Download The Hypothalamic-Pituitary-Adrenal Axis: The Actions of the Central

The Hypothalamic-Pituitary-Adrenal Axis:
The Actions of the Central Nervous System
and Potential Biomarkers
Kelly L. Olson, Ph.D.;
David T. Marc, M.S.; Lindsay A. Grude, B.S.;
Corena J. McManus, M.S.; Gottfried H. Kellermann, Ph.D.
NeuroScience, Inc. (Osceola, WI)
First published as:
“Chapter 10. The Hypothalamic-Pituitary-Adrenal Axis:
The Actions of the Central Nervous System and Potential Biomarkers.”
Kelly L. Olson, Ph.D.; David T. Marc, M.S.; Lindsay A. Grude, B.S.;
Corena J. McManus, M.S.; Gottfried H. Kellermann, Ph.D.
Anti-Aging Therapeutics Volume XIII, 91-100;
(c) American Academy of Anti-Aging Medicine; Chicago, IL USA; 2011. .
Reprint prepared for NeuroScience Inc. by A4M. The A4M does not endorse, in either direct
or implied manner, the Author(s), their Affiliation(s), or the content of their work.
Chapter 10
The Hypothalamic-Pituitary-Adrenal Axis:
The Actions of the Central Nervous System and Potential Biomarkers
Kelly L. Olson, Ph.D.;
David T. Marc, M.S.; Lindsay A. Grude, B.S.;
Corena J. McManus, M.S.; Gottfried H. Kellermann, Ph.D.
NeuroScience, Inc. (Osceola, WI)
ABSTRACT
The adrenal glands are part of an adaptive system involved in the maintenance of a homeostatic
biological balance in response to stress. The adrenal glands release cortisol, epinephrine, and
norepinephrine to preserve a healthy, but dynamic equilibrium. Specific brain nuclei control adrenal gland
function either through the actions of the hypothalamic-pituitary-adrenal (HPA) axis, initiated by traditional
HPA drivers like corticotrophin releasing factor (CRF) from the hypothalamus, or through direct
innervation by stimulated preganglionic sympathetic nerves. These pathways can be activated by
physical or emotional stressors as well as inflammatory processes which can activate adrenal activity
through the signaling of various cytokines. The continuum of hyperstimulation of the HPA axis from an
acute insult to a chronic saturation of the system is led by varying degrees of adrenal collapse eventually
giving way to adrenal fatigue. The functionality of the HPA axis can be evaluated with peripheral
biomarkers such as urinary epinephrine and norepinephrine and salivary cortisol. These HPA biomarkers
help practitioners identify contributing factors to various clinical conditions and provide insight into
potential intervention points. By understanding the pathways that can lead to altered HPA axis activity
and by using biomarkers to assess HPA functionality, health care practitioners can make more informed
clinical decisions to enhance patient care.
Keywords: HPA axis, neurotransmitter, biomarker, central nervous system, adrenal gland, cortisol
INTRODUCTION
Modern day stressors such as relational dysfunctions or physical challenges constantly threaten
the homeostatic balance that a healthy, functioning organism is charged in the maintenance of. However,
when jeopardized by excessive or constant stress, the biological system begins to lose ground in its
ability to maintain chemical stability and instead allows pathological discord to rule.
Stress is defined as “a state of threatened homeostasis,” and any alterations in the ability to
respond to stress may lead to disease.1 During a stress response a number of changes to the
physiological functioning of the organism can occur, primarily led by the release of glucocorticoids and the
catecholamine neurotransmitters epinephrine and norepinephrine from the adrenal glands.2 Epinephrine
and norepinephrine are released from the adrenals as hormones into circulation and act on a variety of
different tissues. Their function is dependent on the type of adrenergic receptor that is expressed on the
tissues. Typically, these neurotransmitters are described as initiators of the fight or flight response, as
they increase respiration and heart rate, and trigger the release of glucose from energy stores.3 The
glucocorticoid cortisol contributes to carbohydrate, protein, and fat metabolism, regulates blood glucose,
and suppresses the immune system. Excess release of neurotransmitters and glucocorticoids from the
adrenal glands, if left unchecked, can advance the development of a number of pathological responses.4
The control and release of these molecules from the adrenal glands is mediated through a network of
central nervous system (CNS) neurons with resultant peripheral nervous system (PNS) effects,
collectively known as the hypothalamic-pituitary-adrenal (HPA) axis. But what are the key brain nuclei in
this intricate central communication and how do they initiate a response? A better understanding of the
consequences of stress on the central nervous system and accordingly, HPA axis function and adrenal
responses, provide solutions to these questions.
In the human body, the CNS and the PNS function together to coordinate the actions of the
endocrine and immune systems, along with all other biological processes. Under healthy conditions,
changes in internal and external milieu are received and processed by the nervous system to elicit an
appropriate action. When faced with excessive stress, whether physical or emotional, adaptive systems
function to maintain a dynamic equilibrium. The autonomic nervous system (ANS) is part of the PNS and
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consists of sympathetic and parasympathetic divisions. The HPA axis is an adaptive system in the
sympathetic division that regulates the biological response to stress through the release of
glucocorticoids, epinephrine, and norepinephrine in the periphery.
These hormones and
neurotransmitters can be measured as biomarkers to assess HPA activity and the determinant central
pathways.5,6
A breadth of research has examined HPA axis function and the relationship between CNS and
PNS biochemistry. The physiological consequences of stress and HPA activation appear as enhanced
attention, accelerated cardiac output and respiration, increased catabolism, and redirection of blood flow
to provide the highest perfusion to the brain, heart, and muscles.1 Interestingly, these resultant
physiological actions of the HPA axis are tightly regulated by specific brain circuits.7 Neuronal impairment
of these brain circuits prevents adrenal neurotransmitters and hormones from performing their required
biological functions, consequently leading to a state of imbalance and various pathological conditions.8
Therefore, measurement of biomarkers has become an important tool to predict the CNS circuitry that
underlies the discordance in HPA axis function.
When considering peripheral biomarkers to assess CNS activity, the validity of such an approach
is called into question. Due to the presence of the blood-brain-barrier limiting the transport of
neurotransmitters from the periphery to the CNS, it is often assumed that the transport of
neurotransmitters from the CNS to the periphery is also limited, when in fact, central neurotransmitters
are carried via transporters to the periphery.9 Additionally, research has clearly illustrated the relationship
and crosstalk between the CNS and PNS.10-14 Therefore, understanding the neural circuits that mediate
this crosstalk and viewing peripheral biomarkers as a reflection of central activity can provide practitioners
with powerful insight into CNS function and a better understanding of the etiology and treatment of HPA
axis dysfunction.
In this review, information will be presented on brain circuits that regulate HPA axis activity, the
use of biomarker measurements to delineate specific neural circuits that control HPA axis function, and
the association between neuronal impairment, biomarkers, and stressful challenges that lead to impaired
HPA axis function and eventual adrenal dysregulation.
THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
The Neurocircuitry of the HPA Axis
The HPA axis is organized into three distinct regions: the hypothalamus, pituitary gland, and
adrenal glands. Specifically, the paraventricular nucleus (PVN) is the hypothalamic region that uses
corticotrophin-releasing hormone (CRH) to stimulate the pituitary.15 Upon stimulation, the anterior pituitary
releases adrenocorticotrophin hormone (ACTH), which is transported in general circulation to the adrenal
cortex of the adrenal glands.16 The adrenal glands rapidly synthesize and release cortisol into the blood
where it participates in the response to stress and maintenance of homeostasis throughout the body.15
The adrenal gland is the effector organ of the HPA axis and its actions are essential to
maintaining homeostasis. Although much research has focused on the hypothalamic-pituitary regulation
of adrenal function, other pathways exist that can alter adrenal activity. Neural projections from the CNS
affect adrenal activity by acting at different levels of the HPA axis.
Sympathetic Innervation of Adrenal Gland
One pathway that regulates adrenal function involves sympathetic preganglionic fibers that
project to the adrenal medulla to elicit the release of epinephrine and norepinephrine as hormones into
circulation (Fig. 1).17 The neural pathways that innervate the adrenal medulla are mediated by the
stimulation of sympathetic preganglionic neurons that originate in the intermediolateral (IML) cell
column.18 The IML cell column extends from the first thoracic through the third lumbar segment and
receives excitatory projections from specific brainstem and hypothalamic regions which can alter adrenal
activity.18 Specifically, the IML receives excitatory projections originating in the lateral hypothalamus (LH)
and rostral ventrolateral medulla (RVLM). Stress can initiate this pathway through the activation of the LH
and RVLM.
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Figure 1. Sympathetic preganglionic fibers, activated by various brain nuclei in response to stress, project
directly to the adrenal medulla to elicit the release of epinephrine and norepinephrine into circulation.
Neural Input to Hypothalamic Paraventricular Nucleus
Stimulation of the adrenal glands via the classical hypothalamic-pituitary pathway is also under
stringent control by the CNS. Specifically, the PVN can be stimulated by excitatory projections from
specific brainstem nuclei, limbic centers, the basal forebrain, and circumventricular organs.19,20 The
brainstem nuclei that send excitatory projections to the PVN include the locus coeruleus (LC) and dorsal
raphe (DR). During times of stress, the LC and DR use norepinephrine and serotonin, respectively, to
stimulate the PVN. From the limbic system, the areas involved include the amygdala and hippocampus,
which are important for emotion, behavior, and memory. Strong emotions or emotional memories can
trigger the amygdala and hippocampus to stimulate the PVN.21,22 Increased PVN activity causes
enhanced cortisol release leading to a rise in vigilance to deal with the stressor (Fig. 2).
Cytokines from an inflammatory response can also contribute to PVN activation. Research has
thoroughly described the relationship between pro-inflammatory cytokines mediated by immune system
activation and adrenal function. Upon insult or injury, cytokines released by immune cells can alter brain
chemistry in two ways. The first is a humoral pathway, whereby cytokines are released into systemic
circulation and can act on circumventricular organs such as the area postrema (AP).13 The
circumventricular organs are areas of the brain that have incomplete blood-brain barriers and can
therefore detect and relay chemical signals (e.g. pro-inflammatory cytokine responses) to the brain. In
this way, cytokines can directly alter CNS function without the use of transport systems. Upon activation,
the AP transmits signals to the nucleus tractus solitarius (NTS). From there, the NTS stimulates the PVN,
which leads to enhanced adrenal gland activity.13
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Figure 2. The paraventricular nucleus of the hypothalamus (PVN) receives input from several areas of the
brain, including brainstem nuclei, limbic centers, and circumventricular organs. The PVN integrates these
signals and activates the HPA axis cascade, resulting in the release of cortisol from the adrenal cortex.
The second way cytokines can alter brain activity is via a neural pathway, whereby cytokines
released by immune cells in lymphoid tissue activate the vagus nerve to signal to the brain that an
inflammatory process is occurring. The vagus nerve projects to the NTS, causing stimulation of the PVN,
which again leads to enhanced adrenal activity and cortisol release.13 Cortisol acts on glucocorticoid
receptors expressed on immune cells to inhibit pro-inflammatory cytokine production and stimulate antiinflammatory cytokine production.23,24 Epinephrine and norepinephrine effect a similar response by
and
binding to β-adrenergic receptors.25 The anti-inflammatory response of glucocorticoids
catecholamines released from HPA activation can decrease pro-inflammatory cytokine levels as a
protective mechanism to avoid tissue damage.26
Specialized Stress Pathways
It is interesting to note that different types of stress, (physiological and emotional), activate the
HPA axis through separate, but convergent, pathways. That is, although different types of stress are
involved in different circuits, the end result culminates in HPA activation and glucocorticoid release.27
Physiological or ‘real’ stress is detected by somatic, visceral, or circumventricular pathways. True,
physical changes in the body, including respiratory and cardiovascular changes, pain, and elevated levels
of circulating inflammatory mediators, represent a current, tangible threat to homeostasis.27 This sensory
information is communicated through ascending vagus nerves and circumventricular organs that
converge on the NTS, which integrates the sensory input and passes it along to the PVN.
Unlike the physiological stress response, which is a reaction to an actual disturbance to
homeostasis, an emotional, or anticipated, stress response can happen without a primary sensory
stimulus. Emotional stress elicits HPA activation in anticipation of a potential homeostatic disruption 27. As
mentioned above, limbic brain regions such as the amygdala and hippocampus are heavily involved in
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emotional processing, behavior, and memory, and will stimulate the PVN when activated. A fear
response triggered by climbing a ladder, for example, would evoke glucocorticoid release, consequently
increasing vigilance to prevent a fall.
Chronic Stress Effects
The HPA axis is an innate system adept at compensating for the detrimental effects of acute
stressors, reining the system back into equilibrium. The system is meant to respond to an acute stressor
and then terminate that response via negative feedback mechanisms. This ebb and flow adaptive effect
is crucial to the survival of an organism (for review see Ziegler & Herman20). However, chronic HPA
stimulation due to ongoing physical or emotional stress can lead to unresponsiveness of hypothalamic
nuclei.28 Additionally, if the adrenals maintain a high level of activity to mobilize cortisol, epinephrine, and
norepinephrine, the stores of these hormones may become depleted. Taken together, these events lead
to adrenal insufficiency, which reduces the gland’s ability to maintain homeostasis. An insufficient
adrenal response to stress or an immune challenge prevents the body from being able to deal with the
stress or fight off infection.28, 29
Overall, the HPA axis receives input from a variety of central and peripheral sources, and it is the
integration of these signals that allows this system to produce the appropriate homeostatic response.
However, excessive stimulation of the HPA axis by one or more of these inputs can disrupt its ability to
maintain homeostasis, which could then lead to a disease state.
Biomarkers of HPA Activity
Neurotransmitter and hormone measurements can be used as indicators of biological imbalances
and may help improve our understanding of complex disease states. In many areas of medicine,
biomarkers aid in diagnosis, prognosis, and predicting treatment efficacy.30 For example, cholesterol is
commonly assessed to determine the risk of cardiovascular disease and subsequently re-tested to
monitor treatment efficacy, and prostate-specific antigen (PSA) is used in the detection of prostate
cancer.
In psychiatry, diagnostic and treatment decisions are made by evaluating subjective measures
such as clinical signs and symptoms. With the development of biomarkers for particular psychiatric
disorders, it is anticipated that more objective criteria for those disorders can be achieved, which would
reduce evaluator bias due to emotions or personal prejudices.30 Schwarz and Bahn31 established the
need for biomarkers in psychiatry to monitor responses to treatment and to predict clinical outcome.
These authors stated that the efficacy of a medication for a particular patient should be assessed using
biomarkers to reduce the chance of selecting unsuccessful treatment for complex diseases.31 In terms of
the HPA axis, urinary epinephrine and norepinephrine and salivary cortisol can serve as indicators to
detect a dysfunctional state and aid in the selection of various treatments to either increase or decrease
adrenal activity.
In the past, biomarker assessments have been viewed as irrelevant to symptomatology because
measures had included peripheral biological fluids, such as blood, urine, and saliva, but not CNS
markers, such as cerebrospinal fluid and brain tissue.32 A common misconception about peripheral
biochemistry is that it cannot serve as a biological indicator of CNS activity due to dissociation of the
systems.33 Although this is a reasonable argument as peripheral biomarkers, such as circulating
neurotransmitters and hormones, are markers of PNS activity, compelling evidence exists to support the
crosstalk between the peripheral and central nervous systems.34 The CNS and PNS must not be viewed
as separate entities. We have demonstrated above that specific CNS nuclei can manipulate peripheral
neurochemistry, and peripheral neurochemistry can affect central pathways (e.g. vagal afferents from
periphery to CNS).35 The pathways described above demonstrate that the CNS and PNS communicate
via direct neuronal projections. Therefore, it is possible to obtain inferences on central profiles through the
measurement of peripheral biomarkers such as urinary neurotransmitters and salivary hormones.36
Using HPA Biomarkers to Assess Clinical Symptoms
Altered HPA axis activity has widespread effects throughout the body, and can contribute to
changes in energy, sleep, mood, cognition, weight, and the cardiovascular system, among others. More
specifically, HPA axis hypoactivity has been associated with chronic fatigue syndrome (CFS), possibly
due to blunted ACTH and CRH responses.37 Studies have shown that there is an association between the
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development of obesity and adrenal activity, evident by elevated urinary norepinephrine and lower urinary
epinephrine.38 Another study demonstrated that in older patients, higher salivary cortisol levels are
correlated with impaired declarative memory.39 These studies support the use of HPA biomarker
measurements to understand the biochemical contributors to various clinical conditions.
Altered HPA axis activity has also been found to have profound effects on mood and behavior
that are characteristic of a variety of psychiatric disorders.40-43 In fact, literature supports the relationship
between psychiatric disorders and abnormal HPA axis activity and has demonstrated the utility of urinary
measures of epinephrine, norepinephrine, and salivary cortisol to assess HPA axis function.38,44-48 For
example, patients with panic disorder were found to have higher morning cortisol levels compared to
controls,49 but also lacked a significant cortisol increase in response to psychosocial stress.50 Whilst
Hughes demonstrated a positive correlation between elevated urinary norepinephrine and cortisol levels
and depression and anxiety symptoms.46 Assessment of epinephrine, norepinephrine, and cortisol, given
their neurochemical involvement in HPA axis activity and their association with psychiatric disorders,
could provide the necessary biochemical targets to determine underlying cause and predict treatment
outcome.51
Adrenal function can also vary according to the nature of the stressor. Miller and colleagues
conducted a meta-analysis to determine why differences in adrenal responses exist among individuals
exposed to chronic stress.52 They discovered that stress which threatens physical integrity, for example
combat, elicits higher cortisol output throughout the day. Whereas stress that poses a threat to social self,
such as divorce, is associated with higher cortisol in the morning and evening. It is hypothesized that the
body increases adrenal activity to mobilize resources when necessary to efficiently evade a stressor. The
question remains as to how these different stressors affect specific brain regions. Much of the research
that examines specific stressors is confounded by the inability to control other stressors initiated by
inflammatory processes or injury.52 Because the HPA axis plays an integral role in responding to different
types of stressors and incorporating signals from the CNS and PNS, it serves as a biological “middleman”
that utilizes specific neurotransmitters and hormones as chemical signals. By understanding the
interactions between these brain pathways and the HPA axis, one can gain a better understanding of how
stress mediated by CNS pathways can provoke alterations in urinary neurotransmitter and salivary
cortisol measurements.
Using HPA Biomarkers to Assess Treatment
Convincing data suggests that urinary neurotransmitters and salivary hormones can predict
treatment outcome and monitor treatment efficacy. Mooney and colleagues assessed the effects of
antidepressants in depressed patients by monitoring urinary neurotransmitter levels. Depressed patients
with a favorable antidepressant response to alprazolam, a benzodiazepine, were found to have
significantly higher pretreatment urinary catecholamine levels than control subjects.53 The antidepressant
response of alprazolam was monitored in responders and non-responders with subsequent urinary
neurotransmitter analysis. The data demonstrated a significant decrease in urinary catecholamines after
eight days of alprazolam treatment, which was consistent with improvements in depressive symptoms.
Additionally, non-responders to alprazolam did not display significant elevations in pretreatment urinary
catecholamine levels compared to control subjects. Alprazolam possesses clear inhibitory effects on the
HPA axis in both animals and humans by suppressing hypothalamic and suprahypothalamic levels of
corticotrophin-releasing hormone.54 The activity of alprazolam in the CNS would predicatively change
circulating levels of catecholamines by manipulation of HPA axis function.53 Thus, changes in circulating
levels of catecholamines could be used to monitor the efficacy of alprazolam, a centrally active
compound.53
Another study showed that after one month of Pycnogenol® treatment, a bioflavonoid extract
from pine bark, norepinephrine levels decreased significantly, which correlated with improvements in
ADHD symptoms.55
HPA biomarkers can also be used to monitor non-pharmacological treatment. In a study using
cognitive-behavioral therapy to treat major depressive disorder, salivary cortisol decreased significantly
more in patients treated in the forest compared to patients treated in a hospital setting, and the decrease
in cortisol corresponded with symptom improvements.56 These findings further illustrate the fundamental
usefulness of urinary neurotransmitter and salivary cortisol measurements in the determination of
treatment selection and effectiveness.
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The fact that there is a direct involvement of the CNS in the release of neurotransmitters in the
periphery explains why the CNS and PNS must be viewed as parts of a single integrated system.35
Although there are clear anatomical separations between the CNS and PNS, their functional roles cannot
be viewed separately. By understanding the neurocircuitry that enables centrally acting compounds to
manipulate peripheral markers and the correlative parallels between the neurotransmitters in the CNS
and the periphery, predictions on treatment choice as well as outcome can be made via the measurement
of peripheral biochemistry.
CONCLUDING REMARKS
The HPA axis is influenced by a variety of brain nuclei in response to stress. Stress is typically
associated with emotional or social demands; however, a broader definition can be applied to stress to
include inflammatory processes due to infection or injury. Whether stress occurs due to a traumatic event,
divorce, or a severe burn, brain pathways are initiated to activate the HPA axis. The coordinated actions
of the brain and HPA axis in response to stress results in the release of cortisol, epinephrine, and
norepinephrine into the periphery. The production of these hormones from the adrenal gland is essential
to overall health and wellbeing. They provide a mechanism in which humans and other organisms
exposed to many different forms of stress can regain homeostasis. However, continuation of stressors
can leave an individual at risk for developing mood disorders or infections caused by pathophysiological
functioning of the adrenal gland. Urinary epinephrine and norepinephrine and salivary cortisol can be
used as HPA biomarkers to help identify contributing factors to various clinical conditions and provide
insight into potential intervention points.
The evidential support from the current literature suggests that urinary epinephrine and
norepinephrine and salivary cortisol testing have an important role in clinical practice as representative
biomarkers of HPA axis activity. There is growing evidence that the central pathways that alter HPA axis
activity are important in the interpretation of these biomarkers.
By understanding the mechanism(s) for treatment and the factors leading to changes in urinary
neurotransmitter and salivary hormone balance, health care practitioners will benefit from these tools to
assist in making more informed therapeutic decisions and monitoring treatment regimens with enhanced
patient care.
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ABOUT THE AUTHORS
Dr. Kelly Olson’s background as a neuropharmacologist began with a Masters in Science from
the University of North Dakota in 1999. She received her Ph.D. in 2007 from the University of Manitoba,
Winnipeg, MB, Canada in Pharmacology and Therapeutics. She accepted a position as Director of
Research and Development with NeuroScience, Inc., a company based out of Wisconsin, focusing
primarily on systems biology. Currently, Kelly works as the Clinical Director of Research and
Development at SleepImage in Denver, CO., examining molecular aspects of sleep neurocircuitry,
developing patents, investigating clinical data, giving presentations to the medical community and
coordinating global research for a sleep monitoring medical device.
Dr. Gottfried Kellermann is the founder, President, and CEO of NeuroScience, Inc. and is
considered a foremost authority in the assessment and clinical application of neurotransmitter-related
health concerns.
100
Kelly Olson, Ph.D.
Dr. Kelly Olson's background as a neuropharmacologist
began with a Masters in Science from the University of North
Dakota in 1999. She received her Ph.D. in 2007 from the
University of Manitoba, Winnipeg, MB, Canada in Pharmacology
and Therapeutics. She accepted a position as Director of
Research and Development with NeuroScience, Inc., a company
based out of Wisconsin, focusing primarily on systems biology.
Currently, Kelly works as the Clinical Director of Research and
Development at SleepImage in Denver, CO., examining
molecular aspects of sleep neurocircuitry, developing patents,
investigating clinical data, giving presentations to the medical
community and coordinating global research for a sleep
monitoring medical device.
Gottfried Kellermann, Ph.D.
Dr. Gottfried Kellermann is the founder, President, and CEO
of NeuroScience, Inc. and is considered a foremost authority
in
the
assessment
and
clinical
application
of
neurotransmitter-related health concerns.