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Ania Korszun, Josephine Astrid Archer, Elizabeth Ann Young: Chapter 7. Psychoneuroendocrinology, in The American
Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff.
Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.417048. Printed
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Chapter 7. Psychoneuroendocrinology
PSYCHONEUROENDOCRINOLOGY: INTRODUCTION
An association between hormones and psychiatric disorders has been long recognized, but it is only
in the past few decades that we have reached an understanding of the mechanisms underlying this
association. A full account of the myriad ways in which the various endocrine systems influence
neurobehavioral function would be beyond the scope of a single chapter. We will therefore focus on
examples of promising research directions in this area: namely, how the stress and reproductive
hormone axes contribute to the pathoetiology of psychiatric conditions, in particular mood and
anxiety disorders.
Major depression is considered to be a maladaptive, exaggerated response to stress, and although
it is accompanied by abnormalities in multiple endocrine systems, it is the
hypothalamic-pituitary-adrenal (HPA) axis that is the main component of the physiological stress
response that plays the key role. Stressful life events, particularly those related to loss, have a
strong causal relationship with depressive episodes. However, not all people who experience such
events develop depression, and an individual’s vulnerability to depression depends on the
interaction of genetic, developmental, and environmental factors. In addition to the role of the HPA
axis in depression, there is growing evidence of HPA axis abnormalities in anxiety disorders and
posttraumatic stress disorder (PTSD).
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
The HPA axis transforms stressful stimuli into hormonal messages that enable the organism to
adapt to environmental change and to maintain the body’s homeostasis. Corticotropin-releasing
hormone (CRH) is synthesized in the hypothalamus and is stimulated by stressors, which can be
either “physical” (e.g., exercise, starvation) or “psychological” (e.g., perceived danger, stressful
life events). The HPA axis is closely linked to the autonomic nervous system, and brain stem
catecholamine systems can also “activate” CRH release (Herman et al. 1990; Plotsky 1987; Plotsky
et al. 1989). CRH stimulates secretion of pituitary adrenocorticotropic hormone (ACTH), resulting in
the secretion of glucocorticoids by the adrenal cortex in a feedforward cascade. Cortisol is the main
glucocorticoid, and its secretion is tightly controlled by negative feedback effects of glucocorticoids
at both pituitary and brain sites. These comprise very rapid real-time inhibition of the stress
response that prevents oversecretion of glucocorticoids (Keller-Wood and Dallman 1984) and
results in a slower effect on messenger ribonucleic acid (mRNA) and subsequent protein stores for
both CRH and the ACTH precursor, pro-opiomelanocortin (Roberts et al. 1979) (Figure 7–1).
FIGURE 7–1. The hypothalamic-pituitary-adrenal axis.Print: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; FSH = follicle-stimulating
hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone.
Stressful stimuli activate all levels of the HPA axis, causing increases in CRH, ACTH, and cortisol
secretion. However, these increases are superimposed on an intrinsic circadian pattern of HPA
activity driven by the suprachiasmatic nucleus (SCN) (Krieger 1979). HPA axis hormone secretion is
pulsatile in nature, with the trough of integrated secretion occurring in the evening and early night
and the peak of secretion occurring just before awakening; active secretion continues throughout
the morning and early afternoon. This rhythm persists even in the absence of corticosteroid
feedback (e.g., adrenalectomy [Jacobson et al. 1989]), and there is evidence that there are intrinsic
neural elements responsible for both initiation and inhibition of the CRH/ACTH/cortisol circadian
rhythm and that glucocorticoids merely act to dampen the overall amount of secretion (Kwak et al.
1993).
HPA Axis in Depression and Anxiety Disorders
Depression
Overactivity of the HPA axis as manifested by an increase in cortisol secretion is now a
well-established phenomenon in depression (Carroll et al. 1976; Sachar et al. 1973). The first
studies (Sachar et al. 1973) showed that up to 50% of depressed patients have higher mean
plasma cortisol concentrations and an increased number and duration of cortisol secretory
episodes, suggesting increased cortisol secretory activity. Numerous studies have subsequently
validated these findings (Carroll et al. 1976; Halbreich et al. 1985; Krishnan et al. 1990a; Pfohl et
- 1985; Rubin et al. 1987). As many as two-thirds of endogenously depressed patients fail to
suppress cortisol, or show an early escape of cortisol, following overnight administration of 1 mg of
dexamethasone (using a cortisol cutoff of 5 g/dL to define “escape”) (Carroll et al. 1981). While
nonsuppression of cortisol in response to dexamethasone is strongly associated with endogenousPrint: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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depression, this finding is less robust in outpatients with depression. Although both
hypercortisolemia and feedback abnormalities in response to dexamethasone are present in
depressed patients, they do not necessarily occur in the same individuals (Carroll et al. 1981;
Halbreich et al. 1985). Other abnormalities, such as reduced glucocorticoid fast feedback (Young et
- 1991) and a blunted ACTH response to exogenous CRH, have also been reported in depressed
patients (Gold et al. 1986; Holsboer et al. 1984; Young et al. 1990).
The blunted response to CRH appears to be dependent on increased baseline cortisol, since
blockade of cortisol production with metyrapone normalizes the ACTH response (Von Bardeleben et
- 1988; Young et al. 1995). It was expected that the increased cortisol would be accompanied by
an increased level of ACTH in plasma, but this has been difficult to validate, although several
studies (Linkowski et al. 1985; Pfohl et al. 1985; Young et al. 2001) have demonstrated small
differences in mean 24-hour plasma ACTH levels between healthy control subjects and depressed
subjects. The demonstration of enhanced sensitivity to ACTH 1–24 in depressed patients suggests
that increased ACTH secretion is not necessarily the cause of increased cortisol secretion
(Amsterdam et al. 1983). However, other studies using very low “threshold” doses of ACTH 1–24
have not been able to demonstrate increased sensitivity to ACTH in depressed patients (Krishnan et
- 1990b), which suggests that increased cortisol secretion is secondary to increased ACTH
secretion. Our 24-hour studies of ACTH and cortisol secretion demonstrated that subjects with
increased mean cortisol also demonstrated increased mean ACTH, supporting a central origin of the
HPA axis overactivity (Young et al. 2001). Further studies with metyrapone in major depression
also support the presence of increased central nervous system (CNS) drive, at least in the evening
(Young et al. 1994, 1997). It appears likely that there is increased CRH/ACTH secretion, which is
then probably amplified by the adrenal, leading to increased cortisol secretion.
These changes in cortisol secretion are commonly considered to be “state” changes that resolve
when the depression resolves. However, almost all studies examining the HPA axis in major
depression in euthymic subjects have examined patients on tricyclic antidepressants, which exert
direct effects on the HPA axis. Three of our recent studies in epidemiological samples and a recent
British study (Bhagwagar et al. 2003) found that salivary cortisol is increased in subjects with
lifetime major depression, most of whom had no current mood symptoms (Bhagwagar et al. 2003;
Young et al. 2000a). The overall picture suggests that depression generally shows both an increase
in activity of circadian activational elements of the system and reduced feedback inhibition.
Anxiety Disorders
The HPA axis has also been studied in patients with anxiety disorders, particularly panic disorder,
with and without comorbid major depression. Both the cortisol response to dexamethasone and the
response to CRH have been examined in pure panic disorder without comorbid depression. The
earliest study with dexamethasone demonstrated a 15% nonsuppression rate in panic disorder
(Curtis et al. 1982). A number of other studies have since been conducted, and the overall incidence
of cortisol nonsuppression is 17% in panic disorder (13 studies), while the incidence for major
depression is 50% (Heninger 1990). Grunhaus et al. (1987) compared patients with major
depression to those with major depression with panic disorder and found a similar rate of cortisol
nonsuppression following dexamethasone administration (approximately 50%) in the two
populations, suggesting that the presence of comorbid panic disorder had little impact beyond that
of depression on dexamethasone nonsuppression. In CRH challenge tests, panic disorder patients
have demonstrated a decreased integrated ACTH response relative to control subjects in some
studies (Holsboer et al. 1987; Roy-Byrne et al. 1986) but a normal response in others (Brambilla et
- 1992). Similar to findings in depression, “baseline” plasma cortisol was increased in panic
patients who showed blunted CRH responses. A study of CRH challenge in panic disorder patients
(Curtis et al. 1997) demonstrated a normal response to CRH challenge.
Studies of the HPA axis in social phobia have not found evidence of baseline hyperactivity by
urinary free cortisol (Uhde et al. 1994), although few challenges other than a social speaking task
have been used. Public speaking challenges in anxiety disorders do not support an exaggeratedPrint: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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ACTH or cortisol response to this stressor (Gerra et al. 2000; Levin et al. 1993; Martel et al. 1999).
A few studies in children with anxiety disorders have also examined the HPA axis. Children with
anxiety disorders coming in for a CO2 challenge demonstrated elevated “basal” cortisol in those
who panicked in response to CO2, suggesting that increased reactivity to a threatening situation
(i.e., anticipation of a procedure that would cause discomfort) was linked to activation of the HPA
axis (Coplan et al. 2002). This interpretation is further supported by an extremely large study of
basal 24-hour cortisol in normal children and children with either anxiety disorders or major
depression, which found lower nighttime cortisol and a sluggish morning rise in cortisol in children
with an anxiety disorder. This suggests that anxiety disorders lead to stress hyperreactivity (in the
case of anxious children, in the context of a threatening experimental procedure of CO2) with
compensatory decreased basal cortisol secretion (24-hour study) (Feder et al. 2004).
Overall, the studies to date do not suggest HPA axis hyperactivity in anxiety disorders to the same
extent as shown in depression (Abelson and Curtis 1996). Feedback elements are generally normal,
and the abnormalities that do exist may reflect “extrinsic” factors that contribute to heightened
reactivity within activational elements of the system. The question of whether stress-activated HPA
axis elements are abnormal in comorbid major depression and anxiety has not yet been well
studied.
Posttraumatic Stress Disorder
Given the stress-related etiology of PTSD, it was expected that PTSD patients would show HPA axis
abnormalities similar to those seen in depressed patients or chronically stressed animals, but this
has not always been the case. An initial study (Mason et al. 1986) found that urinary free cortisol
(UFC) excretion was lower in PTSD than in major depression. However, another study (Pitman and
Orr 1990) found increased UFC excretion in outpatient PTSD veterans compared with
combat-exposed control subjects without PTSD. Since then, there have been various findings, but
the most comprehensive studies of PTSD, those by Yehuda and colleagues (for a review, see
Yehuda 2002), continue to show low cortisol and enhanced cortisol suppression in response to
dexamethasone in combat veterans with PTSD. Interestingly, the presence of comorbid major
depression does not change the neuroendocrine picture. The main criticism of this body of work is
that the sample comprised only male combat veterans and therefore is not representative, given
that in the community, it is women who are most likely to experience PTSD (Breslau et al. 1991,
1995; Kessler et al. 1995). Furthermore, significant confounds with current and past alcohol and
substance abuse occur in the veteran population.
Several studies have sought to address this problem, with the majority examining women with a
history of childhood sexual abuse. While some studies have demonstrated increased UFC in women
with PTSD or a history of abuse compared with control subjects (Lemieux and Coe 1995), others
have demonstrated similar plasma cortisol (Rasmusson et al. 2001), and still others have found
lower cortisol and enhanced cortisol suppression in response to dexamethasone (Stein et al. 1997).
Yehuda (2002) examined Holocaust survivors, who were also predominantly exposed early in life,
and observed lower UFC and enhanced cortisol suppression following dexamethasone
administration in this population. The issue of comorbid depression in the PTSD population has not
been well addressed, with most studies including comorbid individuals and few analyzing the data
by the presence or absence of comorbid depression. The exception is the studies of Heim et al.
(2001), which focused on childhood abuse and major depression and examined multiple HPA axis
challenges in the same subjects. These studies found an effect of early abuse (with comorbid PTSD
in 11 of 13 subjects) and major depression on stress reactivity, with both increased ACTH and
cortisol response to the stressor compared with either healthy control subjects or depressed
patients without childhood abuse. In this same cohort, there was a blunted response to CRH
challenge in patients who had major depression with or without childhood abuse, but an increased
response to CRH in those with early abuse but without major depression. The abused subjects also
showed a blunted cortisol response to ACTH 1–24. Thus, childhood abuse produced an increased
pituitary response with adaptive adrenal compensation, a change compatible with low or normal
basal cortisol. Furthermore, lower cortisol and enhanced feedback to low-dose dexamethasonePrint: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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were found in the same subjects (Newport et al. 2004) regardless of the presence or absence of
PTSD as the primary diagnosis, thus indicating enhanced feedback.
Epidemiologically based samples in adults have focused on natural disasters and have generally
examined exposure with high and low PTSD symptoms (Anisman et al. 2001; Davidson and Baum
1986; Fukuda et al. 2000) but without diagnostic information. However, one study (Maes et al.
1998) that examined PTSD subjects recruited from community disasters demonstrated increased
UFC in PTSD. In general, community-based studies suggest that exposure to disaster increases
plasma (Fukuda et al. 2000) and saliva cortisol (Anisman et al. 2001) and UFC (Davidson and Baum
1986). Studies examining motor vehicle accident survivors (Hawk et al. 2000) found no difference
in cortisol between those with and without PTSD 6 months later. Studies of male and female adults
with exposure to mixed traumas have found either no effect of PTSD on basal cortisol (Kellner et al.
2002, 2003) or elevated basal cortisol (Atmaca et al. 2002; Lindley et al. 2004). Our analysis of
recent trauma exposure in two community samples (Young and Breslau 2004a, 2004b; Young et al.
2004) found increased cortisol in those with past-year exposure to trauma, but no effect of greater
than 1 year past trauma exposure and no effect of childhood abuse on basal saliva cortisol or UFC.
To add further complexity, the majority of studies of trauma and PTSD included subjects with
comorbid depression, and in most studies, the majority of subjects had both PTSD and major
depression. The PTSD studies generally report comorbid depression in their subjects; however,
studies of depression often fail to measure and report trauma histories. As a result, documented
depression confounds much of the PTSD HPA axis literature, and undocumented trauma and abuse
may confound some of the depression HPA axis literature.
In addition to the issue of exposure to trauma, the persistence of the neuroendocrine changes
following recovery from PTSD is unclear. In an early study, Yehuda et al. (1995) reported that
Holocaust survivors with past but not current PTSD demonstrated normal UFC, while later studies of
offspring of Holocaust survivors (Yehuda et al. 2002) suggested that changes in cortisol may
persist beyond the duration of the symptoms and thus may represent a marker of underlying
vulnerability to PTSD. The large analysis by Boscarino (1996) of cortisol data from several thousand
combat veterans showed a very small effect of PTSD on basal cortisol, but a very clear effect of
combat exposure, with increasing levels of severity of combat exposure associated with
increasingly lower cortisol.
Our recent studies of cortisol in PTSD from two epidemiological samples (Young and Breslau 2004a,
2004b; Young et al. 2004) demonstrated normal UFC and saliva cortisol in community-based
individuals with “pure” and comorbid PTSD. The studies also demonstrated a clear effect of lifetime
comorbid major depression on cortisol, showing increased HPA axis activation in the late
afternoon/evening in patients with both major depression and PTSD. Furthermore, the elevated
HPA drive demonstrated by increased evening cortisol levels was greater in the comorbid group
than the elevation already documented in pure major depression.
Studies examining the response to low-dose dexamethasone in PTSD veterans found enhanced
feedback to dexamethasone in veterans who met criteria for PTSD, regardless of the presence of
comorbid major depression (Yehuda et al. 2002). Similar enhanced cortisol suppression in response
to dexamethasone administration has been found in Holocaust survivors with PTSD and their
offspring. In the studies of Yehuda (2002) as well as the report by Stein et al. (1997), the enhanced
suppression was also paired with low baseline cortisol, although other studies did not replicate this
finding (Kellner et al. 2004a, 2004b).
In a CRH challenge study in combat-related PTSD, there was a normal to increased plasma cortisol
at the time of challenge (Smith et al. 1989) and a decreased ACTH response in subjects with high
baseline cortisol. Another study of women with PTSD and a history of childhood abuse (Rasmusson
et al. 2001) showed enhanced cortisol response to CRH and to exogenous ACTH infusion, as well as
a trend toward higher 24-hour UFC. Interestingly, all the women with PTSD had either past or
current major depression, so comorbidity was the rule. In the study by Heim et al. (2001)
examining response to CRH in women with major depression with and without childhood abuse, 14Print: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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of 15 major depressive disorder patients with childhood abuse also met criteria for PTSD. This
group with comorbid major depression and PTSD demonstrated a blunted ACTH response to CRH
challenge similar to that observed in major depression without PTSD. The abused groups also
demonstrated lower baseline and stimulated cortisol both in response to CRH challenge and
following ACTH infusion. These same groups of women showed a significantly greater HPA response
to the Trier Stress Test, despite smaller responses to CRH challenge (Heim et al. 2000).
Several additional studies have evaluated response to stressors. Our early study (Liberzon et al.
1999) using combat noise versus white noise in male veterans with PTSD showed elevated basal
and postprovocation cortisol compared with combat controls but no real evidence of a difference
between the combat and white-noise days. A study by Bremner et al. (2003) of PTSD subjects of
both sexes used a stressful cognitive challenge and found elevated basal saliva cortisol and
continued higher cortisol for 60 minutes postchallenge. Eventually the saliva cortisol of the PTSD
group returned to the same level as that of controls, raising the issue of whether the “basal”
samples were truly basal or were influenced by the anticipatory challenge. Similar data were found
in a study (Elzinga et al. 2003), using trauma scripts, in women with childhood abuse and PTSD
compared with abused women with no PTSD. In that study, salivary cortisol was again significantly
elevated at baseline, increased in response to the challenge (whereas controls showed no
response), and then greatly decreased following the stressor, compatible with “basal” levels
already reflecting exaggerated stress sensitivity in this group. Using a 1-minute cold pressor test, a
recent study (Santa Ana et al. 2006) compared the ACTH and cortisol response in PTSD subjects
with either childhood trauma or adult trauma with that of control subjects and found lower basal
cortisol in the childhood abuse group. However, their data do not support an actual change in ACTH
or cortisol in response to the stressor in any group, so it is difficult to interpret their findings as
reflecting differences in stress response. In addition, sampling was very infrequent and therefore
inadequate to characterize the time course to a very brief stressor. Overall, the existing stress data
suggest an exaggerated stress response in PTSD.
Furthermore, the challenge studies certainly suggest that the picture is complicated in PTSD with
comorbid depression; the findings of some studies look like depression while others look quite
different—for example, showing a smaller response to ACTH infusion whereas patients with major
depression show an augmented response. Age of trauma exposure may be one reason for
contradictory data. Finally, one study by Yehuda (2002) of combat veterans with PTSD
demonstrated greater rebound ACTH secretion compared with controls following administration of
metyrapone in the morning, indicating that increased CRH drive is present in the morning but is
normally restrained by cortisol feedback. The other two studies examining metyrapone challenge in
PTSD found a normal ACTH response to afternoon or overnight metyrapone as well as a normal
response to cortisol infusion in PTSD subjects and panic disorder subjects (Kanter et al. 2001;
Kellner et al. 2004a, 2004b). In summary, these data suggest that there may be no simple
relationship between diagnostic categories and specific HPA axis abnormalities. Timing of trauma
or of onset of depression or anxiety disorders may differentially affect the HPA axis profile,
although definitive studies have not been done.
DEPRESSION AND REPRODUCTIVE HORMONE CHANGES
In women with a previous episode of depression, times of rapidly changing gonadal steroid
concentrations, such as those occurring premenstrually or postpartum, mark particularly vulnerable
times for the occurrence of depressive symptoms. Several studies have shown that in women, a
history of depression increases the risk of both postpartum “blues” and postpartum major
depression (O’Hara 1986; O’Hara et al. 1991; Reich and Winokur 1970) and that hormonal changes
occurring premenstrually may affect mood (Halbreich et al. 1984, 1986). When they were euthymic,
62% of women with a history of major depressive episodes reported the occurrence of
premenstrual mood changes and biological symptoms typical of major depressive disorder. Other
studies found a relationship between the rise in estrogen and testosterone levels and the rising
incidence of depression in girls during adolescence (Angold et al. 1999). More recently in two
epidemiological cohorts (Cohen et al. 2006; Freeman et al. 2006), there was an increased incidencePrint: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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of depressive symptoms and major depression during the menopausal transition. Both high and low
estrogen were associated with depression (Freeman et al. 2004, 2006), and the variability in
estrogen levels may drive depression—that is, those women who show rapid changes from high to
low estrogen and vice versa are those who develop depressive symptoms during the
perimenopause transition. This suggests that examining the reproductive axis in depression may be
a fruitful area of psychoneuroendocrine research.
HYPOTHALAMIC-PITUITARY-GONADAL AXIS
The secretion of the principal gonadal steroids, estrogen and progesterone, is governed by cyclic
changes in ovarian follicular and corpus luteum development over the course of the menstrual
cycle. Critical to the proper functioning and timing of the monthly hormonal cycle is the pulsatile
secretion of gonadotropin-releasing hormone (GnRH). GnRH secretion from the hypothalamus
drives the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from
pituitary gonadotropes (Midgley and Jaffe 1971). During the early follicular phase, FSH plays the
major role in maturing the follicle (diZerega and Hodgen 1981), and the developing follicle secretes
increasing amounts of estradiol as it matures. Maturation-induced increases in estradiol exert a
negative feedback on FSH secretion and both negative and delayed positive feedback effects on LH
secretion (Karsch et al. 1983). The change in estradiol feedback from negative to positive late in
the follicular phase is complemented by rising progesterone and results in the midcycle surge in LH
necessary for ovulation. Following ovulation, progesterone levels continue to rise as a result of
active secretion from the corpus luteum. LH secretion is necessary for the maintenance of the
corpus luteum and subsequent estrogen and progesterone secretion and also facilitates estradiol
production by the follicle and controls the secretion of hormones by the corpus luteum but is
inhibited by progesterone (Chabbert et al. 1998). In the absence of fertilization, regression of the
corpus luteum occurs, with the subsequent fall in estrogen and progesterone leading to the onset of
menses.
The pulsatile secretion of GnRH is driven by a pulse generator in the arcuate nucleus of the
hypothalamus (Knobil 1990). This pulsatile pattern of GnRH secretion is critical for the control of
serum LH, FSH, and ovulation. Indeed, continuous administration of the GnRH agonist leuprolide in
a nonpulsatile pattern suppresses ovulation as effectively as does inadequate secretion of GnRH.
Studies in primates with arcuate lesions have demonstrated that administration of GnRH pulses in
frequencies that are too fast or too slow results in low serum concentrations of LH (Belchetz et al.
1978).
LH secretory pulses in the peripheral circulation are used as the marker of GnRH secretory pulses.
In humans, the follicular phase of the menstrual cycle is characterized by reasonably constant
amplitude LH pulses every 1–2 hours (Reame et al. 1984). During the luteal phase, pulse amplitude
becomes much more variable and pulse frequency decreases. The slowing of the LH pulses during
the luteal phase is due to the actions of progesterone on the GnRH pulse generator (Goodman and
Karsch 1980; Soules et al. 1984; Steele and Judd 1986). Gonadal steroids exert negative feedback
effects on the amplitude and frequency of GnRH pulses and through this mechanism (in addition to
direct actions on the pituitary) inhibit the secretion of LH and FSH. Likewise, central opioids,
particularly -endorphin, exert a tonic inhibition on GnRH secretion (Ferin and Vande 1984).
Circadian changes in LH secretion are not as prominent as those of the HPA axis (Jaffe et al. 1990).
During puberty and following recovery from anorexia- or exercise-induced amenorrhea, nighttime
secretion of LH becomes particularly prominent. Furthermore, nighttime slowing of LH pulses
during the early follicular phase also occurs in normal women (Soules et al. 1985).
Effect of HPA Axis on the Reproductive Axis
Stress has long been known to inhibit the reproductive axis, and the work of Christian (1971)
demonstrating infertility secondary to high population density is often cited as a seminal report.
Shortly after the isolation and sequencing of CRH, it was demonstrated in rats that CRH inhibited LH
secretion (Rivier and Vale 1984) and GnRH secretion (Petraglia et al. 1987), and further primate
studies showed inhibition of LH secretion by injection of CRH (Olster and Ferin 1987).Print: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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While early studies used peripheral administration of high doses of CRH, subsequent studies
demonstrated that intracerebrovascular administration of CRH demonstrated much greater potency
and confirmed a central site of action of the inhibition, pointing to direct inhibition of GnRH by CRH
(Gambacciani et al. 1986; Nikolarakis et al. 1986a, 1986b; Olster and Ferin 1987; Petraglia et al.
1987). However, the peripheral administration of CRH also demonstrated an opioid-mediated
inhibition by CRH that could be abolished by dexamethasone pretreatment, suggesting a role for
pituitary-derived opioids, most probably -endorphin from anterior pituitary corticotropes.
Anatomical studies demonstrate that CRH neurons synapse with GnRH neurons (MacLusky et al.
1988); in vitro studies demonstrate that CRH can function as a secretagogue for -endorphin
secretion from the arcuate -endorphin system (Nikolarakis et al. 1986a). Studies in primates by
the Knobil laboratory (Williams et al. 1990) recording multiunit activity from the arcuate nucleus
(i.e., the GnRH pulse generator) demonstrated that CRH administration induced inhibition of the
rhythmic firing of the arcuate nucleus accompanying LH secretory pulses, as well as abolishing LH
pulses. Studies with a CRH antagonist, -helical CRH9–41, demonstrated the antagonist’s ability to
reverse stress-induced LH suppression in rats, confirming a central CRH-based mechanism by which
stress inhibits LH secretion (Rivier et al. 1986). While the primate and rat studies have clearly
pointed to CRH as the primary mechanism by which stress inhibits GnRH release, this is not true in
all species (e.g., central CRH has no effect on GnRH or LH secretion in sheep [Tilbrook et al. 1999]),
and some stressors act through cortisol (Debus et al. 2002). The demonstration of a central CRH
effect on GnRH release does not preclude an effect of cortisol in both rats and primates, including
humans.
So is there evidence that cortisol may also be involved in the inhibition of reproductive function?
Several studies have demonstrated that ACTH administration reduces the increase in serum LH
concentrations following ovariectomy or orchidectomy in rats (Mann et al. 1982; Schwartz and
Justo 1977). This effect is dependent on the presence of the adrenal but could also involve adrenal
production of gonadal steroids, which is regulated by ACTH (Putnam et al. 1991). Glucocorticoids
also exert inhibitory effects on GnRH secretion or LH responsiveness to GnRH, including direct
effects of cortisol on the gonadotrope (Suter and Schwartz 1985). Radovick et al. (1990)
demonstrated a glucocorticoid-responsive element (GRE) on the GnRH gene, providing the potential
for glucocorticoids to modulate GnRH gene expression. Diminished LH response to GnRH following
long-term prednisolone treatment has been found in women (Sakakura et al. 1975). Patients with
Cushing’s disease, in which cortisol is increased but central CRH is likely to be low because of
excessive glucocorticoid feedback on paraventricular nucleus of the hypothalamus CRH, show
inhibition of LH secretion. Recent studies in ewes have found that 1) LH secretory amplitude is
clearly inhibited by stress; 2) the effects of stress or endotoxin are reversed by metyrapone
inhibition of cortisol synthesis; and 3) infusion of stress levels of cortisol can produce inhibition of
LH pulse amplitude but not frequency, which is blocked by RU486, a glucocorticoid receptor
antagonist (Breen et al. 2004; Debus et al. 2002). Finally, a recent study of exercise-induced
reproductive abnormalities in adolescent girls concluded that “in active adolescents, increased
cortisol concentration may. . . precede gonadotropin changes seen with higher levels of fitness”
(Kasa-Vubu et al. 2004, p. 1). These data suggest that cortisol, in addition to central CRH, may also
play a role in LH disruption.
Other studies in humans have linked hypothalamic-pituitary-gonadal (HPG) axis abnormalities to
HPA axis activation. These include exercise-induced amenorrhea, anorexia nervosa, and
hypothalamic amenorrhea. In all three syndromes, hypercortisolemia has been observed, indicating
overactivity of the HPA axis (Berga et al. 1989; Casanueva et al. 1987; Hohtari et al. 1988; Loucks
et al. 1989; Suh et al. 1988; Villanueva et al. 1986). In all three syndromes, CRH has been used as a
challenge to evaluate pituitary and adrenal function. The response to exogenous CRH challenge
demonstrates diminished ACTH or cortisol responses, suggesting that high baseline cortisol exerts
negative-feedback effects on the hormonal responses to CRH (Berger et al. 1983; Biller et al. 1990;
Gold et al. 1986; Hohtari et al. 1991). In anorexia nervosa, the hormonal abnormalities in both HPA
and HPG axes are secondary to weight loss. Weight restriction and low body weight are also
observed in exercise-induced amenorrhea, and low body weight has been reported in hypothalamicPrint: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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amenorrhea. Even relatively mild degrees of weight loss in normal-weight or obese subjects can
lead to disturbances in both axes, as manifested by resistance to dexamethasone and by
disturbances in menstrual regularity or amenorrhea (Berger et al. 1983; Edelstein et al. 1983; Pirke
et al. 1985). Consequently, these three syndromes present with evidence of increased HPA axis
activation and disrupted HPG functioning and amenorrhea. The disturbances in LH secretion in
anorexia nervosa and hypothalamic amenorrhea have been evaluated primarily by examining the
characteristics of LH pulsatile activity. In anorexia nervosa, LH secretory patterns may revert to
prepubertal levels of low nonpulsatile secretion or to a pubertal pattern of entrainment of LH
secretion to the sleep cycle. Studies by Reame et al. (1985) in women with hypothalamic
amenorrhea demonstrated that LH secretion in the follicular phase is slowed to the rate normally
observed during the luteal phase. In these individuals, LH and FSH responses to GnRH appear
normal, indicating that the reduced pulse frequency is not secondary to pituitary changes but
presumably due to changes in the GnRH pulse generator. Figure 7–2 summarizes the various levels
at which hormones of the HPA axis may impinge on the reproductive axis. Despite suggestions that
reproductive hormones may play a role in mood disorders, the HPG axis has received little
examination in depression.
FIGURE 7–2. Effects of the hypothalamic-pituitary-adrenal axis on the
hypothalamic-pituitary-gonadal axis.
GH = growth hormone; GHIH = growth hormone–inhibiting hormone; GHRH = growth hormone–releasing
hormone; IGF-1 = insulin-like growth factor 1.
Reproductive Abnormalities in Depression
In depression, response to GnRH has been assessed by several groups. Some studies have reported
a normal LH and FSH response to GnRH in pre- and postmenopausal women (Unden et al. 1988;
Winokur et al. 1982). However, given the major differences in LH pulse amplitude and mean LH
levels between follicular and luteal phases, it would be extremely difficult to observe a difference in
basal LH secretion between major depression and control women without strict control of
menstrual cycle phase. However, Brambilla et al. (1990) noted a decreased LH response to GnRH in
both premenopausal and postmenopausal women, with lower baseline LH concentrations in
postmenopausal depressed women. It may be that the increased secretion of LH following removal
of the negative feedback of gonadal steroids in postmenopausal women unmasks a decrease in LH
secretion that is not as easily observed in women with intact estrogen and progesterone feedback.
Other studies examining depressed patients of both sexes, which were not analyzed separately,Print: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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observed no change in baseline or GnRH-stimulated LH and FSH secretion (Unden et al. 1988).
Only recently have studies begun to focus on the pulsatile rhythm of LH secretion in women with
major depression. Thus far, there have been only four published studies examining pulsatile LH
secretion in depressed women: two by Meller et al. (1997, 2001), a third by us (Young et al.
2000b), and a fourth looking at the data from both Meller and Young with spectral analysis
(Grambsch et al. 2004). The data from the Meller studies showed slower LH frequency in the
follicular phase. Our data revealed significantly lower estradiol in the follicular phase in a small
sample of depressed women. Since our publication in December 2000, a large-scale epidemiological
study by Harlow et al. (2003) has found that earlier menopause is accompanied by lower estradiol
in perimenopausal depressed women. Thus, three recent carefully done studies using modern
techniques with sophisticated analyses have found evidence of reproductive axis abnormalities in
depressed women. One study of the reproductive axis in men with major depression (Schweiger et
- 1999) also revealed decreased testosterone and a trend for slower LH pulses, suggesting that
abnormalities in the reproductive axis are also found in men. Consequently, further studies on the
reproductive axis in depression are indicated.
Estrogen and Depression
Because of increased incidence of depression at critical hormonal transition phases such as
postpartum and perimenopause, much speculation has taken place about estrogen’s role as a
precipitant. Recent studies have found increased incidence of depressive symptoms and major
depression during the menopause transition (Cohen et al. 2006; Freeman et al. 2006). The initial
findings of Freeman et al. (2004) in regard to estrogen were that both high and low estrogen levels
were associated with depression. More recently, the data suggest that variability in estrogen levels
may drive depression. A model of differential sensitivity to estrogen has been proposed for
premenstrual dysphoric disorder (PMDD) and also by Cohen et al. (2006) to explain the findings of
increased depression during the menopause transition. Increased FSH, suggesting ovarian aging,
and overall low or variable estrogen were also found to be strongly associated with depression
(Freeman et al. 2006). And in the Freeman et al. study, PMDD was associated with depression
during the menopause transition. Furthermore, the central effects of estrogen are intriguing and
lend credence to a possible role of estrogen in modulating critical neuronal systems involved in
depression. Studies in nonhuman primates have confirmed that estrogen increases tryptophan
hydroxylase, the rate-limiting step in serotonin synthesis (Bethea et al. 2002). Estrogen also
decreases serotonin1A (5-HT1A) autoreceptor binding, which would serve to increase serotonin
levels at the synapse (Bethea et al. 2002). Estrogen modulates the serotonin transporter, leading to
decreases in the transporter mRNA but increases in the transporter expression in the hypothalamus
(Bethea et al. 2002). Estrogen also decreases monoamine oxidase A activity, which would
potentiate actions of norepinephrine in the synapse, and increases tyrosine hydroxylase, the critical
first enzyme for synthesis of norepinephrine (Bethea et al. 2002). However, use of estrogen as a
treatment has produced mixed results, perhaps because not all studies have targeted women with
changing estrogen levels. Early studies found an effect of high-dose estrogen augmentation on
response to antidepressants (Klaiber et al. 1979; Shapira et al. 1985). In situations of recent-onset
estrogen deficiency such as postpartum and perimenopause, estrogen has been demonstrated to be
an effective treatment for depression in randomized, controlled trials (Gregoire et al. 1996; Schmidt
et al. 2000; Soares et al. 2001). However, randomized, controlled trials examining the effects of
estrogen on mood in postmenopausal women have been negative (Hlatky et al. 2002; Morrison et
- 2004), suggesting a loss of beneficial mood response to estrogen following prolonged periods
without estrogen. Finally, if data on estrogen’s role in inhibiting the HPA axis in normal women are
correct, then lower estradiol in depressed women would result in exacerbation of the HPA axis
abnormalities seen in major depression, and these may need to be corrected along with changing
the ovarian hormone milieu.
Premenstrual Dysphoric Disorder
One of the most well-studied mood disorders, with respect to the influence of ovarian steroids onPrint: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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mood, is PMDD. In any studies of this disorder, it is necessary to define carefully the study
population and limit both endocrine investigations and treatment to women with clear luteal phase
depressive symptoms who are well during the follicular phase; many more women report significant
variations in mood premenstrually in retrospective reports than are found to have symptoms with
prospective studies. In a study that used optimal sampling frequency to investigate LH and FSH,
pulse frequency, and amplitude in follicular, midluteal, and late luteal phases of the menstrual cycle
and examined estradiol and progesterone levels at these three time points, there was no difference
between estradiol and progesterone at any time point between women with PMDD and control
women (Reame et al. 1992). LH pulse frequency was also similar in both groups, with parallel
changes across the menstrual cycle. Thus, these and earlier data (Rubinow et al. 1988) do not
suggest an alteration in GnRH secretion or ovarian steroids in women with PMDD. Nevertheless,
several studies have suggested that hormone manipulations can improve the symptoms.
One of the best-documented effective treatments is elimination of menstrual cycling with
leuprolide, a GnRH agonist that improves mood. A number of studies found that leuprolide was
highly effective in reducing symptom severity and cyclicity in PMDD patients (Mortola et al. 1991;
Rosenbaum et al. 1996; Schmidt et al. 1998), although an increased rate of depressive-like
symptoms has also been reported during leuprolide treatment (Steingold et al. 1987; Zorn et al.
1990). Leuprolide also leads to hypoestrogenism, which affects both bone density and
cardiovascular disease; thus, it is necessary to add both steroid hormones. In the study by Mortola
et al. (1991), just the addition of a placebo, with the suggestion that it might make mood symptoms
worse, caused a significant worsening in mood symptoms. However, addition of conjugated equine
estrogen with or without medroxyprogesterone acetate (MPA) while patients were still on
leuprolide did not lead to a relapse in depressive symptoms. Not all studies have agreed that
progesterone can be added back without significant worsening of symptoms. Schmidt and
colleagues studied a group of women with PMDD whose symptoms were significantly improved by
leuprolide, as well as a group of control women with no previous mood symptoms who were also
taking leuprolide. They demonstrated a return of symptoms following administration of estradiol or
progesterone but not with placebo. In the control women, none of the hormone replacements
altered mood (Rubinow and Schmidt 2006). Finally, progesterone itself has been used for the
treatment of PMDD despite its documented lack of effectiveness. The results of a recent Cochrane
Database review of 17 randomized, placebo-controlled trials were equivocal, and the authors were
unable to determine whether progesterone was useful or ineffective in the treatment of PMDD.
They concluded that there was not enough evidence to say whether progesterone was helpful or
ineffective (Ford et al. 2006).
Since it is generally believed that the symptoms of PMDD are related to delayed effects of
progesterone on mood, several studies have investigated the effects of RU486, a progesterone
antagonist, on mood symptoms. In the studies of Schmidt et al. (1991), creation of an artificial
follicular phase during the second half of the menstrual cycle by the use of RU486 plus human
chorionic gonadotropin did not result in a reduction of mood symptoms. Likewise, blockade of
progesterone’s action led to early menses, with depressive symptoms still occurring. The study by
Chan et al. (1994), using a randomized, double-blind, placebo-controlled crossover design for 6
months, showed no effectiveness of RU486 on mood symptoms. Thus, although it is generally
believed that PMDD is related to changes in CNS neurotransmitter systems caused by progesterone,
the data do not support the conclusion that progesterone blockade affects these mood symptoms.
Rubinow and Schmidt (2006) have proposed that PMDD represents an abnormal response to normal
hormone changes or levels that occurs in a small proportion of genetically susceptible women and
is most likely associated with gene polymorphisms involved in the gonadal steroid signaling
pathway.
Another period of increased vulnerability to depression in women is the postpartum period.
Although it is known that this period is accompanied by a sudden drop in progesterone and
estradiol levels, there is limited information available on how this relates to the onset of
depression. Postpartum depression is associated with a history of depression (O’Hara 1986; O’HaraPrint: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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et al. 1991), marital disharmony, and a higher number of stressful life events in the previous year
(Cox et al. 1982). Gregoire et al. (1996) reported that transdermal estrogen is an effective
treatment for depression. However, the group of women studied was small, heterogeneous, and
ill-defined, and no information was available on whether these women had a new onset of
depression or a prior psychiatric history. Furthermore, some of the patients were being
concurrently treated with antidepressants.
GROWTH HORMONE AND THE
HYPOTHALAMIC-PITUITARY-SOMATOTROPHIC AXIS
Growth hormone (GH) or somatotropin is another stress-sensitive neuroendocrine system. GH is
synthesized by the anterior pituitary, and although it can be used as an endpoint in itself for
neuroendocrine research in psychiatry, its predominant use is as a marker of the integrity of the
noradrenergic system following challenge. The hypothalamic-pituitary-somatotrophic (HPS) axis is
under complex regulatory control that is not yet fully understood since cross-species variations in
GH regulation make it difficult to extrapolate to humans from animal studies. It is well established,
however, that the final common pathways for control of GH release from the pituitary are
hypothalamic growth hormone–releasing hormone (GHRH) (stimulation) and somatostatin
(inhibition). The wide variety of metabolic, endocrine, and neural influences that alter GH secretion
do so primarily through effects on GHRH and/or somatostatin. Neural influences may be mediated
by noradrenergic, cholinergic, dopaminergic, aminobutyric acid (GABA)–ergic, and serotonergic
neurotransmission. Clear physiological regulatory roles, however, have only been well documented
in humans for noradrenergic and cholinergic inputs. Dopamine, serotonin, and GABAergic drugs can
alter GH release but do so in contradictory ways, depending on the experimental paradigm, leaving
their roles as GH regulatory agents uncertain at present (Devesa et al. 1992; Muller 1987). In
humans, GH is released by acute stress, but is suppressed by chronic stress. Chronic psychosocial
stress in children can result in growth arrest and even short stature and delayed puberty. A variety
of other endocrine, metabolic, and physiological factors can influence GH release, although the
mechanisms by which they do so are not clear. Factors that can inhibit GH release include free fatty
acids (Penalva et al. 1990) and, most importantly for this review, CRH (Corsello et al. 1992) and
glucocorticoids (del Balzo et al. 1990; Giustina and Wehrenberg 1992). Studies by Wiedemann et al.
(1991) examined GH secretion in healthy control subjects given hourly pulses of ACTH (1 g) or
h-CRH (10 g) between 9 A.M. and 6 P.M. to induce hypercortisolemia. They found an increase in the
number of GH pulses and amount of GH secreted during the daytime but did not find an increase in
the total 8 A.M. to 3 A.M. GH secretion because of blunted nighttime secretion. This pattern is similar
to that seen in depressed patients (Mendlewicz et al. 1985) who have increased daytime GH
secretion and reduced sleep-related GH secretion, suggesting a similar mechanism may occur in
depressed patients. However, our own studies of 26 premenopausal women with major depression
and 26 age- and menstrual-cycle-day-matched control women examining 10-minute secretion of GH
for 24 hours found no changes in GH secretion (Amsterdam et al. 1989).
Current evidence suggests that the normal episodic GH secretory pattern is shaped by an
alternating rhythm of GHRH and somatostatin release (Plotsky and Vale 1985), which has been
called the hypothalamic-somatotroph rhythm (HSR) (Devesa et al. 1992). This is not a regular
alternation but consists rather of four to eight short pulses of GH secretion distributed irregularly
over a 24-hour period, the largest one occurring shortly after the onset of sleep. The significant role
of somatostatin in shaping the HSR is evidenced by its persistence in the face of a constant GHRH
infusion (Hulse et al. 1986; Vance et al. 1985). The intrinsic HSR, in turn, appears to shape the
response to exogenous GHRH (Devesa et al. 1989, 1990, 1991a, 1992; Tannenbaum and Ling
1984). The response is greatest if GHRH is given while plasma GH is rising or near the peak of a
pulse, presumably indicating that somatostatin is suppressed. The GH response is minimal if GHRH
is given while plasma GH is low and stable, presumably indicating predominance of the
somatostatin effect. Currently available human data therefore suggest that clonidine exerts a major
effect on GH release via suppression of somatostatin-mediated inhibition.
It appears that cholinergically mediated suppression of somatostatin plays a significant role inPrint: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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regulating nocturnal GH release (Ghigo et al. 1990; Mendelson et al. 1978; Peters et al. 1986).
Factors that can enhance GH release include estrogen (Devesa et al. 1991b; Ho et al. 1987),
thyroid-releasing hormone, vasoactive intestinal peptide, hypoglycemia, sleep, exercise, and stress
(Devesa et al. 1992; Muller 1987; Uhde et al. 1992). Finally, GH exerts a negative feedback
inhibition of its own secretion (Devesa et al. 1992; Muller 1987). It appears to act at the level of the
hypothalamus and/or median eminence to stimulate somatostatin release (Devesa et al. 1992). It
may also inhibit GHRH release (Devesa et al. 1992). GH also stimulates the production of
somatomedin-C/insulin-like growth factor 1 (IGF-1) in peripheral tissues, including liver.
Somatomedin-C in turn has a dual inhibitory feedback effect. It directly suppresses GH secretion at
the pituitary level and stimulates somatostatin release at the hypothalamic level (Devesa et al.
1992). Levels of somatomedin-C correlate positively with, and can be used to infer, systemic GH
levels during the past 8–12 hours (Copeland et al. 1980; Ross et al. 1987; Vance et al. 1985).
Measurement of somatomedin-C levels thus can provide another means of evaluating the overall
functional status of the HPS axis.
Growth Hormone Studies in Psychiatric Disorders
Adrenergic input to the HPS axis is mediated primarily by the 2-adrenergic receptor. 2-Adrenergic
agonism is a potent stimulus for GH secretion, the effect being blocked by corresponding
antagonists (Devesa et al. 1992; Muller 1987). -Adrenergic stimulation of GH release may also be
antagonized by -adrenergic agonism (Devesa et al. 1992), but the -adrenergic-receptor-mediated
influences are less well researched. In humans, the evidence suggests that the GH-releasing effect
of 2-adrenergic agonism may be due primarily to inhibition of somatostatin release, with perhaps a
secondary stimulation of GHRH. This is based on two main types of evidence. First, for at least 2
hours after a supramaximal dose of GHRH (200 g), the pituitary is refractory to a repeated dose of
GHRH, but the 2-adrenergic agonist clonidine (Valcavi et al. 1988) or insulin-induced
hypoglycemia (Shibasaki et al. 1985) will still evoke a vigorous GH response. Presumably, if the
GH-releasing cells are unresponsive to GHRH, clonidine must stimulate GH release through a
non-GHRH mechanism, the most likely alternative being inhibition of somatostatin release.
Similarly, insulin-induced hypoglycemia is thought to stimulate noradrenergic outflow, which then
suppresses somatostatin secretion (Shibasaki et al. 1985). Whereas the GH response to GHRH
depends on the point in the HSR rhythm at which the GHRH is given, the response to clonidine does
not (Devesa et al. 1990, 1991a, 1992), again suggesting that clonidine acts through a non-GHRH
mechanism, again presumably somatostatin.
Downregulation of GH release in response to clonidine presumably occurs in response to chronic,
excessive noradrenergic outflow from the locus coeruleus, which is thought to play a role in anxiety
states (Uhde et al. 1992). The blunted GH response to clonidine in panic disorder has been
replicated in 8 of 10 studies from 6 of 7 different clinical research groups (Abelson et al. 1991,
1992; Amsterdam et al. 1989; Charney and Heninger 1986; Coplan et al. 1993; Nutt 1989;
Schittecatte et al. 1988, 1992; Uhde et al. 1986, 1991). Both failures to replicate (Schittecatte et al.
1988, 1992) were by the same group. One of those studies (Schittecatte et al. 1988) involved only
seven subjects, and blunting was absent only in the female subjects, in whom birth control pills or
menstrual cycle phase can obscure blunting. Blunted GH response to clonidine is seen in
generalized anxiety disorder (Abelson et al. 1991) and social anxiety disorder (Uhde et al. 1991)
but not in obsessive-compulsive disorder (OCD) (Hollander et al. 1991; Lee et al. 1990). It has also
recently been reported in patients with PTSD (Morris et al. 2004). It is unlikely that the GH blunting
seen in anxiety disorders is an artifact of tricyclic exposure, given that in our own work, 10 of 12
anxiety patients with blunted responses had no significant prior exposure to tricyclic
antidepressants (Abelson et al. 1992) and our recent findings demonstrate a blunted response in
subjects with anxiety (predominantly social phobia) with no tricyclic exposure (Cameron et al.
2004). The nonspecificity of the GH response to clonidine suggests that it could be a secondary
response to the presence of a psychiatric disorder. However, the absence of blunting in patients
with OCD (Lee et al. 1990), schizophrenia (Lal et al. 1983), or heroin abuse (Facchinetti et al.
1985) argues against this interpretation. Although the replicability of the blunted GH response toPrint: Chapter 7. Psychoneuroendocrinology http://www.psychiatryonline.com/popup.aspx?aID=417052&print=yes…
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clonidine in panic disorder is well established, the mechanism remains less certain. It has been
thought to reflect subsensitivity (downregulation) of postsynaptic 2-adrenergic receptors (Siever
et al. 1982). Our own data support the presence of blunted GH response to clonidine in social
anxiety disorder, suggesting that excessive noradrenergic tone is also present in this form of
anxiety (Cameron et al. 2004). These data are consistent with the hypothesis that excessive
noradrenergic outflow from the locus coeruleus plays a pivotal role in anxiety states (Charney and
Heninger 1986).
Numerous studies have also demonstrated reduced GH responses to clonidine in patients with
major and melancholic depression (Amsterdam and Maislin 1990; Amsterdam et al. 1989; Charney
et al. 1982; Checkley et al. 1981; Corn et al. 1984; Lesch et al. 1988; Siever and Uhde 1984), but
not all studies have replicated these findings (Gann et al. 1995; Katona et al. 1993; Mitchell et al.
1991; Schittecatte et al. 1989, 1994). In particular, more recent studies have not found a blunted
GH response to clonidine. It is unclear whether diagnostic changes and subject selection have
affected these failures to replicate, given that several investigators found differences between
endogenous and nonendogenous depression, with more severe blunting in the endogenous groups
(Amsterdam et al. 1989; Checkley et al. 1984; Matussek and Laakmann 1981; Matussek et al.
1980). Furthermore, most of the studies in depression were done before it was realized that
menstrual status (i.e., pre- vs. postmenopausal), menstrual cycle phase, and prior tricyclic
exposure affected the GH response to clonidine. In particular, patients with endogenous depression
are more likely to have been older and postmenopausal, both factors that decrease the GH
response. The altered GH response to clonidine is thought to result from 2-noradrenergic receptor
downregulation, since studies using either GHRH, which acts directly at the pituitary, or
apomorphine, which acts via dopamine input to the GH system, demonstrate normal GH response in
depressed patients (Amsterdam and Maislin 1990; Corn et al. 1984; Krishnan et al. 1988; Lesch et
- 1988; Thomas et al. 1959). Again, this is consistent with increased central noradrenergic
activation in depression, similar to that hypothesized in panic disorder. Our own recent studies
(Cameron et al. 2004) found a normal GH response to clonidine in patients with “pure” depression
(i.e., patients who did not meet criteria for any anxiety disorders). All of our patients had been off
any psychotropic drugs for at least 6 months. Furthermore, there was no relationship between
dimensional measures of anxiety or dimensional measures of depression and GH response. Patients
with melancholic depression did not differ from nonmelancholic patients or control subjects.
Subjects with a high Hamilton Anxiety Scale (Ham-A) score ( 20, n = 13) did not differ from their
matched controls. Thus, our data suggest that blunted GH response to clonidine challenge is
specific to anxiety disorders and is not seen with less severe forms of anxiety or with depression in
the absence of an anxiety disorder.
CONCLUSION
In this chapter we have reviewed ways in which hormonal systems may be altered in psychiatric
disorders that may be linked to the pathoetiology of the disorders. The evidence is strongest for the
HPA system, which has been implicated in at least two disorders, depression and PTSD, both
disorders clearly linked to stress-based etiologies. The evidence for abnormalities in reproductive
hormones is still small, but this is a subject of continued investigation. Most notably, abnormalities
of reproductive hormones have not been found in PMDD, the disorder most responsive to changing
reproductive hormone milieu. Finally, hormones can be used as markers of the functioning of CNS
neurotransmitters or receptors, as is the case for GH. As neuroimaging ligands are developed to
directly measure these receptors, the latter role of neuroendocrinology may be useful. Many of the
critical hormones, like cortisol and estradiol, regulate many other critical neurotransmitter systems,
such as serotonin, as well as regulating gene transcription. The area of psychoneuroendocrinology
continues to expand, and in combination with the major advances occurring throughout the field of
psychiatry, it will become possible to identify the genetic and molecular mechanisms involved in
psychiatric disorders, thereby leading to the development of better treatments.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Psychoneuroendocrinology
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Understanding the Basics of Psychoneuroendocrinology
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The Role of Hormones in Behavior
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Neurotransmitters and Their Impact on the Endocrine System
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Quiz: Key Concepts in Psychoneuroendocrinology
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Case Studies in Psychoneuroendocrinology
The Brain: Structure, Functions, and Hormonal Interactions
The Endocrine System: Understanding Hormonal Regulation
Mind-Body Interactions: Pathways and Processes
Applications and Future Directions in Psychoneuroendocrinology
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