Psychoneuroendocrinology
SERGE CAMPEAU
University of Colorado
I. General Principles of Psychoneuroendocrinology
II. The Hypothalamo–Pituitary–Adrenocortical Axis
III. The Hypothalamo–Pituitary–Thyroid Axis
IV. The Hypothalamo–Pituitary Growth Axis
V. The Hypothalamo–Pituitary–Gonadal Axis
VI. Final Comments
GLOSSARY
adrenal glands Situated just above the kidneys, each gland
consists of an inner adrenal medulla, which secretes the catechola-
mines epinephrine, norepinephrine, and dopamine, and an outer
adrenal cortex, which synthesizes and secretes steroid hormones.
circadian rhythm Diurnal (daily) cycles of body functions.
gonads Endocrine structures (testes in males, ovaries in females)
with dual functions: the production of germ cells (gametogenesis)
and the synthesis and secretion of sex hormones.
homeostasis Complement of various physiological arrangements
that serve to restore the normal state, once it has been disturbed.
hormones Chemicals (amino acid derivatives or peptides) released
by the endocrine glands into the general circulation.
hypothalamus Area composed of distinct collections of neurons
involved in the regulation of basic (homeostatic) vital functions and
located in the basomedial region of the brain.
negative feedback Deviations from a given normal set point that
triggers opposite compensatory changes, which continues until the
set point is again reached.
pituitary gland Located below the brain and suspended on a stalk
connecting it to the hypothalamus, it is composed of two major
regions: the posterior lobe, which resembles neural tissue, and the
anterior lobe, which consists of specialized endocrine secretory cells.
portal blood system Circulatory arrangement that begins in a
capillary bed and leads not to vessels that carry blood directly toward
the heart, but rather to a second capillary bed.
preprohormones Initial gene products in polypeptide hormone
synthesis.
Encyclopedia of the Human Brain
Volume 4
pulsatile release The typical pattern of hormone release, generally
lasting only a few minutes, which occurs in large pulses or surges
several times a day.
steroids Family of hormone molecules derived from cholesterol,
including gonadal steroids, glucocorticoids, and mineralocorticoids,
which easily cross lipid membranes.
thyroid gland Gland at the base of the neck that helps maintain the
level of metabolism at optimal conditions in all body tissues via the
synthesis and secretion of thyroid hormones.
Psychoneuroendocrinology is a multidisciplinary field aimed
at elucidating endocrine functions ultimately con-
trolled by the brain and, in turn, how the hormonal
products of the various organs influence the function-
ing of the brain, mood, and cognition. The main
endocrine functions of the body include development
and growth, reproduction, homeostasis, (temperature,
fluids, and minerals), and survival (stress). Although
endocrine dysfunctions can be linked to organic
disorders, many endocrine disorders have their roots
in the brain. Together with accumulating evidence
indicating direct hormonal effects upon the brain and
the realization that psychological status (the mind or
psyche) can dramatically impact endocrine functions,
the discipline of psychoneuroendocrinology emphasi-
zes the importance of exploring the interrelationships
between mind, brain, organs, and hormones. This
article is aimed at describing the major constituents of
the neuroendocrine systems and how the brain, moods,
and cognition regulate and are regulated by hormones.
I. GENERAL PRINCIPLES OF
PSYCHONEUROENDOCRINOLOGY
Although the systems controlling different endocrine
endpoints are distinct, several parallels can be drawn in
Copyright 2002, Elsevier Science (USA).
83 All rights reserved.
84 PSYCHONEUROENDOCRINOLOGY

their overall functioning. The action of hormones on
the brain also shows similar mechanisms. The follow-
ing discussion focuses on the similarities and parallels
between the various psychoneuroendocrine systems.
A. The Hypothalamus
The human hypothalamus is very small, accounting
for approximately 0.003% of the entire brain mass.
However, it controls an array of vital functions
without which complex organisms simply could not
survive. It is perhaps no accident that the hypothala-
mus is one of the most deeply located cell-containing
regions in the brain, residing in the basomedial part of
the head and shielded by the rest of the brain (Fig. 1). It
was more than 50 years ago that Geoffrey Harris of
Oxford University proposed that neurosecretory cells
of the hypothalamus release substances in the portal
blood system, suggesting for the first time a plausible
regulatory mechanism in the release of anterior
pituitary hormones.
The hypothalamus is often divided into three major
areas: an anterior, a middle, and a posterior region.
The middle third of the hypothalamus contains the
neuroendocrine components that control most of the
posterior and anterior lobes of the pituitary gland. The
important cell groups of the middle hypothalamus in

Figure 1 Schematic diagram of a midsagittal section of the human brain showing the location of the hypothalamus and its main subdivisions.
Adapted from Carpenter, M. B. (1991). Core Text of Neuroanatomy, 4th ed., with permission of Williams & Wilkins.
 PSYCHONEUROENDOCRINOLOGY
regard to neuroendocrine control include the para-
ventricular and arcuate nuclei. The paraventricular
nucleus is further broken down into the parvocellular
cell group and the magnocellular cell group. In most
instances, activity of the parvocellular releasing-factor
neurons (also called hypophysiotropic) can be linked to
the synthesis and secretion of specific pituitary pep-
tides into the general circulation.
B. The Portal Blood System
Unlike the direct projections that exist from the
hypothalamus to the posterior lobe of the pituitary
via axons that join the internal layer of the median
eminence and course through the infundibular stalk, the
anterior lobe of the pituitary does not receive direct
axonal projections from the hypothalamus, as shown
in Fig. 2. Instead, the connections between the
hypothalamus and the anterior lobe are entirely
neurohumoral. In this process, peptides synthesized in
neurons of the middle hypothalamus are carried via
their axons to the external zone of the median
eminence, where they are released into fenestrated
capillaries that coalesce to form portal vessels that run
Figure 2 Schematic diagram of the arrangement of the portal
blood system connecting the median eminence to the anterior lobe of
the pituitary. [From Zigmond et al. (eds). (1999). Fundamental
Neuroscience. Academic Press, San Diego].
85
along the infundibular stalk and terminate in vascular
sinuses in the anterior lobe of the pituitary gland.
C. The Pituitary Gland
Referred to as the ‘‘master gland,’’ the pituitary gland,
also known as the hypophysis, has been recognized for
centuries as a vital organ for survival. The pituitary
gland lies beneath the brain at the mesodiencephalic
junction and is about the size of a garden pea in
humans. Although the pituitary gland, and more
specifically the anterior lobe of the gland, is responsible
for the release of most hormones and tropic peptides
acting on tissues and end organs, the anterior lobe is
somewhat enslaved by the various tropic factors
produced and released by hypophysiotropic neurons
and by feedback effects of the released hormones, as
shown in Fig. 3.
D. Hormones
Each neuroendocrine system described here releases
chemicals (amino acid derivatives, proteins, or peptides),
known as hormones, into the general circulation. Once
released from their respective glands, most hormones are
bound to specialized plasma proteins that help transport
them and increase their half-life by protecting them from
breakdown. However, most hormones have their high-
est biological activity in their free forms. Hormones
travel throughout the body to act on body tissues
wherever their receptors are located (targets). They have
access to most body regions, although steroid hormones
penetrate the central nervous system through the blood–
brain barrier most readily.
E. Tropic Factors
Most of the hypothalamic peptides released into the
external zone of the median eminence act upon the
anterior lobe of the pituitary gland to stimulate the
release of other peptides, so that they are known as
tropic factors (also termed releasing factors). These
should not be confused with trophic factors, which are
generally involved with growth. Because many pitui-
tary peptides released into the general circulation
likewise stimulate the release of end-organ hormones,
they are also termed tropic factors. As an historical
aside, the term factor used to be dedicated for
suspected tropic chemicals or peptides that had not
yet been isolated. Upon isolation, however, these
86 PSYCHONEUROENDOCRINOLOGY

Figure 3 Schematic diagram of the main neuroendocrine systems. See text for abbreviations. [From Zigmond et al. (eds). (1999). Fundamental
Neuroscience. Academic Press, San Diego].

tropic factors were renamed hormones. For instance,
corticotropin-releasing factor has also been known as
corticotropin-releasing hormone (CRH) since its iso-
lation by Wyllie Vale and collaborators in 1981.
F. Negative Feedback
The circulating levels of several hormones in the body
are set to optimal points. Deviations from these points
are often detrimental to organisms. Thus, the regula-
tion of circulating hormone levels is tightly controlled
by several compensatory mechanisms. An important
compensatory mechanism works through negative
feedback inhibition, whereby hormone release acts at
several levels, including the pituitary, hypothalamus,
and even brain areas that project to the hypothalamus,
to reduce its own further release by inhibiting the
synthesis and release of the various hypothalamic and
pituitary factors. This is a mechanism observed in all
neuroendocrine systems. Negative feedback can take
place in different time domains, as will be discussed for
the hypothalamo–pituitary–adrenocortical axis.
G. Pulsatile Release and Circadian Rhythm
All of the neuroendocrine systems to be discussed show
a typical pattern of activity, with hypothalamic factors
and their associated pituitary factors released in only a
 PSYCHONEUROENDOCRINOLOGY
Figure 4 Example of pulsatile release of hypophysiotropic
hormone in the hypothalamo–pituitary–gonadal axis. [From Zig-
mond et al. (eds). (1999). Fundamental Neuroscience. Academic
Press, San Diego].
few minutes, which occurs in large pulses or surges
several times a day, as is shown in Fig. 4 for the
stimulation of luteinizing hormone by gonadotropin-
releasing hormone. In most systems, the exact me-
chanisms resulting in such a pulsatile release are not
known, but several factors have been demonstrated to
influence it. Intrinsic characteristics of hypophysio-
tropic neurons as well as the influence of afferent
innervation to these neurons are important factors in
pulsatile release. The suprachiasmatic nucleus, for
example, is an important biological clock shown to
drive pulsatile release in some neuroendocrine systems.
Feedback inhibition probably plays a role in the
pulsatile release of some systems. In addition, meal
time, exercise, and sleep time all appear to provide
some influence on pulsatile release. Circadian rhyth-
micity refers to some daily recurring fluctuations in
pulsatile release, which is weaker or stronger during
some parts of the day.
II. THE HYPOTHALAMO–PITUITARY–
ADRENOCORTICAL AXIS
The functions of the hypothalamo–pituitary–adreno-
cortical (HPA) axis principally include the restoration
of homeostasis following internal or external challenge
(stress). It also contributes to the normal regulation of
energy metabolism throughout the body. The ultimate
control of glucocorticoid levels in the bloodstream is
intricately regulated positively and negatively by a
series of steps initiated at the level of the hypothala-
mus. Glucocorticoid levels vary significantly over the
course of 24 hr, with the highest levels observed upon
waking up in the morning. The functioning of the HPA
axis thus needs to be understood in the context of both
its tonic activation and its responsive phasic tone.
87
A. Basic Constituents of the Hypothalamo–
Pituitary–Adrenocortical Axis
In humans, cortisol is the major glucocorticoid
produced and released by the adrenal glands, with
corticosterone as a minor component. As will be
discussed following a description of the regulation of
the HPA axis, dysregulation of glucocorticoid levels is
involved in several physical and psychiatric patholo-
gies. Likewise, endogenous psychiatric disorders can
also produce abnormal glucocorticoid secretion.
1. The Adrenal Glands and Cortisol
Glucocorticoids, which are part of a larger family of
steroid hormones, are synthesized in the zona fascicu-
lata cells of the cortical (external) layer of the adrenal
glands. Cortisol, like the gonadal steroids, is synthe-
sized from a series of enzymatic reactions using
cholesterol as the precursor. In contrast to several
other secretory cells, adrenocortical cells do not store
large amounts of readily releasable glucocorticoids.
Secretion is, therefore, tightly linked to de novo
synthesis. The diffusible glucocorticoids, which easily
cross lipid membranes, enter the highly vascularized
blood supply of the adrenal glands, where 90–95% of
glucocorticoids become bound to corticosteroid-bind-
ing globulin (CBG), also known as transcortin, a carrier
protein found in plasma. The half-life of cortisol in
blood is approximately 60–90 min. Because glucocor-
ticoids are biologically active only in their free form,
normally a small fraction of total glucocorticoids is
available for bioactivity. However, CBG levels are
significantly reduced under some conditions (stress),
thus providing one mechanism regulating biologically
active glucocorticoids without altering absolute levels.
Secretion and synthesis of glucocorticoids from
adrenocortical cells are triggered by the activation of a
specific subtype of melanocortin receptor, the adreno-
corticotropin hormone (ACTH) receptor, in response
to the anterior pituitary hormone ACTH. These
receptors are part of the G-protein-coupled, seven-
transmembrane-domain receptor superfamily, and,
once activated, they increase the production of the
second messenger cAMP via the enzyme adenylate
cyclase. The adrenal ACTH receptor is positively
regulated, that is, it can increase its number of
receptors in response to sustained ACTH levels.
2. The Anterior Pituitary Gland and ACTH
The anterior lobe of the pituitary gland is responsible
for the synthesis and release of ACTH. ACTH is a
88 PSYCHONEUROENDOCRINOLOGY
Figure 5 Diagram of one preprohormone, prepro-opiomelano-
cortin, which is cleaved and processed to give several different
products. Abbreviations: ACTH, adrenocorticotropin hormone;
end, endorphin; LPH, lipotropin hormone; MSH, melanocyte-
stimulating hormone. [From Zigmond et al. (eds). (1999). Funda-
mental Neuroscience. Academic Press, San Diego].
39-amino-acid peptide secreted by specialized cells
known as corticotropes, which account for approxi-
mately 10% of the total cell population of the anterior
lobe. ACTH itself is derived from a longer peptide
precursor, pro-opiomelanocortin (preproPOMC), as
shown in Fig. 5. Regulation of the POMC gene has
been studied to a great extent, as it was the first
mammalian endocrine precursor molecule to be cloned.
3. The Hypothalamus and Corticotropin-
Releasing Factors
The secretion of ACTH from corticotropes is signaled
by corticotropin-releasing factors from the medial
parvocellular region of the paraventricular hypotha-
lamic nucleus. So far, the most potent endogenous
factor involved in ACTH secretion is the 41-amino-
acid peptide corticotropin-releasing hormone (CRH),
which was discovered and sequenced by Wyllie Vale
and colleagues some 20 years ago. Parvocellular
neurons send their axons to the external zone of the
median eminence where, upon activation, CRH is
liberated into the portal blood system. Upon destruc-
tion of the PVN, several stressors loose the ability to
produce ACTH secretion, suggesting that the CRH-
containing neurons of the PVN are obligatory for this
function. The secretagogue action of CRH has been
shown to synergize with additional factors, such as the
peptides arginine vasopressin (AVP), oxytocin, and
others, some of which are also coexpressed and
released from CRH-containing neurons of the medial
parvocellular hypothalamic nucleus. Although the
cDNA and genes for CRH and AVP peptides have
been cloned for some time, it was only relatively
recently that the cDNAs encoding the CRH and AVP
receptors were cloned. These receptors are also
members of the G-protein-coupled, seven-transmem-
brane-domain superfamily of receptors and are posi-
tively coupled either to the production of cyclic
adenosine monophosphate (CRH) or to the phospha-
tidylinositol (AVP) second messenger intracellular
pathways. Multiple receptor subtypes have been
cloned for each, cut the CRH1 and V1b subtypes
account for the majority of CRH and AVP receptors
localized on anterior pituitary corticotropes. Pituitary
CRH and AVP receptor peptide levels are rapidly
controlled upon continued activation by CRH and
AVP, with evidence of up- and down-regulation in
response to different manipulations.
B. Control of the HPA Axis
1. Control of Circulating Glucocorticoids
Neurons of the parvocellular hypothalamic area are
responsible for the production of corticotropic-releasing
factors. CRH and AVP mRNAs and peptides from
parvocellular neurons are significantly regulated in
response to a variety of experimental manipulations
comprising acute and repeated stress. An additional
molecule discovered is the corticotropin-releasing hor-
mone-binding protein (CRH-BP), which is found in
blood, the pituitary gland, and various brain areas. This
protein is localized in neurons and astrocytes, and it
binds and inactivates endogenous CRH and other
CRH-like peptides, such as the more recently discovered
urocortin, providing an additional mechanism to con-
trol the levels of CRH reaching the anterior pituitary.
An important level of control over ACTH secretion
is exerted by the glucocorticoids themselves. Because
the constant exposure of organisms to high levels can
produce deleterious effects, including immune sup-
pression, cardiovascular dysfunction, and even death
of certain neuronal populations, glucocorticoids ex-
hibit several mechanisms to restrain their own release.
It is generally recognized that glucocorticoids provide
feedback inhibition at several levels, including the
pituitary, paraventricular hypothalamus, and other
brain areas such as the hippocampus (discussed in the
following section). These inhibitory influences act in
several time domains, including fast, intermediate, and
slow (genomic) feedback. The genomic and, to some
extent, intermediate feedback inhibition is provided by
the action of glucocorticoids upon two well-character-
ized and specific receptors: the mineralocorticoid
(MR) or type I receptor and the glucocorticoid (GR)
or type II receptor. They are members of a superfamily
of cytoplasmic receptors that act as ligand-regulated
transacting factors, as depicted in Fig. 6. Upon
activation, these receptors translocate to the nucleus
where they may interact with other transacting factors
to bind to specific recognition elements on the DNA,
effecting changes in the transcriptional rates of several
genes, including CRH, AVP, and POMC. However,
glucocorticoids are also known to produce feedback
 PSYCHONEUROENDOCRINOLOGY 89

2. Brain Circuits Involved in the Regulation of

the HPA Axis
Several reviews have described the neuroanatomical
afferents to hypothalamic paraventricular neurons
that might be involved in the regulation of the HPA
axis, as shown in Fig. 7. The available evidence
indicates the existence of several distinct afferents that
are suggested to regulate the activity of hypothalamic
neurons. Some of these circuits likely interact with
other hypothalamic–pituitary endocrine systems.

a. Brain Stem and Medullary Afferents Well-

Figure 6 Schematic diagram of glucocorticoid receptor (GR)
function. Once translated in the cytoplasm, GR is quickly stabilized
by a complex including many heat-shock proteins (HSP). Circulating
steroids, including cortisol, easily cross cell membranes to access the
cytoplasm from the circulation and bind to GR. Activation of GR by
steroid binding induces its separation from the HSP complex and its
translocation to the nucleus, where it interacts with DNA (transact-
ing factor) to facilitate or inhibit gene transcription. [From Zigmond
et al. (eds). (1999). Fundamental Neuroscience. Academic Press, San
Diego].
known projections to the hypophysiotropic CRH-
containing neurons originate from medullary catecho-
laminergic neurons of the nucleus of the solitary tract
(C2) and the ventrolateral (A1, C1) and dorsomedial
(C3) medulla. Most of these nuclei are involved in the
processing and transmission of visceral or interocep-
tive information. These catecholamine-containing
neurons appear to play a crucial role in activating
most types of hypophysiotropic neurons in response to
immune activation (e.g., infection, interleukin-1b, and

inhibition that is too rapid to rely on genomic

regulation. This glucocorticoid rate-sensitive regula-
tion has not been well-characterized, but it is likely
exerted via either nongenomic effects of MR or GR
receptor occupancy or via nonclassical glucocorticoid-
sensitive receptors.
Hence, the HPA axis provides a cascade of processes
exerting positive and negative control at several levels,
ultimately participating in the regulation of energy and
metabolic activity throughout the body. Even under
conditions of homeostasis, glucocorticoid levels dis-
play a diurnal rhythm, with higher levels in the
morning than in the evening for humans, anticipating
increased bodily demands during the day. This rhythm
appears to be driven by one of the brain’s main
biological clocks, the suprachiasmatic nucleus, as well
as by the pattern of food intake. Activation of the HPA Figure 7 Schematic view of afferent innervation to the paraven-
axis by events that are deemed stressful by organisms tricular nucleus (PVN) of the hypothalamus. Abbreviations: A1/2,
occurs in the context of this diurnal regulation and is C1/2/3, LC, catecholamine-containing cell groups of the brain stem;
mediated by several putative brain pathways with B6/8, serotonin-containing cell groups of the midbrain; CV,
direct connections to hypophysiotropic neurons. The circumventricular organs; LPB, lateral parabrachial nucleus; LDTg,
PPn, tegmental nuclei; PIN, posterior intralaminar thalamic nucleus;
following section briefly describes these neuronal PP, peripeduncular thalamic nucleus; CG, central gray; Hyp,
circuits, together with their suggested involvement in hypothalamic nuclei. [From Zigmond et al. (eds). (1999). Funda-
the regulation of the HPA axis. mental Neuroscience. Academic Press, San Diego].
90 PSYCHONEUROENDOCRINOLOGY
endotoxins) and several types of visceral and somato-
sensory challenges.
Additional but more limited mesopontine afferents
to the hypophysiotropic hypothalamus have been
traced from serotonergic cell groups (B7, B8, and B9),
some tegmental nuclei (peripeduncular, laterodorsal),
the parabrachial nucleus, and some subregions of the
central gray. Additional thalamic nuclei, including the
peripeduncular nucleus, the posterior intralaminar
nucleus, and the intergeniculate leaf, also provide
afferents. The proposed function of several of these
areas in sensory processing and transmission makes
them likely candidates to provide relatively specific
sensory information (somatosensory, nociceptive,
auditory, and visual) to hypophysiotropic neurons.
b. Circumventricular Afferents Another set of
hypophysiotropic afferents, originating from circum-
ventricular organs, includes the subfornical organ, the
vascular organ of the lamina terminalis, and the closely
related median preoptic nucleus. These nuclei have
been implicated in the activation of the HPA axis by
blood-borne signals. Such signals include circulating
indices of blood volume and ionic concentrations,
which also impinge on the magnocellular neurons of
the paraventricular and supraoptic nuclei to regulate
the release of antidiuretic hormone (vasopressin)
and oxytocin involved in water balance and blood
pressure.
c. Hypothalamic Afferents An additional impor-
tant source of afferents to hypophysiotropic neurons
originates within the hypothalamus. Indeed, most
hypothalamic nuclei contribute afferents to hypophy-
siotropic neurons with the exception of a few nuclei,
namely, the medial and lateral mammillary and
supraoptic nuclei. The principal hypothalamic areas
providing relatively numerous afferents to the para-
ventricular nucleus include several preoptic areas, the
anterior, lateral, and posterior hypothalamic areas, the
dorsomedial and ventromedial nuclei, and the supra-
mammillary nucleus. The suprachiasmatic nucleus,
involved in circadian rhythm entrainment, appears to
influence the HPA axis via projections to the dor-
somedial nucleus. These nuclei are uniquely situated to
significantly influence the activity of the neuroendo-
crine systems. The association of several of these
hypothalamic nuclei with basic physiologic functions
suggests that they might integrate the sum of all stimuli
perceived by an organism at any one moment and then
convey this integrated information to hypophysiotro-
pic neurons to keep an optimum level of functioning
throughout the neuroendocrine systems, including the
HPA axis.
d. Forebrain Afferents Several forebrain areas
appear to influence the activity of the HPA axis,
including the prefrontal cortex, hippocampus, amyg-
dala, and septum. Surprisingly, none of these areas
unambiguously project to hypothalamic paraventri-
cular neurons. Instead, several studies indicate that
these areas might regulate the activity of the HPA axis
via medial hypothalamic relays or, alternatively, via
relays with neurons of the bed nucleus of the stria
terminalis, the only additional forebrain structure
known to project directly to hypophysiotropic neu-
rons. The preceding forebrain structures are of
particular interest because they are all associated with
emotionality. Some of these areas might, therefore, be
essential in the evaluative process involved in deter-
mining or perceiving the stressful character of a
situation.
Neuroanatomically, therefore, hypophysiotropic
CRH-containing neurons receive a rich set of neural
inputs encompassing several categories of stimulus
information. In addition, most of these regions,
together with the rest of the brain, express one or both
glucocorticoid receptors, making the brain an impor-
tant target for circulating cortisol. The influence of the
brain on the activity of the HPA axis, as well as that of
cortisol upon brain functioning thus provides a rich set
of interactions, the dysregulation of which can have
dramatic consequences upon the physical and psycho-
logical well-being of individuals.
C. Dysregulation of Circulating
Glucocorticoids (Cortisol)
Cushing’s syndrome is perhaps the best-known class of
diseases involving hypersecretion of glucocorticoids.
In the early 1930s, Harvey Cushing described a list of
symptoms that was closely associated with pituitary
abnormalities. Glucocorticoid hypersecretion can be
produced by adrenocortical or pituitary tumors, the
latter associated with ACTH hypersecretion. Cases are
also known in which increased hypothalamic CRH
release produces ACTH hypersecretion. The symp-
toms of Cushing’s disease, characterized by several
physical and psychological changes, include thinning
of the skin and hair, increased subcutaneous adipose
(fat) deposits in the face (moon face), upper back and
shoulders (buffalo hump), and abdomen (pendulous
abdomen), appearance of reddish purple skin color
 PSYCHONEUROENDOCRINOLOGY
from skin stretching, hypertension, and osteoporosis.
The psychiatric profile of Cushing’s patients includes
increased appetite, insomnia, euphoria, anxiety, panic,
and unipolar or bipolar disorders. Psychosis (includ-
ing schizophrenia) is rarely observed in Cushing’s
patients. Normalization of glucocorticoid levels in
these patients greatly improves the physical and
mental disorders.
On the other hand, a significant number of indivi-
duals seeking help who are diagnosed with major
depression present signs of adrenal hypertrophy and
increased basal levels (over 24 hr) of circulating
cortisol. These endocrine abnormalities can be nor-
malized in a high proportion of patients with a variety
of antidepressant treatments (behavioral, pharmaco-
logic, or electroconvulsive therapy), which concur-
rently improve their psychological status. The
dexamethasone suppression test (DST) has been a
useful tool to help determine HPA axis dysregulation.
Dexamethasone is a glucocorticoid receptor agonist
that, when injected intravenously, binds GR receptors
at the level of the pituitary corticotropes and perhaps
at the level of the hypothalamus and other brain
regions and initiates feedback inhibition so that the
circulating cortisol levels are suppressed hours after
dexamethasone injection. Interestingly, a high propor-
tion of individuals presenting symptoms of endogen-
ous major depression do not show the normal
suppression of cortisol by dexamethasone; they are
said to escape the DST effect. Thus, abnormal GR
receptor regulation, involved in feedback inhibition,
appears to be linked with affective disorders. The most
popular mechanisms hypothesized to mediate in-
creased basal cortisol levels and reduced feedback
inhibition have implicated an increased drive of central
CRH-containing systems and dysregulation of brain
serotonergic-containing systems. High levels of circu-
lating cortisol levels have also been linked to neuronal
cell death, especially in the hippocampus, a brain
region with some of the highest levels of MR and GR
receptors that is also thought to play a role in negative
feedback of the HPA axis. Cortisol dysregulation thus
provides clear example of the interactions between
hormones and brain and vice versa.
A reduction in circulating cortisol levels is observed
in patients with Addison’s disease. This category of
diseases includes several pathologies (adrenal autoim-
mune disease, tuberculosis, and adrenal cancer) that
lead to adrenal atrophy and insufficiency. Total adrenal
insufficiency is rapidly fatal, but with degenerative
diseases, patients develop marked skin pigmentation
(melanocyte-stimulating hormone activity of ACTH in
91
blood), hypotension and reduced cardiac size. Even
minor stresses can send Addison’s patients into fatal
shock. Adrenal insufficiency is also correlated with a
slower electroencephalogram (EEG of the a rhythm),
irritability, apprehension and mild anxiety, inability to
concentrate, and increased gustatory and olfactory
sensitivity. It is interesting that low circulating cortisol
levels produce some of the same affective disorders
observed with high circulating cortisol levels, but in
milder forms. The mechanisms by which low cortisol
levels affect mood and the chemical senses are ill-
understood. Learning is also affected by circulating
cortisol levels, and evidence of poor memory with either
too much or too little cortisol has been documented.
III. THE HYPOTHALAMO–PITUITARY–THYROID
AXIS
The hypothalamo–pituitary–thyroid (HPT) axis is the
main regulatory system responsible for metabolism in
all body tissues throughout life. Metabolism constitu-
tes all biochemical processes that take place at the
cellular level and includes functions such as synthesis
of protein–lipid–carbohydrate–enzymes, incorpora-
tion of nutrients, and breakdown–synthesis of various
molecules. Circulating thyroid hormones also stimu-
late oxygen consumption in most cells of the body. As
with the HPA axis, the secretion of thyroid hormones
in the bloodstream is intricately regulated at several
levels, beginning at the hypothalamus. See Fig. 3 for a
summary diagram of the HPT axis. The basic con-
stitutive elements of the HPT axis and thyroid
secretion are elaborated first. Central regulation of
the HPT axis and dysregulation of thyroid hormones
levels are then discussed.
A. Basic Constituents of the HPT Axis
In humans, thyroid hormones, composed mainly of l-
thyroxine (denoted as T4) and triiodothyronine (de-
noted as T3), are released by the thyroid gland through
a series of steps described next.
1. The Thyroid Gland and the Secretion of
Thyroid Hormones
The thyroid gland, located at the base of the neck close
to the trachea, synthesizes and stores T3 and T4 to large
glycoproteins called thyroglobulins until they are
secreted into the bloodstream. T3 and T4 are synthe-
sized from the amino acid tyrosine and involve the
incorporation of three (T3) or four (T4) iodine atoms,
92 PSYCHONEUROENDOCRINOLOGY
making it the only molecule in the animal kingdom to
contain iodine. Although the only difference between
T3 and T4 is an additional iodine atom in T4, this
difference provides T3 with much greater biological
activity in all body tissues (3–5 times greater than T4).
In peripheral tissue, T4 is converted to T3 by the
enzyme 50 -deiodinase type I, whereas T4 is directly
taken up by brain and pituitary cells and transformed
into T3 intracellularly by the type II 50 -deiodinase
enzyme. In the bloodstream, thyroid hormones are
bound to carrier proteins, including albumin, thyrox-
ine-binding prealbumin (TBPA), and thyroxine-bind-
ing globulin (TBG), leaving a very low percentage of
free hormones (about 0.2% T3 and 0.02% T4). T4 is
carried to the brain across the blood–brain barrier via
a specific and saturable carrier molecule, transthyretin
(TTR). The half-life of T4 is approximately 1 week and
that of T3 is slightly shorter.
2. The Anterior Pituitary Gland and TSH
The thyroid-stimulating hormone (TSH), also known
as thyrotropin, is responsible for the regulation of
thyroid hormone secretion. TSH controls the uptake
of iodine by the thyroid gland, regulates the rate of
synthesis of thyroid hormones, and controls the
storage and release of T3–T4 into the bloodstream.
As with other neuroendocrine axes, the anterior
pituitary is responsible for the production and release
of TSH. Thyrotropes, the anterior pituitary cells
producing TSH, constitute about 10% of the entire
population of the anterior lobe. Through a hypotha-
lamic factor, TSH is released into the bloodstream and
eventually reaches the thyroid gland to regulate the
synthesis and release of thyroid hormones. TSH
release is pulsatile, and in humans the frequency of
the pulses varies from 10 to 15 every 24 hr. TSH release
also shows a circadian variation, with levels beginning
to rise in late afternoon and peaks in the middle of the
night (around 4:00 AM). The levels decline until noon
and are quiescent until the next rise.
The bloodborne signal from the hypothalamus is
mediated by specific membrane receptors on anterior
pituitary thyrotropes, the TRH receptors. This recep-
tor is a member of the seven-transmembrane, G-
protein-coupled receptor superfamily. Binding of
TRH to its receptors triggers the activation of the
phosphatidylinositol and diacylglycerol second mes-
senger pathways, which eventually leads to increased
transcription of the TSHb gene together with the a
gene common to the glycoprotein hormones (TSH,
luteinizing hormone, follicle-stimulating hormone,
and human chorionic gonadotropin, discussed later
in this article) that encode and produce TSH. As with
the other glycoprotein hormones, TSH is a hetero-
dimer polypeptide derived from two distinct genes and
is heavily glycosylated, which is thought to extend its
half-life.
3. The Hypothalamus and Thyrotropin-
Releasing Hormone
The hypothalamic factor responsible for the release of
TSH is thyrotropin-releasing hormone (TRH). This
hormone was the first hypothalamic-releasing hor-
mone isolated and purified from tons of pig and sheep
brains in the late 1960s, after many years of hard work,
by the research teams of Andrew Schally and Roger
Guillemin, for which they would eventually share a
Nobel prize. TRH is a small, 3-amino-acid peptide
(histidine, proline, and glutamic acid) derived from a
larger 242-amino-acid prohormone that contains 6
copies of the TRH sequence. TRH is synthesized in
hypothalamic neurons located in the periventricular
and parvocellular compartment of the paraventricular
nucleus. In the medial parvocellular region, the TRH-
containing neurons are observed medial to the CRH-
containing neurons. These TRH-containing neurons
send their axons to the external zone of the median
eminence, where TRH is released into the portal blood
circulation bathing the anterior pituitary. Other hy-
pothalamic and extra-hypothalamic regions synthesize
TRH, but these neurons do not directly, if at all,
control thyroid hormone release.
B. Control of the HPT Axis
1. Control of Circulating Thyroid Hormones
As with the HPA axis and glucocorticoids, the HPT
axis exerts rigorous control over thyroid hormone
levels. Rising thyroid hormone levels, especially
through T3, act at the level of the pituitary thyrotropes
and hypothalamic paraventricular neurons to inhibit
further release of TSH and TRH, respectively, in a
classic inhibitory feedback mechanism. This action is
mediated by thyroid hormone receptors, which are
part of a superfamily of cytoplasmic steroid hormone
receptors including estrogen, progesterone, androgen,
and vitamin D receptors. Several isoforms of the
thyroid hormone receptors have been characterized,
including Tra1, TRa2, TRb1, and TRb2, which act in a
manner analogous to the MR and GR receptors as
 PSYCHONEUROENDOCRINOLOGY
transacting factors upon genomic response elements.
TRa1 and TRb2 are the most abundant isoforms,
found in more than 80% of TRH-producing neurons
of the paraventricular nucleus.
2. Brain Circuits Involved in the Regulation of
the HPT Axis
Many of the same circuits described in the neural
control of the HPA axis also appear to be involved in
the control of the HPT axis. The proximity of the
medial parvocellular hypophysiotropic neurons con-
taining CRH and TRH can make it difficult, if not
impossible, to ascribe distinct sets of afferents to the
two endocrine axes. The brain stem catecholaminergic
cell groups are known to innervate and play a part in
the regulation of the HPT axis. Some of the rostral
periventricular TRH-containing neurons also receive a
relatively greater input of terminals from the noradre-
naline-containing locus ceruleus neurons and from the
serotonin-containing neurons of the midbrain raphe
nuclei. The thyroid gland is also directly innervated by
autonomic fibers (both sympathetic and parasympa-
thetic) that control blood flow and, reportedly, the
synthesis of thyroid hormones. These mechanisms can
significantly regulate the levels of T3–T4 released in the
bloodstream. Finally, as is the case with MR and GR
receptors, the brain expresses some of the highest levels
of the different thyroid hormone receptors. Dysregu-
lation of thyroid hormone secretion can, thus, have
dire consequences on physical and psychological
status.
C. Dysregulation of Circulating
Thyroid Hormones
Consideration of the effects of hypothyroidism or
hyperthyroidism can emphasize the importance of
normal levels of circulating thyroid hormones. Hypo-
thyroidism is a condition resulting from inadequate
thyroid hormone production. If this happens during
fetal life, a condition known as cretinism develops, in
which the afflicted individual remains of short stature,
never reaches sexual maturity, and suffers severe
mental deficiencies, hearing and speech defects, spastic
gait, impaired voluntary motor control, and clonus.
This condition can improve if thyroid hormones are
provided during the first few months of life.
In adulthood, hypothyroidism is divided into clin-
ical and subclinical types, with clinical hypothyroidism
93
producing several physical and mental conditions.
Low thyroid secretion rates produced by reduced
thyroid hormone synthesis at the level of the thyroid
gland or insufficient dietary iodine can lead to goiter, a
very apparent enlargement of the thyroid gland
produced by sustained TSH stimulation of thyroid
growth combined with a lack of adequate thyroid
hormone secretion (thus failing to inhibit pituitary
TSH secretion). Other symptoms of clinical hypothyr-
oidism include depression, low energy, appetite and
sleep changes, poor concentration, memory impair-
ments, apathy, muscle cramps, brittle and thinning
hair, husky voice, and elevated levels of cholesterol and
triglycerides. The similarity of these symptoms with
those of endogenous major depression has prompted
clinicians to test thyroid function in order to distin-
guish between the two conditions. Subclinical hypo-
thyroidism, by definition, does not present the clinical
type symptoms, although fatigue, hypothermia, dry
skin, memory impairments, and higher scores on
ratings of anxiety and depression are reported. The
lifetime prevalence of depressive disorders in hypo-
thyroid patients is 56% compared with 20% in
euthyroid (high total, but normal free levels of T4–
T3) individuals. Also, response to tricyclic antidepres-
sant treatment in patients is lower in hypothyroid
individuals, but can be improved by cotreatment with
thyroid hormones. This may be particularly relevant in
women, in whom the incidence of clinical and sub-
clinical hypothyroidism is more than twice that for
men, which is also mirrored in the incidence of
depressive disorders. A higher incidence of thyroid
antibodies is also observed in women, which may be
attributed to the higher stimulation of immunologic
functions by female gonadal hormones, leading to
higher rates of autoimmune diseases. Exactly how
hypothyroidism produces affective disorders, particu-
larly major depression and rapid-cycling bipolar
disorder, has not been clearly ascertained. Lower
thyroid hormone levels have been suggested to reduce
b-adrenergic receptor activity and central serotonin
activity, effects often associated with endogenous
major depression. The higher incidence of both
conditions in women might also be linked to the
homology and interactions between the estrogen and
thyroid receptors, which are known to bind each
others’ hormones.
The reverse interaction between affective illnesses,
particularly major depression, and thyroid hypofunc-
tion has also been documented. Patients presenting
with major depression often display increased cere-
brospinal fluid levels of TRH or a blunting of TSH
94 PSYCHONEUROENDOCRINOLOGY
secretion in response to TRH challenge, suggesting
down-regulation of pituitary TRH receptors in re-
sponse to chronic high levels of hypothalamic TRH.
This also agrees with some reports that depressed
patients show blunted circulating plasma levels of TSH
at night. There is still scant literature concerning the
putative effects of endogenous affective illnesses on the
HPT axis, but the preceding preliminary reports
clearly indicate the need to better understand this
brain–neuroendocrine interaction.
Hyperthyroidism involves conditions in which ex-
cess thyroid hormones are secreted. The highest
percentage of hyperthyroidism in the United States is
caused by Grave’s disease, characterized by an auto-
immune reaction against the thyroid TSH receptors,
which in most cases stimulates the release of excess
thyroid hormones. Some of the physical signs of
hyperthyroidism include weight loss, palpitations,
frequent bowel movements, muscle weakness, thyroid
enlargement, and bulging out of the eyes (exophthal-
mia). Psychiatric symptoms often associated with
hyperthyroidism include insomnia, irritability, agita-
tion, general anxiety disorder, major depression,
attention deficit disorder, or paranoia. General anxiety
is by far the most common psychiatric outcome and
generally improves upon the normalization of thyroid
hormones. Treatment with antidepressants has also
been observed to lower the levels of circulating thyroid
hormones.
IV. THE HYPOTHALAMO–PITUITARY
GROWTH AXIS
No the hyphen is not missing between pituitary and
growth; this is because this endocrine system departs
from other neuroendocrine systems by releasing the
anterior pituitary growth hormone (GH, also known as
somatotropin) directly into the bloodstream to influ-
ence body tissues without the intervention of an
additional organ (as is also the case with prolactin
secretion, discussed later). Growth hormone, as the
name implies, is vital for the normal growth and
development of humans and most other species,
particularly during the perinatal and adolescent peri-
ods. However, together with other factors and hor-
mones, including, but not limited to, thyroid hormones,
insulin, and dietary nutrients, growth hormone is
crucial in the control of carbohydrate metabolism,
protein synthesis, body fat, glucose utilization, and
other metabolic activity. Without it, abnormal organ,
skeletal, and immune functions develop.
A. Basic Constituents of the Hypothalamo–
Pituitary Growth Axis
The hypothalamo–pituitary growth axis also departs
from other neuroendocrine axes in that two hypotha-
lamic factors mainly regulate growth hormone synth-
esis and secretion, with one factor demonstrating
GH release activity whereas the other inhibits GH
secretion.
1. The Anterior Pituitary and Growth Hormone
Growth hormone is released by specialized cells of the
anterior pituitary gland called somatotropes. They are
located predominantly in the lateral ‘‘wings’’ of the
anterior lobe and constitute about 40% of the total
anterior pituitary cells (there is a significant gender
difference, with women averaging lower percentages
than men). In humans, the pituitary gland contains 5–
10 mg of somatotropin, a 191-amino-acid peptide
derived from a gene located on chromosome 17.
The half-life of GH is relatively short, with an
average of approximately 20 min. Upon secretion into
the bloodstream, about half of the GH released
becomes bound to a protein termed growth-hor-
mone-binding protein (GHBP). GH acts in several
different tissues throughout the, body, as discussed
earlier, and this action is mediated by specific GH
receptors (GH-R) located on the membranes of
receptive tissues and organs. Both GH-R and GHBP
are derived from the same gene, although alternative
splicing of the transcribed mRNAs provides for the
two distinct functions of these proteins. Interestingly,
to be biologically active, one GH molecule is required
to bind sequentially to two GH receptors. This
complex then initiates a cascade of events leading to
the activation of transcription factors affecting GH-
regulated genes. A major effect of GH is to stimulate
the production of insulin-like growth factor I (IGF-I),
which mediates many of the effects of GH; IGF-I by
itself can mimic many effects of GH, although the two
molecules are more effective in combination.
GH is secreted by the anterior pituitary upon release
of the growth-hormone-releasing hormone (GHRH)
signal from the hypothalamus, via the portal blood
system, onto GHRH receptors (GHRH-R) of the
somatotropes. These receptors are also part of the
large family of seven-transmembrane, G-protein-cou-
pled receptors, and they are specifically linked to the
stimulatory subtype (Gs) of G-proteins, which
activates the cAMP second messenger pathway.
Additional evidence also indicates that an as yet
 PSYCHONEUROENDOCRINOLOGY
unknown GH-releasing factor from the hypothalamus
binds specifically to a different G-protein-coupled
receptor, one that is specifically linked to the Gq
subtype of G-proteins and appears to synergize,
through the inositol triphosphate and diacylglycerol
second messenger pathways, with the effects of
GHRH-R upon GH secretion. The synthesis of GH
in somatotropes is independently controlled by
GHRH through a slightly different set of transcription
factors associated with cAMP production (cAMP
response element binding protein), acting to enhance
transcription of the somatotropin gene. Independent
regulation of synthesis and release has been shown by
the existence of different diseases that are mediated
specifically at the level of the pituitary gland upon
either GH synthesis or secretion within somatotropes.
The secretion of GH is also negatively regulated by a
second hypothalamic factor, somatostatin (SS). Pitui-
tary secretagogues, including somatotropes, contain a
variety of SS receptors (at least five different variants
with independent genomic origins) that are all linked
to the inhibitory G-protein subunit Gi, which inhibits
the activation of adenylate cyclase and the production
of cAMP. Thus, GH synthesis and secretion are tightly
regulated positively and negatively by hypothalamic
factors.
2. The Hypothalamus, Growth-Hormone-
Releasing Hormone, and Somatostatin
As discussed earlier, the major hypothalamic factor
responsible for the synthesis and release of pituitary
GH is GHRH. Hypophysiotropic GHRH neurons are
located at the base of the brain against the third
ventricle in the arcuate nucleus. The human GHRH
gene is located on chromosome 20 and gives rise to a
preproGHRH precursor of 108 amino acids. Post-
translational processing of proGHRH produces two
forms of GHRH: a 44-amino-acid peptide, to which 4
amino acids are found truncated at the C-terminus in
some forms. Because the bioactivity of GHRH is
restricted to the first 29 amino acids at the N-terminus,
this truncation, albeit unique to humans, confers both
forms with similar biological activity.
The other hypothalamic factor having a major
influence on the control of GH secretion is somatos-
tatin (SS), also known as growth-hormone-release-
inhibiting hormone (GHRIH) or somatotrope-re-
lease-inhibiting hormone (SRIH). Although SS is
found in many cell populations throughout the brain,
the important SS-containing neurons in regard to GH
release are those in the rostral periventricular region.
The human SS gene, located on chromosome 3,
95
encodes a 116-amino-acid preproSS. Posttranslational
processing of preproSS in the hypothalamus produces
two biologically active forms, SS-28 and SS-14,
truncated at the N-terminus. Both forms are released
in the external zone of the median eminence and
display a short half-life of a few minutes to reach the
anterior pituitary somatotropes. A direct inhibitory
action of SS upon GHRH-containing arcuate neurons
also exists, although the source of this SS input likely is
from nuclei other than from the hypophysiotropic SS-
containing rostral periventricular region.
B. Control of the Growth Axis
1. Control of Circulating Growth Hormones
As with other neuroendocrine systems, GH and its
related product, IGF-I, provide feedback inhibition at
both pituitary and hypothalamic levels upon pituitary
GH release and upon SS and GHRH synthesis and
secretion, respectively. At the level of the pituitary
somatotropes, IGF-I is the major inhibitor of GH
synthesis and secretion under basal and GHRH-
stimulated conditions, with GH displaying little, if
any, inhibitory effects. Somatotropes contain IGF-I
receptors, which are in a position to respond to both
locally produced and circulating IGF-I. Although
total IGF-I levels are relatively stable over time, they
exist in both free form, which is biologically more
active, and in bound form to a plasma protein, IGFBP-
3. A number of physiological conditions, such as
hyperglycemia, down-regulate IGFBP-3, thus increas-
ing free, biologically active levels of IGF-I, which can
then mediate increased inhibition of GH. At the level
of the hypothalamus, GHRH- and SS-containing
neurons possess both IGF-I and GH receptors, which
open these cellular populations to the feedback effects
of both molecules. There is limited evidence for IGF-I-
and GH-mediated inhibition of GHRH secretion and
SS stimulation, which is perhaps linked to the limited
crossing of these large peptides across the blood–brain
barrier.
Additional neurotransmitter systems are also known
to play a role in the secretion of GH, which include, but
are probably not limited to, vasoactive intestinal
polypeptide (VIP), pituitary adenylate cyclase activat-
ing peptide (PACAP), TRH, glucocorticoids, andro-
gens, estrogens, galanin, neuropeptide Y (NPY),
interleukins-1 and -2, and the classical neurotransmit-
ters dopamine, noradrenaline, and acetylcholine.
The secretion of GH is also pulsatile, as with most
other hormones of the neuroendocrine system. In
96 PSYCHONEUROENDOCRINOLOGY
humans, there are approximately 12 pulses per 24-hr
period, with most of the release (roughly 70%)
occurring at night during slow-wave (stages 2–4) sleep.
Existing evidence suggests that both GHRH and SS
are implicated in the pulsatile release of GH, with
GHRH being the dominant regulator in mediating the
release of pituitary GH. However, alterations in either
GHRH or SS have been shown to block the
pulsatile release of GH. In the hypothalamus,
GHRH and SS mRNAs also display fluctuating
levels, with GHRH and SS mRNA peaks anticipat-
ing the GH peaks and troughs by several
hours, respectively. There is also a strong
sexual disparity in the amplitude of release, with
higher levels of estrogen in women contributing
to significantly lower GH secretion. Testosterone,
which has higher circulating levels in men, has been
linked to the higher peak amplitude of GH release
in males.
2. Brain Circuits Involved in the Regulation of
the HP Growth Axis
Some of the same circuits described previously control
the arcuate GHRH-containing neurons as well as the
rostral periventricular SS-containing neurons. The
brain stem and medullary catecholaminergic cell
groups innervate and control the activity of arcuate
and periventricular neurons. Other major inputs to the
arcuate nucleus originate within the hypothalamus,
including the anterior periventricular nucleus, the
retrochiasmatic nucleus, the medial parvocellular
region, the medial preoptic area, and the ventral
premammillary nucleus. The bed nucleus of the stria
terminalis also innervates the arcuate nucleus, as is the
case for many other hypothalamic subregions. The
rostral periventricular region demonstrates a pattern
of innervation generally similar to that described for
the paraventricular nucleus described earlier, includ-
ing midbrain, thalamic, hypothalamic, and forebrain
afferents. GH and IGF-I receptors are widely distrib-
uted throughout the human brain and could mediate
some of the effects of circulating growth hormones and
their products. However, peripheral GH and IGF-I
have limited penetration to the brain due to the blood–
brain barrier, and, furthermore, GH and IGF-I are
produced in the brain. Thus, direct effects of circulat-
ing growth hormones on the brain have been difficult
to demonstrate. Similarly, the psychotropic effects of
growth hormones have not been well-characterized
nor explained. Nevertheless, dysregulation of circulat-
ing growth hormones produces marked cognitive and
mood alterations.
C. Dysregulation of Circulating Growth Hormones
Physically a very observable effect of growth hormone
insufficiency during development is dwarfism (short
stature). However, some types of dwarfism result from
the insensitivity of tissues to relatively normal circu-
lating GH levels. The psychotropic effects of GH
insufficiency in children are not reported to alter
intelligence measures, but a higher incidence of
attention deficit disorders, anxiety, depressive mood,
somatic complaints, impulsivity, distractibility, social
adjustment, and attention-seeking are common. The
similarity of these psychological effects in idiopathic
(not produced by GH dysregulation) short stature vs
GH-deficient (GHD) children indicates that environ-
mental and social factors play a role in the develop-
ment of these traits. Nonetheless, the behavioral,
social, and psychological disturbances of GHD chil-
dren are ameliorated to a greater extent following GH
treatment, suggesting a role for circulating GH levels
in these disorders. The impact of GH deficiency in
adults of normal stature also indicates a higher
incidence of affective disorders, lack of energy, and
impaired self-control, which are significantly alle-
viated with GH replacement. Psychosocial dwarfism,
a state of short stature sustained by parental abuse, is
associated with significantly lower circulating GH
levels. Removal of the afflicted children from the
abusive environment will often reverse this condition
without any other intervention. These examples offer
clear instances of the interplay between hormones,
psychological status, and the brain.
Just as striking is the effect of excess circulating
growth hormones during development, leading to
gigantism in children and acromegaly in adults. These
conditions are often associated with pituitary somato-
trope adenomas resulting in hypersecretion of growth
hormones. Children that grow to be giants have
relatively normal features except for their high stature.
These children tend to have mood swings, irritability,
and lack social skills. They tend to be intellectually
normal. The physical and psychological characteristics
can be ameliorated with long-acting somatostatin
agonists, which reduce circulating GH levels, or with
the surgical removal of the adenoma. This growth
hormone condition is distinguished from another form
of early childhood gigantism known as cerebral
gigantism or Sotos syndrome, which originates from
 PSYCHONEUROENDOCRINOLOGY
brain abnormalities and is associated with
abnormal EEG, mental retardation, and other physi-
cal characteristics, particularly of the facial and
cranial bones.
In adults, abnormally high circulating GH levels,
also produced by pituitary somatotrope adenomas,
present a characteristic pattern of physical changes,
including enlarged hands and feet, profuse sweating,
protrusion of the lower jaw, overgrowth of facial and
cranial bones, hirsutism (increased body hair), os-
teoarthritic vertebral changes (humpback), headaches,
and visual field changes (due to pressure of the
pituitary tumor against optic nerves). The psycholo-
gical symptoms of acromegalic adults include affective
disorders (anxiety and major depression), increase in
appetite, and loss of drive and libido. These individuals
also exhibit normal intelligence and memory func-
tions. Surgical intervention or somatostatin agonists
that normalize GH levels ameliorate their physical and
psychological symptoms.
V. THE HYPOTHALAMO–PITUITARY–
GONADAL AXIS
The hypothalamo–pituitary–gonadal (HPG) axis is
responsible for many reproductive functions in hu-
mans and other mammals. It plays a pivotal role in the
development of mature male and female reproductive
organs, secondary sexual traits (breasts, body hair,
vocal pitch), and the sexually dimorphic brains
allowing appropriate male and female behaviors
leading to reproduction, such as courtship and inter-
course and probably mate choices and sex preferences.
However, many of the stereotypic behaviors attributed
to the HPG axis in lower mammals, particularly
courtship, mating, and intercourse behaviors, have,
for most intents and purposes, been lost in humans.
However, sex hormones have been suggested to have
some effect on sexual desire, which alternatively has
not been investigated to any great extent in animals
displaying readily observable stereotypic sexual beha-
viors. Sexual differentiation is determined very early
on during development. The presence of a Y chromo-
some following fertilization directs the development
and maturation of the testes, which begin to produce
testosterone early in utero and lead to the male
phenotype. Without the Y chromosome, the ‘‘default’’
female phenotype emerges. The following section
describes the results of this early differentiation and
how the various HPG functions are derived.
97
A. Basic Constituents of the Hypothalamo–
Pituitary–Gonad Axis
The HPG consists of a relatively classic neuroendo-
crine system, in that the various sex hormones are
regulated by hypothalamic, pituitary, and end organs
(gonads). It is arguably the neuroendocrine system
with the most components, with different sex hor-
mones to regulate and track. The different sex
hormones, the elements that regulate their secretion,
and their effects on various body tissues and repro-
ductive functions are described next.
1. The Gonads and Sex Hormones
The HPG axis is very different between males and
females. The sex hormones, also known as the sex
steroids or gonadal steroids, consist of estrogens,
progesterone, and the androgens, the most well-known
of which is testosterone. Although all of these hor-
mones are found in both men and women, estrogens
and progesterone are observed in much higher levels in
women and testosterone in much higher levels in men.
The sex steroids are all derived from the same
precursor molecule, cholesterol, through a series of
aromatic reactions taking place in the gonads (and
some in the adrenal cortex and placenta of pregnant
women). Most of the sex steroids become bound to
plasma proteins [albumin, transcortin, gonadal-bind-
ing globulin (GBG), or other proteins] upon release in
the bloodstream, leaving approximately 3% of the
released pool free. Steroids are relatively small mole-
cules that easily cross lipid membranes. This feature
allows sex steroids to act on their respective tissues by
interacting with specific receptors (such as the estra-
diol, progesterone, and androgen receptors) located
intracellularly in the cytoplasm of cells, as opposed to
binding cell-surface (membrane) receptors. Binding of
steroids with their specific cytoplasmic receptors
induces a series of reactions that ultimately produces
the translocation of the steroid–receptor complex
(known as a transacting factor) from the cytoplasm
to the nucleus, where it interacts with specific DNA
elements in the promoter region that can increase or
decrease the transcription of associated genes.
In females, estrogens and progesterone are synthe-
sized in the ovaries upon stimulation by the anterior
pituitary hormones luteinizing hormone (LH) and
follicle-stimulating hormone (FSH), together known
as the gonadotropins. More specifically, FSH produces
the growth of follicles within the ovaries (the follicular
98 PSYCHONEUROENDOCRINOLOGY
phase), which produces increasing amounts of estrogens
(estradiol mostly). An LH surge produces ovulation, in
which a follicle releases an ovum, the former being
transformed in the process to the corpus luteum. The
luteal phase is responsible for continued synthesis and
release of estrogens as well as increasing amounts of
progesterone. The concerted effects of estrogens and
progesterone on the uterine endometrium prepare the
uterus for possible implantation by a fertilized egg.
Estrogens and progesterone are also responsible for the
development and maturation of the female secondary
sex characteristics, including breast development and
the female pattern of fat deposits. The regulation of
synthesis and release of estrogens and progesterone
needs to be understood more specifically in the cyclical
context (ovarian or ‘‘menstrual’’ cycle in women) in
which they occur. This will be discussed after all HPG
elements have been introduced.
In males, stimulation by pituitary LH chiefly signals
the production of testosterone by the interstitial
(Leydig) cells of the testes. In conjunction with FSH,
testosterone stimulates spermatogenesis in the semi-
niferous tubules of the testes. Testosterone also plays a
role in the control of penile erection and the synthesis
and secretion of prostate and seminal vesicle fluids.
Testosterone is also responsible for the development of
male secondary sex characteristics, which consist of the
general male body form and more massive muscle
development, male hair distribution, and enlargement
of the larynx, leading to deepening of the voice. The
relatively low female sex steroid levels in the male
circulation also lead to a different pattern of fat
deposition in men. Interestingly, testosterone not only
acts through androgen receptors but is also converted
to a significant degree to estradiol, particularly in the
brain and pituitary, where the converted products act
on local estrogen receptors.
2. The Anterior Pituitary Gland and
Gonadotropins
As discussed earlier, LH and FSH are gonadotropins
that are synthesized and released by the gonadotropes,
constituting less than 10% of the total cells of the
anterior lobe. The half-life of human FSH is about
3 hr, whereas that of LH is approximately 60 min. LH
and FSH are glycoprotein hormones derived from a
common a gene (located on chromosome 6) but two
distinct b genes: LHb, located on chromosome 19, and
FSHb, located on chromosome 11, respectively. Upon
signaling mediated by hypothalamic gonadotropin-
releasing hormone (GnRH), also known as luteiniz-
ing-hormone-releasing hormone (LHRH), cell-surface
GnRH receptors (mapped to chromosome 4 in hu-
mans), which are parts of the G-protein-coupled
receptor family, activate the cAMP second messenger
pathway to stimulate the synthesis and release of LH
and FSH. A relatively robust correlation has been
observed between pulses of GnRH and LH release in
the general circulation. However, the concordance
between GnRH pulses and FSH release is variable due
to the action of additional factors, such as the peptide
inhibin, which is produced in the gonads and appears
to repress the synthesis and release of FSH.
3. The Hypothalamus and Gonadotropin-
Releasing Hormone
The release of gonadotropins is regulated by hypotha-
lamic GnRH-containing neurons. The GnRH-contain-
ing neurons are scattered throughout the extent of the
hypothalamus, unlike other releasing hormone cell
groups. In humans, they are mostly localized to the
medial preoptic area near the optic chiasm and to the
arcuate nucleus (ventral) hypothalamus near the med-
ian eminence, with some additional cells in the lateral
hypothalamus and medial septal complex. Approxi-
mately 70% of hypothalamic GnRH-containing neu-
rons send their axons to the external zone of the median
eminence, where they release GnRH in the hypophyseal
portal blood system and target the gonadotropes.
GnRH is a relatively small 10-amino-acid peptide that
is also derived from a larger preproGnRH product of
92 amino acids. In humans, a single gene codes for
hypothalamic preproGnRH located on chromosome 8.
Studies have indicated the existence of a second,
distinct GnRH gene on chromosome 20 that is
expressed in extrahypothalamic areas and peripheral
tissues. The function of this extra-hypothalamic-de-
rived GnRH has not been determined.
4. The Anterior Pituitary Gland and Prolactin
Although not part of the HPG axis, prolactin’s best-
known function is in lactation and, thus, warrants its
inclusion with other reproductive hormones. Prolac-
tin, a 198-amino-acid peptide derived from prepro-
prolactin, is released by anterior pituitary lactotropes
(also known as mammotropes). Unlike other anterior
pituitary tropic hormones, prolactin is under negative
control by an inhibitory factor from the hypothala-
mus, known as prolactin-inhibiting factor (PIF), likely
to be dopamine. Thus, upon transection of the
pituitary stalk, removal of PIF actions leads to
hyper-prolactinemia. Like other pituitary hormones,
 PSYCHONEUROENDOCRINOLOGY
pulsatile release is observed with prolactin, with a
circadian rhythm displaying greater release during
sleep. Both men and women show circulating prolactin
levels, with slightly higher levels observed in women.
Prolactin acts through specific, multiple forms of its
receptors found throughout the reproductive axis of
women and men, in addition to the liver, kidneys,
adrenals, pancreas, lymphoid tissues, intestines, hy-
pothalamus, and skin.
During pregnancy, circulating levels of prolactin
rise significantly but decline rapidly approximately 1
week following childbirth. Suckling then initiates
significant bursts of prolactin secretion, which stimu-
late the synthesis of maternal milk proteins. Patholo-
gically high circulating prolactin levels are associated
with gonadal dysfunctions in both women and men, in
addition to headaches and visual field disturbances.
Hyper-prolactinemia is reportedly the most common
form of hypothalamopituitary disorder in humans,
which can normally be treated in several ways to
restore normal circulating prolactin levels.
B. Control of the HPG Axis
1. Control of Circulating Gonadal Hormones
Control of circulating sex hormones is determined to a
large extent by the sex of the individual, and in women
it is determined further by the period within the
ovarian cycle. As observed with the other neuroendo-
crine systems, there is a strong component of feedback
inhibition provided by the sex steroids at the pituitary
and hypothalamic levels. The pulsatile nature of
GnRH release could be mediated by the documented
extensive connections between the several GnRH
neuron populations or by afferent connections. It is
clear, however, that the GnRH population of the
arcuate nucleus is necessary to derive the pulsatility of
GnRH secretion.
In women, it is customary to define the menstrual
cycle as beginning on the first day of the menstrual
period, which is easily detected by women experiencing
vaginal bloody discharges consisting of the endome-
trial tissue breaking down and being released (slough-
ing) because fertilization has not taken place. At this
point (beginning of the follicular phase), the hypophy-
siotropic GnRH-containing neurons generate a pulsa-
tile LH release approximately every hour, which is a
time at which estrogens are relatively low. As the
ovarian follicles grow, they release increasing amounts
of estrogens, which feed back at the level of the
hypothalamus and reduce the frequency of LH and
99
FSH release to 1 pulse per 90 min. At the same time, the
most developed follicle also synthesizes increasing
amounts of LH and FSH receptors, thus providing
increased gonadotropin sensitivity in the face of
decreasing gonadotropin release from the pituitary.
The follicle begins to synthesize and secrete large
amounts of estradiol, which, through ill-understood
mechanisms, produce a positive feedback effect at the
level of both the pituitary gonadotropes and the
GnRH-containing neurons of the hypothalamus,
triggering a gonadotropin surge (large amounts of
LH and FSH released in the circulation) at approxi-
mately midcycle (14 days). This surge is responsible for
ovulation and the transformation of the follicle into
the corpus luteum. In the luteal phase of the cycle,
increasing amounts of progesterone and moderate
levels of estrogens are secreted, which feed back upon
the pituitary and hypothalamus to reduce the frequen-
cy of LH pulses to 1 every 6–12 hr. The rising levels of
progesterone and inhibin lead to an inhibition of FSH
release as the ovarian cycle progresses. However, at the
end of the cycle, with lack of fertilization of the ovum,
the corpus luteum degenerates and significantly re-
duces its release of estrogens and progesterone. Lower
levels of sex steroids release FSH from feedback
inhibition and allow the cycle to repeat itself.
In men, LH pulse frequency remains relatively
constant throughout adulthood, with a frequency of
1 pulse every 2–3 hr. High testosterone levels, however,
can significantly inhibit LH release, but FSH release is
not altered by testosterone. This inhibition thus occurs
at the level of the anterior pituitary gonadotropes.
Inhibin, a 3l-amino-acid peptide produced in the testes
and ovaries, inhibits the release of FSH in men, which
is thought to act mainly at the pituitary level.
Some of the feedback inhibition mediated by
estrogens occurs at the level of the anterior pituitary.
Estradiol, through interactions with their receptors,
reduces the effectiveness of hypothalamic GnRH upon
the gonadotropes, thus reducing the ‘‘amplitude’’ of
LH pulses but not their frequency. The feedback
inhibition mediated by progesterone, on the other
hand, is mediated exclusively at the level of the
hypothalamus. Hypothalamic feedback inhibition
initiated by gonadal steroids is unlikely to be mediated
at the level of the hypophysiotropic GnRH-containing
neurons because studies have failed to detect gonadal
steroid receptors in these neurons. However, many
neural systems contacting hypophysiotropic GnRH
neurons express these receptors. Thus, the brain
circuits providing innervation to hypophysiotropic
GnRH-containing neurons appear to be an important
100 PSYCHONEUROENDOCRINOLOGY
component regulating circulating gonadal steroids.
The large number of developmental (fetal life, child-
hood quiescence, puberty) and environmental factors
(daylight, nutrition, stress, exercise) regulating the
HPG axis also point to the importance of the circuitry
controlling it.
2. Brain Circuits Involved in the Regulation of
the HPG Axis
As discussed earlier, the presence of sex steroids,
particularly testosterone, around birth is crucial for
the development of the male phenotype and, particu-
larly, the brain regions involved in reproduction. These
dimorphic sex differences include larger nuclei in the
brains of men, including a region of the medial
preoptic, suprachiasmatic, and anterior hypothalamic
nuclei. Given the multiple origins of GnRH-contain-
ing neurons in the medial septal complex and hypo-
thalamus, the neural regulation of GnRH activity thus
could be very complex. There are a few well-character-
ized inputs that may play an important role in
reproduction. For instance, the sexually dimorphic
preoptic area receives afferents from the medial part of
the bed nucleus of the stria terminalis, the ventral part
of the lateral septal nucleus, the medial amygdaloid
nucleus, and the amygdalohippocampal area. These
areas are rich in sex steroid receptors and, in animals,
are known to contribute significantly to copulatory
behaviors as well as to sexual interest (perhaps desire).
The medial preoptic area also receives projections
from the sexually dimorphic medial preoptic nucleus,
as well as from some medullary catecholaminergic
neurons that contain estrogen receptors, which may
mediate, in part, the activational effects of catechola-
mines on GnRH release. Several other neurotransmit-
ter systems appear to directly stimulate or inhibit
GnRH release, including serotonin, GABA, substance
P, neuropeptide Y, CRH, and opiate peptides.
C. Dysregulation of Circulating Gonadal
Hormones
Observed gonadal hormone dysregulation has several
etiological causes. In women, menopause provides a
natural cause of long-term reduction in circulating
estrogens and progesterone, because the ovaries pro-
gressively lose their sensitivity to gonadotropins.
Surgical removal of the ovaries and various degenera-
tive ovarian diseases also account for reduced circu-
lating sex steroid levels in women. Low levels of
circulating sex steroids lead to larger pulsatile releases
of LH and FSH. The LH pulses are associated with
‘‘hot flashes,’’ a sensation of warmth spreading from
the trunk to the face. However, LH is not directly
involved in these hot flashes because hypophysectomy
does not abolish them; thus, a hypothalamic signal
responsible for both the LH surge and the hot flashes
appears to be responsible for this condition. Estrogen
replacement usually ameliorates the hot flashes and the
psychological fluctuations (irritability, depressed
mood) associated with menopause.
It is also the case that women have a much higher
incidence of depressive disorders than men. Attempts
to correlate reproductive hormone status with depres-
sion have generally suggested that women are most
susceptible to depression at the times in their ovarian
cycles when they experience the largest variations in
circulating hormones. Thus, women in the perimeno-
pausal period as well as after childbirth (post partum)
show increased risks of depressive illnesses, particu-
larly if they have a prior history of depressive mood. In
addition, the late luteal phase is associated with the
premenstrual syndrome (PMS), a period characterized
by increased cramps, bloating, breast tenderness, and
headaches physically and by significant moodiness,
anger, anxiety, and even depression psychologically in
some 30% of cycling women. In carefully controlled
studies, no differences between circulating estrogens,
progesterone, or LH could differentiate women with
or without PMS.
Nevertheless, effective treatment of PMS involves
the elimination of ovarian cycling, suggesting, some-
how, the involvement of circulating reproductive
steroids in this condition. Disturbances in memory
retrieval have also been associated with women
experiencing PMS. Estrogens have been shown to
interact significantly with subtype-specific serotonin
receptors (5-HT2A) in some limbic cortices and the
nucleus accumbens, areas putatively involved in
mood. This may provide the basis for the observation
that serotonin-specific re-uptake inhibitors (SSRIs),
one of the latest class of antidepressant drugs, may
have beneficial effects in menopausal depressed
women, particularly in combination with estrogen
replacement.
The testes usually continue to respond to gonado-
tropins throughout life even if it somewhat declines
with age; thus, men do not experience menopause.
However, the loss of the testes either surgically
(orchidectomy) or by diseases almost invariably leads
to a decline in sexual desire and impotence. Physically,
the lack of circulating testosterone also reduces some
 PSYCHONEUROENDOCRINOLOGY
of the secondary male sex characteristics, including
muscle loss, reduced body and facial hair, and
deposition of fat around the hips. Hot flashes also
are experienced by orchidectomized (castrated) men.
Testosterone replacement can reverse all of these
conditions, just as estrogen replacement reverses the
effects of low circulating estrogen levels in women.
Although aggressive behavior has been linked with
slightly higher circulating testosterone levels in men,
the general belief is that these might be reactive effects,
not the mediators of aggression as such. The possibility
still exists, however, that some violent–aggressive
types of behaviors might be correlated with higher
circulating testosterone levels. As is the case with the
ovaries, there are virtually no known conditions
leading to consistently high circulating testosterone
levels.
VI. FINAL COMMENTS
It is obvious from the preceding discussion that there
are clear psychologic and psychiatric outcomes asso-
ciated with endocrine imbalances. It is also remarkable
that one of the major psychologic outcomes of
hormonal dysregulation, be it due to hypo- or
hyperfunction, involves mood disorders. Restoration
of hormonal balance ameliorates the associated mood
disturbances in many instances. Likewise, endogenous
psychiatric conditions encompassing affective disor-
ders such as general anxiety and major depression have
a significant impact on several hypothalamo–pituitary
endocrine systems. Effective treatment of these condi-
tions also normalizes, in most cases, endocrinologic
functions. These observations strongly suggest a close
association between the brain substrates underlying
affect, on the one hand, and the control of endocrine
systems, on the other hand. Exactly how dysregulation
in one results in disruption of the other remains to be
determined. However, their close interactions further
101
suggest that the same brain systems responsible for
affect will also be prominently responsible for the
control of psychoneuroendocrine functions.
See Also the Following Articles
CHEMICAL NEUROANATOMY d CIRCADIAN
RHYTHMS d COGNITIVE PSYCHOLOGY, OVERVIEW d
HOMEOSTATIC MECHANISMS d NEUROPSYCHO-
LOGICAL ASSESSMENT d NEUROTRANSMITTERS d
PAIN AND PSYCHOPATHOLOGY d PEPTIDES,
HORMONES, AND THE BRAIN AND SPINAL CORD d
PSYCHONEUROIMMUNOLOGY d PSYCHOPHYSIOLOGY
d SEXUAL DIFFERENTIATION, HORMONES AND d
STRESS: HORMONAL AND NEURAL ASPECTS
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