Endocrinology Vol. 139, No. 2 437-440
Copyright © 1998 by The Endocrine Society
Editorial: Ultradian, Circadian, and Stress-Related Hypothalamic-Pituitary-Adrenal Axis Activity—A Dynamic Digital-to-Analog Modulation
George P. Chrousos, M.D.
Chief, Section on Pediatric Endocrinology
Developmental Endocrinology Branch
National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland 20892-1862
Address all correspondence and requests for reprints to: George Chrousos, M.D., NIH, Building 10, Room 10N262, Bethesda, Maryland 20892-1862.
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Introduction
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The hypothalamic-pituitary-adrenal (HPA)
axis helps to maintain basal and stress-related homeostasis of central
nervous system (CNS), cardiovascular, metabolic, and immune functions
(1, 2). Disregulation of this axis is involved in several behavioral,
circulatory, endocrine/metabolic and immune disorders. In this issue of
the journal, Windle et al. (3) report a detailed assessment
of the ultradian rhythmicity of corticosterone secretion in the rat.
Using an automated, frequent blood sampling technique, they
demonstrated that the end-hormone of the HPA axis was secreted in an
ultradian pulsatile fashion, with secretory episodes occurring in a
constant frequency but with a variable amplitude. The nocturnal
circadian rise of corticosterone secretion resulted from increases in
the amplitude of the pulses, whereas a brief stressor increased or
failed to stimulate the secretion of corticosterone, depending on its
timing, during or after a secretory episode, respectively. These
findings make a lot of sense and merit commentary.
The main regulation of the ultradian, circadian, and
stress-related activity of the HPA axis occurs at the level of the
hypothalamus, in particular the parvocellular components of the
paraventricular (PVN) nuclei (1, 2). There, a finite number of neurons
produce and secrete CRH and arginine vasopressin (AVP) into the
hypophyseal portal system (Fig. 1
). The
majority of these neurons secrete CRH or AVP, whereas a minority
secretes both neuropeptides. CRH and AVP appear to enhance the activity
of each other and they synergistically stimulate ACTH secretion by
corticotroph cells (4, 5, 6). In certain situations, AVP secreted by
collateral neuronal fibers of magnocellular neurons from the PVN and/or
supraoptic (SON) nuclei participates in ACTH stimulation (7). Studies
from experimental animals and humans have suggested that both
parvocellular CRH and AVP are secreted in an ultradian pulsatile
fashion and participate in the generation of a circadian ACTH and
cortisol rhythm and in the elevation of the concentrations of these
hormones during acute stress, by increasing the amplitude rather than
the frequency of their ultradian secretory episodes (8, 9, 10, 11, 12, 13, 14, 15).
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Figure 1. The hypothalamic-pituitary-adrenal axis and its
regulatory inputs. CRH and AVP secreted by parvocellular neurons of the
paraventricular nucleus (PVN) of the hypothalamus into the hypophyseal
portal system, synergistically stimulate corticotroph cells of the
anterior pituitary gland to release ACTH. This, in turn, activates
cortisol secretion by the zona fasciculata of the
adrenal cortices. AVP secreted by collateral fibers of the
magnocellular AVP-secreting neurons from the PVN and supraoptic nucleus
participates in the stimulation of ACTH, when such neurons are
activated in response to blood volume/pressure or osmotic stimuli. The
parvocellular CRH and AVP neurons secrete their products in a pulsatile
fashion with a relatively constant ultradian frequency. The amplitude
of these secretory episodes is regulated by circadian, homeostatic, and
stress-related signals. The sensitivity of the pituitary corticotroph
and the adrenal zona fasciculata are influenced by
endocrine and/or neurocrine signals and by the functional/structural
status of these organs.
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In the early 1980s, when ovine (o) and human (h) CRH became
available for clinical studies and development of specific RIAs,
Schulte et al. (12) administered large doses of oCRH as a
continuous infusion to normal male volunteers. The circulating levels
of oCRH attained were approximately 10 times higher than the
concentrations of this neuropeptide in the hypophyseal portal system of
rats. In response to these constantly elevated levels of oCRH, the
frequently measured plasma ACTH and cortisol concentrations were
increased, however, they retained their ultradian pulsatile and
circadian patterns of secretion. These data suggested that a second CRF
was secreted in an ultradian pulsatile and circadian fashion, which
allowed retention of the typical secretory pattern of these hormones,
in spite of the constant exposure of the corticotroph to high
concentrations of CRH. Subsequent studies in rats (9, 11), sheep (10),
horses (8), monkeys (14), and humans (13, 15) suggested that CRH and
AVP are both secreted episodically at the relatively constant and
similar frequencies of 1 to 3 secretory episodes per hour, with a
temporal overlap of approximately 80% (Fig. 2A). The synchrony and amplitudes of
these pulsations increase, the latter severalfold, in a circadian
fashion and during stress (Fig. 2B).
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Figure 2. A heuristic representation of the secretory
episodes of CRH and AVP in the hypophyseal portal system and of the
resultant ACTH and cortisol/corticosterone concentrations in the
systemic circulation. Note the relatively constant ultradian frequency
and increasing circadian (A) and stress-related (B) amplitude of the
CRH, AVP, ACTH, and cortisol/corticosterone pulses.
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Thus, the generation of the baseline ultradian pattern of the
activity of the HPA axis depends on a relatively constant oscillation
of the parvocellular CRH, AVP, and CRH/AVP neurons, with the
superimposition of several constitutive inputs, all expressed primarily
as changes in amplitude (1, 2). These include: positive circadian
input(s) from one or more pacemakers, tonic positive input from the
locus caeruleus/norepinephrine (LC/NE) and dopaminergic
mesocorticolimbic systems, tonic negative input from the hippocampus
and prefrontal cortex and negative feedback input from the arcuate
nucleus-POMC-peptidergic system and the end-hormone of the HPA axis
cortisol or corticosterone, depending on the species. It appears that
the CRH component of the HPA axis is more sensitive to the suppressive
effect of glucocorticoids than the AVP component, and this includes not
only the secretion of CRH vs. AVP but also the ability of
these hormones to stimulate ACTH secretion; the hypothalamic
magnocellular AVP-secreting neurons, on the other hand, may not be
suppressed by glucocorticoids (16, 17).
The generation of the stress-related increase in the activity of
the HPA axis also depends on the relatively constant ultradian
oscillation of the parvocellular CRH, AVP, and CRH/AVP neurons, and the
superimposition of stress-related inputs, resulting in amplitude
increases (1, 2). These are exerted directly and/or via activation of
the locus caeruleus/norepinephrine (LC/NE) system and include:
emotional stress inputs from the amygdala and the dopaminergic
mesocorticolimbic system and prefrontal cortex, circulatory stress
signals from changes in blood volume or pressure through vagal afferent
nerves, osmotic, and chemical signals sensed humorally and through
vagal afferent signals, as well as inflammatory and pain inputs, also
sensed humorally and neurally, through vagal and sensory afferent
nerves. Hypovolemia, hypotension, and hypersmolality also activate
magnocellular AVP neurons, which secrete in both the hypophyseal portal
system and the systemic circulation (7).
Additional influences on the activity of the HPA axis are exerted
by the reproductive system, primarily through positive estrogen input
on the CRH, AVP, and LC/NE systems, and by the leptin/neuropeptide Y
system, primarily through inhibition of the CRH/AVP and stimulation of
the LC/NE systems (18, 19). The former explains the sexual dimorphism
of the stress response generally characterized by an increased HPA axis
activity in the female; the latter explains the hyperactivity of the
HPA axis/hypoactivity of the LC/NE system in malnutrition and anorexia
nervosa. Finally, sleep-related, estrous, menstrual, gestational and
circannual inputs to the HPA axis system play important roles in the
physiology and pathophysiology of this system.
The formulation of the secretory dynamics of the HPA axis
described above agrees with many but not all reports on the ultradian,
circadian and stress-related activity of this axis in animals and man.
It is important to mention several technical caveats in the
interpretation of pulsatility data, which may explain some of the
controversy. First, the frequency of sampling should be higher than the
secretory frequency of the hormone examined to avoid missing hormonal
spikes; second, the sampling interval should be at least half of the
plasma half-life of the hormone in the distribution compartment
measured (portal blood, venous blood, etc.); secretory episodes of a
hormone may not be detected if the intervals between secretory stimuli
are briefer than the half-life of the hormone; third, the assay of the
hormone measured should be sensitive enough to detect meaningful
(bioactive) concentrations of the hormone and as least variable as
possible to avoid detection of false pulsations.
Assuming that all of the above criteria are fulfilled, one could
attempt to address the findings of a number of human studies based on
the minimum requirement of an oscillatory CRH/AVP neuron system with a
relatively constant ultradian rhythm and many superimposed inputs as
modifiers of its amplitude. This formulation explains why the ultradian
and circadian ACTH and cortisol pulsatility persist in the presence of
continuously high concentrations of oCRH in plasma of normal volunteers
or surgically cured patients with Cushing’s syndrome with tertiary
adrenal insufficiency due to adrenal suppression (12, 20); it also
explains why in the third trimester human pregnancy, the highly
elevated but noncircadian levels of circulating placental CRH are
accompanied by ultradian and circadian ACTH and cortisol secretion (21)
and why in melancholic depression most recent studies have found
constant frequency of the ultradian pulsatility of ACTH and cortisol
with increases in the evening amplitude of these pulses. This
formulation also explains data from major abdominal surgery: presence
of ultradian CRH secretory episodes with a frequency of 1–2 pulses per
hour, a constantly elevated plasma AVP concentration, and a gradually
increasing plasma cortisol during approximately 5 h of surgery
(13). By extrapolation from these data, one would expect increased
amplitude ACTH and cortisol pulses in hypercortisolemic states other
than melancholic depression, including chronic inflammatory stress, for
example multiple sclerosis (22) or suboptimately controlled diabetes
mellitus (23), and decreased amplitude ACTH and cortisol secretory
episodes in states characterized by low CRH secretion, such as atypical
depression, postpartum blues/depression, the chronic
fatigue/fibromyalgia syndromes and climacteric depression (24, 25, 26, 27).
A good understanding of the above formulation is important to our
investigations of the multitude of conditions that are associated with
chronic disregulation of the HPA axis and to our providing optimal
diagnostic and therapeutic management in several such states. We know
for example that the number of parvocellular CRH, AVP, and CRH/AVP
neurons increase with age in humans (28), and this is paralleled by
increases in the cerebrospinal fluid levels of CRH (29). We also know
that patients with melancholic depression have 2- to 3-fold more of
these neurons than nondepressed persons (28). Whether this increase is
a reflection of genetics or prior experience or both is not known as
yet, but it could be used as a trait diagnostic criterion in this
condition. Novel imaging methods or provocative endocrine tests could
be developed to ascertain such information which could be useful in
taking preventive measures or making therapeutic decisions. Finally, on
the basis of this formulation, one could venture predicting that novel
therapies with nonpeptidic CRH receptor type 1 antagonists will exert
their expected anxiolytic/anti-depressant effects without abolishing
the basal rhythmicity of the HPA axis or its ability to respond to
stress–both prerequisites of chronic therapy with such agents
(30).
Received November 26, 1997.
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Introduction
References