Hormones and Mood, From Menarche To Menopause and Beyond - Depresion2003

Journal of Affective Disorders 74 (2003) 6783
www.elsevier.com/ locate/ jad

Research report
Hormones and mood: from menarche to menopause and beyond
1
*
Meir Steiner , Edward Dunn , Leslie Born
Departments of Psychiatry & Behavioural Neurosciences and Obstetrics & Gynecology, McMaster University, Womens Health
Concerns Clinic and Father Sean OSullivan Research Centre, St. Josephs Healthcare, Hamilton, Ontario L8N 4A6, Canada
Received 11 June 2001; accepted 6 July 2001
Abstract
The lifetime prevalence of mood disorders in women is approximately twice that of men. The underlying causality of this
gender difference is not yet understood. There is increasing scientic attention to the modulation of the neuroendocrine
system by uctuating gonadal hormones. This review attempts to summarize our current state of knowledge on the role and
potential relevance of estrogen and other sex steroids to psychiatric disorders specic to women from menarche to
menopause.
The sudden appearance of higher levels of estrogen in puberty alters the sensitivity of the neurotransmitter systems.
Moreover, the constant ux of estrogen and progesterone levels throughout the reproductive years portends constant
modication of the neurotransmitter systems. Premenstrual syndromes may be the result of an altered activity or sensitivity
of certain neurotransmitter systems. Pregnancy and delivery produce dramatic changes in estrogen and progesterone levels as
well as signicant suppression along the HPA axis, possibly increasing vulnerability to depression. At menopause, estrogen
levels decline while pituitary LH and FSH levels increase. The loss of modulating effects of estrogen and progesterone may
underlie the development of perimenopausal mood disorders in vulnerable women.
The pattern of neuroendocrine events related to female reproduction is vulnerable to change and is sensitive to
psychosocial, environmental, and physiological factors. Further research is needed to be able to identify specic genetic
markers which might help us better understand how the balance between estrogen, progesterone, testosterone, and other
steroid hormones affect neurotransmitter function.
2002 Elsevier Science B.V. All rights reserved.
Keywords: Women; Mood disorders; Neurotransmitters; Sex hormones
1. Introduction
*Corresponding author. Tel.: 11-905-522-1155x3605; fax:
The lifetime prevalence of mood disorders in
11-905-521-6098.
women is approximately twice that of men. This
E-mail address: mst@mcmaster.ca (M. Steiner).
1
higher incidence of depression in women is primarily
Dr. Dunn is now with the Centre for Addiction and Mental
Health, Toronto, Ontario. seen from puberty on and is less marked in the years
0165-0327/ 02/ $ see front matter 2002 Elsevier Science B.V. All rights reserved.
doi:10.1016/ S0165-0327(02)00432-9
68 M. Steiner et al. / Journal of Affective Disorders 74 (2003) 6783
after menopause (Weissman and Olfson, 1995), with tions of estrogens and progesterone are probably the
the exception of an additional perimenopausal blip trigger of premenstrual complaints in women with
(Kessler et al., 1993). The underlying causality of premenstrual syndrome (Fink et al., 1996; Sumner
this gender difference in mood-related disorders is and Fink, 1997). The interaction between neuro-
not clear at this time. Since mood disorders occur in transmitters and steroid hormones is extremely com-
both men and women it is assumed that a unied plex and delicately balanced. Each system appears to
basis for the development of these diseases exists. have a modulatory function on the other and changes
The principal constituent of this unied theory is in one system may have a dramatic effect on the
believed to be related to genetic predisposition. other systems.
Multiple environmental stressful events cause bio- Glucocorticoid and gonadal steroid receptors are
chemical changes in a host of neuroendocrine sys- abundant in different areas of the brain. Gonadal
tems and neuroanatomical areas. The genetic pre- steroid receptors are found in the amygdala, hip-
disposition, which is multi-factorial, determines how pocampus, basal forebrain, cortex, cerebellum, locus
stressful life events are interpreted and predicts the ceruleus (LC), midbrain raphe nuclei, pituitary gland
response, which can lead to the development of and hypothalamus (Stomati et al., 1998). Estrogen
mood disorders. The higher prevalence of mood receptors are located in the preoptic area and
disorders in women could be related to either an amygdala (McEwen, 1988) and the ventromedial
increased genetic predisposition, an increased vul- nucleus and arcuate nucleus of the hypothalamus
nerability/ exposure to stressful life events, modula- (Herbison et al., 1995).
tion of the neuroendocrine system by uctuating Activation of cholinergic, dopaminergic or adren-
gonadal hormones, or a combination of any or all of ergic neurotransmitter systems can alter concentra-
these factors. tions of cytosolic hypothalamic estrogen receptors.
We have previously proposed a biological suscep- Muscarinic agonists and antagonists can increase
tibility hypothesis to account for gender differences estrogen-binding sites in the female rat hypothalamus
in the prevalence of mood disorders based on the (Lauber and Whalen, 1988). Estrogen, progesterone
idea that there is a disturbance in the interaction and glucocorticoid receptors can also be activated by
between the HPG axis and other neuromodulators in insulin-like growth factor 1 (IGF-1), epidermal
women (Steiner and Dunn, 1996; Dunn and Steiner, growth factor (EGF), transforming growth factor
2000). According to this hypothesis, the neuroen- alpha (TGF-alpha), cyclic AMP, protein kinase ac-
docrine rhythmicity related to female reproduction is tivators and by various neurotransmitters (Culig et
vulnerable to change and is sensitive to psychosocial, al., 1995). Thus, activation of neurotransmitter sys-
environmental and physiological factors. Thus, pre- tems can have a direct modulatory effect on binding
menstrual dysphoric disorder (PMDD), depression of gonadal hormones in the central nervous system
with post-partum onset (PPD), and mood disorders (CNS).
associated with the perimenopause or with meno- Conversely, steroid hormones can modulate neuro-
pause, may all be related to hormone-modulated nal transmission by a variety of mechanisms. They
changes in neurotransmitter function. may affect the synthesis and/ or release of neuro-
Control of mood and behaviour involves many transmitters, as well as the expression of receptors,
different neurotransmitter systems, including gluta- membrane plasticity and permeability. It has been
mate, GABA, acetylcholine (ACh), serotonin (5-HT), suggested that steroid hormone receptors function as
dopamine (DA), noradrenaline (NA) and neuropep- general transcription factors to achieve integration of
tides. Given the observation that prevalence and neural information in the CNS (Mani et al., 1997).
symptomatology of mood disorders is often different Steroids are believed to act primarily by classical
between males and females, it is presumed that genomic mechanisms through intracellular receptors
gonadal steroid hormones are somehow involved. to modulate transcription and protein synthesis. This
For example, declining levels of estrogen in women mechanism involves the binding of the steroid to a
have been associated with postnatal depression and cytoplasmic or nuclear receptor. The hormonere-
post-menopausal depression, and the cyclical varia- ceptor complex then binds to DNA to trigger RNA-
M. Steiner et al. / Journal of Affective Disorders 74 (2003) 6783 69
dependent protein synthesis. The response time for (MD) in adolescents and young adults (15 to 24
this mechanism is of the order of several minutes, years of age) has been reported as 20.6% for females
hours or days. Recently however, it has been shown and 10.5% for males (Kessler and Walters, 1998).
that steroids can also produce rapid effects on Lifetime rates of MD in early- as well as late-
electrical excitability and synaptic function through maturing girls, were even higher (30% vs. 22% and
direct membrane mechanisms, such as ligand-gated 34% vs. 22%, respectively) when compared to on-
ion-channels, G-proteins and neurotransmitter trans- time girls.
porters (Wong et al., 1996). These short-term (sec- There is conicting opinion regarding the age at
onds to minutes) effects of steroids may occur which gender differences in rates of MD emerge:
through binding to the cell membrane, binding to researchers are divided between the 12 to 14 and the
membrane receptors, modulation of ion-channels, by 15 to 19 year age brackets (Cohen et al., 1993;
direct activation of second messenger systems (Moss Hankin et al., 1998; Lewinsohn et al., 1998).
et al., 1997), or by activation of receptors by factors An integrative theory of depression in adolescents
such as cytokines and dopamine (Brann et al., 1995). has been introduced (Lewinsohn et al., 1998), al-
Topical application of estrogen or progesterone to though a persuasive explanation of the sharp rise in
nervous tissue has been shown to result in a rapid the prevalence of depression in females after menar-
change in membrane potential and sex steroids can che has yet to be elucidated.
affect membrane uidity thereby modifying ion The onset of puberty is heralded by a growth
transport or receptor function (Maggi and Perez, spurt, which begins with rapid growth in height and
1985). weight typically between 7.5 and 11.5 years of age.
The role and potential relevance of estrogen and Following this initial burst, physical growth con-
other sex steroids to psychiatric disorders is the focus tinues at a slow pace for several years. The rst sign
of current scientic attention. Estrogen has been of sexual maturation in girls is breast budding at
described as a 5-HT, NA and Ach agonist; it also about 10.5 years, followed by growth of pubic hair
modulates DA receptors. The implications to the which begins at about 11.5 years, growth of the
2
reproductive life cycle of women will be briey uterus and vagina, and the enlargement of the labia
reviewed. Specically, the impact of hormonal uc- and clitoris. Menstruation begins after these changes
tuations during menarche, premenstrually, during occur. Finally, axillary hair appears, hips broaden,
pregnancy and postpartum, and perimenopausally and fat deposits increase. On average, these changes
will be discussed. take 4 to 5 years, however, considerable variation
exists in the sequence and tempo of these events.
In North America and Europe, the age of menar-
2. Menarche and mood disorders in adolescence che has declined about 4 months per decade since
1850; in North America, menarche now occurs
Epidemiological studies consistently show that around 12.5 years of age on average (Tanner, 1968).
beginning at menarche, mood disorders are at least This dramatic decline in the age at which girls reach
twice more common in women than in men. Why puberty is one of the strongest examples of en-
these gender differences exist and why they start at vironmental factors that affect hormonal responses.
puberty is perhaps one of the most intriguing and The search to isolate the particular environmental
least understood phenomena in clinical psychiatry factors involved in this acceleration, however, has
(Lewinsohn et al., 1998). been only marginally helpful. It has been suggested
Prior to adolescence, the rates of depression are that urbanization has a major role in this change as
similar in girls and boys (or are slightly higher in well as improvements in general health, nutrition,
boys); yet with the onset of puberty, the gender and other socio-cultural factors. But other environ-
proportion of depression dramatically shifts to a 2:1 mental factors also seem to be implicated in the
female to male ratio (Kessler and Walters, 1998; timing of menarche. Girls who are blind with some
Lewinsohn et al., 1998). In the US general popula- perception of light reach menarche earlier than
tion, the lifetime prevalence of major depression normally sighted girls, and totally blind girls with no
light perception reach puberty even earlier observed. For example, investigators have found that
(Zacharias and Wurtman, 1964). Moreover, fewer negative affect was signicantly related to a rapid
girls start to menstruate during spring and summer increase in estradiol levels (Warren and Brooks-
time as compared to during seasons of reduced Gunn, 1989). Negative affect in healthy girls was
amounts of daylight (fall and winter) (Bojlen and also associated with higher levels of testosterone and
Bentzen, 1974). cortisol, and lower levels of dehydroepiandrosterone
The relationship between psychosocial develop- sulphate (Susman et al., 1991).
ment and physical maturation has been widely There is both direct and indirectalbeit limited
examined. Girls undergoing pubertal change are evidence of the involvement of the serotonergic
thought to experience greater distress and to be more system in the etiology of depressive disorders in
vulnerable to stress than pre- or post-pubertal girls child and adolescent depression. In a comparative
(Caspi and Moftt, 1991). Two parameters of puber- study of psychiatric in-patients and normal controls
tal change in particular have received much atten- (aged 7 to 17 years), levels of whole-blood 5-HT
tion: pubertal status and pubertal timing. Pubertal were lowest in patients with mood disorders (Hughes
status is dened as the current level of physical et al., 1996). There is some indication of the
development of an adolescent relative to the overall responsiveness of children and adolescents with MD
process of pubertal change (a biological factor), to serotonergic but not noradrenergic agents; re-
usually denoted by a series of stages from prepuber- searchers have hypothesized that, in childhood, the
tal (stage I) to adult (stage V) according to Tanner serotonergic systems may mature at an earlier rate
(1962). Pubertal timing, on the other hand, is dened than the noradrenergic systems (Ryan and Varma,
as the maturation of an adolescent relative to her 1998). Gonadal hormones effect the production of
peers (a psychosocial factor). 5-HT receptors at the transcriptional level, and the
There appears to be a relatively sharp demarcated altered distribution or function of 5-HT receptor
period in mid-puberty when girls become more subtypes brought on by changes in the hormonal
vulnerable to depression than boys. In a recent report milieu at menarche may increase vulnerability to
on 1073 US children, 9 to 13 years of age, the mood disorders.
depression rates in girls rose signicantly in mid- It is nevertheless still unclear how the dramatic
puberty, i.e., with the transition to Tanner stage III. changes in the hormonal milieu associated with
In contrast, the prevalence of depression in boys menarche and a host of psychosocial stressors com-
declines from Tanner stage II (Angold et al., 1998). bine to produce depressive symptoms. One possible
Further, it has been determined that in girls, pubertal unifying hypothesis suggests that disruption of bio-
status (versus the age at puberty per se) better logical rhythms, such as disturbed sleep patterns
predicted the emergence of the sex ratio in depres- (Armitage et al., 2001) or irregular menstrual cycles,
sion rates. Thus, the onset of menarche may signal together with psychosocial losses causing the disrup-
an increased but latent biological vulnerability to tion of social rhythms (also known as social zeitgeb-
mood dysregulation in women (Nolen-Hoeksema ers) could trigger the onset of a major depressive
and Girgus, 1994). episode in vulnerable individuals (Ehlers et al.,
Although changes in affect, mood, and behaviour 1988). Another complementary theory emphasizes
are considered to be related to cyclic hormonal the neurobiology of stress and the dysregulation of
changes, studies of female adolescents and premen- affect during female biological transitions such as
strual syndrome (PMS) are inconclusive with one menarche, a transition which may be associated with
study reporting no relationship between menstrual changes in the reactivity of the stress system (Dorn
cycle phase and negative affect (Golub and Harrin- and Chrousos, 1997). The newly uctuating levels of
gton, 1981) and others show that PMS is associated gonadal hormones as well as gonadotropins, which
with other distress factors in this age group (Raja et mark the onset of menarche and the establishment of
al., 1992; Freeman et al., 1993). Notwithstanding, menstrual cycles, introduce a major change in the
relationships between changes in pubertal hormones hormonal milieu to which the rest of the systems
and negative affect in female adolescents have been have to adjust. This is the period during which the
hypothalamicpituitaryadrenal (HPA) axis has to phenomena (as opposed to psychological or psycho-
mature and be sensitized to a variety of new feed- social events) is primarily underscored by recent,
back mechanisms. This is also the time during which convincing evidence of the heritability of premen-
the HPA axis may be more vulnerable to external strual symptoms (Kendler et al., 1998) and the
psychosocial stressors, to sleep deprivation as well as elimination of premenstrual complaints with suppres-
to the inuences of nicotine, alcohol and other drugs, sion of ovarian activity (Schmidt et al., 1998) or
resulting in a higher incidence of HPA axis dysregu- surgical menopause (Casson et al., 1990). The
lation and mood instability. current consensus seems to be that normal ovarian
Taken together, it is suggested that pubertal and function rather than simple hormone imbalance is the
other hormonal changes should be monitored pros- cyclic trigger for biochemical events within the
pectively along with individual, genetic, constitution- central nervous system and other target tissues which
al, and psychological characteristics in our efforts to unleash premenstrual symptoms in vulnerable
predict the development of negative affect during women (Roca et al., 1996). This viewpoint is
puberty (Steiner et al., 2000). attractive in that it encourages investigation of the
neuroendocrine-modulated central neurotransmitters
and the role of the hypothalamicpituitarygonadal
3. Premenstrual dysphoria axis in PMDD. Notwithstanding, a surge of recent
research has encompassed other etiological inu-
The recent inclusion of research diagnostic criteria ences including female biological rhythms (sleep,
for PMDD in the DSM-IV recognizes the fact that body temperature), and psycho-social factors.
some women in their reproductive years have ex- The role of the female sex hormones in premen-
tremely distressing emotional and behavioural symp- strual symptomatology has been considered of cen-
toms premenstrually (American Psychiatric Associa- tral importance, yet in women with PMDD, the
tion, 1994a). Through the use of these criteria, ovarian axis is apparently functioning normally with
PMDD can be differentiated from premenstrual normal hormone (estrogen and progesterone) levels
syndrome (PMS) which has milder physical symp- (Schmidt et al., 1998). Recently, attention has shifted
toms, i.e. breast tenderness, bloating, headache and from a focus on estrogen and progesterone to the role
minor mood changes (World Health Organization, of androgens in premenstrual dysphoria.
1996a). PMDD can also be differentiated from Early investigations of androgens have suggested
premenstrual magnication (concurrent diagnoses of that women with PMS or PMDD have elevated
PMS or PMDD and a major psychiatric or an levels of serum testosterone in the luteal phase
unstable medical condition) and from premenstrual compared with controls (but still within the normal
exacerbation of a current psychiatric disorder or range), which may contribute primarily to the symp-
medical condition (Steiner and Wilkins, 1996). tom of irritability (Eriksson et al., 1992; Dunn et al.,
Epidemiological surveys have estimated that as 2001; Ho et al., 2001). This hypothesis of increased
many as 75% of women with regular menstrual androgenicity is backed both by animal and human
cycles experience some symptoms of premenstrual studies of androgens and irritability and/ or aggres-
syndrome (Johnson, 1987). PMDD, on the other sion. Androgens promote sexual drive in humans,
hand, is much less common. It affects only 3 to 8% and also, have been tentatively linked with mood
of women in this group (Johnson et al., 1988; (e.g. depression, and premenstrual irritability) and
Ramcharan et al., 1992; Angst et al., 2001), but it is impulsive behaviour (e.g. compulsions, and binge
more severe and exerts a much greater psychological eating). Enhanced serotonin availability (e.g. with
toll. These women report premenstrual symptoms the use of SSRIs), on the other hand, is associated
that seriously interfere with their lifestyle and rela- with reduction in irritability, depression, impulsive
tionships (Freeman et al., 1985; OBrien et al., behaviour, as well as reduced libido. An inverse
1995). relationship between serotonin and androgens, and
The etiology of PMS and PMDD is still largely their effects on human behaviour has been proposed;
unknown. That PMS and PMDD are biological the behavioural effects of androgens may be there-
fore partly mediated by a reduction in serotonin found in a small group of women with premenstrual
activity (Eriksson et al., 2000). symptoms but that PMDD should not be viewed as a
Reduction of premenstrual dysphoria with an- masked form of hypothyroidism (Schmidt et al.,
drogen antagonists in women with PMS who showed 1993; Korzekwa et al., 1996).
higher mean levels of total testosterone in the late Of the neurotransmitters studied to date, increas-
luteal phase also lends support to the idea of ing evidence suggests that 5-HT may be important in
increased androgenicity (Rowe and Sasse, 1986; the pathogenesis of PMDD (Rapkin, 1992; Steiner et
Burnet et al., 1991). Others, however, have not al., 1997). PMDD shares many features of other
observed differences in plasma testosterone in com- mood and anxiety disorders linked to serotonergic
parisons of women with or without PMS (Dougherty dysfunction. In addition, reduction in brain 5-HT
et al., 1997), and one study has reported signicantly neurotransmission is thought to lead to poor impulse
lower total and free testosterone plasma levels in a control, depressed mood, irritability, and increased
sample of 10 women with PMS (Bloch et al., 1998). carbohydrate cravingall mood and behavioral
Further comparative studies of women with PMS and symptoms associated with PMDD.
PMDD are therefore required. The serotonergic system is in close reciprocal
There is increasing attention to the metabolite of relationship with gonadal hormones. In the hypo-
progesterone, allopregnanolone in the manifestation thalamus, estrogen induces a diurnal uctuation in
of premenstrual symptomatology. Treatment studies 5-HT (Cohen and Wise, 1988), whereas progester-
have suggested that progesterone and progestagens one increases the turnover rate of 5-HT (Ladisich,
may actually provoke, rather than ameliorate, the 1977).
cyclical symptom changes of PMDD (Hammarback More recently, several studies concluded that 5-
et al., 1985). Allopregnanolone, on the other hand, is HT function may also be altered in women with
thought to modulate gamma aminobutyric acid PMDD. Some studies used models of neuronal
(GABA) receptor functioning and produce an an- function (such as whole blood 5-HT levels, platelet
xiolytic effect (Rapkin et al., 1997); quantitative uptake of 5-HT, and platelet tritiated imipramine
differences in progesterone and allopregnanolone binding) and found altered 5-HT function during all
levels between PMS subjects and controls have been phases of the menstrual cycle (Ashby et al., 1988;
examined. The ndings to date in women are con- Rapkin, 1992; Steege et al., 1992). Other studies that
tradictory (Rapkin et al., 1997; Schmidt et al., 1994; used challenge tests (with L-tryptophan, fenuramine,
Wang et al., 1996; Bicikova et al., 1998; Monteleone buspirone, m-chlorophenylpiperazine) suggested ab-
et al., 2000), although a recent study in an animal normal serotonin function in symptomatic women
model is more promising. In a progesterone-with- but differed in their ndings as to whether the
drawal paradigm, designed to mimic PMS and response to 5-HT is blunted or heightened (Bancroft
postpartum depression in female rats, Smith et al. et al., 1991; Bancroft and Cook, 1995; FitzGerald et
have found that decreased levels of allopregnanolone al., 1997; Su et al., 1997; Steiner et al., 1999). Acute
lead to increased production of the a4 subunit of the tryptophan depletion (suppressing brain 5-HT syn-
GABA receptor. This changes the sensitivity of the thesis) was signicantly associated with exacerbation
A
GABA receptor to endogenous ligands, resulting in of premenstrual symptoms, in particular irritability
A
symptoms associated with PMS (Smith et al., 1998). (Menkes et al., 1994). Additional evidence sug-
An alternative strategy to measuring various hor- gesting the involvement (although not necessarily
mone plasma levels in an attempt to discern the etiologic) of the serotonergic system has emerged
etiology of PMDD has been to search for endocrine from treatment studies: drugs facilitating serotoner-
abnormalities that have been repeatedly associated gic transmission, such as selective serotonin reuptake
with various other forms of psychopathology. The inhibitors (SSRIs), are very effective in reducing
main advantage of this approach is its potential to premenstrual symptoms. These studies imply, at least
help further our understanding of PMDD as well as in part, a possible change in 5-HT receptor sen-
1A
its relation to other psychiatric disorders. The current sitivity in women with premenstrual dysphoria
literature suggests that thyroid dysfunction may be (Steiner and Born, 2000).
The current consensus is that women with premen- Postpartum blues is considered the most mild of
strual dysphoria may be behaviourally or biochemi- the postpartum mood disturbances; its prevalence has
cally sub- or supersensitive to biological challenges been reported to be 2685%, depending on the
of the serotonergic system. It is not yet clear whether diagnostic criteria used (Stein et al., 1981). The
these women present with a trait or state marker symptoms of this syndrome typically begin within
(alternatively, both conditions could be possible) of the rst week following childbirth, peak on the fth
premenstrual syndromes. day and resolve by the 12th day postpartum. Symp-
The serotonergic system is in close reciprocal toms include dysphoria, mood lability, crying, anxie-
relationship with the gonadal hormones and has been ty, insomnia, poor appetite, and irritability. The
identied as the most plausible target for interven- mood disturbance characterizing postpartum blues is
tions. Thus, beyond the conservative treatment op- considered transient and insufcient in and of itself
tions such as lifestyle and stress management, and to cause serious impairment of a womans func-
the more extreme interventions that eliminate ovula- tioning (OHara et al., 1991). In some women,
tion altogether (e.g. ovarian suppression, using long- however, the disturbance may persist beyond the
term treatment with GnRH agonists, which is not initial postpartum period, leading to more serious
only associated with the untoward effects of intro- PPD (Cox et al., 1993).
ducing early menopause but may also increase Epidemiologic studies of the nature, prevalence
depressive symptoms; Warnock et al., 1998), the and course of an episode of major PPD have found
SSRIs are emerging as the most effective treatment that between 10 and 15% of women exhibit depres-
options for this population. sive symptoms in the rst weeks following delivery
Results from several randomized placebo-con- (Carothers and Murray, 1990; Pop et al., 1993), and
trolled trials in women with PMDD, with predomi- that the great majority of these depressive episodes
nantly psychological symptoms of irritability, ten- resolve spontaneously within 3 to 6 months (Cox et
sion, dysphoria and lability of mood, have clearly al., 1993; Cooper and Murray, 1995). The symptom
demonstrated that the SSRIs have excellent efcacy prole of PPD resembles that of a major depressive
and minimal side effects. More recently, several episode experienced at other times in life, but it is
studies indicate that intermittent (premenstrually unique in its timing and in that it always involves at
only) treatment with SSRIs is equally effective in least the motherbaby dyad and in most cases an
these women and, thus, may offer an attractive entire family unit.
treatment option for a disorder that is itself intermit- Postpartum psychosis is much more rare and more
tent (Steiner and Born, 2000). severe than either depression or the blues. It has a
prevalence of |1 in 5001000 births, and a rapid
onset within the rst few days to 2 weeks postpartum
4. Postpartum depression (Brockington et al., 1982). Postpartum psychosis,
believed to be in most cases an episodic presentation
The specic link and the uniqueness of psychiatric of a manic-depressive illness, severely impairs the
disorders precipitated or triggered by pregnancy or affected womans ability to function. In the most
childbirth have recently been acknowledged by the extreme cases, the risks of suicide or infanticide are
American Psychiatric Association (1994b). Based high (Millis and Kornblith, 1992), requiring admis-
primarily on the work of the Task Force on DSM-IV sion to a psychiatric hospital (Kendell et al., 1987).
(Purnine and Frank, 1996) the manual now has a Pregnancy and childbirth have an enormous com-
course-specic designation postpartum onset, that bined psychological, physiologic and endocrine ef-
can be applied to both psychotic and non-psychotic fect on a womans body and mind. Since the changes
postpartum mental disorders. Thus, major depressive in mood coincide with these profound changes in
disorders, bipolar disorders (manic and depressed), hormones and other humoral agents related to preg-
schizoaffective disorders, and psychotic disorders nancy and childbirth, a causal link has been sup-
(not otherwise specied) will have the qualier with posed probable (Steiner, 1998). In the animal king-
postpartum onset. dom, maternal behaviour is mediated by hormonal
and neurochemical changes associated with re- maternal approach behaviour (Fleming et al., 1987).
production (Rosenblatt et al., 1988). In animals, it None of the other hormones measured (estradiol,
has been suggested that the various neuromodulators progesterone, testosterone and thyroid indices) were
be divided into groups which dene their proposed correlated with any of the maternal behaviours
role in maternal response: primersmost important measured (Fleming et al., 1987, 1995). These results
during late pregnancy (e.g. steroid hormones and suggest that cortisol does not induce maternal be-
prolactin); triggersreleased during parturition (e.g. haviour directly but it probably facilitates maternal
oxytocin); and modiersof oxytocin release (e.g. attitudes, which may then be expressed as emotions
beta-endorphins, other neurotransmitters) (Keverne and/ or behaviour.
and Kendrick, 1994). There is, of course, a consider- Thyroid dysfunction has been implicated in mood
able scope for interactions between these changes disorders and it has been suggested that transient
and varying repertoires of maternal behaviour across thyroid dysfunction following childbirth is associated
different species (Fleming and Corter, 1988) and the with PPD (Pederson et al., 1993b). In some women,
relevance to human behaviour is as yet unclear. pregnancy and the postpartum period are associated
The peak in mood disturbance during the blues at with pathological changes in thyroid function. A
around the fth day postpartum coincides with review of the literature in this area clearly indicates
extreme hormonal uctuations that are a natural the possibility that a subgroup of women with PPD
consequence of parturition. These hormones act have a basis for the depressed mood in thyroid
within the central nervous system at a variety of disorder. More specically, in some women depres-
limbic sites known to be involved in emotional sive symptoms are associated with positive thyroid
responses, arousal and reinforcement. Only a handful antibody status during the postpartum period (Harris
of studies attempted to measure these changes, et al., 1992). It is believed that 1% of all postpartum
especially in gonadal hormones and prolactin. To women will show a mood disorder associated with
date, the results do not seem to correlate strongly transient thyroid dysfunction and treatment of the
with changes in mood and are mostly disappointing thyroid condition must be part of the management.
and inconsistent. For example, a rapid fall in proges- The direct and/ or indirect effect of the rate of the
terone showed a weak but signicant relationship to postpartum withdrawal of some of the other major
the development of the blues in one study (Harris et hormones and neuromodulators involved is neverthe-
al., 1994) but not in another (Heidrich et al., 1994). less still intriguing. It has been suggested that
Similarly, increased plasma cortisol levels corre- women who experience a more rapid beta-endorphin
lated with the blues and with PPD in one study withdrawal are more prone to mood changes (Smith
(Okano and Nomura, 1992) but not in others (Smith et al., 1990). A sharp fall in circulating estrogen
et al., 1990; OHara et al., 1991). Preliminary results concentrations after delivery has been associated
suggest that natural killer-cell activity is lower in with acute onset of postpartum psychosis (Wieck et
postpartum dysphorics and that this decrease is al., 1991). These changes are believed to be the
related to higher levels of cortisol (Pedersen et al., triggers to a cascade of changes at central and
1993a). In contrast, negative or false-positive results peripheral monoamine centres. Very preliminary data
with the dexamethasone suppression test do not suggest an increased sensitivity of dopamine re-
correlate with mood changes indicating that the HPA ceptors in acute postpartum psychosis (Wieck et al.,
axis is physiologically hyperactive postpartum 1991) and an abnormality in alpha -adrenoceptor
2
(ceiling effect) and measurements along this axis sensitivity associated with the blues (Best et al.,
as an indicator for depression in this population are 1988). Changes in sensitivities of serotonergic re-
probably invalid (Steiner et al., 1986; Smith et al., ceptors have been documented in PPD (Hannah et
1990; OHara et al., 1991). The HPA, rather than the al., 1992), but not in women with the blues (Katona
HPG axis may in fact play a unique role in human et al., 1985).
maternal behaviour. Euthymic new mothers with More recently it has been hypothesized that PPD
positive maternal attitudes and high levels of cortisol may be caused by transient-hypothalamic corticot-
postpartum exhibit the highest level of postpartum ropin-releasing hormone (CRH) suppression
(Magiakou et al., 1996). The HPA axis is pro- terone levels (Glaser et al., 1990). It is argued that
gressively hyperactive throughout pregnancy, with postpartum withdrawal of gonadal hormones may
increasing levels of circulating CRH of placental cause changes along the serotonergic cascade which
origin and decreasing levels of CRH-binding protein. may lead to a mood disorder in vulnerable or
Both these phenomena, together with the elevated genetically predisposed women. (It should therefore
levels of estradiol of pregnancy which also stimulate be possible to treat the disturbance by adjusting the
the HPA axis, particularly during the third trimester, levels of the hormone (the trigger) (Henderson et al.,
contribute to the elevated levels of CRH, ACTH and 1991) or by reversing the sensitivity (predisposi-
cortisol (Cizza et al., 1997). After parturition the tion).) Results from some preliminary studies on
source of placental CRH is removed, and together preventative interventions with lithium prophylaxis
with the postpartum estrogen withdrawal which is (Stewart et al., 1991; Cohen et al., 1995) and with
further prolonged by breastfeeding (Kim et al., 2000) SSRIs (Stowe et al., 1995; Appleby et al., 1997) are
may lead to a prolonged state of HPA axis hypoac- very encouraging. Since mood disorders associated
tivity. Indeed, it has been demonstrated that in a with childbearing have different times of onset in
subgroup of women with PPD, the suppression of the different women and are heterogenous in their
HPA axis was more severe and lasted longer than presentation, concomittant measurements of the
that of women who had no postpartum mood in- changes over time in gonadal hormones and the
stability (Magiakou et al., 1996). biochemical changes in the monoamine system are
CRH has been associated with the neurobiology of crucial.
stress and depression (Chrousos and Gold, 1992). Further evidence of a biological component of
PPD also appears to be a state of central CRH postpartum mood disorders comes from family and
dysregulation. With the additional established evi- family history studies. A study of women with
dence of direct estrogenic regulation of the CRH postpartum mood disturbances and their rst-degree
gene expression (Vamvakopoulos and Chrousos, relatives found that at least one family member met
1993) it is therefore not surprising that estrogen has criteria for a past or present psychiatric disorder in
been proposed as a treatment for PPD (Sichel et al., 71% of the cases for which the information was
1995; Gregoire et al., 1996; Ahokas et al., 2001). In available. Positive histories for MD and alcoholism
the only double-blind, placebo-controlled study pub- were found in 48% and 30% of these families,
lished to date, a 3-month course of 200 mg/ day of respectively (Steiner and Tam, 1999). Further analy-
17b-estradiol signicantly improved the clinical sis of these data revealed an interesting gender
symptoms of severely depressed women postpartum distribution of psychiatric disorders in the rst-de-
(Gregoire et al., 1996). Unfortunately further re- gree relatives of the postpartum women. A
search on the role of estrogen therapy for PPD has female:male ratio greater than 2:1 was found in
not yet emerged. Similarly, progesterone has been relatives with a past or present diagnosis of MD, in
widely used for the treatment of postnatal depression the case of alcoholism, a male:female ratio of 4:1
but without controlled trials (OBrien and Pitt, was evident. This lifetime prevalence of mood-re-
1994). lated disorders in the rst-degree relatives of women
The role of hormone replacement therapy is of presenting with postpartum mood disorders is much
interest beyond the realm of the postpartum period higher than in the population at large and may
and as discussed in the next section is of major indicate potential genetic or familial components of
relevance during the perimenopausal and menopausal the disorders.
years and beyond. Despite the fact that most animals share the same
The reciprocal relationship between the serotoner- physiological events at parturition, the differences in
gic system and gonadal hormones has not as yet been behavioral response between humans (as well as
studied during pregnancy or in postpartum women. other primates) and nonprimate mammals are re-
However, preliminary results from studies in post- markable. The differences between primates and
partum rats indicate that 5-HT receptor changes in nonprimates are mainly in the organization of social
the limbic area are negatively correlated with proges- structures, the complex inuences of the family unit,
and the constant exposure of all members of a group sometimes seems as if the only thing worse than
to the young. It is therefore easy to assume that, in being subjected to the raging hormonal inuences of
humans, even thinking about children may be suf- the female cycle is to have those inuences subside
cient to stimulate maternal responsiveness. The (Parlee, 1976). The notion of universal hormone
psychosocial literature to date has advanced several replacement for all menopausal women was so
psychological and social stress factors as potential rampant that the WHO convened a special session
etiologic theories of primary nonpsychotic PPD. and eventually came out with a consensus statement
These factors include lack of social support, negative to counter the above which read: Menopause is part
life events, occupational instability, lack of prior the normal aging process which in itself does not
experience with children, unplanned pregnancy and require therapeutic intervention. The health status of
antenatal pessimism, dissatisfaction with the mari- women during this period is not recognized as being
tal relationship (or being unmarried), and a poor a simple endocrine-deciency state which could or
relationship between the affected woman and her should be corrected by attempting to create for each
own mother (Paykel et al., 1980; Murray et al., woman a premenopausal normal environment
1995). (World Health Organization, 1981).
In summarizing these studies, no unifying conclu- Changes most commonly associated with estrogen
sion can be reached, and it is impossible at this stage depletion (and/ or unpredictable uctuations) include
to translate any of these results into predictive, vasomotor symptoms such as hot ushes and night
diagnostic, therapeutic, prognostic or preventative sweats (Guthrie et al., 1996; Freedman, 2000),
applications. It seems more likely that an intrinsic urogenital dryness/ atrophy causing dyspareunia as
abnormal reaction to some of the hormonal changes well as an increased risk over time of osteoporosis
rather than the changes themselves, is responsible for and cardiovascular disease (Mitchell and Woods,
the disorder. If the psychobiological factors (or their 1996). The relationship between the perimenopause/
interactions) responsible for the emotional disorders menopause and mood disorders is less well under-
associated with childbearing could be shown, our stood. The majority of postmenopausal women do
understanding of the etiology not only of PPD but not experience prominent symptoms of depression
also of a wider range of psychiatric disorders might (epidemiologic data), but a higher than expected
be enhanced. prevalence of depressive-like symptoms has been
observed in peri- and postmenopausal women attend-
ing gynaecologic clinics (clinic-based surveys) (Avis
and McKinlay, 1991; Schmidt and Rubinow, 1991).
5. Perimenopause, menopause and beyond It is unclear as to whether there is decline in new
onset episodes of major depression in females of this
The transition into menopause is a major hormonal age group as suggested by the ECA study, a nding
event and is associated in many women with both not supported by data from the NCS. The role of
physical and psychosocial symptoms. The term sociocultural factors and demographic differences
perimenopause describes the period immediately have been the focus of much study but the results are
before the menopausefrom the time when the controversial (Anderson et al., 1987; Hay et al.,
hormonal and clinical features of approaching meno- 1994).
pause commence till the end of the rst year after Some cross-cultural differences are nevertheless
menopause (World Health Organization, 1996b). noteworthy: Japanese women experience very few
The physiologic hallmark of the transition into physical as well as emotional symptoms around
menopause is gradual estrogen depletion. In the menopause. It has been proposed that these ndings
1960s and 1970s depletion was equated with are indicative not only of cultural and demographic
deciency and menopause, representing a state of differences but also reect the inuence of bio-
estrogen deciency, and was therefore considered a logical, genetic and nutritional / dietary factors (Lock,
medical disorder warranting treatment. A famous 1994; Nagata et al., 1998).
quote from that era highlights this approach: It The most prevalent mood symptoms during the
perimenopausal include irritability, tearfulness, anxi- perimenopausal women with major and minor de-
ety, depressed/ labile mood, lack of motivation/ pression (Schmidt et al., 2000; Soares et al., 2001).
energy, poor concentration and interrupted sleep. Estrogen specically maintains verbal memory in
These symptoms have been linked to predictable women and may prevent or forestall the deterioration
uctuations in estradiol, especially abrupt withdrawal in short- and long-term memory that occurs with age
from very high erratic levels, rather than to times (Sherwin, 1999b). There is also evidence that es-
when levels are slowly and gradually declining trogen may have a role in the prevention and
(Prior, 1998). treatment of Alzheimers disease (AD). Theoretically
Several lines of evidence point to the link between estrogen could be the perfect anti-Alzheimers treat-
estrogen depletion/ deciency and mood disorders in ment (Garcia-Segura et al., 2001). Estrogen has the
vulnerable or predisposed women. Estrogen has properties of an antioxidant, can modify inamma-
direct effects on the CNS in areas which are not tory response, increases growth of ACh neurons, can
strictly relevant to reproduction. For example, es- affect amyloid precursor protein cleavage, inhibits
trogen regulates synaptogenesis, has a general ApoE levels, stimulates glucocorticoid levels, in-
trophic effect on cholinergic neurons and stimulates creases glucose utilization and increases cerebral
a signicant increase in 5-HT binding sites in blood ow. Unfortunately the clinical data to date
2A
areas which are involved in regulating both mood are somewhat mixed: the estimated risk of AD
and cognition. It is therefore not surprising that decreases signicantly in women who have been on
estrogen has been shown to improve psychological long-term ERT (Paganini-Hill and Henderson, 1994;
functioning and well-being in non-depressed post- Kawas et al., 1997) but others have reported only
menopausal women (Ditkoff et al., 1991; Palinkas 50% reduction in incidence (Waring et al., 1999),
and Barrett-Connor, 1992) and that estrogen replace- with some benet in early onset AD only and some
ment therapy (ERT) has a positive effect on mood protection against further deterioration (Costa et al.,
states (Zweifel and OBrien, 1997). The ability of 1999) whereas others have seen no benecial effect
estrogen to act as a 5HT agonist / modulator is of at all (Mulnard et al., 2000).
particular signicance. Estrogen not only increases The use of ERT continues to be controversial with
the number of 5HT receptor binding sites but also the risk of breast and endometrial cancer in long-
2A
3
increases 5HT synthesis, uptake and [ H]imipramine term users still looming. At the same time, the search
binding; it decreases 5HT receptor binding sites and for the perfect selective estrogen receptor modulator
1
5HT transporter mRNA and increases the prolactin (SERM) is ongoing. The ideal SERM would have
response to 5HT agonistsall in line with antide- negative receptor activity on breast and endometrial
pressant-like action (Biegon and McEwen, 1982; cells and positive receptor activity on bone, car-
Halbreich et al., 1995; Fink et al., 1996; Pecins- diovascular and brain. So far there is evidence that
Thompson et al., 1998). The clinical relevance of raloxifene is effective in preventing osteoporosis and
these effects to the pathophysiology of women-spe- has protective cardiovascular properties and also
cic mood and anxiety disorders remains to be seems to reduce the risk for breast cancer (Delmas et
determined. al., 1997; Cauley et al., 2000) but its effect on
The strongest evidence to date for estrogens cognitive function in humans has not been estab-
ability to improve mood and cognitive functioning lished. There is some indication that it may lower the
comes from studies in young surgically menopausal risk of decline in attention and memory (Yaffe et al.,
women treated with ERT (Sherwin, 1988; Sherwin 2001) and in animals there is some indication that
and Suranyi-Cadotte, 1990). It is also encouraging to raloxifene plus estradiol induces neurite outgrowth to
note that several very preliminary studies seem to a greater extent than raloxifene or estradiol alone
indicate the benecial effects of combining ERT (Nilsen et al., 1998).
with SSRIs in the treatment of postmenopausal Progesterone, which in the past has been promoted
depressed women (Schneider et al., 1997). Prelimin- by some as an antidepressant, can by itself not only
ary evidence also indicates the efcacy of transder- cause depression but seems also to reverse the
mal 17b-estradiol alone in the treatment of estrogen-induced receptor expression. Progestogens
also have potent anaesthetic properties and dampen mitter systems. Behaviours such as moodiness, ir-
ritability and conicts with parents around this time brain excitability; they also increase the concen-
may in part reect this increased sensitivity. The tration of monoamine oxidase, the enzyme that
constant ux of estrogen and progesterone levels catabolizes 5HT in the brain, whereas estrogen
continues throughout the reproductive years. The
decreases the enzyme, thereby increasing the con-
neurotransmitter systems are thus constantly being
centration of 5HT (Luine et al., 1975; Sherwin,
attenuated or amplied. PMS and PMDD may be the
1999a).
result of an altered activity (or sensitivity) of certain
Testosterone is also an extremely important psy-
neurotransmitter systems. Pregnancy and delivery
choactive compound and its relevance to womens
produce dramatic changes in estrogen and progester-
well being is just beginning to be recognized (Tuiten
one levels as well as signicant suppression along
et al., 2000).
the HPA axis, possibly increasing vulnerability to
While we are awaiting results of the ongoing
depression. Finally, at menopause, estrogen levels
long-term prospective studies with ERT and SERM,
decline while pituitary LH and FSH levels increase.
it is important to recognize that depressive symptoms
The loss of modulating effects of estrogen and
are a signicant risk factor for mortality in older
progesterone may underlie the development of
women (Whooley and Browner, 1998). Whether
perimenopausal mood disorders in vulnerable
depressive symptoms are a marker for, or a cause of,
women.
life-threatening conditions remains to be determined.
Since these hormonal changes occur in all women,
Nevertheless, treatment for depression may not only
it seems safe to speculate that the development of
enhance the quality of life but may also reduce
mood disorders requires more than just uctuating
mortality in this population.
levels of hormones, but also a genetic predisposition.
These genetic as yet unidentied defects probably
relate to subtle alterations in number and function of
6. Conclusion
various receptors and enzymes and to subtle structur-
al and anatomical differences in the CNS. These
The complex integration of the neurotransmitter
differences caused by genetic polymorphism, com-
and steroid hormone systems implies that circulating
bined with the ux in the hormonal milieu determine
steroid hormones from peripheral endocrine glands
how the system reacts to multiple environmental
can directly regulate brain function and modulate
stresses and predicts the development of mood
behaviour. Regulation occurs through a variety of
disorders. Further research into this complex system
mechanisms including, for example, direct interac-
is needed to be able to identify specic genetic
tion with or up-regulation of specic receptors on
markers which might help us better understand how
neuronal cells. Thus, the hormonal milieu surround-
the balance between estrogen, progesterone, testo-
ing a neuronal cell will, in part, determine the
sterone, and other steroid hormones affect neuro-
response of that cell to various stimuli.
transmitter function.
Adrenal and gonadal steroids regulate the tran-
scription of most of the major neurotransmitter
system.
Acknowledgements
Steroid hormones also have direct effects on
neuronal cell function by non-genomic mechanisms
The authors would like to thank Janice Rogers and
inuencing the sensitivity and responsiveness of the
Carol Ballantyne for their assistance in the prepara-
neurons.
tion of this manuscript.
Levels of estrogen and progesterone vary sig-
nicantly across the female lifespan. At puberty
there is an increase in estrogen and initiation of
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