is love in the air? facts and fantasies about human pheromones” - acs.org · most suggest that...

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Pheromones are in the Air: Friends, Lovers or Foes

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Dr. George Preti Member,

Monell Chemical Senses Center

Dr. Charles Wysocki Member,




Dr. Dave Harwell Assistant Director,

Industry Member Programs,

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"Pheromones are in the Air:

Friends, Lovers or Foes"

George Preti, Ph.D.1,2 and Charles J. Wysocki, Ph.D.1,3

Members, 1Monell Chemical Senses Center 2Department of Dermatology, School of Medicine

3Department of Animal Biology,

School of Veterinary Medicine

University of Pennsylvania

For pheromones or chemical signals to be “in the air” the molecules that trigger the response must be in the vapor phase

4/6/2015

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Volatile Organic Compounds (VOCs)

• VOCs < 300 daltons: most common aromas

• non-ionic

• finite vapor pressure between ambient and 250°C

Peptides/Proteins ≠ VOCs

• Charged (ionic); > molecular weights

• To reach vapor phase or nose they need a transport

system

• Peptides may be airborne; carried on plant or animal

cellular debris or dust

Olfactory

receptor

cells

Olfactory Blindness to VOCs ?

~ 1,000 olfactory

receptor (OR)

genes in

mammals

Humans ~ 350

functional genes

However, not

everyone

expresses the

same set of

ORs*

*this differential expression gives rise to “Specific Anosmias”

5-10%

4/6/2015

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Audience Trivia Question

The Pheromone concept and first isolates

with pheromonal activity were in?

• Rats

• Humans

• Insects

• Monkeys

• Rabbits

Pheromone defined 55 years ago

From insect research (1959):

“substances which are secreted to the outside by

an individual and received by a second individual

of the same species, in which they release a

specific reaction, for example, a definite

behavior or a developmental process.”

Usually thought to be a

single compound or a

simple mixture.

4/6/2015

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Pheromones: Facts and Definitions

Important:

Pheromone concept and first isolates with pheromonal activity were in insects

a) These pheromones = specific, well-defined responses;

genetic basis? Responses include overt displays of

attraction and copulation. Chemical signals that elicit

such behaviors are described as releasers.

b) In Mammals - releasers have been demonstrated in

estrogen-primed pigs (androstenone / androstenol) and

elephants (Z - 7 - dodecenyl acetate).

13

149

810

1712

11

15

16

75

6

18

19

1

4

2

3

H

H

H

O

13

149

810

1712

11

15

16

75

6

18

19

1

4

2

3

H

H

H

OH

O O

These two steroids as well as a third,

4,16-androstadien-3-one (androstadienone) are

found in human axillary secretions in pico-to-nanogram amounts

13

149

810

1712

11

15

16

75

6

18

19

1

4

2

3

H

H

H

O

4/6/2015

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Pheromones: Facts and Definitions

continued..

c) Humans - responses confounded by past experiences, context and other sensory inputs; difficult to see observable releaser effects in humans - none have been adequately documented in adult humans; however, newborns will move in the direction of their mothers breast odor.

Unfortunately, the concept of a specific, rapid response and “sexual attraction” have become “inseparable” from “pheromone” in the minds of many writers, internet entrepreneurs and many well-educated individuals.

Human Pheromones on the Internet

Many internet sites advertise pheromone/sex attractant products for

men. These products generally contain trace amounts of the volatile

steroids androstenone, androstadienone and/or androstenol (which

do have releaser pheromone activity in pigs) as the alleged “active

ingredient.” Most suggest that women will be irresistibly drawn to the

wearer – many fewer products exist for women.

4/6/2015

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Human Pheromones:

on the Internet,“Keeping it Real”

Many products are hawked and suggested to work via sensory

stimulation of the vomeronasal organ (VNO; more on the next

slide).

Despite web-site advertisements and suggestions in some

peer-reviewed pubs, there have not been any bioassay-guided

studies that have identified a human chemical signal: i.e., no

specific compounds identified.

Regardless, the human axillae is a source of human chemical

signals: Primer Pheromones, Modulators (stress, fear odors)

and Signaler compounds may be found there. Rather than

through the VNO, these chemical signals are likely processed

through olfaction.

VNO in non-primate mammals a) Independent of the olfactory sensory system

b) Located in the very front of the nose

c) Nerves communicate with parts of the brain that influence

reproductive physiology and behavior

d) Does process some (but not all) pheromones

VNO in primates a) Present and functional in New World Monkeys

b) A shell of the VNO can be found in Old World Primates &

humans

c) No sensory cells hence no sensory connections with the brain

d) Most genes for pheromone receptors absent of non-functional

e) Hence, vestigial and non-functional

4/6/2015

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Human Pheromones: “Keeping it Real”

Primer Pheromones: affect endocrine or neuroendocrine

responses (estrogen, lutenizing hormone [LH]), menstrual

cycle timing and pregnancy disruption.

Modulator Pheromones: chemosensory cues that modulate

mood or context of other people (Jacob and McClintock, 2000;

Preti et al., 2003), e.g., odors from stressful or fearful

conditions.

Signaler Chemosignals: provide information, e.g., sex,

reproductive status, age, dominance; mediated by individual

“odor print,” which is a complex mixture of compounds and

properly should not be classified as a pheromone.

The Human Axillae: a Source of Primer

Pheromones

Female and male axillary secretions alter the length and

timing of the menstrual cycle (Russell et al., 1980; Preti et

al., 1986; Cutler et al., 1986).

Phase-specific parts of the menstrual cycle either

shorten (follicular) or lengthen (ovulatory) recipient cycles

(Stern and McClintock, 1998)

Male axillary secretions alter female neuroendocrinology

(Preti et al., 2003). More later.

4/6/2015

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The Human Axillae: Source of Modulator

Pheromones

Male axillary secretions alter female mood (Preti et al.,

2003)..

Axillary secretions from individuals in highly emotional

states impact the perceiver:

• axillary secretions collected while watching “frightening

movies” were distinct and different from those collected

while watching “neutral” or “comedy” films.

• axillary secretions of people who watched a terrifying film

(“smell of fear”) can be detected (by women judges).

• axillary odors from donors who had experienced fear or

disgust evoked similar emotions in subjects who sniffed

them, suggesting “emotional contagion.”

• No structural characterization of odorants involved, as yet

The previous slides present a background regarding “what is out there.”

Only a “smidgen” of the mis-information surrounding human pheromones was

presented, but as we also explained axillary secretions contain potentially

powerful, physiologically active compounds. Hence the axillae are the focus

of basic and applied research: academic, consumer products (billions are

spent each year on axillary products in US) as well as forensic scientists and

the military.

1. Unique human odorants

2. Human odor signatures

3. Human Pheromones

are produced there

4. Stress-related odors

4/6/2015

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Cutaneous bacteria

Staphylococcus

epidermidis (Staph.

epi.)

Corynebacterium

lipophilicus….(CLC)**

Corynebacterium

minutissimum….(C.

min.)

Corynebacterium

xerosis….(C. xerosis)

Human Apocrine Gland Secretions

1. Secondary sexual characteristic-becomes active near

puberty-Androgen Sensitive

2. Secretions contain axillary odor precursors: Proteins (~

0.4%); as well as cholesterol; C19-volatile and non-volatile

steroids and sulfates

3. Secretion becomes odoriferous when acted upon by

bacteria

4. Apocrine secretions are produced by emotional situations:

stress, fear and sexual arousal

5. Experimentally, apocrine secretions may be elicited by

epinephrine injections

6. Ethnic variation (Caucasian/African versus Asians)

7. Many scent glands are apocrine-like in structure

4/6/2015

15

Donors must

shower 1x/day with

a plain soap

1.Not use any

underarm products

for 14-21 days

2. Have correct type

and density of

Bacteria

3. Wear pads in their

axillae 3x/week for 8-

10hr

RT: 9.87 - 42.01

10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42

Time (min)

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

Re

lative

Ab

un

da

nce

38.86

33.96

21.37 30.6820.29 40.09

23.6119.44 37.4126.15

30.3125.99 29.04

32.5127.32

15.7118.20 21.61 41.14

36.1028.44

24.3031.5817.60

13.08 16.24 22.8415.5111.80

NL:

6.74E7

TIC F: MS

1ul

Whitfield

May1995

RT: 9.97 - 25.17

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Time (min)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

Re

lative

Ab

un

da

nce

21.3720.29 23.6119.4415.71 18.20 24.3017.6013.08 16.24 22.8414.3111.80 21.95

12.87 20.69

15.1317.43

10.8112.13

13.67 22.65

10.32

11.20

NL:

2.44E7

TIC F: MS

1ul

Whitfield

May1995

Body odor extracts: very

complex with some very

small components;

regardless of peak size,

may have high olfactory

impact.

Complexity necessitates

the use of GC-

Olfactometry to identify

retention times of

important axillary

odorants: GC/MS

Odors sniffed;

judge writes

impression and

retention time.

4/6/2015

16

AXILLARY ODOR SUMMARY

Using a variety of analytical techniques: Combined Male and Female

Extracts

Characteristic odors = C6 - C11 straight-chained, branched and

unsaturated acids. Largest in males is E-3-methyl-2-hexenoic acid

(trans) (3M2H)*; in females C6 - C11 straight-chained acids are >

3M2H.

Bruce_1203_&_1205 #2427 RT: 28.23 AV: 1 NL: 5.45E4

T: {0,0} + c EI det=350.00 Full ms [ 40.00-440.00]

50 60 70 80 90 100 110 120 130 140 150

m/z

0

10

20

30

40

50

60

70

80

90

100

Re

lative

Ab

un

da

nce

42.9

66.854.9 99.868.9

112.9

52.9 94.9

44.9 127.981.955.9 70.9111.086.964.9 71.950.9 115.080.9 101.0 129.087.9 159.0143.0118.9 146.8

O

OH

O

OH

7-octenoic acid*

patented as unique human odorants (Sawano, et al., US patent 5,141,921, 1992)

Development of Novel Deodorant Methods

• Creation of peptide mimics to “fool” the axillary; bacterial-interaction with

these mimics releases 11-dodecenoic acid to kill bacteria

• Cross-adaptation with pleasant-smelling structural analogues to 3-

methyl-2-hexenoic acid: The first step in the synthesis of E-, and Z-

3M2H = formation of pleasant-smelling ethylesters

• Cross-adaptation with certain fragrance chemicals

4/6/2015

17

ASOB1, Electroelute,

hydrolyze, GC/MS: ~

4.4ng 3M2H plus other

acids; axillary odor

ASOB2, electroelute,

hydrolyze; GC/MS ~ 1.0ng

3M2H plus other acids

Axillary odor

ASOB2 = apolipoproteinD

by mass spectrometry

ApoD is a lipocalin!

No other protein bands

yielded 3M2H, regardless

of molecular size

O

OH

Axillary Odor Biogenesis:

Apocrine water layer yields odors; organic none

Apocrine Secretion Proteins separated by SDS-

gel electrophoresis: 6 male Subjects

Apocrine secretion odor binding

protein is a lipocalin

• Lipocalins are a family of proteins that transport small

hydrophobic molecules, e.g., steroids, retinoids and lipids.

• Lipocalins have been associated with many biological

processes, including immune response, cancer cell

interactions, retinoid binding, and pheromone transport in

non-human mammals.

• This suggests a remarkable similarity between the human

axillae and non-human mammalian odor sources used in

chemical signaling.

4/6/2015

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Do Male Axillary Extracts Alter

Female Neuroendocrinology and

Mood?

1) Exogenous Stimuli, which alter menstrual cycle length & timing, should affect gonadotropin releasing hormone (GnRH) --> look at LH in blood;

2) LH pulsing -- Differs in frequency and amplitude with time of cycle;

3) Since olfactory mediated signals pass thru the amygdala, mood/emotions may also be effected;

4) Examine LH pulses and mood during extract and blank application during 12hr. stay in CRC.

Do Male Axillary Extracts Alter

Female Neuroendocrinology and

Mood?

1) Exogenous Stimuli, which alter menstrual cycle length & timing, should affect gonadotropin releasing hormone () --> look at luteinizing hormone (LH) in blood;

2) LH pulsing -- Differs in frequency and amplitude with time of cycle;

3) Since olfactory mediated signals pass thru the amygdala, mood/emotions may also be effected;

4) Examine LH pulses and mood during extract and blank application during 12hr. stay in CRC

Energetic, Sensuous,

Sexy, Anxious, and

Relaxed

Tense, Tired, Calm,

and Active

4/6/2015

19

Audience Trivia Question

What type of pheromones do humans

produce?

• Primer Pheromones

• Signaler Pheromones

• Modulator Pheromones

• Primer and Modulator Pheromones

• All of the above

“

Results: Humans produce primer and

modulator pheromones.

We demonstrated that male extracts contain

ingredients that alter female neuroendocrinology

and mood (Preti, G., Wysocki, C.J. et al., Biol. Reproduction, 68, 2107-

2113, 2003)**

Extract Control

Type of Application

40

50

60

70

Av

era

ge

La

ten

cy

to

Ne

xt

LH

Pu

lse

En

ergeti

c

Sen

suou

s

TE

NS

E

Tir

ed

Calm

Sexy

An

xio

us

Fati

gu

ed

RE

LA

XE

D

Acti

ve0

1

2

3

4

5

6

Rati

ng

Mood Ratings(1-7, Least to Most)

Control Male Extract

0.01

0.05

p <

p =

4/6/2015

20

Female Body Odors Contain Primer and Modulator

Pheromones

When exposed to female sweat collected on T-shirts Males:

• Increase circulating testosterone

• Increase positive mood (willing to engage in riskier

behavior)

• These effects are present using sweat collected during

the peri-ovulatory period but not when using non-

ovulatory phases in the cycle (e.g., luteal phase)

• These results demonstrate that human female axillary

secretions also contain potent, albeit unknown, anxiolytic

compounds that also affect neuroendocrine responses

and hence, sex steroid levels

Miller & Maner (2010). Scent of a woman: Psychol. Sci. 21:276-283.

Miller, S. L., Maner, J. K. (2011). Ovulation as a male mating prime: J. Personality Soc. Psychol.

100:295-308.

RT: 10.14 - 59.91

15 20 25 30 35 40 45 50 55

Time (min)

10

20

30

40

50

60

70

80

90

100

Re

lative

Ab

un

da

nce

17.58

26.3324.35

55.53

43.97

22.27

30.90

21.87 48.9558.42

28.5932.3720.14 37.21

32.74 40.84 45.7210.34

36.78 51.1311.18 15.97

NL:

2.49E6

TIC MS

Bruce_120

3_&_1205

“Characteristic Odor”

S

O O

O

OH

O

OH

OH

O

OH

O

OOH

OH

OO

OH

O

OH

We know a lot about axillary chemistry and odor

formation; however, which of these are physiologically

active?

4/6/2015

21

Summary and Conclusions:

• Male body odor alters female neuroendocrine levels (Primer

Pheromone);

• Male body odor reduces tension and increases relaxation in

females. This is a surprise finding, but suggests that male

axillary secretions contain a Modulator Pheromone.

• Currently, we believe that each effect is caused by different

components of the extract.

• Female secretions have a similar effect on males: ovulatory

secretions increase male testosterone (Primer effect)

• Female secretions also effect male mood (Modulator effect)

Summary and Conclusions:

• Stress and fear may produce a recognizable axillary odor-

different from “normal”

• The human axillae is a natural product source: human

pheromones that control the length and timing of the

menstrual cycle and mood are found there.

• Axillary extracts may be thought of as a “medicinal

tea/potion” (re: foxglove tea and willow bark) which must be

teased-apart to yield its active ingredients;

• Current and future studies are examining our own “natural

products” for indicators of stress, individual identity and

disease biomarkers.

4/6/2015

22

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American Chemical Society

The ACS Science and Human Rights Webinar Series presents:

“Science Diplomacy as a Bridge

to Peace in the Middle East”

February 20, 2014 at 3:00 p.m. ET

Dr. Zafra M. Lerman, President of the Malta Conferences Foundation, will speak during this

webinar on the importance of science diplomacy in working toward stability in the Middle East.

This session will be moderated by Dr. Norman Neureiter, Acting Director of the American

Association for the Advancement of Science (AAAS).

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