Hormones and Behavior: Basic Concepts

R. J. Nelson, Ohio State University, Columbus, OH, USA

ã 2010 Elsevier Ltd. All rights reserved.

Introduction arrays and genetic manipulations including interfering

with RNA and use of viral gene vectors to deliver novel
Behavioral endocrinology is the scientific study of the genes directly into the brain. Because hormones must inter-
interaction between hormones and behavior. This interac- act with specific receptors to evoke a response, many of
tion is bidirectional: hormones can affect behavior, and these techniques are used to influence or measure hormone
behavior can feedback to influence hormone concentra- secretion, hormone binding, or the physiological and behav-
tions. Hormones are chemical messengers released from ioral effects that ensue after hormones bind to their respec-
endocrine glands that influence the nervous system to tive receptors.
regulate the physiology and behavior of individuals. Over
evolutionary time, hormones regulating physiological pro-
cesses have been co-opted to influence behaviors linked to Hormones
these processes. For example, hormones associated with
gamete maturation such as estrogens are now broadly Hormones are organic chemical messengers produced
associated with the regulation of female sexual behaviors. and released by specialized glands called ‘endocrine
Such dual hormonal actions ensure that mating behavior glands.’ Endocrine is derived from the Greek root words
occurs when animals have mature gametes available for endon, meaning ‘within,’ and krinein, meaning ‘to release,’
fertilization. Generally speaking, hormones change gene whereas the term hormone is based on the Greek word
expression or cellular function, and affect behavior by hormon, meaning ‘to excite.’ Hormones are released from
increasing the likelihood that specific behaviors occur in these glands into the bloodstream (or the tissue fluid
the presence of precise stimuli. Hormones achieve this by system in invertebrates), where they act on target organs
affecting individuals’ sensory systems, central integrators, (or tissues) generally at some distance from their origin.
and/or peripherial effectors. To gain a full understanding Hormones coordinate the physiology and behavior of an
of hormone–behavior interactions, it is important to moni- animal by regulating, integrating, and controlling its bodily
tor hormone values, as well as receptor interactions in the function. Hormones are similar in function to other chemi-
brain. Because certain chemicals in the environment can cal mediators including neurotransmitters and cytokines.
mimic natural hormones, these chemicals can have pro- Indeed, the division of chemical mediators into categories
found effects on the behavior of humans and other animals. mainly reflects the need by researchers to organize biological
systems into endocrine, nervous, and immune systems, rather
than real functional differences among these chemical sig-
Behavioral Endocrinology Techniques nals. Hormones often function locally as neurotransmitters
and also interact with neurotransmitters and cytokines to
A number of methods are used to gather the evidence influence behavior.
needed to establish hormone–behavior relationships. Hormones can be grouped into four classes: (1) peptides
Much of the recent progress in behavioral endocrinology or proteins, (2) steroids, (3) monoamines, and (4) lipid-
has resulted from technical advances in the tools that allow based hormones. Generally, only one class of hormone is
us to detect, measure, and probe the functions of hormones produced by a single endocrine gland, but there are some
and their receptors. These techniques, with a brief descrip- notable exceptions. It is important and useful to discrimi-
tion, are listed in Table 1. Several of these techniques are nate among the four types of hormones because they differ
the result of advanced research in behavioral endocrinology, in several important characteristics, including their mode
including the time-honored ablation-replacement techni- of release, how they move through the blood, the location
ques, bioassays, as well as modern assays that utilize the of their target tissue receptors, and the manner by which
concept of competitive binding of antibodies that include the interaction of the hormone with its receptor results in a
radioimmunoassay (RIA), enzyme-linked immunosorbent biological response. The major vertebrate hormones and
assay (ELISA; enzyme-linked immunoassay (EIA)), autora- their primary biological actions are listed in Table 2.
diography, and immunocytochemistry. Other techniques Although exceptions always exist, the endocrine sys-
commonly used in behavioral endocrinology include neural tem has several general features: (1) endocrine glands are
stimulation and single-unit recording, techniques that acti- ductless, (2) endocrine glands have a rich blood supply,
vate or block hormone receptors with drugs, and gene (3) hormones, the products of endocrine glands, are

97
98 Hormones and Behavior: Basic Concepts

Table 1 Common techniques in behavioral endocrinology

Ablation (removal or extirpation) of the suspected source of a hormone to determine its function is a classic technique in endocrinology.
Suspected brain regions that may regulate the behavior in question can also be ablated. Typically, four steps are required: (1) a gland
that is suspected to be the source of a hormone affecting a behavior is surgically removed; (2) the effects of removal are observed;
(3) the hormone is replaced, by reimplanting the removed gland, by injecting a homogenate or extract from the gland, or by injecting a
purified hormone; and (4) a determination is made whether the observed consequences of ablation have been reversed by the
replacement therapy.
Radioimmunoassay (RIA) is based on the principle of competitive binding of an antibody to its antigen. An antibody produced in
response to any antigen, in this case a hormone, has a binding site that is specific for that antigen. Antigen molecules can be ‘labeled’
with radioactivity, and an antibody cannot discriminate between an antigen that has been radiolabeled (or ‘hot’) and a normal,
nonradioactive (‘cold’) antigen. A standard curve is produced with several tubes, each containing the same measured amount of
antibody, the same measured amount of radiolabeled hormone, and different amounts of cold purified hormone of known
concentrations. The radiolabeled hormone and unlabeled hormone compete for binding sites on the antibody, so the more cold
hormone that is present in the tube, the less hot hormone will bind to the antibody. The quantity of bound hormone can be determined
by precipitating the antibody and measuring the associated radioactivity resulting from the radiolabeled hormone that remains bound.
The unknown concentration of hormone in a sample can then be determined by subjecting it to the same procedure and comparing
the results with the standard curve.
Enzymoimmunoassay (EIA), as RIA, works on the principle of competitive binding of an antibody to its antigen. EIAs do not require
radioactive tags; instead, the antibody is tagged with a compound that changes optical density (color) in response to binding with
antigen. Other than home pregnancy tests, most EIAs are developed to provide quantitative information. A standard curve is
generated so that different known amounts of the hormone in question provide a gradient of color that can be read on a spectrometer.
The unknown sample is then added, and the amount of hormone is interpolated by the standard curves. A similar technique is called
‘enzyme-linked immunosorbent assay’ (ELISA).
Immunocytochemistry (ICC) techniques use antibodies to determine the location of a hormone in cells. Antibodies linked to marker
molecules, such as those of a fluorescent dye, are usually introduced into dissected tissue from an animal, where they bind with the
hormone or neurotransmitter of interest. For example, if a thin slice of brain tissue is immersed in a solution of antibodies to a protein
hormone linked to a fluorescent dye, and the tissue is then examined under a fluorescent microscope, concentrated spots of
fluorescence will appear, indicating where the hormone is located.
Autoradiography is typically used to determine hormonal uptake and indicate receptor locations. Radiolabeled hormone is injected into
an individual or into dissected tissue. Suspected target tissues are sliced into several very thin sections; adjacent sections are then
subjected to different treatments. One section of the suspected target tissue is stained in the usual way to highlight various cellular
structures. The next section is placed in contact with photographic film or emulsion for some period of time, and the emission of
radiation from the radiolabeled hormone develops an image on the film. The areas of high radioactivity on the film can then be
compared with the stained section to determine how the areas of highest hormone concentration correlate with cellular structures.
This technique has been very useful in determining the sites of hormone action in nervous tissue, and consequently has increased our
understanding of hormone–behavior interactions.
Blot tests use electrophoresis to determine in which cells specific DNA, RNA, or proteins are located. Homogenized tissue of interest is
placed on a nitrocellulose filter, which is subjected to electrophoresis that involves application of an electric current through a matrix
or gel that results in a gradient of molecules separating out along the current on the basis of size (smaller molecules move farther than
larger molecules during a set time period). The filter is then incubated with a labeled substance that can act as a tracer for the protein
or nucleic acid of interest: radiolabeled complementary deoxyribonucleic acid (cDNA) for a nucleic acid assay, or an antibody that has
been radiolabeled or linked to an enzyme for a protein assay. If radiolabeling is used, the filter is then put over film to locate and
measure radioactivity. In enzyme-linked protein assays, the filter is incubated with chromogenic chemicals, and standard curves
reflecting different spectral densities are generated. Southern blots assay DNA; Northern blots assay RNA, whereas Western blots
test for proteins.
In situ hybridization is used to identify cells or tissues in which mRNA molecules for a specific protein (e.g., a peptide hormone) are
produced. The tissue is fixed, mounted on slides, and either dipped into emulsion or placed over film and developed with
photographic chemicals. Typically, the tissue is also counterstained to identify specific cellular structures. A radiolabeled cDNA probe
is introduced into the tissue. If the mRNA of interest is present in the tissue, the cDNA will form a tight association (i.e., hybridize)
with it. The tightly bound cDNA, and hence the messenger RNA (mRNA), will appear as dark spots. This technique can be used to
determine whether a particular substance is produced in a specific tissue.
Pharmacological techniques are used to identify hormones and neurotransmitters involved in specific behaviors. Some specific
chemical agents can act to stimulate or inhibit endocrine function by affecting hormonal release; these agents are called ‘general
agonists’ and ‘antagonists,’ respectively. Other drugs act directly on receptors, either enhancing or negating the effects of the
hormone under study; these drugs are referred to as ‘receptor agonists’ and ‘antagonists,’ respectively.
Brain imaging techniques reveal brain activation during behaviors. Paired with endocrine manipulations or monitoring, imaging can
provide important information about hormone–behavior interactions. Positron emission tomography (PET) scanning permits detailed
measurements of real-time functioning of specific brain regions of people who are conscious and alert. PET gives a dynamic
representation of the brain at work. Computer-assisted tomography (CT) scanner shoots fine beams of X-rays into the brain from
several directions. The emitted information is fed into a computer that constructs a composite picture of the anatomical details within
a ‘slice’ through the brain of the person. Magnetic resonance imaging (MRI) does much the same thing, but uses nonionizing radiation
formed by the excitation of protons by radiofrequency energy in the presence of large magnetic fields. Functional MRI (fMRI) uses a
very high spatial (1 mm) and temporal resolution to detect changes in brain activity during specific tasks or conditions. When
neurons become more active, they use more energy, and require additional blood flow to deliver glucose and oxygen. The fMRI
scanner detects this change in cerebral blood flow by detecting changes in the ratio of oxyhemoglobin and deoxyhemoglobin.

Continued
 Hormones and Behavior: Basic Concepts 99

Table 1 Continued

Gene manipulations. In behavioral endocrinology research, common genetic manipulations include the insertion (transgenic or knockin)
or removal (knockout) of the genetic instructions encoding a hormone or the receptor for a hormone. In knockout mice, behavioral
performance can then be compared among wild-type (+/+), heterozygous (+/ ), and homozygous ( / ) mice, in which the gene
product is produced normally, produced at reduced levels, or completely missing, respectively. Inducible knockouts when specific
genes are inactivated in adulthood promise to become important tools in behavioral endocrinology. An alternative approach involved
gene silencing via RNA interference (RNAi), which is used to deplete protein products made in cells.
Gene arrays can be used to determine relative gene expression during the onset of a behavior, or a change in developmental state, or
among individuals that vary in the frequency of a given behavior or hormonal state. Essentially, a miniscule spot of nucleic acid of
known sequence is attached to a glass slide (or occasionally nylon matrix) in a precise location often by high speed robotics. This
identified, attached nucleic acid is called ‘the probe,’ whereas the sample nucleic acid is the target. The identification of the target is
revealed by hybridization, the process by which the nucleotides link to their base pair.

secreted into the bloodstream, (4) hormones can travel in anterior pituitary gland where it diffuses locally to influ-
the blood to virtually every cell in the body and can thus ence thyroid-stimulating hormone (TSH) secretion
potentially interact with any cell that has appropriate (paracrine). Many chemical mediators display similar
receptors, and (5) hormone receptors are rather specific diversity in function.
binding sites, embedded in the cell membrane or located Some hormones are water-soluble proteins or small
elsewhere in the cell that interact with a particular hor- peptides that are stored in the endocrine cell in secretory
mone or class of hormones. As mentioned, the products granules, or vesicles. In response to a specific stimulus for
of endocrine glands are secreted directly into the blood, secretion, the secretory vesicle fuses its membrane with
whereas other glands, called ‘exocrine glands,’ have ducts the cellular membrane, an opening develops, and the
into which their products are secreted (e.g., salivary, sweat, hormones diffuse into the extracellular space via a process
and mammary glands). Some glands have both endocrine called ‘exocytosis.’ The expelled hormones then enter the
and exocrine structures (e.g., the pancreas). Recently, the blood system from the extracellular space. Other hor-
definition of an endocrine gland also had to be reconsid- mones, such as steroid hormones, are lipid soluble (i.e.,
ered. For example, adipose tissue produces the hormone, fat soluble), and because they can move easily through the
leptin, and the stomach produces a hormone called ‘ghre- cell’s membrane, they are not stored in the endocrine cells.
lin.’ Probably the most active endocrine organ, and the Instead, a signal to an endocrine gland to produce steroid
one that produces the most diverse types of hormones is hormones essentially serves as a signal to release them into
the brain. the blood as soon as they are produced by the cellular
As single cells evolved into multicellular organisms, machinery.
chemical communication within and between cells, as Hormone receptors, that are either embedded in the
well as between individuals and populations, developed. cell membrane or located elsewhere within the cell, inter-
The endocrine system evolved to become a key compo- act with a particular hormone or class of hormones.
nent of this complicated intra- and intercellular commu- Receptor proteins bind to hormones with high affinity
nication system, although other systems of chemical and generally high specificity. As a result of the high
mediation exist. For example, chemical mediation of affinity of hormone receptors, hormones can be very
intracellular events is called ‘intracrine mediation.’ Some potent in their effects, despite their very dilute concen-
intracrine mediators may have changed their function trations in the blood (e.g., 1 ng ml 1 of blood). However,
over the course of evolution and now serve as hormones when blood concentrations of a hormone are high, bind-
or pheromones. Autocrine cells secrete products that may ing with receptors that are specific for other related
feed back to affect processes in the cells that originally hormones can occur in sufficient numbers to cause a
produced them. For example, many steroid–hormone- biological response (i.e., crossreaction). Also, many hor-
producing cells possess receptors for their own secreted mones are structurally similar so that antibodies designed
products. Chemical mediators released by one cell that to attach to one hormone may cross react with other
induce a biological response in nearby cells are called similarly shaped molecules (e.g., growth hormone and
‘paracrine agents’; nerve cells are well-known paracrine prolactin, the sex steroids, and the glycoproteins, viz.,
cells. In several cases, a single hormone (especially pep- luteinizing hormone, follicle-stimulating hormone, and
tides) can have autocrine, paracrine, or endocrine func- thyroid-stimulating hormone).
tions. For example, leptin stimulates expression of itself But generally, hormones can directly influence only
and its receptor. Generally, leptin is produced in adipose cells that have specific receptors for that particular hormone
tissue and it functions as a hormone when released into and served as target cells. The interaction of a hormone
the blood by regulating energy balance at the level of the with its receptor begins a series of cellular events that
hypothalamus. However, leptin is also produced in the either eventually lead to activation of enzymatic pathways
100 Hormones and Behavior: Basic Concepts

Table 2 Vertebrate hormones

Glands/hormone Abbreviation Source Major biological action

Adrenal glands
Mineralocorticoids
Aldosterone Zona glomerulosa of Sodium retention in kidney
adrenal cortex
11-Deoxycorticosterone DOC Zona glomerulosa of Sodium retention in kidney
adrenal cortex
Glucocorticoids
Cortisol (hydrocortisone) F Zona fasciculata and Increases carbohydrate metabolism; antistress
z. reticularis of hormone
adrenal cortex
Corticosterone B Zona fasiculata and Increased carbohydrate metabolism; antistress
z. reticularis of hormone
adrenal cortex
Dehydroepiandro-sterone DHEA Zona reticularis of Weak androgen; primary secretory product of fetal
adrenal cortex adrenal cortex
Ovaries
Estradiol Follicles Uterine and other female tissue development
Estriol Follicles Uterine and mammary tissue development
Estrone Follicles Uterine and mammary tissue development
Progesterone P Corpora lutea, placenta Uterine development; mammary gland development;
maintenance of pregnancy
Testes
Androstenedione Leydig cells Male sex characters
Dihydrotestosterone DHT Seminiferous tubules Male secondary sex characters
and prostate
Testosterone T Leydig cells Spermatogenesis; male secondary sex characters
Peptide and protein hormones
Hormone Abbreviation Source Major biological action
Adipose tissue
Leptin (Ob protein) Adipocytes Regulation of energy balance
Adiponectin Adipocytes Modulates endothelial adhesion molecules
Plasminogen activator PAI-1 Adipocytes Regulation of vascular hemostasis
inhibitor-1
Adrenal glands
Met-enkephalin Adrenal medulla Analgesic actions in CNS
Leu-enkephalin Adrenal medulla Analgesic actions in CNS
Gut
Bombesin Neurons and endo- Hypothermic hormone; increases gastrin secretion
crine cells of gut
Cholecystokinin CCK Duodenum and CNS Stimulates gallbladder contraction and bile flow; affects
(pancreozymin) memory, eating behavior
Gastric inhibitory polypeptide GIP Duodenum Inhibits gastric acid secretion
Gastrin G-cells of midpyloric Increases secretion of gastric acid and pepsin
glands in stomach
antrum
Gastrin-releasing peptide GRP GI tract Stimulates gastrin secretion
Ghrelin Stomach mucosa/GI Regulation of energy balance
tract
Glucogon-like peptide-1 GLP-1 L cells of intestine Regulates insulin secretion
Motilin Duodenum, pineal Alters motility of GI tract
gland
Secretin Duodenum Stimulates pancreatic acinar cells to release
bicarbonate and water
Vasoactive intestinal VIP GI tract, hypothalamus Increases secretion of water and electrolytes from
polypeptide pancreas and gut; acts as neurotransmitter in
autonomic nervous system
Peptide YY PPY GI tract Regulation of energy balance/food intake
Heart
Atrial naturetic factor ANF Atrial myocytes Regulation of urinary sodium excretion
Hypothalamus
Agouti-related protein AGRP Arcuate nucleus Regulation of energy balance

Continued
 Hormones and Behavior: Basic Concepts 101

Table 2 Continued

Glands/hormone Abbreviation Source Major biological action

Arg-vasotocin AVT Hypothalamus and Regulates reproductive organs

pineal gland
Corticotropin-releasing CRH Paraventricular nuclei, Stimulates release of ACTH and b-endorphin from
hormone anterior anterior pituitary
periventricular nuclei
Gonadotropin-releasing GnRH Preoptic area; anterior Stimulates release of FSH and LH from anterior pituitary
hormone hypothalamus;
suprachiasmatic
Gonadotropin-inhibiting GnIH Species-dependent Inhibits release of LH (in birds)
hormone loci
Kisspeptin KISS Arcuate and Critical for normal puberty
anteroventral
periventricular nuclei
Luteinizing hormone-releasing LHRH Nuclei; medial basal
hormone hypothalamus
(rodents and
primates); arcuate
nuclei (primates)
Somatostatin (growth Anterior periventricular Inhibits release of GH and TSH from anterior pituitary
hormone-inhibiting nuclei inhibits release of insulin and glucagon from pancreas
hormone)
Somatocrinin (growth GHRH Medial basal hypothala Stimulates release of GH from anterior pituitary
hormone-releasing mus; arcuate nuclei
hormone)
Melanotropin-release MIF (DA) Arcuate nuclei Inhibits the release of MSH (no evidence of this peptide
inhibitory factor (Dopamine) in humans)
Melanotropin-releasing factor MRF Paraventricular nuclei Stimulates the release of MSH from anterior pituitary (no
evidence of this peptide in humans)
Neuropeptide Y NPY Arcuate nuclei Regulation of energy balance
Neurotensin Hypothalamus; May act as a neurohormone
intestinal mucosa
Orexin A and B Lateral hypothalamic Regulation of energy balance/food intake
area
Prolactin-inhibitory factor PIF (DA) Arcuate nuclei Inhibits PRL secretion
(Dopamine)
Prolactin-releasing hormone Paraventricular nuclei Stimulates release of PRL from anterior pituitary
Substance P SP Hypothalamus, CNS, Transmits pain; increases smooth muscle contractions
intestine of GI tract
Thyrotropin-releasing TRH Paraventricular nuclei Stimulates release of TSH and PRL from anterior
hormone pituitary
Urocortin Lateral hypothalamus CRH-related peptide
Liver
Somatomedins Liver, kidney Cartilage sulfation, somatic cell growth
Angiotensinogen Liver, blood Precursor of angiotensins, which affect blood pressure
Ovaries
Relaxin Corpora lutea Permits relaxation of various ligaments during
parturition
Inhibin (folliculostatin) Follicles Inhibits FSH secretion
Gonadotropin surge- GnSAF Follicles Control of LH secretion during menstruation
attenuating factor
Activin Sertoli cells Stimulates FSH secretion
Pancreas
Glucagon a-cells Glycogenolysis in liver
Insulin b-cells Glucose uptake from blood; glycogen storage in liver
Somatostatin d-cells Inhibits insulin and glucagon secretion
Pancreatic polypeptide PP Peripheral cells Effects on gut in pharmacological doses
of pancreatic islets
Pituitary
Adrenocorticotropic hormone ACTH Anterior pituitary Stimulates synthesis and release of glucocorticoids
Vasopressin (antidiuretic ADH or AVP Posterior pituitary Increases water reabsorption in kidney
hormone)
b-endorphin Intermediate lobe of Analgesic actions
pituitary

Continued
102 Hormones and Behavior: Basic Concepts

Table 2 Continued

Glands/hormone Abbreviation Source Major biological action

Follicle-stimulating hormone FSH Anterior pituitary Stimulates development of ovarian follicles and
secretion of estrogens; stimulates spermatogenesis
Growth hormone GH Anterior pituitary Mediates somatic cell growth
Lipotropin LPH Anterior pituitary Fat mobilization; precursor of opioids
Luteinizing hormone LH Anterior pituitary Stimulates Leydig cell development and testosterone
production in males; stimulates corpora lutea
development and production of progesterone in
females
Melanocyte-stimulating MSH Anterior pituitary Affects memory; affects skin color in amphibians
hormone
Oxytocin Posterior pituitary Stimulates milk letdown and uterine contractions during
birth
Prolactin PRL Anterior pituitary Many actions relating to reproduction, water balance,
etc.
Thyroid-stimulating hormone TSH Anterior pituitary Stimulates thyroid hormone secretion
(thyrotropin)
Placenta
Chorionic gonadotropin CG Placenta LH-like functions; maintains progesterone production
during pregnancy
Chorionic CS (PL) Placenta Acts like PRL and GH
somatomammotropin
(placental lactogen)
Testes
Müllerian inhibitory hormone MIH Fetal Sertoli cells of Mediates regression of Müllerian duct system
testes
Inhibin (folliculostatin) Seminiferous tubules Inhibits FSH secretion
(and ovaries)
Activin Sertoli cells Stimulates FSH secretion
Thyroid/parathyroid
Calcitonin CT C-cells of thyroid Lowers serum Ca2+ levels
Parathyroid hormone PTH Parathyroid gland Stimulates bone resorption; increases serum Ca2+ levels
Thyroxine (tetraiodothyronine) T4 Follicular cells Increases oxidation rates in tissue
Triiodothyronine T3 Follicular cells Increases oxidation rates in tissue
Parathyroid-related peptide PTHrP Parathyroid gland (and Regulation of bone/skin development
other tissues)
Thymus
Thymosin Thymocytes Proliferation/differentiation of lymphocytes
Thymostatin Thymocytes Proliferation/differentiation of lymphocytes
Monoamine hormones
Adrenal glands
Hormone Abbreviation Source Major biological action
Epinephrine (adrenaline) EP Adrenal medulla (and Glycogenolysis in liver; increases blood pressure
CNS)
Norepinephrine NE Adrenal medulla (and Increases blood pressure
(noradrenaline) CNS)
Central nervous system
Dopamine DA Arcuate nuclei of Inhibits prolactin release (and other actions)
hypothalamus
Serotonin 5-HT CNS (also pineal) Stimulates release of GH, TSH, ACTH; inhibits release of
LH
Pineal gland
Melatonin Pineal gland Affects reproductive functions
Lipid-based hormones (eicosanoids)
Hormone Abbreviation Source Major biological action
Leukotrienes LT Lung Long-acting bronchoconstrictors
Prostaglandins E1 and E2 PGE1 and Variety of cells Stimulates cAMP
PGE2

Continued
 Hormones and Behavior: Basic Concepts 103

Table 2 Continued

Glands/hormone Abbreviation Source Major biological action

Prostaglandins F1a and F2a PGF1a and Variety of cells Active in dissolution of corpus luteum and in ovulation
PGF2a
Prostaglandin A2 PGA2 Kidney Hypotensive effects
Prostacyclin I PGI2 Variety of cells Increased second messenger formation
Thromboxane A2 TX2 Variety of cells Increased second messenger formation

Reproduced from Nelson RJ (2005) An Introduction to Behavioral Endocrinology. Sunderland, MA: Sinauer Associates.

or to a genomic response wherein the hormone acts directly via degradation or excretion. The metabolism of a hor-
or indirectly to activate genes that regulate protein syn- mone is reported in terms of its biological half-life, which
thesis. The newly synthesized proteins may activate or is the amount of time required to remove half of the
deactivate other genes, causing yet another cascade of hormone (radioactively tagged) from the blood. Gener-
cellular events see section ‘Steroid Hormone’ below. ally, larger protein hormones have longer half-lives than
When sufficient receptors are unavailable because of smaller peptide hormones (e.g., growth hormone has
a clinical condition, or because previous high concentra- 200 amino acids and a biological half-life of 20–30 min;
tions of a hormone have occupied all the available recep- thyroid-releasing hormone has three amino acids and a
tors and new ones have yet to be made, a biological biological half-life of <5 min in humans). Again, a gut
response may not be sustained (see later). Such a reduc- hormone such as cholecystokine (CCK) may function in
tion in the numbers of receptors may lead to a so-called a paracrine manner when released locally in the brain to
endocrine deficiency despite normal or even supernormal affect behavior.
levels of circulating hormones. For example, a deficiency
of androgen receptors can prevent the development of
male traits despite normal circulating testosterone con- Steroid Hormones
centrations. Conversely, elevated receptor numbers may
produce clinical manifestations of endocrine excess The adrenal glands, the gonads, and the brain are the most
despite a normal blood concentration of the hormone. common sources of steroid hormones in vertebrates. Ver-
Thus, in order to understand hormone–behavior interac- tebrate steroid hormones have a characteristic chemical
tions, it is sometimes necessary to characterize target structure that includes three six-carbon rings plus one
tissue sensitivity (i.e., the number and type of receptors conjugated five-carbon ring. In the nomenclature of ste-
possessed by the tissue in question) in addition to mea- roid biochemistry, substances are identified by the num-
suring hormone concentrations. ber of carbon atoms in their chemical structure. The
precursor to all vertebrate steroid hormones is choles-
terol. The cholesterol molecule contains 27 carbon atoms
Protein Hormones (a C27 substance), although cholesterol itself is not a true
steroid and can be stored within lipid droplets inside cells.
Most vertebrate hormones are proteins. Protein hormones Because steroid hormones are fat soluble and move
that comprise only a few amino acids in length are called easily through cell membranes, they are never stored,
‘peptide hormones,’ whereas larger ones are called ‘pro- but leave the cells in which they were produced almost
tein’ or ‘polypeptide hormones.’ Protein and peptide hor- immediately. A signal to produce steroid hormones is also
mones include insulin, the glucagons, the neurohormones a signal to release them. The range of responses can be a
of the hypothalamus, the tropic hormones of the anterior rather slow one: the delay between stimulus and response
pituitary, inhibin, calcitonin, parathyroid hormone, the in biologically significant steroid production may be
gastrointestinal (gut) hormones, ghrelin, leptin, adiponec- hours, although ACTH stimulates corticoid secretion
tin, and the posterior pituitary hormones. Protein and within a few minutes and LH acts quickly to affect pro-
peptide hormones can be stored in endocrine cells and gesterone production during the periovulatory surge.
are released into the circulatory system by means of In most cases, however, the signal to produce steroids
exocytosis. Protein and peptide hormones are soluble in is relatively slow; steroid hormones are not very water
blood, and therefore, do not require a carrier protein to soluble. In the circulatory system, steroid hormones must
travel to their target cells, as do steroid hormones. How- generally bind to water-soluble carrier proteins that
ever, protein and peptide hormones may bind with other increase the solubility of the steroids and transport them
plasma proteins, which slow their metabolism by pepti- through the blood to their target tissues. These carrier
dases in the blood. Hormones are removed from the blood proteins also protect the steroid hormones from being
104 Hormones and Behavior: Basic Concepts

degraded prematurely. The target tissues have receptors (affinity) with which the steroid hormone is bound to its
for steroid hormones and accumulate steroids against a plasma carrier protein. Recently, it has been determined
concentration gradient. that different ‘types’ of steroid receptors exist. For exam-
Upon arrival at the target tissues, steroid hormones ple, three versions of the estrogen receptor (a, b, and g)
dissociate from their carrier proteins and either interact are currently recognized. Multiple versions of steroid
with receptors embedded in the membrane or diffuse receptors represent another mechanism by which respon-
through the cell membrane into the cytoplasm or nucleus siveness to steroid hormones can be regulated. Also, it
of the target cell, where they bind to cytoplasmic receptors. appears that the brain can produce steroid hormones de
The amino acid sequence of steroid hormone receptors is novo and that the local effects of these steroids can have
highly conserved among vertebrates. Each steroid hormone dramatic behavioral effects without altering blood con-
receptor comprises three major domains: the steroid hor- centrations of these hormones. These paracrine effects of
mone binds to the C-terminal domain, the central domain steroids in the brain present special challenges to asses-
is involved in DNA binding, and the N-terminal domain sing hormone–behavior interactions.
interacts with other DNA-binding proteins to affect tran-
scriptional activation. Steroid receptors are kept inactive
by the presence of corepressors (consisting mainly of heat- How Might Hormones Affect Behavior?
shock proteins (HSP)), which bind to the internal receptors
and keep them inactive. It is the release of these HSP after All behavioral systems, including animals, comprise three
formation of the hormone–receptor complex that acti- interacting components: (1) input systems (sensory systems),
vates the steroid receptor, and if not there already, the (2) integrators (the central nervous system), and (3) output
activated steroid–receptor complex is transported into systems, or effectors (e.g., muscles). Again, hormones do
the cell nucleus, where it binds to DNA sequences called not cause behavioral changes. Rather, hormones influence
‘hormone response elements’ and stimulates or inhibits these three systems so that specific stimuli are more likely
the transcription of specific mRNA. The effects of environ- to elicit certain responses in the appropriate behavioral or
mental, social, or other extrinsic or intrinsic factors on social context. In other words, hormones change the prob-
the regulation of specific coactivators have been understu- ability that a particular behavior will be emitted in the
died and represent yet another process by which individ- appropriate situation. This is a critical distinction that
ual variation in hormone–behavior interactions may be affects conceptualization of hormone–behavior relation-
mediated. Environmental factors such as day length can ships. For example, female rodents must adopt a rigid
determine whether photoperiod regulates whether steroids mating posture (called ‘lordosis’) for successful copulation
affect physiological and behavioral processes via slow to occur. Females only show this posture when blood
(hours to days) genomic or fast (seconds to minutes) non- estrogen concentrations are high coincident with the
genomic pathways. For instance, in beach mice, estrogen maturing ova. Females adopt the lordosis posture in
rapidly (<15 min) increases aggression in short-but not repsonse to tactile stimuli provided by a mounting male.
long-day mice. This suggests that estrogen increases aggres- Estrogens affect sensory input by increasing the receptive
sion via nongenomic actions on short days, but not on long field size in sensory cells in the flanks. Estrogen affects
days. Moreover, gene chip analyses indicated that estrogen- protein synthesis, the electrophysiological responses of
dependent expression of genes containing estrogen re- neurons, and the appearance of growth-like processes on
sponse elements in their promoters was decreased in the neurons in the central nervous system, thus altering the
brains of short-day mice compared with that of long-day speed of processing and connectivity of neurons. Finally,
mice suggesting that the environment regulates the effects estrogen affects the muscular output that results in lordosis,
of steroid hormones on aggression in by determining the as well as chemosensory stimuli important in attracting a
molecular pathways that are activated by steroid receptors. mating partner.
Transcribed mRNA migrates to the cytoplasmic rough
endoplasmic reticulum, where it is translated into specific
structural proteins or enzymes that produce the physiolog- How Might Behavior Affect Hormones?
ical response.
Thus, the actions of steroids on target tissues are based The female rodent mating posture example demonstrates
on three factors: (1) the steroid hormone concentrations in how hormones can affect behavior, but, as noted previ-
the blood, (2) the number of available receptors in the ously, the reciprocal relation also occurs, that is, behavior
target tissue, and (3) the availability of appropriate coac- can affect hormone concentrations. For example, chemo-
tivators. Blood concentrations of steroid hormones are sensory cues from males may elevate blood estradiol con-
also dependent on three factors: (1) the rate of steroid centrations in females, and thereby stimulate proceptive
biosynthesis; (2) the rate of steroid inactivation by catabolism, or male-seeking behaviors. Similarly, male mammals
which occurs mainly in the liver; and (3) the ‘tenacity’ that lose an aggressive encounter decrease circulating
 Hormones and Behavior: Basic Concepts 105

testosterone concentrations for several days or even weeks of techniques, such as the radioimmunoassay, has increased
afterward. Similar results have also been reported in the precision with which hormone concentrations can be
humans. Human testosterone concentrations are affected measured, but because of the multiple difficulties asso-
not only in those involved in physical combat, but also ciated with obtaining reliable covariant hormone–behavior
in those involved in simulated battles. For example, tes- measures, obtaining the first two classes of evidence usually
tosterone concentrations are elevated in winners and has been considered sufficient to establish a causal link in
reduced in losers of regional chess tournaments. hormone–behavior relations.
The unique conditions of the laboratory environment
may themselves cause changes in an animal’s hormone
Types of Evidence for Establishing concentrations and behavior that may confound the
Hormone–Behavior Interactions results of experiments; thus, it has become apparent that
hormone–behavior relationships established in the labo-
What sort of evidence would be sufficient to establish ratory should be verified in natural environments. The
that a particular hormone affected a specific behavior or verification of hormone–behavior relationships in natural
that a specific behavior changed hormone concentrations? environments is challenging, but useful for differentiat-
Experiments to test hypotheses about the effects of hor- ing laboratory artifacts from true biological phenomena.
mones on behavior must be carefully designed, and, gener- Establishing hormone–behavior interactions in the field
ally, three conditions must be satisfied by the experimental presents other challenges including difficulties in reli-
results to establish a causal link between hormones and ability, treatment with exogenous hormones, and recap-
behavior: (1) a hormonally dependent behavior should dis- tures for hormone determinations. These difficulties can
appear when the source of the hormone is removed or the be overcome by noninvasive hormone determinations
actions of the hormone are blocked, (2) after the behavior (e.g., fecal steroid assays), but again, coordination between
stops, restoration of the missing hormonal source or lab and field studies is needed for a full appreciation of
its hormone should reinstate the absent behavior, and hormone–behavior interactions.
(3) finally, hormone concentrations and the behavior in
question should be covariant, that is, the behavior should See also: Field Techniques in Hormones and Behavior.
be observed only when hormone concentrations are rela-
tively high and never or rarely observed when hormone
concentrations are low.
Further Reading
The third class of evidence has proved difficult to obtain
because hormones may have a long latency of action, and
Balthazart J and Ball GF (2006) Is brain estradiol a hormone or a
because many hormones are released in a pulsatile manner. neurotransmitter? Trends in Neurosciences 29: 241–249.
Also, some pharmaceutical grades of steroids (e.g., esterfied Brosens JJ, Tullet J, Varshochi R, and Lam EW (2004) Steroid receptor
steroids) have been altered to remain in circulation longer action. Best Practices in Research and Clinical Obstetrics and
Gynaecology 18: 265–283.
than endogenous steroids. Pulsatile secretion of hormones Chen C, Chang YC, Liu CL, Chang KJ, and Guo IC (2006b) Leptin-
presents difficulties with making hormone–behavior infer- induced growth of human ZR-75-1 breast cancer cells is associated
ences. For example, if a pulse of hormone is released into with up-regulation of cyclin D1 and c-Myc and down-regulation of
tumor suppressor p53 and p21WAF1/CIP1. Breast Cancer
the blood, and then is not released for an hour or so, a Research and Treatment 98: 121–132.
single blood sample will not provide an accurate picture of Hadley M and Levine JE (2007) Endocrinology. New York, NY: Benjamin
the endocrine status of the animal under study. Completely Cummings.
Kiran SK, Scotti M-AL, Newman AEM, Charlier TD, and
different conclusions about the effect of a hormone on Demas GE (2008) Novel mechanisms for neuroendocrine
behavior could be obtained if hormone concentrations regulation of aggression. Frontiers in Neuroendocrinology
were assessed at their peak rather than at their nadir. This 29: 476–489.
Nelson RJ (2005) An Introduction to Behavioral Endocrinology.
problem can be overcome by obtaining measures in several Sunderland, MA: Sinauer Associates.
animals or by taking several sequential blood samples from Nelson RJ and Trainor BC (2007) Neural mechanisms of aggression.
the same animal and averaging across peaks and valleys. Nature Reviews Neuroscience 8: 536–546.
Norris DO (2007) Vertebrate Endocrinology. San Diego, CA: Elsevier
Another problem is that biologically effective amounts of Academic Press.
hormones are vanishingly small and difficult to measure Trainor BC, Lin S, Finy MS, Rowland MR, and Nelson RJ (2007)
accurately. Effective concentrations of hormones are usu- Photoperiod reverses the effects of estrogen on male aggression via
genomic and non-genomic pathways. Proceedings of the National
ally measured in micrograms (mg, 10 6 g), nanograms Academy of Sciences of the United States of America 104:
(ng, 10 9 g), or picograms (pg, 10 12 g). The development 9840–9845.