link the social-environmental "nurture" and the genetic constitutional "nature" of behavior, which is consistent with a proposal by McEwen (1988). In addition, "...extensive transneuronal regulatory events produced by the primary olfactory afferents are specific with respect to both neuronal type and even to phenotype within neurons" (Ehrlich, et al. 1990, p. 120). This suggests that even without their effects on LH/FSH ratios, steroidogenesis, and behavior via the hypothalamic-pituitary-gonadal (HPG) or the hypothalamic-pituitary-adrenal (HPA) axes, pheromones may play a role in neuronal plasticity. [para 8]

Human Pheromones

Evidence from human studies that suggests we produce pheromones and that we are not exempt from prenatally­predisposed mammalian olfactory­genetic­neuronal­hormonal relationships involving pheromones, genes in GnRH neurosecretory neurons, and the influence of GnRH secretion on levels of other hormones, is found in the following: [para 9]

(1) an increase in levels of LH and of T occurs during the first few hours after birth in the human male neonate, but not in the female (Corbier, et al. 1990). This effect seems consistent with reports of prenatal sexual differentiation of the mammalian olfactory systems (Segovia & Guillamon, 1993) and subsequent exposure to maternal (i.e., opposite-sex) pheromones; [para 10]

(2) human ovarian synchrony and its disruption may be controlled both by a common air supply and by E secretion (Weller & Weller, 1993; Cutler, et al. 1985; McClintock, 1971), which are affected by mammalian female pheromone production; [para 11]

(3) the entrainment of hormone cycles in couples (Persky, et al. 1977), and perhaps in homosexual men (Henderson, 1976) or in homosexual women (Sanders & Reinisch, 1990), may be explained either by mammalian male or by mammalian female pheromone production; [para 12]

(4)coitus-induced human ovulation (Jochle, 1975) may be explained by mammalian male pheromone production; [para 13]

(5) a human "vomeropherin" appears to alter adult LH and FSH pulsatility (Berliner, et al. 1996). Pheromonally induced alterations of LH and of FSH are common in terrestrial mammals. [para 14]

(6) men who are exposed to the ovulatory "copulins" of women exhibit an increase in testosterone. The mechanisms involved appear to be some form of "chemical warfare" through which unattractive women may, in the presence of their pheromones, induce a male sexual response similar to that induced by attractive women (Grammer, Juette, & Fischmann, 1996); [para 15]

(7) olfactory sexual dimorphism, namely that females detect androstenone at lower thresholds than do males, seems to be a cause of behavioral dimorphism (Grammer, Juette, & Fischmann, 1996); [para 16]

(8) humans can detect odor differences in mice varying only by genes at the major histocompatibility complex (MHC) locus (Gilbert, et al. 1986); [para 17]

(9) human MHC-encoded odor receptors may be involved in detection of human MHC-determined odor types (Fan, et al. 1995); [para 18]

(10) a human immune response is associated both with odor and with fetal wastage (Ober, et al. 1992); [para 19]

(11) some genetically determined odor components can be important in human mate choice (Wedekind, Seebeck, & Paepke, 1995; Ober et al. 1993; Eggert, et al., 1996) [para 20]

The evidence above suggests that human pheromones may fulfill the biological criteria required for linking at least one sensory-based aspect of the social environment (e.g., olfaction) to the genetically determined olfactory-neuronal-hormonal substrates of human behavior. It is proposed that the early prenatal development of the olfactory systems and of the GnRH neuronal system allow postnatal exposure to pheromones to exert organizational and activational effects on the mammalian brain and on behavior, whenever in life this exposure occurs. This proposal is more fully detailed below. [para 21]

Prenatal Sexual Determination

As early sexual determination proceeds, the embryonic migration of GnRH neurosecretory neurons from the human olfactory placode into the brain along the nerve bundles of the terminal and vomeronasal nerves in the nasal mucosa to the olfactory bulb, and further on to the hypothalamus establishes neural substrates both in the olfactory systems and in the brain (Kjaer & Hansen, 1996). GnRH-containing neurons form a rostal-to-caudal continuum from the ventromedial forebrain and olfactory tubercle, through the medial septal and preoptic areas, to the hypothalamus and median eminence of the tuber cinereum (Schwanzel­Fukuda & Pfaff, 1991, p. 565). This pattern appears to be a vertebrate-wide pattern of GnRH cell development (Schwanzel­Fukuda, et al. 1996, p. 556). In the nose, GnRH-immunoreactivity has been localized in axons and in a population of ganglion cells of the terminalis nerve. [para 22]

The prenatal development of the GnRH neuronal system is an important genetically determined factor in gonadal development. Binstock (1994; 1995a) elaborated upon evidence of genomic­level sex differences, which occur prior to the formation of the gonadal ridge. These differences appear to be independent of the testis­determining gene (Sry) on the human Y chromosome (Haqq, et al. 1994). In addition to these genomic-level sex differences, Sry itself, as well as maternal steroids, may affect GnRH neurons either prior to or during their migration. For instance, Lahr, et al. (1995) have been able to detect transcripts of the Sry gene, but only in the adult male mouse brain, not in the female brain. Furthermore, "...recent reports for SRY in humans suggest that it may be expressed in other fetal and adult tissues" as early as day 1 of in­utero life. (op. cit.) Such evidence suggests that genes may affect sexual determination and subsequent sexual differentiation of the GnRH neuronal and other neuronal systems quite independently of the hormones secreted by the fetal gonad. For instance, if neurons have the capability of realizing their genetic sex in a "cell­autonomous" fashion, genomic-level sex differences could impact development of sex differences in neuronal systems. Furthermore, among these neuronal systems, the olfactory systems would express some of these sex differences because at least some genetic sex differences exist in each GnRH neuron (e.g., the X and Y RNA proteins), and because there are links between the GnRH neuronal system and the olfactory systems (Ruggarli & Ballabio, 1993). Maternal and placental hormones may also influence prenatal human sexual differentiation of the GnRH neuronal and other neuronal systems; for example, maternal diethylstilbestrol seems to affect the fetus, as witnessed by later behavior (Meyer­Bahlburg, et al. 1985) and sexual orientation (Meyer­Bahlburg, et al. 1995). [para 23]

Numerous studies (Segovia & Guillamon, 1993) have shown that, in the rat, the vomeronasal projection circuit is sexually dimorphic, with males having greater numbers of neurons at sites of synaptic transmission. These sites were described recently by Bressler and Baum (1996). "Vomeronasal afferents project to the mitral cells of the accessory olfactory bulb (AOB), which in turn make dendro-dendritic contacts with granule cells within the AOB and project to the anterior as well as the posterior portions of the medial amygdaloid nucleus. The anterior medial amygdala is reciprocally innervated with the posterior medial amygdala, where many neurons also contain estradiol and androgen receptors. Neurons of the anterior medial amygdala project via the ventral amygdalofugal pathway to the intermediate portion of the posterior bed nucleus of the stria terminalis (BNST) and to the lateral subdivision of the medial preoptic area (POA). Neurons of the posterior medial amygdala project via the stria terminalis to the medial subdivisions of the posterior BNST and medial POA, respectively." (p. 1063). Any or all of these sites may be affected by genetic and hormonal factors that influence both the development of the GnRH neuronal system and of sexually dimorphic olfactory systems. Furthermore, Segovia and Guillamon (1993) have linked many of these sites to sexually dimorphic reproductive behaviors. [para 24]

No studies have demonstrated sex differences either in the number or in the distribution of GnRH neurons in adult mammals, but sex differences in GnRH immunoreactive (GnRH-ir) cells that seem consistent with sex differences in behavior have been noted in the POA of tropical fish (Rissman, 1996). Since only a small number of implanted GnRH neurons may be required to induce a mammalian GnRH pulse (Silverman, et al. 1992), it may be that other connecting neurons and neuronal systems--many of which may be sexually dimorphic in their structure and function--are more important to the regulation of GnRH pulsatility. For example, noradrenergic, dopaminergic, serotoninergic, and opiotergic pathways; inhibitory neurotransmitters (e.g., gamma­aminobutyric acid) and excitatory amino acids (e.g., glutamic and aspartic acids); and other brain peptides including pineal secretions (melatonin) and corticotropin­releasing hormone, and the complex interactions among them are subtle but functional species­specific influences on the electrochemical transmission of neuronal signals that the hypothalamus translates to the chemical signal GnRH (Grumbach & Styne, 1992, p. 1164). Individually, many of these influences on the frequency and amplitude of the GnRH pulse are linked through pharmacology and therapeutic drugs to reproductive function, to behavior, and to various neurodegenerative diseases. Collectively, these influences also make it difficult to establish whether, or how, reciprocal relationships among GnRH pulsatility, the secretion of other hormones, and neurotransmission influence human behavior. Nonetheless, though variations in sensitivity to changes in GnRH pulsatility may occur among species, in animal and in human studies two things seem clear: (1) When GnRH pulse frequency increases, levels of LH and of either T or E increase. (2) When GnRH pulse frequency decreases, levels of FSH increase (Haisenleder, Dalkin, & Marshall, 1994, p. 1799-1800). [para 25]

Tobet and Fox (1992, p. 62-4) review evidence that more GnRH neurons migrate to the hypothalamus of mammalian males than of females during prenatal development. Within the conceptual framework of the hypothalamic GnRH pulse generator, this evidence correlates well with the likelihood that more GnRH neurons or their sexually-dimorphic connectivity allow for a more frequent GnRH pulse, which directs the comparatively increased production both of LH and of androgens that normally occurs in human males and in the males of other species (Matsumoto, Gross, & Bremner, 1987, p. 267-8). Conversely, that fewer GnRH neurons may be found in the hypothalamus of females than in males--the sexually-dimorphic connectivity of GnRH neurons, not withstanding--correlates well with the likelihood that a less frequent GnRH pulse is responsible for the normal occurrence of comparatively increased production of FSH and estrogens in human females and in the females of other species (Everett, 1994, p. 1519). [para 26]

Pre- and Postnatal Sexual Determination

Evidence that both the prenatal and the postnatal sexual differentiation of the mammalian, including the human, olfactory and GnRH neuronal systems may influence olfactory-genetic-neuronal-hormonal-behavioral reciprocity is found in the following: [para 27]

(1) Boehm, Roos, and Gasser (1995) found GnRH-expressing cells in the nasal septum of human fetuses. [para 28]

(2) Zheng, Caldani, and Jourdan (1988) offer evidence that GnRH fibers in the medial septal nucleus, the vertical limb of the diagonal band of Broca, the olfactory tubercule, and the ganglionated plexus of the terminalis nerve are sources of significant amounts of GnRH in the rat and that GnRH may be released into the bloodstream both from the main and from the accessory olfactory bulbs. [para 29]

(3) Segovia and Guillamon (1993) found evidence of sexual dimorphism in the vomeronasal pathway of rats, which correlated with sex differences in reproductive behaviors (e.g., lordosis and maternal behavior). [para 30]

(4) Brennan, Hancock, and Keverne (1992) showed that mating and pheromone exposure activate c-fos (i.e., gene) expression within the olfactory systems, as is believed to be required in memory formation in mice. [para 31]

(5) Dluzen and Ramirez (1983) showed that immunoreactive GnRH is preferentially located in the olfactory bulbs of male mice and that GnRH neuroregulation upon social exposure to opposite sex conspecifics correlates well with levels of LH and thus with neuroendocrine regulation of reproductive processes. [para 32]

(6) Dudley, Rajendren, and Moss (1992) published findings on olfactory pathways in female rats suggesting that, following exposure to male conspecifics, signals to the VNO modulate the hormonal environment. This modulation may occur directly by the effects of odors, particularly pheromones, on GnRH secretion even if the effects of odors on GnRH secretion occur indirectly through neuronal systems that are connected to GnRH neurons. [para 33]

(7) Padmanabhan, et al. (1995) concluded that close temporal relationships in GnRH-receptor (GnRH-R) messenger RNA (mRNA) and c-jun mRNA expression during the ovine estrous cycle, coupled with the ability of GnRH to induce c-fos and c-jun mRNAs, raise "...the intriguing possibility that immediate early genes may serve as transduction signals in the regulation of GnRH-R gene transcription." (p. 268). [para 34]

(8) Monti­Block, et al. (1994) found that the adult human VNO is a functional chemosensory organ with a sexually dimorphic specificity to patented chemical stimuli called "vomeropherins," which seem to fit the definition of pheromones. The adult human VNO also appears to have the ability to transduce social-environmental chemical signals, which modulate certain autonomic functions (e.g., electrodermal activity and body temperature). [para 35]

(9) Moran, et al. (1995) provide evidence that there are several neural pathways by which the human VNO may be connected to the brain. [para 36]

(10) Jennings-White (1995) noted that the VNO receptors of men are particularly sensitive to estratetraenol, and that the VNO receptors of women are particularly sensitive to androstadienone. These compounds, estratetraenol and androstadienone, are described by Berliner (1994) as naturally occurring human pheromones. [para 37]

This evidence (e.g., 1-10) suggests that mammalian, including human, pheromones may have a significant impact on aspects of the postnatal development of olfactory-genetic-neuronal-hormonal-behavioral reciprocity that are described below. [para 38]

Tonic or Cyclic Hormone Secretion

Embryonic, fetal, prepubertal, pubertal, and adult developmental variations in the reciprocal relationships among the frequency and amplitude of the hypothalamic GnRH pulse generator, the LH/FSH ratio, levels of T, E, other steroid hormones, neuronal system development, and neurotransmission appear to establish varying degrees of cyclic and/or tonic hormone secretion in mammalian males and females. Cyclic hormone secretion seems to be most capable either of enabling or of conditioning the neuroanatomical pathways that allow the positive feedback of E on LH, a characteristic of the adult female ovulatory cycle. Tonic hormone secretion, the result of negative feedback of T on LH is characteristic of the adult male (Grumbach & Styne, 1992, pp. 1153-9). [para 39]

Many hypotheses on the GnRH­directed development either of a cyclic or of a tonic "hormone-control system" recognize only the presence of the tonic pattern of hormone control that corresponds with acyclic hormone secretion both in prepubertal males and in prepubertal females. However, though the GnRH pulse generator appears to be suppressed and--as a consequence, the pituitary gonadotropin-gonadal axis appears to be quiescent--there is abundant evidence both that GnRH is secreted episodically (e.g., Jakacki, et al. 1982) and that LH is secreted in a pulsatile manner (e.g., Levine & Cutler, 1982) long before physical signs of puberty become apparent (see Grumbach & Styne, 1992, p. 1150). Furthermore, men may exhibit positive LH feedback when the hypothalamic-pituitary-gonadal (HPG) axis is supraphysiologically primed with E (Kulin & Reiter, 1976). Thus, it appears that the cyclic hormone-control system, which enables the positive feedback mechanism, matures before puberty both in men and in women. Furthermore, since both T and E exert negative feedback on LH, prepubertal masking of GnRH­ and LH/FSH-directed cyclic hormone secretion is likely to occur both in males and in females until higher levels of T in males neutralize the mechanism that naturally allows the adult cyclic hormone secretion that is characteristic of women to occur. [para 40]

 The Influence of Human Pheromones on Tonic and Cyclic Hormone Secretion and Behavior?

In some species, GnRH neural control mechanisms that influence both the onset of puberty and the development of the adult cyclic and tonic hormone secretion that is characteristic of women and men respectively, are exquisitely sensitive to the social environment. For example, olfaction and pheromones have an important influence, by way of the central nervous system (CNS), on gonadotropin secretion (Grumbach & Styne, 1992, p. 1159). GnRH also facilitates mating behavior in a number of species when injected subcutaneously or intracerebroventricularly. Thus, it seems likely that the prepubertal influence of human pheromones on GnRH pulsatility may influence the central nervous system, gonadotropin secretion, and human behavior. [para 41]

The prepubertal influence of human pheromones on GnRH may begin at birth. For instance, Corbier, et al., (1990) have shown that the HPG axis is active in human male neonates, and that a sudden discharge of hypophyseal LH into the bloodstream precipitated by parturition is consistent with the neonatal T response, which is not exhibited by human females. Some causes for this sex difference (e.g., chorionic gonadotropin levels and differences in the birth process) in the neonatal LH and T response, which is common in mammals (e.g., mice, ferrets, and horses), are partially ruled out. Thus, this sex difference in the neonatal LH and T response may tentatively be attributed to the action of maternal pheromones on sexually differentiated olfactory and GnRH neuronal systems. [para 42]

A neonatal sex difference in gonadotropin and steroid hormone secretion may be important in the development of human sexuality for the reason that follows. "In male rats, perinatally elevated levels of testosterone play an important role in promoting behavioral masculinization and defemininization, and also appear to suppress the development of mechanisms for positive feedback. In mice, neonatal exposure to testicular androgens has a potent effect on the development of hormone-sensitive mechanisms for aggression. In monkeys, prenatal exposure to testicular androgens has important effects on both anatomical and behavioral sexual differentiation..." (op. cit.) These findings support a potential impact of maternal pheromones on sexually differentiated olfactory and GnRH neuronal systems that might lead to the neonatal LH and T response, which may influence mammalian, including human, behavior. [para 43]

Furthermore, the number of synaptic contacts on GnRH cell bodies in female monkey brains varies with gonadal status (Witkin, et al. 1991), and it is generally agreed that the number and types of neurons and the number and types of synapses between them (i.e., neuroanatomical structure) determine function, which in neuroanatomical studies often is associated with various sexually­dimorphic characteristics. Evidence that mammalian olfactory systems are sexually differentiated prenatally, (e.g., Segovia & Guillamon, 1993) suggests a causal relationship among maternal pheromones, previously unexplained sex differences in the neonatal LH and T response, masculinization, defemininization, mechanisms for the positive feedback of E on LH, hormone-sensitive mechanisms for aggression, and anatomical and behavioral sexual differentiation. [para 44]

It may be several years until researchers determine whether a demonstrable change in LH/FSH ratios occurs in women who are exposed to the axillary secretions (i.e., pheromones) of men (Wysocki, 1995). Nonetheless, there are mammalian models (e.g., Meredith & Howard, 1992) and human models (e.g., Berliner, et al. 1996; Grammer, Juette, & Fischmann, 1996) of

inter­individual pheromonal influence upon intra­individual hormonal status. Replicable findings, namely that human pheromones induce change either in LH/FSH ratios or in T responsiveness, from controlled human studies are predictable, because such findings are expected to be consistent with the mammalian model both of neuroendocrine system development and of behavioral development. [para 45]

For example, Bakker, Baum, and Slob (1996) have shown that neonatal treatment with 1,4,5-androstatriene-3,17-dione (ATD), which blocks the aromatization of T to E, affects sexual differentiation of olfactory pathways and causes male rats to respond with bi­sexual behavior in the presence of chemosensory stimuli either from females or from other males. This behavioral response is consistent with reports of pheromonal activation of c­fos expression in olfactory pathways. "Presumably, the vomeronasal system of ATD males resembles that of females." Furthermore, ATD males show a female­like vomeronasal system and female­like behavioral responsiveness to the odors of sexually active males. This response may be mediated by the pre- and neonatal development of the GnRH neuronal system. [para 46]

Perkins, Fitzgerald, and Moss (1995) link levels of LH, T, or E with perception of olfactory input from potential mates and with sexual orientation in sheep. This perception of olfactory input and its affect on sexual orientation also may be mediated by the pre- and neonatal development of the GnRH neuronal system. [para 47]

Meredith and Fernandez­Fewell (1994) link some of the collection of studies cited above with cognition, learning, and memory. The linkage among olfaction, levels of hormones, perception, sexual orientation, cognition, learning, and memory is difficult to demonstrate in human studies. However, the confirmed presence both of a functional adult human VNO (Monti­Block, et al. 1994) and of a human neuroendocrine response to pheromones (e.g., Berliner, et al. 1996; Grammer, Juette, & Fischmann, 1996) suggests that the presence of the VNO throughout life's continuum may enable human pheromones to exert neonatal, prepubertal, and adult influences on gene expression in GnRH neurosecretory neuron­modulated hormone control systems, which may influence the perceptual, cognitive, learned, and remembered behavior of all male and female terrestrial mammals. Furthermore, it would be remarkable if mammalian models of olfactory-pituitary (e.g., Berliner, et al. 1996) or of olfactory-pituitary-gonadal (e.g., Grammer, Juette, & Fischmann, 1996) interaction did not extend to humans. [para 48]

Is a Mammalian Model Applicable to Human Behavior?

Kohl and Francoeur (1995) review physiological evidence of pheromonally­induced, GnRH­directed effects that are consistent with anecdotal evidence of a subtle link between olfaction and human sexuality. Such social-environmentally activated neuroendocrine and behavioral correlates are expected, given two interactive modes of human information processing: rational (e.g., cognitive) and experiential (e.g., with or without awareness), both of which may influence behavior (Epstein, 1994). Correlates among olfaction, GnRH-directed neuroendocrinology, information processing, and behavior also are supported by mammalian models of pheromonal influences upon both hormonal and behavioral status, which are experienced by the individual and thus encoded in various long­term­potentiation mechanisms throughout the brain. Though such correlates cannot prove causation, physiological and anecdotal evidence of pheromonally­induced causal effects in humans seem especially convincing when one considers that, experientially, pheromones appear to influence the behavior of many non-human species--from single-celled organisms to other primates--without awareness. [para 49]

Additional empirical support for the concept of human pheromones comes from the study of molecules that are associated with genetic variability only at the major histocompatibility complex (MHC) in rats. These molecules also are associated with unique olfactory signatures that may identify conspecifics from a wide range of phenotypic characteristics (Singh, Brown, & Roser 1987). [para 50]

Evidence that women may learn to identify the genetically-determined "odor" type of their infant before the infant is born (e.g., Beauchamp, et al. 1995); and additional evidence that odors may be involved in human mating for genetic diversity (e.g., Eggert, et al. 1995) also is consistent with known causal effects of mammalian pheromones both on physiology and on behavior (see Kohl & Francoeur, 1995 for review). [para 51]

There also is a wide body of anecdotal evidence supporting cross­species comparisons with innate differences in human sexual behaviors and with conditioned pheromonally­induced differences in human sexual behaviors. Media representations linking human odor production, human odor distribution, and human sexuality offer additional support and validity for the concept of human pheromones (See Kohl & Francoeur, 1995, p. 13-4). [para 51]

It is difficult to validate cross-species comparisons because of inherent difficulties either in carrying out controlled human studies of olfactory transduction or of its association with odor hedonics, mood, memory, motivation, expressions of effect, cognitive behavioral state, potentiating responses to other stimuli (see Ehrlichman & Bastone, 1992 for review), and neural circuitry. This failure to validate cross-species comparisons contributes to a common belief among scientists and laypersons: that--unlike many other mammals--humans learn more through visual cues than through social­environmental chemical cues. However, just as a child born blind does not learn to prefer one color to another, a child who is born anosmic does not develop odor preferences. Similarly, innate differences in visual or other sensory acuity suggest that many mammalian, including human, behaviors are initially genetically predisposed. Subsequently, behaviors appear to be conditioned through olfactory and other sensory stimuli (Kirk-Smith, 1996). For instance, it seems likely that our food preferences are based upon innate differences in the chemical senses (taste and olfaction), which are present before we are able to respond to a food's visual appeal and that, subsequently, food preferences may be based upon the pairing of olfactory (or taste) stimuli with a visually conditioned response to the sight of an appetizing item. [para 53]

Additional evidence (e.g., Cooper, et al. 1994) suggests that mammalian neuroanatomical pathways link vision and olfaction and that social­environmental odor cues, which male rats may learn to associate with sexual activity, can be used to condition LH release (Graham & Desjardins, 1980). Thus, it seems likely that odor­induced GnRH­directed conditioning of human LH release may be used to evoke functional changes in the mammalian neuroendocrine pathways that mediate the release of T and E, with or without visual awareness of any associated conditioning stimuli. Furthermore, given mammalian models, such a conditioned (e.g., classically or operantly) GnRH-directed neuroendocrine response would likely be manifest in behavior. [para 54]

Not only does GnRH act indirectly on behavior, through the HPG axis and thus, in part, through the HPA axis, but a fraction of mammalian GnRH also may act directly, either as a neurotransmitter or a neuromodulator with extrapituitary effects (see Schwanzel­Fukuda, et al. 1992 for review). Therefore, it also seems likely that both immediate, short­term, non­genomic effects and delayed, long­term, genomic effects of odor stimuli on GnRH secretion may impact neurotransmission and reproductive sexual behavior throughout life. This would allow odor­induced changes in GnRH pulsatility to play distinctive roles in the initiation, in organization, and maintenance of the mammalian sexual response, and therefore--as some empirical evidence suggests--of the human sexual response as well (see Moss, Dudley, & Riskind, 1991 for review). Simply put, mammalian pheromones may induce both activational and organization effects on behavior. [para 55]

Visual Stimuli Versus Olfactory Stimuli

It is obvious that selection incorporates a visual image with other sensory preferences. These preferences may include odor preferences that are based in earlier learning experiences--whether or not they are remembered. The wide variety of marketing strategies that incorporate odor in subtle ways suggests that odors influence learned behavior, which may be manifest as personal preference through selection (Gibbons, 1986, p. 357). Selection, therefore, may be conscious, as in the choice of a pine­scented cleaning product over one with a lemon scent, despite their equal effectiveness. [para 56]

Similarly, when it comes to sexuality, there is evidence (e.g., Ober, et al. 1993; Wedekind, Seebeck, & Paepke, 1995) that mate selection may be influenced by a subliminal chemical "scents." It seems likely that an olfactory signature prompts the HPG and the HPA axes, as well as the neurotransmitters or neuromodulators that are associated either with their function or with direct intracerebral effects on behavior, to react to human pheromones in a manner that reminds an individual of something good or bad from a GnRH-directed physiological past (Schellinck, et al. 1993). Nonetheless, such a reminder may not enter the realm of consciousness. Indeed, human consciousness would be likely to cause us to "think" our response originated with other sensory, primarily visual, input. [para 57]

Cross-species Comparisons

Though empirical evidence for a proposal linking human pheromones, olfaction, neuroendocrinology, and behavior comes primarily from the study of other mammals, the interaction between sensory input and neuroendocrinology appears to be a general rule in endocrine relationships that underlie behavior (LeMagnen, 1982, p. 8). This general rule seems to apply to human behavior. For instance, in human studies, Schneider, et al. (1958) found that GnRH­driven estrogens appear to increase olfactory acuity, while GnRH-driven androgens appear to decrease it, and both may influence olfactory specificity. Kopala, Good, and Honer (1995) found evidence linking olfactory deficits, E secretion and behavior in schizophrenic women. Furthermore, Dorries, Adkins-Regan, and Halpern (1995) offer evidence that olfactory sensitivity to the odor of androstenone, an identified and well-characterized pheromone in domestic pigs, is sexually dimorphic to a degree similar to the sex difference found in humans. In pigs this olfactory sexual dimorphism, namely that females detect androstenone at lower thresholds than do males, is a cause of behavioral dimorphism. [para 58]

In mammalian models of sexual behavior, it appears that pheromonal induction of GnRH release may influence the HPG axis, resulting in higher levels and occupancy rates of E receptors in the mediobasal hypothalamus (MBH) of hormone-treated male rats exhibiting lordosis (Samama & Aron, 1989), and in lower levels and occupancy rates of E receptors in the amygdala of untreated rams exhibiting a full range of proceptive homosexual behaviors (Perkins, Fitzgerald, & Moss, 1995). Both the MBH and the amygdala often are considered integral parts of the mammalian limbic system--the "emotional center" of the human brain. The hypothalamus and the amygdala also communicate with each other through neural pathways. And mammalian neural pathways from both the accessory olfactory system and from the main olfactory system converge at the amygdala (Licht & Meredith, 1987). Summarily, one might then tentatively conclude from the male rat model of lordotic behavior (Samama & Aron, 1989), from the male rat model of odor-induced bi-sexual behavior (Bakker, Baum, & Slob, 1996), and from the ram model of homosexuality, (Perkins, et al. 1995) that olfactory stimuli may influence neural pathways and limbic structures, which exert significant cumulative effects on the HPG axis (effects on the HPA axis notwithstanding), or--more specifically--on E receptors, and on both behavior and sexual orientation. This focus on E receptors may eliminate concerns with regard to cross-species comparisons of behavioral posturing and whether posture correlates with sexual orientation. Given the genetically predisposed nature of mammalian olfactory­genetic­neuronal-hormonal­behavioral interaction in both males and females, it then appears that, minimally, there are three models (e.g., Samama & Aron, 1989; Bakker, Baum, & Slob, 1996; Perkins, et. al, 1995) leading to the tentative conclusion that pheromones and olfaction are involved both in mammalian heterosexual and in mammalian homosexual receptivity and proceptivity. Given this mammalian model, perhaps further research will help to explain variations in human sexual orientation. [para 59]

Organizational Versus Activational Effects of Pheromones and Aging

Besides their likely GnRH/HPG and HPA axes­driven, long­term, genomic effects on E receptors, pheromones also may induce an intracerebral release of GnRH with short­term, non­genomic, (e.g., neuromodulatory and extrapituitary) effects on GnRH receptor systems, which undergo important age­dependent changes. For example, GnRH receptors in the human hippocampus may increase with aging, as they appear to do when young infrahuman animals are castrated--a condition that is completely reversed by the simultaneous administration of estrogen in combination with progesterone or androgens (Marchetti, et al. 1988, p. 208). Such disparate effects suggest that an important modulatory role of sex steroids is exerted at the hippocampus in the control of GnRH receptor activity (see Harrelson & McEwen, 1987 for review). Furthermore, it is believed that the hippocampus is involved both in the regulation of gonadal functions and in behavioral functions, which are linked to its function in learning and memory (McEwen, et al. 1987). Additionally, the hippocampal formation, a complex of interrelated areas on the ventromedial temporal lobe partially adjoining and variously interconnected with amygdala subareas, contributes to the regulation of the HPA axis (Jacobson & Sapolsky, 1991 as cited in Binstock, 1995b). [para 60]

As stated above, olfaction and GnRH secretion are linked via hormone-control systems to learning, memory, and behavior. A similar link may be found between olfaction and GnRH receptor activity in the hippocampus, a brain structure involved in learning, memory, and behavior. In the absence of steroid hormone replacement therapy, GnRH receptor activity might be associated with the reduced secretion either of gonadal or of adrenal (e.g., dehydroepiandrosterone) steroid hormones that is common in reproductive senescence. This may link the reduced olfactory acuity and specificity that progresses with aging (Doty, 1991a), to the disruption of the GnRH neuronal system and the initial decline of reproductive function (see Rubin, et al., 1995). For instance, a failure of odor-induced olfactory transduction to activate gene expression in the GnRH neuronal system might contribute to reduced gonadotropin secretion and thus to reduced levels of androgens and estrogens that could affect GnRH receptor activity in the hippocampus. [para 61]

Furthermore, the hippocampal formation appears to function as an interface between cognition and the emotional components of reward or punishment. It is believed to be a central component in affective disturbances such as endogenous depression and manic-depressive illness, and in disordered thought processes, such as psychosis associated with depression or schizophrenia (McEwen, et al., 1987). Thus, given evidence that a modulatory role of sex steroids is exerted at the hippocampus in the control of GnRH receptor activity (e.g., Harrelson & McEwen, 1987), both the disruption of the GnRH neuronal system and the initial decline of reproductive function may be associated with many of the more common effects that are manifest in aging. Therefore, it is noteworthy that the olfactory losses in Alzheimer's disease are severe and are substantially worse than in age­matched controls for suprathreshold tasks. Losses in recognition and identification of odors are striking in the earliest phases of this disease, and decrements in the ability to remember odorants have also been found (Doty, 1991a, p. 190; Doty, 1991b). [para 62]

In results from a study of estradiol levels in pre- and postmenopausal women, Kopala, et al. (1995) suggest "...that assessment of olfactory function may serve as a behavioral probe for determining the functional integrity of brain regions reported to be abnormal in patients with schizophrenia" (p. 61). Similarly, endocrine disorders have been reported to influence smell function. Patients with hypogonadotropic hypogonadism often exhibit congenital anosmia (Crowley Jr., & Jameson, 1992), as do women who are suffering from primary amenorrhea (Marshall & Henkin, 1971). Several studies also suggest that patients with Parkinson's disease show deficits in olfactory ability (Doty, et al. 1991; Zucco, Zaglis, & Wambsganss, 1991). The clinical significance of such findings recently became more clear when a test battery including smell testing was reported to expedite the diagnosis of Parkinson's disease (Montgomery & Koller, 1995). [para 63]

Besides Alzheimer's or Parkinson's, several dementia­related disorders are accompanied by olfactory deficits or disturbances. These include Huntington's chorea, Korsakoff's psychosis, and--as noted above--schizophrenia. It has even been proposed that the olfactory system could be the route of invasion of etiologic factors that are responsible for some of these diseases (Doty, et al., 1991; Doty, 1989). [para 64]

Extending Mammalian Models to Humans

Modern research on the chemotherapy of neuropsychiatric disorders selectively targets new drugs to act on the primary transmitter receptors of the synapse that is believed to be malfunctioning in that particular disease state. Yet many of the drugs used in psychiatry appear to act nonselectively; it is not known either how or where some drugs exert their effects. A general lack of knowledge regarding the action of human pheromones either on primary transmitters or on their receptors contributes to the unspecified effects of these subliminal scents. Thus, human pheromones also appear to act nonselectively; it is not known either how or where pheromones exert their effects. However, recently issued United States patents (e.g., Cutler, Preti, & Garcia, 1992; Berliner, 1994), and United States patents pending (Berliner, 1995) assert that pheromones may be found to be effective in a form of physiologically-based aromatherapy, which is currently used despite little scientific proof of its effectiveness (Hardy, Kirk­Smith, & Stretch, 1995). [para 65]

It seems clear that the inability either to consciously perceive social­environmental chemical stimuli, or to subliminally detect them, may contribute to the disruption of the GnRH neuronal system. Thus, the proposal is advanced that the influences of olfaction and of human pheromones on the GnRH pulse and on the GnRH neuronal system also are primary contributing factors in certain age­related disorders. Accordingly, from the beginning of life in the womb until death, the development of our olfactory systems and the influence of human pheromones may be particularly important to our quality of life--the purpose of which, for species survival, is to reproduce. [para 66]

Pheromones and Human Reproductive Sexual Behavior

If they are defined as chemical stimuli, odors, including pheromones, are essential components of reproductive sexual behavior in most, if not all, other species. Mammalian GnRH ensures successful reproduction by directing and coordinating a complex series of biological events that are occurring in different organs at the appropriate time (Marchetti, et al. 1988, p. 207). Two factors suggest that the influence of odors on GnRH pulsatility is involved in successfully timed human reproductive sexual behavior. First, there is the developmental staging of the GnRH neuronal system and presence of this key decapeptide and its receptors both in the limbic system and in various other regions of the CNS as far anteriorly as the olfactory bulbs (Silverman, Livne, & Witkin, 1994)--outside the regions known to be involved in the control both of LH and of FSH release. Second, there is either the measurable release of GnRH, or its implied release (e.g., by the measurement of LH or of T) with contact between the sexes in many species (Meredith & Howard, 1992). Human evidence (e.g., Berliner, et al., 1996), of GnRH release induced by contact between the sexes, which appears to result either in changes in LH/FSH pulsatility or in T secretion (Grammer, Juette, & Fischmann, 1996), and the likelihood of finding changes in the LH/FSH ratios in women exposed to the axillary odor of men, suggests that GnRH might be involved very early in the initiation of a sexually organized response. Furthermore, the postnatal organization of this "sexual" response (Moss & Dudley, 1990) may begin with the detection of pheromones and proceed to the induction of mating behavior (Marchetti, et al. 1988, p. 207). [para 67]

Support for this Conceptualization

-------------------------------------------------------------

_____________________________________________________________

Many "primary" researchers have offered evidence supporting the conceptualization in Figure 1. The examples that follow are in chronological order. [para 68]

Finger and Mook (1971) discussed mammalian "basic drives" and proposed that the incentive value of a female and her novelty as a partner may depend on olfactory cues that act as hypothalamic stimuli, which activate neural substrates not of drives but of fixed action patterns. A past stimulus may subsequently affect physiology and behavior via plasticity and reward (op. cit., p. 29-30). [para 69]

Hormones may influence behavior by altering peripheral sensory mechanisms (Komisaruk, Adler, & Hutchison, 1972), and olfaction is altered by hormones in humans (Doty, et al. 1981; Doty, 1986). [para 70]

Small variations in the GnRH pulse may represent a significant factor in the control of LH release (Lasley, Wang, & Yen, 1976). [para 71]

There may be a learned association between musk and sexual experience (Filsinger & Monte, 1986). [para 72]

Men aroused by erotic videotapes have higher LH levels, but total T did not correlate with arousal (Rowland, et al. 1987). In similar studies, total T and E levels may not correlate closely with social influences on behavior because they are too far removed from social-environmental influences on GnRH pulsatility. [para 73]

With aging in men, LH showed a close association with several sexual behavior dimensions, while total T, E, and prolactin did not. Free T was best associated both with LH and with behavior (Schiavi, et al. 1991). [para 74]

An LH response that is believed to be pheromonally­driven in heterosexual rams does not occur in homosexual rams when they are exposed to estrous females (Perkins & Fitzgerald, 1992). [para 75]

Elias and Valenta (1992) discuss consistencies among the neuronal density of hypothalamic nuclei (see LeVay, 1991) and heterosexual activity in non-human primates and in homosexual and heterosexual men. They suggest anatomic differences in the anterior hypothalamic nuclei that regulate sexual orientation in males may lead to alteration in GnRH pulse frequency and to a more female-type pattern of gonadotropin secretion in homosexual males. [para 76]

Human olfactory pathways exhibit both sexually dimorphic specificity to social­environmental chemical stimuli and the ability to transduce these chemical signals, which may modulate certain autonomic functions (Monti­Block, et al. 1994). [para 77]

LH suppression occurs from day 8 of the pill cycle when women take monophasic oral contraceptives compared to day 13 when women take triphasic oral contraceptives. This hormone difference correlates with differences in sexuality: Young women who use triphasic pills experience greater sexual interest and response than those using monophasic pills, which appear to have longer lasting effects on LH inhibition (McCoy & Matyas, 1996). [para 78]

Human Pheromones: A Subject for Debate

Both the past and the ongoing problems involved in discussions either of how the brain is sexually differentiated or of how nature and nurture are involved in sexual differentiation of the brain and of behavior seem to reflect a theme regarding the social basis of scientific knowledge, and odors seem to have played a major role in cultural development. There are also enduring cross-cultural truths regarding reciprocity among odors, olfaction, and behavior (See Kohl & Francoeur, 1995 for review). If one subscribes to the philosophy that in science, in art, or in life, only what is true to culture is true to nature (Fleck, 1979, p. 35.), then one is compelled to consider the underlying ontogenetic and phylogenetic aspects of the following statement, for which there is no likelihood of "hard" scientific proof, but which nonetheless appears to be true: [para 79]

The influence of human pheromones on GnRH pulsatility appears to rationalize putative human olfactory­genetic­neuronal­hormonal ­behavioral relationships, and offers another perspective from which to examine human sexuality. [para 80]

Extending the Concept of Human Pheromones Too Far?

The works reviewed in this text--and a thorough review of associated interdisciplinary studies--allow for strong assertions, many of which are merely restated from their original representation for congruity. All of these assertions seem to be consistent with evidence that supports the neuroendocrine sequence portrayed in Figure 1. Nonetheless, the following assertions are highly speculative; they are provided only to inspire additional research. Furthermore, the content of some of the works cited has been liberally interpreted. [para 81]

The X­linked Kalig­1 codes for a protein that is required for the prenatal migration of GnRH neurons to the hypothalamus (Ruggarli & Ballabio, 1993). A "gay" gene might encode a similar protein--one that is required for the prenatal migration of GnRH neurons to specific regions of the hypothalamus. These specific regions of the hypothalamus might include either the INAH­3 (Hamer & Copeland, 1994, p. 163) or regions of limbic and olfactory structures, which are necessary both for olfactory processing and for gonadotropin secretion (Legouis, et al. 1991). [para 82]

The early prenatal migration of GnRH neurons to the hypothalamus determines the frequency and amplitude of the GnRH pulse (Tobet & Fox, 1992), and therefore directs the prenatal secretion of LH, (Hoffman, et al. 1990) FSH, T, and E. [para 83]

Though some sexual differences may exist prior to the formation of the gonadal ridge (Binstock 1994; 1995a), the prenatal secretion both of E and of T is primarily responsible for establishing traditionally conceived sexual dimorphism both in the olfactory systems and in many other neuronal pathways and neurohormonal systems of all terrestrial mammals by acting on apoptosis, (Nordeen, et al. 1985), on synaptogenesis, and on synaptolysis (Arai, Matusumoto, & Nishizuka, 1986). [para 84]

Either endogenous or exogenous steroid hormones alter the frequency of the prenatal GnRH pulse and thus predispose sexual orientation and sexual behavior or both (Adkins­Regan, 1988; Giusti, et al. 1995). Similar effects might be induced by prenatal stress on GnRH pulsatility and thus on steroid hormone secretion (Kinsley, 1995). [para 85]

In some mammals, only males exhibit an immediate, sexually dimorphic, perinatal response to birth stimuli, which cause both a surge in LH and in testosterone (Corbier, et al., 1990). In the human male, this response is both genetically and prenatally predisposed, as it appears to be in other mammals (Coquelin, et al. 1984). This response also is the result of exposure to maternal pheromones, which may further differentiate the POA, the amygdala, the BNST (Zhou, et al., 1995) and the neuronal pathways that are linked both to olfaction and to mammalian reproductive sexual behavior (Meredith & Fernandez­Fewell, 1994). Such a response could render inoperative the neural circuity required for the preovulatory release of GnRH from the forebrain neurons of adult males, which is activated by olfactory/vomeronasal input in adult females (Lambert, Rubin, & Baum, 1992). [para 86]

The neural plasticity of these pathways is further influenced by exposure to pheromones both from same­sex and from opposite­sex conspecifics throughout life as indicated by prepubertal sex differences in gonadotropin secretion (Kulin & Reiter, 1976; Jakacki, et al. 1982; Levine & Cutler, 1982) especially during "critical periods," in which pheromonal stimuli exert stronger influences than do inherent prenatal predispositions on hormone-control systems; on human sexual orientation; and on human sexual behavior. [para 87]

Human sexuality is thereby conditioned via a neuroendocrine response to olfactory stimuli (Graham & Desjardins, 1980), which are paired with other consciously perceived and subliminally detected sensory stimuli (Cooper, et al. 1994). [para 88]

Pheromonal influences on GnRH­directed rhythmicity of hypothalamic function are of key importance with respect to humans falling in love (Money & Lewis, 1990), and pheromones remain a factor in properly timed human reproductive sexual behavior (Persky, et al. 1977; Poran, 1994). [para 89]

The influence of human pheromones on the GnRH neuronal system, or the lack thereof, is one of the etiologic factors involved either in endocrine or in neurodegenerative age­related disease (Doty & Snow Jr., 1988). [para 90]

Humans are not microsmatic (Schaal & Porter, 1991); we merely appear to rely on visual sensory stimuli both to confirm and to further condition an innate olfactory­genetic­neuronal­ hormonal­behavioral response common to many other mammals. [para 91]

Conclusions

The concept of human chemical communication is not new. Among others, Havelock Ellis (Ellis, 1914, p. 44-112), Irving Bieber (Bieber, 1959), Alex Comfort (Comfort, 1971), John Money (see Karlen, 1971, p. 402), and Lewis Thomas (Thomas, 1971; Thomas, 1980) either have examined or have commented on aspects of human chemical communication and its likely effects. [para 92]

Furthermore, it now appears that sex­specific organizing effects of steroid hormones in the human do not prevent activating effects of steroid hormones from becoming manifest in both cognition and behavior (Van Goozen, et al. 1995). Human pheromones may exert both organizing and activating effects via their influence on GnRH pulsatility, which may either directly affect neurotransmission, or indirectly affect neurotransmission via steroidogenesis. [para 93]

What is "sexual chemistry?" So far as is known, there is no other developmental neuroendocrine theory of human sexuality that progresses from social-environmental activation of gene expression in the cells of tissues that are essential to the formation of organs in organ systems that have repeatedly been shown to influence behavior. Given this thesis, it may now be possible to further detail the importance of human olfaction and of human pheromones on sexuality, using both human and other mammalian models that link "nature" to "nurture" via the steroid hormones, which seems consistent with the psychoneuroendocrine approach to behavior detailed in McEwen (1988). [para 94]

Acknowledgements. I am grateful to Teresa Binstock, Scott Wersinger, and to John Kohl for their comments on the first draft of this review. [para 95]

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