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INTRODUCTION:
I. Stress and depression
Depressive disorders are widely regarded as stress-related conditions. While genetic
vulnerability is critical to the development of depression, in the absence of environmental stressors,
the incidence of depressive disorders is very low (Kendler et al. 1995a); and in approximately 75%
of cases of depression there is a precipitating life event (Brown & Harris 1978; Frank et al., 1994).
Living organisms survive by maintaining a complex dynamic equilibrium or homeostasis that is
constantly challenged by intrinsic or extrinsic stressors. These stressors set in motion responses
aimed at preserving homeostasis, including activation of a wide variety of neurotransmitters and
neuromodulators. The hypothalamic pituitary adrenal (HPA) axis is the body's main stress
hormonal system. Corticotropin releasing hormone (CRH), is the principal central effectors of the
stress response (Chrousos and Gold 1992). CRH triggers the release of adrenocorticotropic
hormone (ACTH) from the anterior pituitary corticotrope which, in turn, triggers the release of
adrenal glucocorticoids. The stress response is terminated by glucocorticoid feedback at brain and
pituitary sites.
Depression has been conceptualized as maladaptive, exaggerated responses to stress.
Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis, as manifested by
hypercortisolemia and disruption of the circadian rhythm of cortisol secretion, are well established
phenomena in depression (Carroll et al. 1976; Sachar et al. 1973). The assumption that the
pathophysiology of depression involves exaggerated responses to stress is supported by evidence
that CRH, is activated in these patients (Altemus et al. 1992; Charney et al. 1987; Butler and
Nemeroff, 1990; Southwick et al, 1993, Bhagwagar et al, 2003; Young et al, 2001a; Raadsheer et
al, 1994)
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Sex differences in depression:
As well as their association with stress, another striking feature of mood disorders is the
increased prevalence of these conditions in women. Several lines of evidence indicate that sex
steroid hormones play a role in the increased vulnerability of women to anxiety disorders and
depression. Women have an increased incidence of unipolar depression (Weissman and Olfson
1995) which arises at puberty. The immediate postpartum period, in particular, is a time of greatly
increased risk for new onset or recurrence of mood disorders (Altshuler et al. 1998; Dean et al.
1989). In some women, recurrent depressive symptoms occur only during the premenstrual period
and in others, chronic depression is often exacerbated premenstrually (Rubinow and Roy-Byrne
1984). Recent reports indicate that estrogen may be an effective treatment for postpartum (Gregoire
et al. 1996) and perimenopausal depression (Zweifel and O'Brien 1997).
Hypothalamic-Pituitary-Adrenal (HPA) Axis Abnormalities in Depression: Overactivity of the
HPA axis, as manifested by an increase in cortisol secretion, is a well-established phenomenon in
depression (Sachar et al., 1973; Carroll, Curtis et al., 1976). The original studies of Sachar and
colleagues ( Sachar et al., 1973) demonstrated increased cortisol secretory activity in depressed
patients as measured by mean plasma cortisol concentration, the number of cortisol secretory
episodes and the number of minutes of active secretion. Later studies have continued to validate
this hypercortisolemia in depression (Carroll, Curtis et al., 1976, Rubin et al., 1987, Halbreich U,
Asnis GM, Schindledecker R, Zurnoff B, Nathan RS 1985, Pfohl B, Sherman B, Schlecte J, Stone,
R 1985). 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 cut-off of 5 µg/dl to define “escape” (Carroll, Feinberg, 1981). While non-
3
suppression of cortisol to dexamethasone is strongly associated with endogenous depression, this
finding is less robust in outpatients with depression. Although both hypercortisolemia and
feedback abnormalities to dexamethasone are present in depressed patients, they do not necessarily
occur in the same individuals (Halbreich et al., 1985, Carroll, Feinberg et al.,1981). Abnormal
glucocorticoid fast feedback (Young, Haskett et al., 1991) and a blunted ACTH response to oCRF
have also been reported in depressed patients (Gold et al., 1986; Holsboer et al., 1984, Young,
Watson et al., 1990). The blunted response to oCRF appears to be dependent upon increased
baseline cortisol, since blockade of cortisol production with metyrapone normalizes the ACTH
response (von Bardeleben et al., 1988, Young, Akil et al., 1995). It was expected that the increased
cortisol would be accompanied by an increased level of ACTH in plasma, but this expectation has
been difficult to validate. Some studies (Pfohl et al., 1985, Linkowski et al., 1985, Young, Carlson
et al., 2001b) have been able to demonstrate small differences between normal controls and
depressed subjects in their mean 24 hr plasma ACTH levels. 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 an
increased sensitivity to ACTH in depressed patients (Krishnan KRR et al., 1990), which suggests
that increased cortisol secretion is secondary to increased ACTH secretion. Our 24H 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 EA et al, 2001b). Finally our studies with metyrapone in major depression support the
presence of increased CNS drive, at least in the evening (Young EA et al, 1994, Young EA et al,
1997). It appears likely that there is increased CRF/ACTH secretion, which is then probably
amplified at the adrenal level leading to increased cortisol. These changes in cortisol secretion are
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commonly considered to be “state” changes and 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. Two
recent studies of ours as well as a recent report by Bhagwagar and colleagues have found that
saliva cortisol is increased in subjects with lifetime major depression, in subjects who had no
current mood symptoms (Young et al, 2000; Young and Breslau, in press; Bhagwagar et al,
2003). The overall picture in depression if of increased production of activational elements of the
HPA axis together with a reduction in feedback inhibition.
Chronic antidepressant treatment inhibits stress responsive systems at multiple sites, through
reductions in CRH and tyrosine hydroxylase activity, enhanced glucocorticoid receptor activity
(Brady et al.1991; Barden, Reul and Holsboer, 1995), and down regulation of arousal producing ßadrenergic receptors (Heninger and Charney 1987). Chronic treatment with antidepressant agents
also reduces both the behavioral and endocrine responses to stress (Murua and Molina 1992; Reul
et al. 1993; Barden, Reul and Holsboer, 1995). Consequently, antidepressant actions may be
through stress systems as well as classical neurotransmitter systems that affect neurobiological
systems involved in the pathophysiology of depression.
Sex Differences In HPA Axis Regulation in Depression
Morning and Evening Cortisol Hypersecretion. We studied baseline cortisol secretion in the
morning in 16 depressed patients and 16 age-and sex-matched control patients and found
predictably increased cortisol secretion in the group as a whole (Young et al. 1991). However,
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there were also clear sex differences: male patients and their matched controls demonstrated the
same plasma cortisol concentration, whereas female depressed patients demonstrated a
significantly higher mean plasma cortisol concentration (11.3 ± 0.9 µg/dl) than that of the
matched control group (8.1 ±0.95 µg/dl; significant by a two-tailed t-test, p=0.033). Removal of
glucocorticoid negative feedback by metyrapone demonstrated increased central drive in
depressed patients in the evening (Young et al. 1994). The response to metyrapone also showed
sex differences; in that only the female depressed patients manifested rebound -LPH/-end
secretion in comparison to their matched controls (ANOVA, F=8.8, df=1, p=.01); whereas the
males did not.
Dexamethasone Non-Suppression and Menopause.
We also examined the effect of loss of
gonadal steroids at menopause on HPA axis regulation in depressed women (Young et al. 1993).
We conducted studies using a protocol examining baseline and post-dexamethasone secretion of
-LPH/-end and cortisol over the course of the day (8 AM-4 PM). These were carried out on
51 depressed women; 36 of whom were premenopausal and 15 postmenopausal.
The
premenopausal women demonstrated a significantly lower incidence of pituitary (-LPH/-end)
non-suppression (44%; n=36) than the postmenopausal women (Non-Suppressor=81%; n=15).
To determine which of a number of potential variables were associated with -LPH/-end nonsuppression in women, a step-wise regression analysis was used.
Independent variables
included: age, menopausal status, baseline -LPH/-end and cortisol, severity of depression
(Hamilton Depression rating scores), and the number of previous episodes of depression. The
dependent variable was -LPH/-end non-suppression. We found that age had a significant effect
on pituitary non-suppression, but when age and menopausal status were compared, menopausal
6
status showed a stronger correlation and combined with cortisol gave a correlation coefficient of
0.817. This suggests that menopausal status, in conjunction with cortisol hypersecretion, is a
critical variable in the development of HPA dysregulation, as manifested by resistance to
dexamethasone, and accounts for 65% of the variance.
In summary, depressed women demonstrate greater HPA axis activation than depressed men.
Furthermore, this activation is linked to insensitivity to dexamethasone, and thus appears to
reflect the development of glucocorticoid receptor down-regulation following a period of
hypercortisolemia. Menopause is not associated with increases in plasma cortisol concentrations
in depressed women, but it is associated with an increase in dexamethasone resistance.
EFFECTS OF GONADOSTEROIDS ON THE HPA AXIS:
Animal studies
Studies in rodents support the existence of sex differences in several of the elements of the HPA
axis. Female rats appear to have a more robust HPA axis response to stress than do male rats, and
there is evidence that estrogen is at least partly responsible for this sexual dimorphism. For
example, compared with male rats, female rats have a faster onset of corticosterone secretion after
stress and a faster rate of rise of corticosterone (Jones et al. 1972). The increased corticosterone
response is accompanied by a greatly increased ACTH response to stress in female rodents (Young
1996). Furthermore, corticosteroid binding globulin (CBG) is positively regulated by estrogen and
thus higher in female rats; however, estrogen and progesterone have been demonstrated to affect
the HPA axis independent of the effects of CBG (Young, 1996). In addition, chronic estrogen
treatment of ovariectomized female rats enhances their corticosterone response to stress, and slows
their recovery from stress (Burgess and Handa 1992). Studies by Viau and Meaney (1991)
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demonstrate a greater ACTH and corticosterone stress response in acute estradiol treated rats
compared with ovariectomized female rats, or with estradiol plus progesterone treated female rats,
after short-term (24h) but not long-term (48h) estradiol treatment. However, our studies (Young
and Altemus, 2001) found that two centrally active estradiol antagonists, tamoxifen and CI-628,
led to a greater stress response in intact female rats.
Also, estradiol replacement acted of
ovariectomized rats led to decreased stress responses. Similar inhibitory effects of estradiol on
stress response have been found in sheep and humans. (Komesaroff et al, 1998 and 1999). Studies
showing inhibitory effects of estradiol on the stress response have used lower doses of estradiol
than those showing activation of the axis.
Work by Keller-Wood and colleagues (Keller-Wood et al. 1988) in pregnant ewes and ewes
given progesterone infusions, demonstrate that progesterone can diminish the effectiveness of
cortisol feedback on stress responsiveness in vivo. In addition, progesterone demonstrates antiglucocorticoid effects on feedback in intact rats in vivo and in vitro (Svec 1988; Duncan and
Duncan 1979). Progesterone binds to the glucocorticoid receptor; while it does so with a faster
binding time than glucocorticoid itself, progesterone binding is to a different site on the receptor
than glucocorticoid binding (Svec 1988). Progesterone can also increase the rate of dissociation of
glucocorticoids from the glucocorticoid receptor (Rousseau et al. 1972). In addition, binding
studies with expressed human mineralocorticoid receptor (MR) have demonstrated an affinity of
progesterone for MR receptor in a range similar to that of dexamethasone (Arriza et al. 1987).
Furthermore, there was an increase in MR binding following progesterone treatment of female rats
(Carey et al. 1995). Finally, female rats have a greater number of glucocorticoid receptors in the
hippocampus than male rats (Turner and Weaver 1985), and progesterone modulates
immunoreactive glucocorticoid receptor distribution in the hippocampus of rats (Ahima et al.
8
1992). It should be noted that binding studies do not distinguish agonist effects from antagonist
effects, therefore even increases in number could result from antagonist effects at GR.
Human Studies
Until recently, the lack of a reliable stress test limited studies on sex differences in stress
response in humans. In the Trier Social Stress Test, subjects undergo a mock job interview in front
of a panel of interviewers who are instructed not to provide any verbal or non-verbal feedback; it is
a reliable and robust stressor in normal subjects (Kirschbaum et al. 1995). It has now been shown
that oral contraceptives decrease the free cortisol response to a social stressor in women
(Kirschbaum et al. 1995), while the treatment of normal men with estradiol for 48 hours results in
an enhanced ACTH and cortisol response to a social stressor (Kirschbaum et al. 1996). These data
of estrogen treatment in men are consistent with results of studies in rats (Burgess and Handa 1992;
Viau and Meaney 1991). However, results from studies of oral contraceptives are harder to
interpret because they are synthetic steroids given at constant doses for a prolonged period of time
and may differ from endogenous steroids in their effects. Direct comparison of the ACTH response
to this social stressor in men and women has demonstrated a smaller ACTH response in women
but a similar cortisol response in both sexes (Kirschbaum et al, 1999; Young , Abelson and
Cameron, 2004). These data are in agreement with studies demonstrating that estradiol decreases
stress responsiveness in women (Komesaroff et al, 1999)
With respect to the influence of changes in ovarian hormones across the menstrual cycle in
women, recent studies by Altemus and colleagues (1997) have found increased resistance to
dexamethasone suppression during the luteal phase of the menstrual cycle, compared to during the
follicular phase, a change that may again be related to either increased estradiol or progesterone
during the luteal phase. In addition, ACTH, vasopressin and cortisol responses to stress are
9
enhanced in the luteal phase compared to the follicular phase of the menstrual cycle (Altemus et al.
1997; Galliven, et al 1997) suggesting that decreases in glucocorticoid receptors may explain the
decreased response to dexamethasone. In a design which allowed investigators to distinguish the
effects of progesterone from those of estrogen, Roca and coworkers (1998a;1998b. 2003) studied
control women first treated with Lupron, a gonadotrophin-releasing hormone (GnRH) agonist,
which causes suppression of both estrogen and progesterone secretion, and then given sequential
replacement of the two hormones. They examined the response to exercise stress as well as to
dexamethasone feedback, and found that the exercise stress response was increased. Response to
dexamethasone feedback was decreased during the progesterone "add back" phase but not during
the estrogen "add back" phase. Again, these data suggest that progesterone acts as a glucocorticoid
antagonist. Thus, data from human studies suggest that ovarian steroids may modulate stress
responses in opposite directions so that estradiol decreases stress response while progesterone
decreases sensitivity to negative feedback.
II. Genetic Vulnerability to Depression.
While stress is clearly a precipitating factor in the onset of depression, not everyone who
experiences stress develops a depressive episode suggesting an underlying vulnerability
(Kendler, K. S., 1998). It has long been known that depression clusters in families and extensive
evidence has now accumulated that depression is a complex disorder resulting from the
interaction of genetic and environmental factors (Jones, et al, 2002). Twin studies of unipolar
depression have shown variable degrees of heritability depending on the type of sample and the
definitions of depression used. In a recent meta-analysis of twin data, Sullivan (Sullivan et al,
2000) estimated the heritability of depression to be 37% with a significant contribution of
environmental events specific to individuals but only a small contribution from shared familial
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environmental effects. However, in studies of subjects recruited from psychiatric treatment
centers, rather than community samples, the heritability was much higher (60-70%) (Kendler, et
al, 1995).(McGuffin et al, 1996) indicating a possibly greater heritability of more severe forms of
depression.
Twin studies have examined the genetic risk factors for major depression separately in men and
women with conflicting findings. Two studies have suggested that there is equal heritability for
depression in the two sexes (McGuffin et al, 1996; Kendler et al, 1995). However, in studies
where a broader definition of depression was used, genetic factors accounted for a significantly
greater proportion of the liability to develop depression in women compared with men (Bierut et
al, 1999; Lyons et al, 1998). Although the genes that influence risk for depression in the two
sexes are correlated, they are probably not entirely the same and it is possible that genes
conferring risk for depression differ in men and women (Kendler et al, 2001). Kendler goes on to
suggest that environmental factors may bring out distinct genetic variation in the two sexes or,
alternatively, that biological factors, such as hormonal variations during the menstrual cycle and
pregnancy, could elicit discrete genetic variation in women and men. Genetic influences may also
operate through temperamental dimensions such as neuroticism and through the effect of
different developmental influences such as the onset of puberty marking an increased
vulnerability to depression resulting from negative life events in girls (Rutter, M., 2002).
III. Neuroanatomical Basis of Depression:
Post-mortem studies of depressed patients have often involved patients who die by suicide, thus
conflating depression with suicide, which only occurs in a small minority of patients and may
involve comorbid disorders, particularly alcohol and substance abuse. Furthermore, because of
the nature of post-mortem studies, a priori hypotheses are usually tested rather than new
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hypotheses about functional systems and their relationship to depression. Post-mortem data have
confirmed low serotonin in the CSF of suicide victims, as well as down-regulation of 5HT1a
terminal receptors in cortical regions (Asberg; Mann and Arrango review). They have also
demonstrated increased CRH and vasopressin in the hypothalamus and down-regulation of CRH
receptor binding in the frontal cortex (Raadsheer et al, 1994) . Structural MRI studies have
found smaller hippocampi, often taken to indicate hypercortisolism associated with depression
(Sheline et al, 1996, 2003). Functional imaging gives us another opportunity to understand the
networks involved in depression. However, abnormalities found on functional imaging may not
necessarily identify the "anatomical lesion" of depression but may also demonstrate
compensatory coping mechanisms.
The majority of functional imaging studies have identified abnormalities in the prefrontal cortex,
particularly dorsolateral and ventrolateral areas as the primary finding in depression (Mayberg,
1994: Mayberg et al, 1994; Ketter et al, 1996; Drevets, et al, 1992; Buchsbaum et al, 1986,
Baxter et al, 1989; George et al, 1994) Studies of emotion in normal subjects find these same key
areas activated in response to sad mood (George et al, 1995) Other areas identified in some
studies include limbic areas such as amygdala, temporal cortex and insula but there is less
consensus for these findings. Mayberg has outlined a functional circuit in depression involving
brainstem nuclei, striatum, and thalamus (Mayberg et al, 2000). Treatment data suggest that
pharmacological therapies target the brainstem, limbic and subcortical areas in addition to frontal
cortical areas, while psychotherapies target the frontal cortical abnormalities (Mayberg, et al,
2000; Mayberg et al 2002).
The issue of sex differences have not yet been addressed in either post-mortem or in vivo imaging
studies.
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IV. Serotonin and Depression
A fundamental hypothesis of the etiology of depressive disorders is that these disorders may be due
to a relative deficiency of serotonin. Major depression is accompanied by downregulation of
5HT1A receptors and mRNA, in brain and lymphocytes, as seen in post-mortem studies (López et
al, 1997; Arango et al, 2001) or in vivo imaging (Drevets et al, 1999; Drevets et al, 2000) as well
as increased 5HT2a binding (Arango et al, 1990; Hrdina et al, 1993; Yates et al, 1990).
Furthermore, these two serotonin receptors are targets for antidepressant action, particularly
tricyclic antidepressants. Rodent studies have shown that chronic antidepressant administration
results in functional "upregulation" of the postsynaptic 5-HT1a receptor in the hippocampus (Blier
et al, 1994). Some studies have also reported a modest increase in 5-HT1a receptor number in
hippocampus following antidepressant administration to rodents (Welner et al, 1989; Klimek et al,
1994). Studies have reported decreases in 5-HT2a binding in the prefrontal cortex after chronic
antidepressant administration (Peroutka, Snyder 1980). These findings have led some investigators
to propose that postsynaptic 5-HT1a and 5-HT2a receptors have functionally opposing effects
(Schreiber, De Vry, 1993), that a disturbed balance of these receptors may be contributing to the
pathophysiology of depression (Berendsen, 1995), and that restoration of this balance is necessary
for effective antidepressant action (Borsini, 1994).
Both stress and glucocorticoids modulate serotonin transmission. Acute stress levels of
glucorticoids increase serotonin turnover and increase the responsiveness of hippocampal neurons
to 5HT1A receptor stimulation (Meijer and de Kloet, 1998; McEwen, 1995). When elevated levels
of glucocorticoids persist, such as following chronic social stress, downregulation of hippocampal
13
5HT1A receptors occur while 5HT2 receptors in the cerebral cortex are upregulated (McEwen,
1995).
In addition, 5HT2C receptors are increased following corticosterone adrenectomy, and
normalize following corticosterone replacement (Meijer and de Kloet, 1998). Animal studies
demonstrate that chronic treatment with high doses of glucocorticoids lead to decreased serotonin
receptor mediated responses, similar to the picture observed in depressed patients, although the
exact mechanism of this hypofunctional serotonin state is unclear (Meijer and de Kloet, 1998).
This hypofunctional serotonin state may have further consequences for glucocorticoid secretion,
since serotonin appears to be an important regulator of glucocorticoid feedback. Antidepressants
which increase serotonin cause increases in glucocorticoid receptor number and can reverse the
increased glucocorticoid secretion seen in depressed humans and in transgenic mice who have been
genetically altered to demonstrate reduced glucocorticoid receptors and increased glucocorticoid
secretion (partial GR knockout) (Barden et al, 1995). Lesions of the serotonergic input to the
hippocampus, an important site in inhibiting glucocorticoid secretion, does produce decreased
glucocorticoid receptor expression and increased glucocorticoid secretion (Seckl and Fink, 1991).
Sex differences in serotonin systems:
Gonadal steroids appear to modulate mood, at least in part, through effects on serotonergic
systems. Overall, the literature suggests that estrogen enhances the efficiency of serotonergic
neurotransmission. Basic science studies indicate that there are clear sex differences in brain
serotonin systems some of which may depend upon estrogen and others upon testosterone. The
serotonin content and uptake in multiple areas of forebrain, hypothalamus and limbic system are
higher in females then males (Haleem et al, 1990, Borisova et al, 1996, Carlsson & Carlsson,
1988). 5HT1C and 5HT2 receptor binding in the dentate gyrus or CA4 regions of the
hippocampus is similar in males and females in rats; however, the 5HT1A receptor binding in CA1
14
region of hippocampus is higher in female rats and ovariectomy had no effect on this sex
difference (Mendelson & McEwen 1991). Stress has been shown to cause greater increases in
serotonin in female rats in multiple areas of brain (Heinsbroek et al, 1990). More recent studies
have found that estradiol increased serotonin transporter binding in female rat brains (McQueen et
al, 1997), as well as stimulating an increase in 5HT2A binding sites in limbic cortex (Fink et al
1996). Limited evidence suggests that like estrogen, progesterone may upregulate 5HT2 receptors
(Biegon et al. 1983), and increase serotonin content (Pecins-Thompson et al., 1996). However, no
consistent effects of progesterone administration on serotonin function have been identified. There
also is evidence that testosterone has opposing effects to estrogen on serotonergic activity.
Reductions in androgenic steroid have been associated with enhancement of central serotonergic
activity (Bonson et al. 1994; Fishette et al. 1984; Matsuda et al. 1991). In addition, administration
of testosterone has been associated with reductions in central serotonergic activity (MartinezConde et al. 1985; Mendelson and McEwen 1990).
Studies of sex differences in serotonin systems in humans are more limited.
Sex
differences in the prolactin and cortisol responses to serotonin agonists have been reported, with
women showing greater response to the serotonergic challenges (Monteleone et al, 1997; Ryan et
al, 1992, Lerer et al, 1996, Gelfin et al, 1995). However, estrogen regulates prolactin synthesis as
well as cortisol secretion so greater responses in women do not necessarily indicate serotonin
receptor differences. One study examining 5HT2 receptors on platelets in children, found a
suggestion of increased binding in teenage girls after the age of 14, but the study was clearly
limited by a small sample size of post pubertal adolescents (Biegon and Greuner, 1992).
Incubation of human platelets with sex steroids had no direct effects on serotonin uptake
(Ehrenkranz, 1976). Depressed women have a higher density of 5HT2 receptors on platelets than
male depressed patients (Hrdina et al, 1995). No sex differences have been found in serotonin
15
metabolites in cerebrospinal fluid of normal subjects (Leckman, 1994; Yoshino, 1982). One
postmortem study examining serotonin binding in human brain found no sex differences
(Marcusson et al, 1984); while another reported increased 5HT2 binding in frontal cortex in
women (Arato et al, 1991). One PET imaging study found a sex differences in 5HT2A in brain
with men showing more 5HT receptors than women. (Biver et al, 1996). It should be noted that
many of the human studies were conducted before an understanding of multiple serotonin receptors
existed, so many of the compounds used to detect serotonin receptors were non-specific. It is
likely that there are sex differences in serotonin systems in humans and the differences may be
larger in depressed women compared to depressed men than the differences seen in normal
subjects. Of note, the two illnesses shown to have a specific response to serotonergic
antidepressants, premenstrual syndrome (Eriksson et al. 1995) and obsessive-compulsive disorder
(Greist et al. 1995) appear to be particularly sensitive to changes in gonadal steroids.
CONCLUSIONS
The fact that women have much greater and repetitive fluxes in reproductive hormones
over the lifespan may enhance the potential for dysregulation of a wide variety of brain
neurochemical systems. In addition, as noted above, organizational differences between male and
female brains result fromexposure to high levels of gonadal steroids during the pre- and peri-natal
periods. The interactions of these organizational effects in females with cyclical gonadal steroid
hormone changes following puberty, then followed by menopause when there isloss of these same
steroids, suggest that stress responsiveness and susceptibility to stress related disorders could vary
16
substantially over the lifetime of women. There is certainly evidence that women's increased
vulnerability to depression arises at puberty, when gonadal steroids could further enhance HPA
axis responsiveness (Kessler et al. 1993). Additionally, the evidence linking stress and
glucocorticoids to hippocampal damage and subsequent memory problems (Issa et al. 1990), and
the important role that gonadal steroids may play in protection from these effects in premenopausal
women, imply that further research is needed into the interaction of stress, menopause and memory
impairment.
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