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Hormones and Behaviour

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Hormones and Behaviour
Rae Silver, Columbia University, New York, New York, USA
Lance J Kriegsfeld, Columbia University, New York, New York, USA
Hormones are chemical messengers that are produced by the body and act on target tissue
within the same individual. Importantly, not only can hormones act to influence behaviour,
but the behaviour of an individual can also affect its own hormones.
Hormones: The Within-body Signalling
System
The term ‘hormone’ was initially applied to molecules
which were synthesized in endocrine glands, secreted into
the bloodstream, and then transported to distant target
sites. Originally, only three classes of hormones were
recognized: proteins and peptides (e.g. gonadotropin-
releasing hormone, luteinizing hormone), steroids (e.g.
testosterone, oestradiol) and amino acid-related hormones
(e.g. noradrenaline (norepinephrine), adrenaline (epi-
nephrine)). Today, the term hormone is used more broadly
to include all chemical messengers synthesized by the body
that act by binding with high affinity to target cells within
the same individual. Some scientists also regard as
hormones, molecules that leave the body to act on another
individual, while others refer to these as pheromones.
There are over 100 known hormones, and this list is
growing. It is no longer feasible to group hormones into the
simple categories noted above.
Our deepening understanding of hormones and their
actions has shifted our views of ‘what hormones are’ and
‘what hormones do’. The modern definition takes the view
that a hormone is any substance that acts at the cellular
level to initiate, stop or modulate a cellular process. The
site of action can be nearby or at a distant target.
Hormones are synthesized not only by glands but also by
neurons and other cell types in specialized tissues,
including uterus and heart. Hormones can act via
paracrine, autocrine or intracrine mechanisms. It is not
uncommon for a given hormone both to act locally and to
travel through the bloodstream to act at distant target sites.
The endocrine system
Classically, the endocrine system of the body has three
main components: brain–pituitary–target organ. Neuro-
secretory cells in the brain synthesize neurohormones,
which reach the specialized portal blood supply of the
pituitary gland. When stimulated by these brain hormones,
the pituitary gland secretes its products into the general
blood supply of the body. Pituitary hormones, such as
follicle-stimulating hormone (FSH) and luteinizing hor-
mone (LH) stimulate target cells in the ovary and testis to
ENCYCLOPEDIA OF LIFE SCIENCES © 2001, John Wiley & Sons, Ltd. www.els.net
Introductory article
Article Contents
. Hormones: The Within-body Signalling System
. Hormone–Receptor Interactions
. Hormones, Development and Adult Behaviour
. Organizational and Activational Effects of Hormones
on Behaviour
. Hormones, Immune Function and Disease
. Summary
secrete gonadal steroid hormones. These steroids, in turn,
travel in the blood to reach targets all over the body. In the
brain, the steroids have a negative feedback effect,
regulating the brain’s secretion of neurohormones. A
similar three-part system of control operates for other
glands in the body, such as the adrenal and thyroid glands.
Hormone–Receptor Interactions
An endocrine gland is an anatomically distinct organ made
up of cells that synthesize and store hormones. Classical
endocrine glands release their products into the general
circulatory system, or into specialized portal systems (liver
and pituitary). In the traditional view, hormones are
carried to their target sites by the blood.
In order for a hormone to influence a target cell and then
modify behaviour, it must first bind to a receptor. A
hormone will not bind to just any receptor – only to those
receptors with a high affinity and specificity for that
particular hormone. Different classes of hormones have
specialized receptors, thereby differentially affecting cel-
lular physiology and behaviour. For example, because
peptide hormones are not lipid-soluble, they must bind to
receptors located on the plasma membrane of a cell. These
receptors typically span the lipid bilayer of the plasma
membrane and are often coupled to G proteins, which
activate a second messenger. After a peptide hormone
binds to its receptor, G proteins activate a cascade of events
that eventually alter biochemical activity within a cell. In
contrast, because steroid hormones are lipid-soluble, they
can interact directly with intracellular receptors. The
mechanisms by which steroid hormones interact with their
receptor is the focus of this section.
Steroid hormones bind to receptors that are
also transcription factors
Hormones such as the sex steroids, thyroid hormones,
glucocorticoids, retinoic acid and vitamin D are small,
lipid-soluble molecules that freely diffuse across the plasma
membrane. Steroid hormones are synthesized from the
1
 Hormones and Behaviour

Plasma cholesterol

17α-Hydroxylase
Pregnenolone

3 β-HSD II 17α-Hydroxypregnenolone

Progesterone
3β-HSD II

17 α-Hydroxylase
21-Hydroxylase

17α-Hydroxyprogesterone
21-Hydroxylase

17 α-Hydroxylase

11-Deoxycorticosterone 11-Deoxycortisol

Androstendione

11 β-Hydroxylase 11 β-Hydroxylase

17β-HSD I
Corticosterone Cortisol

Testosterone

5α-Reductase Aromatase

Oestradiol-17β

5 α-Dihydrotestosterone

Figure 1 The biosynthetic pathway for the production of steroid hormones from plasma cholesterol. Cholesterol is first converted to pregnenolone,
which serves as a prohormone (i.e. precursor) for all other steroid hormones. Relevant enzymes are depicted in italics. HSD, hydroxysteroid dehydrogenase.

precursor cholesterol (Figure 1). The intracellular receptors
to which they bind are transcription factors. Each of these
receptors has the same basic structure: they contain a
deoxyribonucleic acid (DNA)-binding domain, a hor-
mone-binding domain, and a domain responsible for
transcriptional regulation. The first two of these domains
confer specificity of action; for example, a hormone-
binding domain that recognizes oestrogen will not bind
glucocorticoids with high affinity. Although hormone
receptors only bind one particular hormone with high

2
 Hormones and Behaviour

DNA

Acceptor site
mRNA

Nucleus

Protein
synthesis Rough ER Cytosol

= Steroid hormone
= Steroid receptor
= DNA-binding domain
= Heat-shock protein

Figure 2 Interaction between a steroid hormone and its receptor. The lipid-soluble steroid passes through the cellular membrane and enters the target
cell. Subsequently, the steroid molecule enters the cell nucleus and binds to its receptor. The binding of the steroid to its receptor causes the DNA binding
domain of the receptor protein to dissociate from a heat-shock protein (HSP). Following dissociation from the HSP, the hormone–receptor complex
binds to an acceptor site on the DNA and initiates a process whereby a gene is transcribed into mRNA. The mRNA then exits the nucleus and serves as a
template for protein synthesis on the ribosomes of the rough endoplasmic reticulum (ER).

affinity, most receptors will also bind other hormones with
lower affinity. Thus, hormones may have unanticipated
effects due to binding to low-affinity receptors; for
example, progesterone can bind to androgen receptors
with low affinity and have small androgenic effects.
Steroid receptors – intracellular receptors
Unlike peptides, steroid hormones are lipid-soluble and
can readily cross the plasma membrane. Thus, steroid
hormone receptors are typically localized to the cytosol
and nucleus of a cell, although membrane-bound receptors
have been postulated (see below). Controversy exists
regarding whether steroid receptors reside within the cell
nucleus or the cytoplasm. For the purpose of simplicity,
each model will be discussed in turn.
Steroid receptors residing in the nucleus contain a
steroid-binding region and a DNA-binding region
(Figure 2). When a receptor is not occupied by a steroid,
the steroid-binding region inhibits the DNA-binding
region and prevents inappropriate interactions with
DNA. When unbound, the DNA-binding portion of a
steroid receptor is thought to be coupled to a heat-shock
protein (HSP) in order to prevent binding to DNA. When a
hormone enters a cell and binds to a steroid receptor, the
HSP dissociates from the DNA-binding region of the
receptor, and the hormone–receptor complex becomes a
transcription factor capable of binding to DNA and
altering gene synthesis. Once a gene is transcribed into
messenger ribonucleic acid (mRNA) from DNA, the
mRNA is transported to the ribosomes on the rough
endoplasmic reticulum in the cytoplasm, where it serves as
a template for protein synthesis. Gene transcription leads
to alterations in the number of receptor proteins, or the
amount of neurotransmitter, peptides, proteins or hor-
mones synthesized and stored within a cell.

3
 Hormones and Behaviour
In the two-stage model, steroid receptors are thought to
reside in the cytosol of the cell and, after binding to its
receptor, the hormone–receptor complex is translocated to
the cell nucleus. Each cell contains a full complement of
DNA, thus genes may be activated in any cell to transcribe
any protein in the body. Because an intracellular
hormone–receptor complex binds to DNA to alter protein
synthesis, these effects have been termed the genomic
actions of steroid hormones.
Genomic (also called ‘indirect’) actions of steroid
hormones (discussed above) require a significant amount
of time to exert their effects, typically hours to days.
Nongenomic effects of steroid hormones are more rapid,
typically a matter of seconds (discussed below).
Nongenomic actions of steroid hormones
There is increasing evidence that steroids can act non-
genomically, potentially on membrane-bound receptors.
After application of steroid hormones to specific neurons,
rapid changes in firing frequency are observed. These rapid
effects on neuronal activity are not influenced by protein
synthesis inhibitors, suggesting that gene transcription is
not necessary. Likewise, progesterone administration can
facilitate female reproductive behaviour within minutes,
suggesting a nongenomic mechanism of action.
Nongenomic mechanisms of steroid action have been
extensively studied in the roughskin newt (Taricha
granulosa). When a male newt encounters a female in
reproductive condition, he initiates courtship by grasping
the female in an amplectic clasp. During periods of stress,
reproductive behaviour (and hence clasping) is inhibited.
This inhibition is regulated by increases in the stress
hormone, corticosterone. Administration of corticoster-
one can inhibit clasping behaviour within minutes,
suggesting a nongenomic mechanism of action. The
identification of membrane-bound corticosterone recep-
tors in Taricha lends further support to this hypothesis.
In addition to membrane-bound corticosterone recep-
tors, receptors for other steroids, including testosterone,
oestradiol and progesterone, have been localized to cell
membranes. Further evidence for membrane receptors for
steroid hormones comes from studies where large mole-
cules (i.e. too large to pass through the cell membrane) are
conjugated (coupled) to steroid hormones to determine if
the effects of these hormones are blocked. For example,
progestagens conjugated to bovine serum albumin remain
capable of altering the release of dopamine from striatal
neurons. Taken together, the identification of membrane-
bound steroid receptors, along with evidence of their rapid
behavioural effects, suggests that steroid hormones may
act by nongenomic, as well as genomic, means.
Steroid hormones may also act on receptors that have a
higher affinity for other ligands; for example, the effects of
progesterone in facilitating female reproductive behaviour
4
in rodents may be due to the effects of progesterone on the
g-aminobutyric acid (GABA) receptor complex. Drugs
that block the GABA receptor inhibit the ability of
progesterone to facilitate lordosis behaviour in female
rodents. Thus one must be careful when evaluating the
influence of hormones because these modulators can act at
diverse locations by a variety of means.
Electrical activity
Neuronal communication occurs by means of both fast
transmission, mediated by neurotransmitters, such as
acetylcholine, and by slow transmission, mediated by
neuropeptides. Some synapses have messengers for both
slow and fast responses. In fact, over 40 different
neuropeptides have been identified in the brain. The
precise functions of peptides released at synapses within
the central nervous system is not well understood. Part of
the problem derives from the complexity of the neuro-
chemical organization of the brain. Most of our evidence
comes from the peripheral nervous system, where synapses
can be experimentally manipulated and where specific
functions are easier to define. Studies of the frog
sympathetic ganglion, for example, show that a luteinizing
hormone-releasing hormone (LHRH)-like hormone can
activate slow, excitatory postsynaptic responses that last
many minutes. The hormone also diffuses into the
extracellular medium and acts on cells that do not make
direct synaptic contact with the presynaptic cell. In this
way, neuropeptides can change the time course, size and
shape of the excitatory and inhibitory potentials mediated
by small molecule neurotransmitters.
Hormones, Development and Adult
Behaviour
The differentiation of the neural circuitry regulating adult
sex-typical behaviour is modulated by precisely-timed
exposure to steroid hormones such as oestrogen, testoster-
one, cortisol and aldosterone. The neural circuitry of the
vertebrate central nervous system is established by
exposure to sex steroids during critical periods of devel-
opment, associated first with neurogenesis and early
differentiation and then with the expression of sex
differences in behaviour in adulthood. The relatively
permanent changes in the neural substrates regulating
adult behaviour have been termed the organizational
effects of hormones, while the effects of hormones on these
established circuits on the expression of adult behaviour
have been termed the activational effects of hormones.
Hormones and the control of development
The process whereby males and females develop differently
is known as sexual differentiation. This process orches-
 Hormones and Behaviour

Chromosomal sex? XX XY

SRY gene

Gonads? Ovaries Testes

Testosterone? No Yes

Seminal vesicles,
Internal ducts ? Uterus,
prostate,
fallopian tubes
vas deferens

External genitalia? Vagina Penis/

scrotum

Behaviour?

Figure 3 The process of sexual differentiation in mammalian vertebrates. This diagram highlights the importance of hormones in regulating the sexual
differentiation of both secondary sexual characteristics and behaviour. Additional details on the process of sexual differentiation can be found in the text.

trates changes in many parts of the body, including the
external genitalia, the internal duct systems of the external
genitalia, and the brain. Excellent evidence is available on
the development of physical sex differences; sex differences
in the structure of the brain and in behaviour have been
more difficult to assess, especially in humans.
Early in development, both XX (female sex chromo-
somes) and XY (male sex chromosomes) genotypes have
gonads that are ‘indifferent’ and can develop into either
ovaries or testes. A gene on the Y-chromosome, termed the
sex-determining region on the Y gene, or SRY gene, directs
the development of this indifferent gonad into a testis. If
the SRY gene is not present, the indifferent gonad becomes

5
 Hormones and Behaviour
an ovary. The next steps in sexual differentiation are driven
not by the sex chromosomes but directly by the hormones
secreted by the gonads (Figure 3). In other words, the
internal ducts and external genitalia of males and females
develop as a result of the hormones secreted by the gonads
(ovary and testis).
The SRY gene codes for a protein that mediates the
formation of a testis. Once the gonad develops into a testis,
several hormones are secreted during the perinatal period,
and these hormones instruct the body to develop a vas
deferens, epididymis, scrotum, penis, etc., characteristic of
the male. In the absence of the SRY gene, the indifferent
gonad develops into an ovary. The ovaries do not secrete
large amounts of oestrogen until after sexual differentia-
tion has occurred. Thus, in the absence of gonadal steroid
secretions, the external genitalia develop into a vagina and
the internal duct system develops into a uterus and
fallopian tubes, characteristic of a female.
The steroids oestrogen and testosterone, which are
produced by the ovary and the testis, also play an
important role in the development of the nervous system.
This is especially true with regard to brain regions that
influence sexual behaviour of the adult. The nervous
system of a developing fetus, like the undifferentiated
gonad, is the same in males and females, and has the
capacity to develop as a male or as a female. That is, both
male and female genotypes are compatible with either the
male or female brain phenotype. Brain development in a
male or female direction is determined by exposure to
specific steroid hormones during a critical period in
development. Steroid hormones create a different ‘blue-
print’ in each sex. In adulthood this leads to the expression
of specific sex-typical behaviours in response to hormones
that are secreted, starting at puberty (termed the activa-
tional effects of hormones). The actions of steroid
hormones on the developing nervous system are structural
and permanent.
As described above, the formation of male genitalia,
internal ducts and neural circuitry requires the secretion of
testosterone from the fetal testes. The hormonal control of
brain differentiation is slightly more complex. In males,
circulating testosterone crosses the blood–brain barrier
(BBB) and is subsequently metabolized into oestradiol in
relevant neurons by the enzyme aromatase. Thus, male
neural circuitry is formed not by the presence of androgens
but by the actions of oestrogen. Given that maternal
oestrogens readily cross the placenta, why are female
brains not masculinized? Hormones are typically carried
through the blood bound to carrier proteins that facilitate
transport and prevent hormone degradation. During fetal
development, a carrier protein called a-fetoprotein binds
to oestrogen and prevents oestrogens from crossing the
BBB. Thus, females are protected from the masculinizing
effects of oestrogens during fetal development.
The result of the sexual differentiation of the brain can be
seen morphologically; for example, the size and number of
6
neurons in the medial preoptic nucleus (MPN) of the
hypothalmus, are larger in males than in females. This size
difference is produced by exposure to steroids during a
critical period early in development, and does not depend
on further exposure to hormones. Not only is the size of the
cell nucleus and the number of neurons larger in males than
in females, but there are also sex differences in the size and
number of neuronal processes and synaptic connections.
While these morphological features have been described in
a number of species, the function(s) of this brain area is not
yet fully understood.
In the spinal cord, the function of a sex difference in the
morphology of nervous organization has been character-
ized. A discrete cluster of neurons in the sacral portion of
the spinal cord of male rats innervates muscles that
regulate penile function. These spinal nuclei and the
associated musculature innervating the penis are found in
numerous mammalian species, including humans. These
muscles and the associated spinal motor nucleus is missing
in females. A male spinal motor organization can be
produced in females by injecting testosterone in the
neonatal period, demonstrating clearly the considerable
role of hormones in organizing the nervous system.
Sex differences in brain structure have also been found in
humans. An area of the human brain that is homologous to
the rodent MPN, the interstitial nucleus of the anterior
hypothalamus (INAH), is sexually dimorphic in humans.
INAH can be subdivided into discrete nuclei; some of these
subdivisions are sexually dimorphic, others are not.
INAH-3 has been found to be consistently larger in males
than females. There are several reports suggesting that a
similar sexual dimorphism may exist for INAH-1 and
INAH-2 as well. Recently, an ‘orientation dimorphism’
has been found for INAH-3; this nucleus appears to be
smaller in homosexual men than heterosexual men.
Because studies where hormone levels are strictly con-
trolled during human development are impossible ethi-
cally, the role of hormones in mediating these observed
sexual dimorphisms in brain structure remain elusive.
Future studies of brains of individuals exposed to
abnormal concentrations of hormones during develop-
ment, as the result of endocrine abnormalities, may
provide some insight into the hormonal basis of these
differences. Another fast-moving field of knowledge
involves the analysis of genetic mechanisms regulating
sexual and reproductive function. Our understanding of
the genes, enzymes and proteins regulating development
has been enhanced by the analysis of a number of genetic
mutations which result in reproductive dysfunction,
including syndromes such as aromatase deficiency, 17a-
hydroxylase deficiency, luteinizing hormone resistance,
androgen receptor insensitivity. Each of these states can be
understood in terms of the metabolic and physiological
mechanisms discussed in this article.

Organizational and Activational Effects
of Hormones on Behaviour
Sexual behaviour
As previously mentioned, the vertebrate brain is bipoten-
tial and is either masculinized by exposure to steroid
hormones or is feminized in the absence of sex steroid
hormones during development. In 1959, a classic study
conducted by Phoenix, Goy, Gerall and Young provided
the basis of the so-called organizational/activational
effects of steroid hormones. In this work, exposure of
pregnant guinea-pigs to testosterone resulted in offspring
with a female genotype that had an increased propensity to
mount (i.e. male-like behaviour) an oestrous (i.e. in
reproductive condition or ‘heat’) female when given
testosterone in adulthood, compared with control females
treated with testosterone. Likewise, male guinea-pigs that
were castrated before completion of sexual differentiation,
and were given oestradiol and progesterone in adulthood,
displayed an increased likelihood of exhibiting the female
mating posture (lordosis) when mounted by a male in
adulthood, compared with control males given oestradiol
and progesterone.
Importantly, females exposed to testosterone in utero
were less likely to display female-typical behaviour after
being primed with oestrogen and progesterone compared
with controls. Normally, female rodents exposed to
oestrogen, followed 48 h later by progesterone, will be
sexually receptive when mounted by a male conspecific;
however, females exposed to testosterone in utero are less
likely to exhibit receptive behaviour when mounted by a
stud male compared with control females. Similarly, males
that were castrated early in development were less likely to
mount an oestrous female after being given testosterone.
Based on these results, the authors of this seminal paper
concluded that the neural circuits controlling behaviour
are organized in a male- or female-like direction early in
development and these alterations are relatively perma-
nent. The authors also concluded that hormones in
adulthood act on these previously organized circuits to
alter the probability of exhibiting male or female beha-
viour. Thus, if the brain is organized in a female direction,
male-like behaviour, even in the presence of testosterone, is
unlikely. Hence, hormones do not cause behaviour but
they alter the probability that a particular behaviour will be
exhibited in response to the appropriate stimulus.
Because testosterone can be metabolized into either
oestradiol (by the enzyme aromatase), or 5a-dihydrotes-
tosterone (DHT; by the enzyme 5a reductase), further
studies have sought to determine which of these hormones
is actually responsible for the organizational/activational
effects of sex steroids. Most evidence suggests that the
neural circuitry regulating sexual behaviour is organized
by the aromatization of testosterone into oestradiol in
Hormones and Behaviour
males; female circuitry develops in the absence of sex
steroids. In adulthood, androgens are required to activate
male sexual behaviour, while female sexual behaviour is
activated by oestrogen and progesterone. The preoptic
area appears to be important for the activation of sexual
behaviour in most rodent species studied to date.
Manipulating prenatal and postnatal hormone concen-
trations in humans is not possible for obvious ethical
reasons. Thus, one must infer causality in human studies of
sexual differentiation of brain and behaviour using human
populations ‘naturally’exposed to abnormal hormone
concentrations during development and/or adulthood.
For example, studies of young girls and women with
congenital adrenal hyperplasia (CAH), a disorder char-
acterized by adrenal gland production of large amounts of
androgens rather than cortisol, have revealed a potential
role for androgens in human sexual differentiation. Girls
born with CAH exhibit moderate to pronounced mascu-
linization of the external genitalia, thereby supporting the
contention that, as in animal studies, individuals with an
XX genotype can develop masculinized external genitalia if
exposed to abnormally high concentrations of androgens.
These anomalies can typically be corrected by surgical
means shortly after birth. However, as these girls mature,
they often exhibit behaviours characterized as ‘masculine’
(e.g. rough play, choosing to play with toys generally
preferred by boys). In adulthood, a larger proportion of
CAH females than that seen in the general population
classify themselves as homosexuals.
Some genetic males (i.e. XY genotype) are born with
androgen insensitivity syndrome, an inability to ‘respond’
to androgens. These males are born with normal female
external genitalia, although the internal duct system and
gonads are masculinized, consistent with animal studies of
sexual differentiation. In studies of rodents, androgens are
necessary to masculinize the brains of males, while the
brains of females are thought to develop in a relatively
ahormonal environment. If this is the case in humans, then
males with androgen insensitivity syndrome should have a
female gender identity and normal ‘female’ behaviour.
Indeed, this seems to be the case. Most males with
androgen insensitivity syndrome are raised as females
and live normal lives as adult females. Hormone treat-
ments typically begin around the time of puberty in order
to facilitate breast growth and female body morphology.
Although there is some disagreement on the importance of
hormones versus environment (i.e. learning) in the devel-
opment of gender identity and sexual orientation, it is
likely that human sexual differentiation is a function of the
same mechanisms uncovered in animal studies.
Aggressive behaviour
Male rodents are typically aggressive when they encounter
a male conspecific until a dominance hierarchy is
7
 Hormones and Behaviour
established. In contrast, female rodents do not typically
display aggressive behaviour, excluding maternal aggres-
sion while caring for offspring. This sexual dimorphism in
aggressive behaviour suggests that hormones may act to
organize and activate the neural circuitry regulating
aggressive behaviour. Aggression is typically studied in
rodents by placing two animals together in a new cage
(neutral arena), or by placing an ‘intruder’ mouse into the
established cage of another, ‘resident’, mouse. Although
controversy exists, these tests are thought to test offensive
and defensive aggression, respectively.
Similar to results obtained with sexual behaviour,
testosterone is necessary to activate aggressive behaviour
in male mice; castrated males display very low levels of
aggression, and testosterone administration restores ag-
gressive behaviour to precastration levels. Female mice
exposed to testosterone in adulthood also show increased
aggressive behaviour, although longer exposure to testos-
terone is necessary. This finding suggests that the neural
circuitry controlling aggression in mice may be organized
by hormonal exposure to alter the sensitivity to adult
hormone concentrations.
In male mice, testosterone is most effective in reestablish-
ing aggressive behaviour in castrated males, although there
is some evidence that oestrogens can also reestablish
aggression. In female mice, only testosterone or nonar-
omatizable androgens (i.e. androgens that cannot be
metabolized into oestrogen) increase aggressive behaviour.
Thus, organizational effects of steroid hormones are
required to induce responsiveness to oestrogen in adult-
hood.
Similar results have been obtained in laboratory rats,
although their behaviour is far less studied. Sex differences
in aggression in rats do not appear to be as pronounced as
those seen in laboratory mice. None the less, castration
abolishes aggression in rats, while testosterone or DHT
replacement restores aggression to precastration levels.
The results with oestrogen administration are equivocal,
although several reports suggest that oestrogens are
capable of restoring aggression in castrated male rats.
Aggression in female rats has received very little
attention. Unlike female mice, female rats will attack a
female intruder placed into the home cage; however, a
female intruder will rarely be attacked by a male resident.
The fact that female rats also show aggressive behaviour
suggests that organizational effects of steroid hormones
may not be important for aggressive behaviour in rats. One
study found that testosterone was equally capable of
stimulating aggressive behaviour in gonadectomized male
and female rats. As seen in mice, oestrogen was capable of
increasing aggressive behaviour in male rats, but not
females.
Although most studies suggest little organizing effects of
hormones on adult aggressive behaviour in rats, neonatal
castration of male rats greatly reduces aggression, even
after testosterone replacement in adulthood. Taken
8
together, these studies suggest that organizational effects
of hormones may have subtle influences on the neural
circuitry regulating aggressive behaviour in rats and mice,
while activational effects of hormones are necessary for the
expression of aggression in adulthood.
As with studies on sexual differentiation in humans,
ethical constraints make human data on hormones and
aggression difficult to interpret. For example, studies of
human aggression are often based upon hormone mea-
sures before and after athletic competitions. Typically,
testosterone concentrations after the athletic event are
higher in the male winners than in the losers. These data are
consistent with those obtained in animals studies of
aggression. Other studies of aggression in humans are
either based on correlations between testosterone concen-
trations and self-reported aggression using a question-
naire, or testosterone concentrations and criminal records.
Although testosterone concentrations were not associated
with self-reported aggression, testosterone concentrations
are positively correlated with aggressive behaviour in male
and female prison inmates. Both males and females
convicted of violent crimes tended to have higher
concentrations of testosterone than inmates convicted of
nonviolent crimes. Taken together, these studies suggest a
potential role for androgens in human aggressive beha-
viour.
Additional evidence for a role of androgens in human
aggression comes from studies of anabolic steroid abuse in
athletes. One of the best-known side effects of anabolic
steroid abuse is extremely pronounced aggressive beha-
viour, known as ‘roids rage’. Anabolic steroid users
typically use doses of the drug that result in concentrations
of androgens much higher than those that are prescribed
for therapeutic reasons, and are also drastically higher than
endogenous steroid levels in a normal adult. Thus, these
studies provide evidence that androgens may be involved in
human aggression but provide little data on the means by
which endogenous androgens may modulate ‘normal’
levels of aggression in humans.
Hormones and appetite/homeostasis
In most nonmonogamous mammalian species there is a
pronounced sexual dimorphism in body size and weight,
whereby males are larger than females. In many species, the
sexual dimorphism in body mass appears at around the
time of puberty, suggesting activational influences of sex
steroids on this size dimorphism. In general, oestrogens are
catabolic, whereas androgens are anabolic. Castration of
male rodents typically leads to reductions in body weight
and food intake, whereas ovariectomy typically leads to
increased eating and weight. The effects of castration can
be reversed by testosterone administration; those of
ovariectomy can be reversed with oestrogen but not
progesterone.

In female rodents, further evidence for oestrogenic
effects on eating and body weight can be seen surrounding
the oestrus cycle. During ovulation, when oestrogen
concentrations are high, food intake is reduced. Likewise,
food intake increases following ovulation, concomitant
with decreased concentrations of oestradiol. Responsive-
ness to the suppressive effects of estrogen does not
generally appear until puberty in female rodents; oestrogen
treatment prior to puberty has little effect on eating. The
effects of oestrogen on body mass are not simply the result
of increased food intake: ovariectomized females restricted
to the quantity of food eaten by control animals continue
to gain body weight. These findings suggest that oestrogen
affects body weight by altering metabolism as well as food
intake.
As previously mentioned, testosterone is generally
anabolic (i.e. weight/muscle promoting), although phar-
macological (i.e. greater than values normally seen in the
blood) doses of testosterone have been reported to decrease
feeding and body weight. This decrease in feeding with high
doses of testosterone is likely to be due to aromatization of
excess testosterone into oestradiol. DHT also leads to
increases in body weight and food intake, although the
effects of testosterone are more potent. Unlike the results in
female rats, testosterone administration can affect body
mass of rats prior to puberty; however, because castration
does not influence feeding or body weight before puberty,
the physiological significance of these findings remains
questionable.
Sex steroid hormones may alter body mass by changing
food preference; for example, oestrogen reduces the
relative proportion of calories obtained from carbohy-
drates compared to other macronutrients. Likewise,
testosterone treatment leads to a preference for proteins
over other macronutrients. Thus, alterations in body mass
seen after steroid treatment are likely to be due to a
combination of metabolic influences, alterations in feeding
behaviour and changes in food preference.
Few studies have been conducted on the organizational
effects of sex steroid hormones and feeding. There is some
evidence that neonatal hormone treatment may lead to
permanent alterations in body size/weight; however,
neonatal manipulation of sex steroid hormones has little
effect on adult responsiveness to steroid hormones on
feeding and body weight.
Recently, a hormone secreted by cells from adipose
tissue has been found to regulate body weight and feeding
in mice and other species. The hormone is a product of the
ob gene and has been termed leptin (Gr. leptos thin). Mice
missing the ob gene (ob/ob) do not produce leptin and
become extremely overweight. Thus, it appears that leptin
signals the brain and provides an indication of the current
body fat of an animal. When fat content is low, leptin
concentrations decrease, thereby signalling the brain to
increase food intake. In turn, when body fat content is
high, increased concentrations of leptin limit feeding.
Hormones and Behaviour
Leptin concentrations are highly, positively correlated
with body fat mass. Likewise, food-deprived animals have
low leptin concentrations and leptin administration can
inhibit feeding in food-deprived animals. Interestingly,
although leptin concentrations are correlated with body fat
mass, female rats tend to have higher leptin concentrations
than male. This difference is potentially modulated by sex
steroids; ovariectomy can decrease leptin synthesis.
In humans, obesity is also associated with increased
leptin concentrations, and body mass index is positively
correlated with circulating leptin; however, because obese
individuals appear to have reduced responsiveness to
leptin, satiety may not be a result of high leptin
concentrations. As in rodents, human females have higher
leptin concentrations than males. Oestrogen concentra-
tions are uncorrelated with leptin, yet declining testoster-
one concentrations during ageing are negatively correlated
with leptin. Taken together, these findings indicate that
leptin likely represents a hormonal signal by which current
body state can be communicated to help maintain home-
ostasis, and may help to account for body weight
dimorphisms seen across species.
Hormones, Immune Function and
Disease
Gonadal steroids can have a pronounced influence on
immune function and disease. One indirect line of evidence
for an effect of a gonadal steroid on immune function
comes from studies demonstrating a pronounced sexual
dimorphism in immune function. In general, females have
a stronger immune response and higher immunoglobulin
(IgG) concentrations than do males. Likewise, in skin graft
rejection studies, female animals reject grafts faster than do
males, suggesting a more robust immune response. This sex
difference in immune function is apparently modulated by
gonadal steroids: oestrogens generally enhance, while
androgens typically suppress, immune function.
The immunoenhancing effects of oestrogens and greater
immune response in females can be detrimental. Normally,
the immune system is capable of distinguishing between
foreign pathogens and ‘self’ tissue. However, in certain
cases, the immune system erroneously attacks self tissue as
if it were foreign. These disorders have been termed
autoimmune disorders. Apparently, one adverse effect of
oestrogens on immune function is an increased likelihood
of autoimmune diseases. In some cases, the female:male
ratio for autoimmune disease is as high as 19:1 (auto-
immune thyroiditis). Treatments for autoimmune diseases
in humans typically involve the use of gonadal steroids.
Androgens have been shown to ameliorate the symptoms
of several autoimmune diseases, whereas oestrogens
typically potentiate the course of the disease. In addition,
female patients with Klinefelter syndrome produce excess
oestrogen and have an increased incidence of autoimmune
9
 Hormones and Behaviour
disease compared with the general population. The data
obtained from individuals with autoimmune disease
provide further support for the role of sex steroids in
immune function.
Gonadal hormones appear to act directly on immune
cells to influence their function; receptors for oestrogen
and testosterone have been identified on lymphoid tissue.
Likewise, when immune studies are conducted in vitro,
gonadal steroids are capable of having direct effects on
cultured immune cells. Numerous hormones (e.g. prolac-
tin, melatonin, thyroid hormone, dehydroepiandrosterone
(DHEA)) in addition to gonadal steroids are capable of
influencing immune function. In turn, immune cells are
capable of influencing hormone concentrations. Thus,
reciprocal crosstalk between the immune and endocrine
systems helps to maintain homeostasis within both
systems.
Another class of steroid hormones, glucocorticoids,
have also been implicated in immune function. In humans,
the primary glucocorticoid is cortisol; the principal
glucocorticoid in rodents is corticosterone. Glucocorti-
coids are produced and released from the outer ‘shell’ of the
adrenal gland, the cortex. Glucocorticoids are involved in
carbohydrate metabolism, but are also released in response
to stressful stimuli (either psychological or somatic).
Numerous studies have provided convincing evidence for
glucocorticoid/stress regulation of the immune response;
for example, animals treated with an antigen (e.g. sheep red
blood cells (SRBC)) have lower inflammatory responses
than animals that have been adrenalectomized or treated
with glucocorticoid antagonists. Glucocorticoids can
affect a number of cytokines; for example, incubation of
macrophage-activation factor (MAF), colony-stimulating
factor (CSF), interferon g (IFNg) or interleukin 2 (IL-2)
with dexamethasone (a synthetic glucocorticoid) and
mitogen inhibits cytokine proliferation in a dose-depen-
dent manner. Production of the cytokines IL-1 and IL-3 is
also blocked by glucocorticoid administration in vitro.
Thus, glucocorticoids are also capable of regulating
immune function, and their effect is usually inhibitory.
Summary
An interesting issue relates to the fact that many hormones
on the market today are not regulated by the Food and
Drug Administration (FDA) thereby making the purity of
these hormones questionable and the doses variable. One
might wonder why some homones are termed ‘dietary
supplements’ and are not regulated by the FDA, while
others are strictly regulated and sold only with prescrip-
tions from medical doctors. Dietary supplements are
products intended for digestion as a supplement to the
diet. These include vitamins, minerals, herbs and many
other plant-derived substances. These agents may not be
sold as treatments or cures, but may be sold as dietary
10
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supplements. Although termed dietary supplements, these
food additives can be identical to hormones known to
circulate in the body. Further information on this topic is
available from the FDA.
The focus of the preceding discussion has been on the
hormonal systems that have been well characterized. While
some evidence of the interactions among hormonal
systems has been presented, this is a complex topic lying
at the borders of our knowledge. Recently, there have been
numerous reports advocating the use of hormonal treat-
ments for disorders ranging from reduced sex drive (e.g.
DHEA) to jet lag (e.g. melatonin). The news media
broadcasts ‘miracle’ cures promoting the use of hormones
to enhance immune function, slow down the ageing process
and increase sex drive. Because hormones are capable of
travelling in the blood to sites all over the body, these
agents can have a broad impact throughout the body; thus,
it is impossible to focus hormone administration solely on
the problem (e.g. jet lag) one is trying to combat.
Some aspects of research on hormonal treatments are
‘immature’: often, long-term side effects of these sub-
stances have not been evaluated. Medical doctors who
advocate the use of hormones, such as melatonin, may cite
the fact that extremely high doses of melatonin will not kill
laboratory animals. Certainly, one’s criteria for treatment
should not simply be whether or not administration of the
drug will lead to death; thus, one should resist the
temptation to use hormones unnecessarily until long-term
clinical studies are conducted to determine whether any
unforeseen side effects result from their use.
In addition to unanticipated long-term side effects, one
hormonal system typically interacts with other hormonal
systems; for example, hormones of the immune system,
called cytokines, interact with numerous other hormones,
including gonadal steroids, glucocorticoids, prolactin and
thyroid hormone. Thus, altering one hormone concentra-
tion typically has far-ranging effects on numerous other
hormonal systems. Unforeseen side effects of self-treat-
ment with hormones can be a result. The knowledge of how
hormones affect the body, from the preceding sections,
together with these cautionary notes will hopefully provide
a theoretical framework within which the reader can
evaluate ongoing research in behavioural endocrinology.
Further Reading
Brown RE (1994) An Introduction to Neuroendocrinology. Cambridge:
Cambridge University Press.
Cooke B, Hegstrom CD, Villeneuve LS and Breedlove SM (1998) Sexual
differentiation of the vertebrate brain: principles and mechanisms.
Frontiers in Neuroendocrinology 19: 323–362.
Food and Drug Administration (2000) [http://www.FDA.gov] [Infor-
mation on the regulation of the prescription and sale of hormones.]
Nelson RJ (2000) An Introduction to Behavioral Endocrinology, 2nd edn.
Sunderland, MA: Sinauer.
Norman AN and Litwack G (1997) Hormones. San Diego: Academic
Press.