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Dear Colleague,
I thought I would add this piece of information to the VNO discussion.
Although it does not directly address the initial question, I believe that
it does have some relevance.
Charles J. Wysocki
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Human Pheromones: Releasers or Primers Fact or Myth
(Advances in Chemical Signals in Vertebrates, edited by R.E. Johnston, D.
Muller-Schwarze, and P. Sorensen, Plenum Press, New York, 1999, 315-331).
George Preti1,2 and Charles J. Wysocki1,3
1Monell Chemical Senses Center, 3500 Market Street, 2Department of
Dermatology, School of Medicine, and 3Department of Animal Biology,
School of Veterinary Medicine, University of Pennsylvania, Philadelphia,
PA 19104
ABSTRACT
Historically, insect pheromones and the responses to them were thought to
have a high degree of specificity and a considerable degree of genetic
programming. The latter, which include overt displays of attraction and
copulation mediated solely by chemical signals, are described as releaser
effects on behavior. More subtle neuroendocrine effects, i.e., primer
effects, resulting in changes in reproductive cycle-length, timing and
success, have been demonstrated in mammals. Humans have potential
sources of chemical signals and a sensory system to receive them. Recent
studies suggest the presence of a vomeronasal organ (VNO) in humans;
however, other observations suggest only scant evidence for the presence
of an anatomically complete VNO with connections to the central nervous
system (CNS).
One would not expect to see observable "releaser" pheromone effects in
humans, which are primarily behavioral and immediate. Despite the lack
of evidence, numerous fragrances, or additives to fragrances, whose
advertisements perpetuate the myth that an odor can make one irresistible
to members of the opposite sex, have been or are being sold. Studies
conducted over the past two decades present evidence that humans emit
primer pheromones, which can alter the length and timing of the menstrual
cycle. The human axillae is a likely source of these chemosensory
signals. The molecular identity and chemoreceptive and endocrine
pathways by which they operate remain to be elucidated.
1. INTRODUCTION
Chemical communication among humans has been the subject of considerable
speculation and discussion in both the popular press and the scientific
literature, frequently focusing upon the question of whether humans emit
pheromones. The term pheromone was first introduced and defined by
Karlson and Lüscher (1959) who conducted studies on insects. The term is
defined as a substance secreted or excreted into the environment by one
individual which, on being received by a conspecific, elicits a
definitive behavioral, developmental or endocrine response. Two broad
categories of pheromones have been distinguished: releaser pheromones,
which generate immediate and primarily behavioral responses, and primer
pheromones, which generate longer-term physiological/endocrine responses
(Albone, 1984). Some chemical signals may provide information but do not
necessarily elicit a response, e.g., odors from the environment, food
odors and even chemical signals from other conspecifics (e.g., individual
odor identity may fall into this category; Yamazaki, et al., 1980).
These definitions have been modified by several authors (Beauchamp, et
al., 1976, 1979; Katz & Shorey, 1979), who have pointed out that
mammalian responses may depend upon intricate combinations of chemical
and non-chemical cues as well as a mammal's physiological state and past
experience (all of which have been found to modify responses to
pheromones in insects as well). To complicate matters further, humans
also have cultural factors to incorporate into an already complex situation.
Other authors have suggested broadening the term, while still others have
sought to narrow it to "isolated chemicals shown to be relatively
species-specific which elicit a clear and obvious behavioral or
endocrinological function and which produce effects involving a large
degree of genetic programming, influenced little by experience" (Martin,
1980). Consequently, there has been considerable debate within the
scientific literature regarding the definition and use of the term
"pheromone." In this review we rely on the primer and releaser
definitions noted above.
In many animals the sensory receptors for some pheromones are a
specialized group of neurons located in the vomeronasal organ (VNO) or
Jacobson's organ, named after the investigator who was one of the first
to focus considerable research efforts on the VNO (Jacobson, 1811). From
his memoirs (Jacobson, 1811) it is noted that Jacobson thought the organ
was absent in humans even though one of the earliest descriptions of a
VNO in humans was published over a century earlier (Ruysch, 1703). In
humans, openings to a putative VNO structure are present on either side
of the base of the nasal septum, about 1 cm from the anterior opening of
the nasal cavity, as 1-2 mm pits. Each pit opens into a sack or
diverticulum of approximately 2-8 mm in length (Boehm & Gasser, 1993).
However, whether this putative VNO structure in adult humans contains
functional neurosensory tissue, has neural connections to the brain, or
is even a VNO, is a subject of debate, as will be discussed below.
2. HUMAN ODOR PRODUCTION
Many body odors result from the metabolic processes of bacteria.
Consequently, skin-dwelling microorganisms play an important role in the
production of human odors. The type and density of bacteria in different
body locations are determined by several factors: type and density of
skin glands; moisture levels; and the availability oxygen (Leyden,
McGinley and Nordstrom, 1991). Combinations of the above factors lead to
odors characteristic of specific body areas.
Insert Table 1. The Odor-Producing Areas in Humans.
The odor-producing areas of humans are listed in Table 1. Moist areas,
such as the mouth, axillae, genital region and feet support greater
varieties and numbers of bacteria because they are moist due to their
function (e.g., mouth and vaginal barrel). The type and number of
different microorganisms on different body areas, interacting with
different glandular secretions, give rise to a variety of odors from
different body sites. Odor producing areas are of interest commercially,
since we spend several billions of dollars in the U.S. alone on products
to clean and deodorize our bodies. Numerous investigators have utilized
secretions collected from several different body areas in
perceptual/psychophysical paradigms to determine what, if any,
information is carried by volatile constituents of the body (Cernoch &
Porter, 1985; Doty, et al., 1978; Doty, 1981; Porter & Moore, 1981;
Porter, et al., 1986; Russell, 1976; Schleidt, 1980; Schleidt, Hold &
Attili, 1981).
The odor producing areas that have attracted the most attention as
potential human pheromonal sources are the genital/vaginal area and the
axillae. Organic-analytical studies of these areas have revealed a
complex mixture of volatile, organic molecules, many of which contribute
to the characteristic odor of the area (Huggins & Preti, 1981; Zeng, et
al., 1991, Zeng, Leyden, et al., 1996). As noted in these publications,
many of the odorants may be part of the characteristic odor of the body
area. Consequently, without a knowledge of a behavioral or physiological
effect (a potential "pheromonal effect") it is not possible to use the
techniques of organic-analytic chemistry to determine the active
ingredients. Hence a bioassay is needed to guide the analytical effort.
3. THE VOMERONASAL ORGAN AND PHEROMONE RECEPTION
Throughout many decades of comparative research, it became clear that
some amphibians, most reptiles and mammals, including New World primates,
have a VNO. In mammals it is best developed among the marsupials and
monotremes (platypus). Its structure and function, however, has been
extensively examined in rodents, lagomorphs, and ungulates, where studies
have shown that the organ detects chemical signals used in social
interactions and reproduction (Wysocki & Meredith, 1987). Although birds
possess a VNO during embryogenesis, adults of this class lack this
structure (see Wysocki, 1979). Historically, problems were encountered
once descriptions of primates became available. There is no question
that prosimians and New World primates have a fully developed VNO (e.g.,
Aujard, 1997; Evans & Schilling, 1995). Whether Old World primates
possess a VNO (and hence an accessory olfactory system in general)
remains questionable, and the opinions are split (Preti, Spielman &
Wysocki, 1997; see Wysocki, 1979 for a review). If Old World primates
have this organ, then it is possible that humans also have a functional
VNO. Otherwise one would have to argue either that all other Old World
primates lost the VNO while the humanoid line retained theirs, or that
the VNO re-emerged with the advent of Homo sapiens, which is unlikely.
Furthermore, a functional VNO requires that nerves from this structure
should project to the accessory olfactory bulb. This has not been
demonstrated for adult humans or for any other Old World primate. To the
contrary, Boehm, Ross & Gasser (1994) report an absence of a vomeronasal
nerve in their oldest sample (36 weeks) of human fetal tissue. Indeed,
they go on to speculate that "...the vomeronasal nerve disappears when
the LHRH-ir cells have reached the brain, leaving only a vestigial
structure in the nasal septum" (luteinizing hormone releasing hormone
immunoreactivity derives from a subset of neurons within nervus
terminalis, which originates from the same region of the olfactory
placode that gives rise to the VNO). All that should be said is that
adult humans have two small pits on either side of the nasal septum that
fit the description of openings to the VNO. Whether this putative VNO is
identical in function to the VNO in other species (such as rodents or New
World primates), or even functions at all, is not yet known.
Recent studies purport to show that activation of the human VNO is
possible with certain chemosensory cues or "vomeropherins" (Monti-Bloch,
et al., 1994; Berliner, et al., 1996). Although "vomodors" has been
proposed as the term for chemosensory cues that are sensed by the VNO
(Cooper & Burghardt, 1990), recent investigators have ignored this term
and instead have created reference to another neologism. "Vomeropherins"
are steroidal in structure and are alleged to be isolated from human skin
or are synthetic analogs of skin-derived steroids. Human subjects did
not report smelling anything during administration of these chemosensory
cues, suggesting that olfactory receptors were not stimulated. Electrical
responses, equivalent to generator potentials, were recorded from the
putative VNO of humans (Monti-Bloch & Grosser, 1991; Monti-Bloch, et al.,
1994). These responses differed with the type of chemical used and the
gender of the subject. One should be cautious in interpreting the origin
of these responses. It is possible to generate electrical responses from
activation of free-nerve endings of the trigeminal nerve, which
innervates this area of the human nose, or from smooth muscles
surrounding the myriad vasculature in the nasal cavity. As for the
reported sexual dimorphism, this could be due to differences in the mucus
layer or cellular membrane resulting from differences in endogenous,
sex-steroid priming. Gender differences in nasal mucosa have been
reported, e.g., males have more of the antioxidant uric acid in their
nasal mucous than do females (Housley, Eccles & Richards, 1996). In
addition, the steroid compounds being employed as "synthetic
vomeropherins" closely resemble naturally occurring estrogen, androgen
and progestin hormones. Thus, since actual steroid hormones have not
been used in control studies, one can speculate that metabolic enzyme
systems in the nose (Krishna, et al., 1992) altered the "vomeropherin"
structures to become an active steroid hormone.
In another study, the same investigators (Berliner, et al., 1996)
employed a single, synthetic "vomeropherin" (a progesterone-like
structure; pregna-4,20-diene-3,6-dione) to obtain circumstantial evidence
that the human VNO has neural connections with the brain, similar to
other mammals. In this study the molecule was puffed into the human VNO
pit which resulted in a subsequent alteration in male LH pulses normally
seen in blood. While this was interpreted as direct proof of both
steroid receptors in the VNO and a neural connection to the hypothalamus,
some cautions should be noted when considering this report. The
investigators used a "synthetic vomeropherin" but did not demonstrate any
effects on male LH pulses by either a "skin extract," where
naturally-occurring "vomeropherins" are alleged to originate, or from
pure, naturally-occurring "vomeropherins" from skin. In the absence of
demonstrating an effect from a naturally occurring source or compound,
one must wonder what is really being demonstrated. Furthermore, the
study lacked a critical control, viz., exposing the olfactory or
non-sensory, respiratory epithelium to the "vomeropherin" with
concomitant blood LH measures. These controls, if they generated
negative results, could have demonstrated the specificity of the
response. We assume that since no depolarization of the olfactory
epithelium was seen when it was exposed to the synthetic vomeropherin, it
was felt that this control not warranted. However, depolarization of the
olfactory epithelium may not be necessary if the mechanism of action is
to alter endocrine function especially if a steroid analogue of
progesterone can be absorbed into the nasal vasculature and have direct
effects upon CNS function.
In animals that possess a functioning VNO, the medial wall of the lumen
is lined with bipolar receptor cells. The axons of these cells penetrate
the basement membrane of the sensory epithelium, exit the VNO, traverse
the nasal septum, cross the cribriform plate, enter the brain, bypass the
main olfactory bulbs and synapse in the accessory olfactory bulbs
(Wysocki, 1979). It is the peripheral, bipolar, receptor cells that
critics say are lacking in humans. Four studies address this issue. The
first purports to have found, in adult humans, several cells in the VNO
that have bipolar appearance (Takami, et al., 1993). The cells stain
positively for neuronal markers; however this may be due to a positive
reaction to neuroendocrine cells in this tissue and not neurosensory
cells because the markers do not discriminate between neural and
neuroendocrine cells. Importantly, the same cells did not stain for
olfactory marker protein, present in bipolar receptor neurons in other
species with a functional VNO, nor were they reported to penetrate the
basement membrane (Takami, et al., 1993), which is also characteristic of
bipolar cells as they send their axons to the CNS. The second study
reports the presence of bipolar cells in the early, but not later, stages
of fetal development, suggesting that a vomeronasal epithelium is present
only during early embryonic life and regresses as the fetus reaches term
(Boehm, Ross & Gasser, 1994). Recent studies, reach more extreme
conclusions: Kjęr and Fisher-Hansen (1996a, b) present histological
evidence that the VNO in the human fetus degenerates between gestational
ages 11-16 weeks. Only 1 of 7 fetuses that were > 17 weeks gestational
age showed evidence of the remnants of a VNO. These data are in contrast
to those presented by Boehm, Ross & Gasser (1994) who reported an absence
of bipolar, receptor cells, but the continued expression of a pit, behind
which could be found a lumen lined by a ciliated, columnar epithelium.
Three additional reports also demonstrated the presence of a VNO in
fetuses up to 28 weeks gestational age (Smith, et al., 1996, 1997,
1998). These latter studies suggest evidence for the anatomical
existence of a human VNO. They do not, however, provide evidence of a
functioning VNO with intact neural connections to the brain. Given the
confusion, whether a human VNO exists (regardless of the absence of
bipolar receptors cells) remains an unanswered question.
Finally, two families of genes that may encode VNO-based receptors in
rats and mice have been cloned. The genes appear to express two sets of
unique receptor proteins in the VNO sensory epithelium. In one family,
there is no homology to any other known receptors, including putative
olfactory receptors (Dulac & Axel, 1995). A subset of this family of
genes in humans possesses a stop codon in the encoding region, indicating
the presence of non-expressed "pseudogenes." The second family of
receptor-like genes expressed in the VNO appears to be related to
metabatropic glutamate, and calcium-sensing receptors (Herrada & Dulac,
1997; Matsunami & Buck, 1997; Ryba & Tirindelli, 1997). Here too, the
expression of functional genes in humans is questionable. These data do
not exclude a functional human VNO-like organ, however, since similar
findings plagued initial attempts to isolate human olfactory receptors.
If it is found that humans have putative VNO receptor genes that appear
to be able to express functional proteins, then one must entertain the
possibility that humans have VNO receptors somewhere in the nose. If,
however, all human homologues of rodent VNO receptor genes are found to
contain stop-codon insertions or terminate prematurely, then one must
entertain the likelihood that humans lack a functional VNO.
In summary, current evidence suggests the presence, in adults, of
bilateral pits on the nasal septum that open into a lumen or sac.
Whether these structures are remnants of the VNO remains an open
question. As yet, there are no well-defined sensory cells described in
adults, nor have there been any descriptions of a connection between a
sensory epithelium in the VNO and the central nervous system. The
reports that describe the use of "vomeropherins" to stimulate the
putative VNO, which subsequently results in changes in hormone secretion,
can be explained in several different ways. At the very least, they
raise a number of serious questions and, when combined with the reports
from other independent laboratories, described above, suggest a level of
ambiguity at best. However, the possibility of chemical communication
among people does not necessitate a functional VNO. Many species,
including at least one mammal (the pig; Dorries, Adkins-Regan & Halpern,
1997), exhibit responses to pheromonal cues without the use of a VNO.
4. DO HUMANS SECRETE RELEASER OR PRIMER PHEROMONES?
4.1. Releaser Pheromones
As noted above, both the pheromone concept and the compounds that were
first described as having pheromonal activity were defined and/or
isolated from insects. Many pheromones in insects cause specific,
well-defined responses, perhaps involving some degree of genetic
programming, which include overt displays of attraction and copulation.
Chemical signals that elicit such behaviors are described as releasers.
With respect to mammals, releasers have been demonstrated in
estrogen-primed pigs (Melrose, Reed & Patterson, 1971) and hamsters
(Singer, et al., 1986). In these species, chemical signals emitted by
one sex may lead to attraction and mating.
Humans have both sources of putative chemical signals and the sensory
apparatus to receive them; however, our overt responses to chemical
signals are confounded by past experiences, other sensory inputs and the
context in which they are perceived. Therefore, one would not easily
expect to see observable releaser effects in humans. No peer-reviewed
data supporting the presence of endogenous, human-derived "pheromones"
that cause rapid behavioral changes, such as attraction and/or
copulation, have been documented. In spite of this, numerous fragrances
or additives for one's favorite fragrance have been or are being marketed
to perpetuate the myth that an odor can make one attractive, irresistible
or sexually potent. Some of these are discussed in Section 6.
4.2. Primer Pheromones
Chemical signals have been shown to cause a number of
neuroendocrine-mediated effects in non-human mammals. Consequently,
primer pheromones have a long, detailed, research history. Numerous
studies have demonstrated the alteration of reproductive events by
chemical signals in rodents (Bronson & Desjardins, 1974; Bruce, 1959;
Gray, et al., 1974; McClintock, 1978; Vandenberg, 1969; Whitten, Bronson
& Greenstein, 1968) and domestic animals (cows, Izard & Vandenberg, 1982;
sheep, Signoret, 1991). Males and females, or their chemical signals,
can advance or delay the onset of puberty (Bronson & Desjardins, 1979;
Vandenberg, 1969) or estrus (Gray, et al., 1974; Whitten, et al., 1968).
Chemical cues can cause pregnancy block in recently mated female mice
(Bruce, 1959; Yamazaki, et al., 1983, 1986) or across the entire
gestational period in prairie voles (Stehn & Richmond, 1975). Rodent
urine has been shown to be an important and potent source of chemical
signals. However the fleece of sheep (Signoret, 1991) and the vaginal
secretions of cows (Izard & Vandenberg, 1982) and hamsters (Macrides, et
al., 1974; Pfeiffer & Johnston, 1992, 1994) also contain chemicals that
appear to alter neuroendocrine events and hence estrous cycles. Primer
pheromones are also involved in the reproductive biology of Old World
primates such as crab-eating monkeys (Macaca fascicularis; Wallis, King &
Roth-Myer, 1986), chimpanzees (Pan troglodytes; Wallis, 1985) and baboons
(Papio cynocephalus; Wallis, 1989). Menstrual synchrony has been
documented in each of these primates; vaginal secretions may be
responsible, in part.
In humans, several studies have indicated that interpersonal relations
among women, as well as between men and women, alter reproductive
endocrinology. These relations include the now well-accepted effect of
menstrual synchrony, first documented by McClintock (1971) in all-female
groups and later replicated in a variety of other situations (Graham &
McGrew, 1980; Quadagno, et al., 1981; Weller & Weller, 1992, 1993b, c,
1995a, b; Weller, Weller & Avinir, 1995). In non-human mammals, such as
rodents, estrus synchrony has been shown to be mediated by airborne
chemical signals (McClintock, 1978; Schank & McClintock, 1997).
Additional data from McClintock and others show that male stimuli also
appear to alter menstrual-cycle length and regularity. McClintock (1971)
reported that women who stated that they were in the company of men three
or more times/week tended to have shorter cycles than those who spent
less time with males. Additional data from other studies support this
correlation. Large samples of prospectively gathered menstrual-cycle
data have repeatedly shown cycle-length averages to be 29.5 + 3 days
(Vollman, 1977). In addition, the incidence of anovulatory, non-fertile
cycles increases as cycle length diverges from this average (Treloar, et
al., 1967; Vollman, 1977). Infertile women tend to have either short (<
26 days) or long (> 33 days) cycles. A study by Cutler, Garcia & Krieger
(1980) indicated that women who had weekly, intimate contact with males
had a greater probability of menstrual cycles that were 29 + 3 days in
length. Women with sporadic or no intimate contact with men tended to
have significantly greater numbers of long (> 33 days) or short (< 26)
cycles. A subsequent study showed that women who had regular, weekly
contact with males were more likely to show regular, biphasic,
ovulatory-type cycles than women whose contact with males was sporadic or
non-existent (Cutler, et al., 1985). This study also suggested that
sub-fertile cycles tended to show a shortened luteal phase rather than an
absence of ovulation. An inadequate luteal phase (< 12 days of
hyper-thermic basal body temperature) is reflective of a condition known
as the "luteal phase defect," a common form of infertility in the United
States (Suh & Betz, 1993).
5. BODY ODOR CHEMISTRY: THE HUMAN AXILLAE AS A SOURCE OF HUMAN
PRIMER PHEROMONES
Numerous studies with humans have examined the perception of odors
collected on T-shirts and pads from the upper part of the body and the
axillae (Russell, 1976; Doty, et al., 1978; Schleidt, 1980; Schleidt, et
al., 1981). These odors allow individuals to identify their own smell as
well as that of their spouse and close kin (Porter & Moore, 1981; Cernoch
& Porter, 1985; Porter, et al., 1986; Hepper, 1988). Analytical studies
of axillary secretions collected from women across the menstrual cycle
suggest changes in the ratios of both the odor-producing bacteria
(Reilly, et al., 1996) and odorants (Preti, et al., 1987; Reilly, et al.,
1996). These studies suggest that chemical cues from the axillae contain
sufficient differences in the concentration of odorants to allow for
discrimination of individuals and phase in the menstrual cycle in female
subjects.
Russell, Switz & Thompson (1980) were the first to present evidence that
menstrual synchrony could be mediated by axillary secretions. In depth,
double-blind studies conducted in our laboratory, employing axillary
extracts from both males and females, also suggested that extracts from
the axillary secretions of a donor group of females during the menstrual
cycle could be used to bring a recipient group of females into synchrony
with the donor (Preti, et al., 1986).
Extracts of male axillary secretions also have been applied to the nasal
area of women with a history of irregular cycle lengths. The lengths of
the menstrual cycles of these women showed a statistically significant
shift (vs. controls) toward the normal cycle-length of 29.5±3 days
(Cutler, et al., 1986).
Although provocative in their findings, the above studies, suggesting
that axillary extracts contain physiologically active components, have
been criticized regarding methodological and statistical issues as well
as for having too few subjects (Doty, 1981; Wilson, 1987, 1992; Weller &
Weller, 1993a). However, the studies did endeavor to find an objective
measure of primer pheromone activity that has been noted in non-human
animals (viz., a change in menstrual-cycle length).
Further support for axillary compounds having primer-pheromone activity
is contained within a recent report by Stern and McClintock's (1998).
The results of their experiments show that exposing women with normal
menstrual cycles to axillary extracts from women in their follicular
phase (the days following menses but several days prior to ovulation)
shorten the recipient's menstrual-cycle length by 1.7 ±0.9 days.
Exposing similarly normally cycling subjects to axillary extracts
collected near the time of ovulation of the donors lengthens the
recipient's menstrual cycle by 1.4 ±5 days. Interestingly, similar
effects on the estrous-cycle lengths of rats, when they were exposed to
the follicular and ovulatory odors of other rats, have been noted
(McClintock, 1984; Schank & McClintock, 1997).
5.1. The Chemistry of Axillary Odor
The studies described above present evidence that axillary secretions
contain one or more components that are capable of altering the
neuroendocrine system that influences menstrual- cycle length and
timing. It is not currently known which constituents of the mixture of
odorants found in axillary secretions are responsible for altering the
menstrual cycle. Considerable analytical efforts have focused upon the
identity of the interesting odorants found there.
A number of investigations of axillary secretions have focused upon the
steroid molecules found in the underarm area. Both radioimmunoassay
techniques and combined gas chromatography/mass spectrometry (GC/MS) were
employed to identify volatile, odoriferous steroids in the axillae (Gower
& Ruparelia, 1993; Labows, Preti, et al., 1979; Rennie, Gower & Holland,
1991), particularly 5 -androst-16-en-3- -ol (androstenol) and 5
-androst-16-en-3-one (androstenone). These compounds have musky,
urine-like odors that were thought by some authors to be suggestive of
axillary odors. However, our recent organoleptic (sensory based) and
analytical chemistry studies have presented evidence to demonstrate that
the mixture of C6-C11 branched, straight-chained and unsaturated acids,
present in axillary sweat, constitute the characteristic axillary odor
(Zeng, et al., 1991, 1992, Zeng, Leyden, et al., 1996). In terms of
relative abundance, these acids, in particular (E)-3-methyl-2-hexenoic
acid (E-3M2H), are present in far greater quantity than are the C19- 16
volatile steroids. In the combined male samples that we analyzed,
(E-3M2H) was the dominant component, present at far greater concentration
than androstenone: ~ 357 ng/µl for E-3M2H vs. ~ 0.5 ng/µl for
androstenone (Zeng, et al., 1991). In combined female samples, the
straight-chain acids were present in greater relative abundance than
E-3M2H; further, no androstenone was seen in female extracts.
Androstenol was present, albeit in far lower concentration than E-3M2H or
the other acids: 3.5 ng/µl extract androstenol vs. ~ 150 ng/µl extract
of E-3M2H (Zeng, Leyden, et al., 1996). The Z-isomer of 3M2H was also
present in each gender, however in less relative abundance: 10:1 (E:Z) in
males and 16:1 (E:Z) in females.
Several studies have demonstrated that the precursors of axillary odor
reside in the apocrine glands (Leyden, McGinley & Nordstrom, 1981;
Labows, McGinley & Kligman, 1982; Rennie, Gower & Holland, 1991). The
characteristic axillary odors are a result of the interactions between
axillary microorganisms and odorless, aqueous-soluble precursors present
in apocrine secretions. We have examined epinephrine-induced apocrine
secretions from males and females and found that the water soluble
components contain 3M2H and other constituents of the characteristic
axillary odor bouquet bound, in some fashion, to non-volatile molecules
(Zeng, et al., 1992; Zeng, Leyden, et al, 1996). These odorants can be
released by base hydrolysis (5% NaOH) or by incubation with bacteria
(Zeng, et al., 1992). Separation and hydrolysis (by NaOH or enzymes) of
the proteins found in male apocrine secretions have demonstrated that
3M2H is carried to the skin surface bound to two proteins which we have
designated as Apocrine Secretion Odor Binding proteins 1 and 2 (ASOB1 and
2). ASOB1 and ASOB2 have apparent molecular weights of 45 and 26 kDa,
respectively, by sodium dodecylsulfate-polyacrylamide gel electrophoresis
(Spielman, et al., 1995).
Antisera to ASOB1 and 2 were employed to probe, by Western blotting, the
proteins from a variety of body fluids (e.g., tears, forehead and areolar
sweat, submaxillary and parotid saliva, urine, ear wax, serum and nasal
secretions). All fluids, except urine, contained an immunoreactive
protein with the same electrophoretic migration pattern as ASOB1; areolar
sweat and ear wax were also positive for ASOB2 (Spielman, et al., 1995).
These results suggest a wide-spread distribution of an ASOB1-like protein
and perhaps its bound odorants in a variety of body fluids, albeit at far
lower concentrations than in apocrine secretion.
Female apocrine proteins also have been electrophoretically separated and
probed with antisera to ASOB1 and 2. The electrophoretic pattern of
proteins and Western blotting results were qualitatively similar to that
for male apocrine proteins (Spielman, et al., 1998).
Both the actual molecular weight and structure of ASOB2 have been
determined using enzymatic digestion, separation of the resulting
peptides (by high-performance liquid chromatography) and structure
determination by matrix-assisted laser-desorption-ionization,
time-of-flight-mass spectrometry (Zeng, Speilman, et al., 1996). The
results determined that the primary amino acid sequence of ASOB2 is
identical to that of apolipoprotein D (apoD). This, as well as in situ
hybridization using an anti-sense oligonucleotide probe for apoD mRNA,
demonstrate that the site of expression for apocrine apoD is indeed the
apocrine gland. We also found that the glycosylation pattern of apoD
from apocrine secretion differs markedly from that found for apoD in
serum (Zeng, Speilman, et al., 1996). This demonstrates that apocrine
apoD is produced in the apocrine glands and is structurally different
from serum apoD.
ApoD is a member of the 2µ-microglobulin superfamily of proteins (also
known as lipocalins; Flower, 1994). The physiological role of plasma
apoD is not known. Although several, putative ligands have been
suggested by in vitro studies and theoretical considerations (Milne,
Rassart & Marcel, 1993), our studies identified, for the first time, an
in vivo ligand for apoD as it appears in apocrine secretion. We also
determined that there is a 2:1 molar ratio of 3M2H to apocrine apoD.
These chemical studies demonstrated that axillary odorants are carried to
the skin surface bound to apoD, a lipocalin protein. When considered
together with the studies of menstrual-cycle alteration, this suggests an
interesting analogy between the human axillae and odor-producing areas
that emit chemical signals in non-human mammals. Odors with
physiological impact are bound to proteins that are members of the
lipocalin family of lipid carrier proteins in the urine of mice
(Robertson, Benyon & Evershed, 1993), vaginal secretions of hamsters
(Singer, et al., 1986) and saliva of pigs (Booth & White, 1988).
The neuroendocrine mechanisms by which human axillary components may
exert primer pheromone effects, such as menstrual-cycle alteration,
remain to be elucidated. However, when it is identified, this mechanism
may provide a bioassay to guide analytical efforts to isolate and
identify the active substances.
6. PRODUCTS MARKETED AS CONTAINING HUMAN PHEROMONES
Table 2 contains a non-exhaustive list of products that have been and are
being marketed as having pheromonal effects. Most allege to have
releaser properties despite no hard evidence to back the claims.
Insert Table 2. Some Commercial Products (Past and Current) With Alleged
Pheromonal Properties.
Copulins are a mixture of C2-C5 aliphatic acids found in the vaginal
secretions of female Rhesus monkeys at the time of optimum fertility.
These acids also are found in the vaginal secretions of some human
females (Michael, Bonsall & Warner, 1974; Huggins & Preti, 1981).
Several studies, published in the early, 1970's, suggested that female
Rhesus monkeys scented with copulins (both naturally or synthetically
derived) caused male Rhesus monkeys to respond sexually and to mate with
them (Curtis, et al., 1971; Keverne & Michael, 1971; Michael & Keverne,
1970; Michael, Keverne & Bonsall, 1971). The behavioral responses were
later questioned and could not be reproduced in a separate population of
the same species (Goldfoot, et al., 1976). Nevertheless, this acid
mixture was patented with claims that it promoted sexual attraction
between humans (Michael, 1972). At least one major fragrance company may
have put small amounts of this acid mixture into its perfume fragrances
created during the early to mid-70's. However, a double-blind,
placebo-controlled study with human couples showed no increase in sexual
activity attributable to copulins (Morris & Udry, 1978).
More recently, alleged pheromone-containing products are claimed to alter
or affect mood or act to enhance confidence and attractiveness (e.g.,
Realm® and Athena® products). A more thorough discussion of several of
these products is warranted.
Studies stemming from corporate research have led to renewed interest and
research activity into the possibility that humans possess a functioning
VNO. Many of the recent reports were cited above (Section 3). This
research lead to fragrances ("Realm for Men" and "Realm for Women")
purported to contain skin-derived steroids (see Table 2) that are alleged
to be human pheromones ("vomeropherins") because these compounds
"stimulate" the human VNO (i.e., they generate "pheromone-induced"
electrical responses within the VNO cavity). Prior to these studies, the
criterion that a compound must stimulate the VNO before it could be
called a pheromone was not part of the pheromone definition (note:
insects lack a VNO). Consequently, a new definition of pheromone appears
to have been created. Interestingly, the first mammalian pheromone to be
identified, viz., boar taint (androstenone), does not rely upon an intact
VNO to elicit its releaser response (i.e., assuming a mating posture by a
sow in heat; Dorries, et al., 1997). Furthermore, the alleged outcome of
"VNO stimulation" by Realm is not an objective, physiological/endocrine
endpoint, as has been experimentally documented in other mammalian
pheromone systems, but rather a more nebulous, "relaxed, self-confident
feeling" that makes one attractive to others.
As noted above (Section 3) and often cited in the popular press, the
alleged active substances in Realm products appear to be synthetic
versions of compounds originally derived from human skin (Steingarten,
1993; Blakeslee, 1993), specifically, skin samples scrapped from the
inside of casts worn by injured skiers. No studies have appeared to
document how the active molecules were isolated from these skin samples.
By their very nature, skin extracts contain a very complex mixture of
organic compounds (Nicolaides, 1974; Zeng, et al., 1991; Labows & Preti,
1992). How were the structures of the putative human pheromones actually
determined? Furthermore, gender-specific Realm fragrances are said to
contain "a number of known human pheromones" (Jennings-White, 1995) in
proportions that are trade secrets. No demonstration of the alleged
pheromonal effects of these fragrances has appeared in a peer-reviewed
publication.
Other products of recent vintage listed in Table 2 that are promoted to
increase one's confidence and attractiveness are Pheromone 1013 and
Pheromone 10X. These are allegedly designed for women and men,
respectively, and are said to contain "synthesized human pheromones,"
(product advertisements and Athena Institute World Wide Web page)
including the nonvolatile steroid, dehydroepiandrosterone (DHEA).
Although the ingredients that comprise these two products have yet to be
identified by the manufacturer, analysis of the men's product (Pheromone
10X) has been performed by GC/MS. This analysis suggests that the
product contains the volatile steroids androstenone and androstenol, as
well as synthetic musks, lipids and silicon compounds (Dr. Brian
Andresen, Lawrence Livermore Laboratories, personal communication to GP).
An important characteristic that appears common to the products listed in
Table 2 is the apparent lack of peer-reviewed evidence from any published
research to indicate what, if any, physiological/behavioral responses
these compounds evoke in double-blind controlled trials and the type of
bioassays employed to identify and quantify the "active" materials.
However, considerable personal testimonials to the effectiveness of the
products are available in their print media advertisements and World Wide
Websites.
7. CONCLUSIONS
Humans possess rich repositories of odors, one of which, the axillae, has
been implicated as the source of semiochemical information. There is,
however, no substantial body of evidence to allow one to conclude that
releaser-pheromone effects can be ascribed to human odors. While there
has been, and undoubtedly will continue to be, a stream of products
claiming to use sex attractants and behavior modifiers isolated from
humans, the absence of experimental data backing the efficacy of the
claims may also be a trademark. Evidence addressing product efficacy may
be presented in the form of personal testimonials, magazine/newspaper
advertisements or the "discoverer's" appearance on a T.V. talk-show.
Where data on such discoveries has appeared in patents, e.g., the copulin
mixture, it can be subjected to an experimental protocol to determine
validity. Eventually this will occur with other compounds claimed to be
human pheromones and packaged for consumer purchase (caveat emptor).
Humans have an olfactory system capable of detecting thousands of
chemical cues; however, evidence for a functioning VNO is inconclusive at
best. Further, in at least one other mammal with a functional VNO (the
domestic pig, Dorries, et al., 1997), the olfactory system apparently
transduces pheromonal cues to release the stereotypical behavioral
response. Hence the presence of a pheromonal response need not require a
functional VNO.
Human chemosensory cues produced in the axillae appear to act as primer
pheromones that affect the human menstrual cycle. While data from
studies demonstrating these effects have been criticized, they represent
a valid scientific attempt to resolve interesting and important
questions. The putative primer molecules produced in the axillae have
the potential to alter menstrual-cycle length and timing, presumably by
altering neuroendocrine levels. Consequently they represent a potential
pathway for fertility enhancement and control, heretofore untried.
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9. ACKNOWLEDGMENTS
This work was supported in part by research grants DC 10072 (to G.P.) and
DC 00298 (to C.J.W.) as well as P50 DC 00214 from the National Institute
on Deafness and Other Communication Disorders.
Table 1. The Odor Producing Areas in Humans*.
Area References
Scalp/Hair Labows, McGinley, et al., 1979
Mouth/Breatha,b,c Preti, et al., 1995; Tonzetich, 1971;
Tonzetich, Preti & Huggins, 1978
Axillae/Underarmsa,b Zeng, et al., 1991, 1992; Zeng, Speilman,
et al., 1996; Zeng, Leyden, et al., 1996
Chest Spielman, et al., 1995
Genital/Vaginala,b Huggins & Preti, 1981
Feet Kanda, et al., 1990
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*There are several metabolic disorders that may produce abnormal body
odors and/or bad breath in adults (Preti, et al., 1995). In addition the
odors in several of these body areas may be influenced by gendera,
physiological stateb, dietc, and/or age.
Table 2. Some Commercial Products (Past and Present) with Alleged
Pheromonal Properties.
COPULINS:
- Mixture of C2-C5 aliphatic acids
- Alleged releaser pheromone in rhesus monkeys
- French patent claims similar effects in humans (Michael, 1972)
- Added to many fragrances (ca., 1970-1979)
- Tested in double blind study with no effect (Morris & Udry, 1978)
ANDROSTENONE/ANDROSTENOL:
- Present in sweat (see Section 5a) and boar saliva
- Releaser pheromone in pigs
- Androstenol added to Andron® fragrances (Jovan; ca., 1979-1986)
- No support for a releaser pheromone in humans (Black & Biron, 1982)
- Products with androstenol or musks available via ads in
tabloids or mail order
- Companies advertise on the World Wide Web pheromone/sex
attractant products for men containing androstenone or androstenol as the
alleged "active ingredient," e.g., "The Scent," "The Secrete" "Yes
Pheromone, Sex Attractant for Men," each suggesting that women will be
irresistibly drawn to the wearer with the exception of "Athena 1013," no
similar products for women
REALM MEN®/ REALM WOMEN®:
- Fragrances that contain "vomeropherins" "pheromones that
simulate or send messages through the human vomeronasal organ"
- "Vomeropherins" volatile and non-volatile androstenes,
progestins and estrogens said to be isolated from the skin; no published,
peer-reviewed studies describe the isolation and identification process
- "Wearer will feel more relaxed and self-confident, hence more attractive"
PHEROMONE 1013
- Alleged to make women more confident and attractive and
increase their love-life
- Added to an individual's favorite fragrance
- Contain dehydroepiandrosterone (DHEA), a non-volatile steroid
in ethanol
PHEROMONE 10X
- Alleged to increase attractiveness and romantic encounters
- Added to men's cologne or aftershave
- May contain volatile and non-volatile steroids, synthetic
musks, lipids and silicon compounds
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