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Subject:

human VNO

From:

"Charles J. Wysocki" <[log in to unmask]>

Reply-To:

Charles J. Wysocki

Date:

Tue, 29 Feb 2000 08:55:56 -0500 (EST)

Content-Type:

text/plain

Parts/Attachments:

Parts/Attachments

text/plain (1062 lines)


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
=====================


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
________________________________________________________________________
*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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