hormones and mood,from menarche to menopause and beyond.depresion2003

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

Research report

H ormones and mood: from menarche to menopause and beyond

1*Meir Steiner , Edward Dunn , Leslie BornDepartments of Psychiatry & Behavioural Neurosciences and Obstetrics & Gynecology, McMaster University, Womens HealthConcerns 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 thisgender difference is not yet understood. There is increasing scientific attention to the modulation of the neuroendocrinesystem by fluctuating gonadal hormones. This review attempts to summarize our current state of knowledge on the role andpotential relevance of estrogen and other sex steroids to psychiatric disorders specific to women from menarche tomenopause.

The sudden appearance of higher levels of estrogen in puberty alters the sensitivity of the neurotransmitter systems.Moreover, the constant flux of estrogen and progesterone levels throughout the reproductive years portends constantmodification of the neurotransmitter systems. Premenstrual syndromes may be the result of an altered activity or sensitivityof certain neurotransmitter systems. Pregnancy and delivery produce dramatic changes in estrogen and progesterone levels aswell as significant suppression along the HPA axis, possibly increasing vulnerability to depression. At menopause, estrogenlevels decline while pituitary LH and FSH levels increase. The loss of modulating effects of estrogen and progesterone mayunderlie 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 topsychosocial, environmental, and physiological factors. Further research is needed to be able to identify specific geneticmarkers which might help us better understand how the balance between estrogen, progesterone, testosterone, and othersteroid hormones affect neurotransmitter function. 2002 Elsevier Science B.V. All rights reserved.

Keywords: Women; Mood disorders; Neurotransmitters; Sex hormones

1 . Introduction

*Corresponding author. Tel.: 1 1-905-522-1155x3605; fax: The lifetime prevalence of mood disorders in1 1-905-521-6098.

women is approximately twice that of men. ThisE-mail address: [email protected] (M. Steiner).1 higher incidence of depression in women is primarilyDr. Dunn is now with the Centre for Addiction and MentalHealth, 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 thethe 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; Sumnerthis 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 unified plex and delicately balanced. Each system appears tobasis for the development of these diseases exists. have a modulatory function on the other and changesThe principal constituent of this unified theory is in one system may have a dramatic effect on thebelieved to be related to genetic predisposition. other systems.Multiple environmental stressful events cause bio- Glucocorticoid and gonadal steroid receptors arechemical changes in a host of neuroendocrine sys- abundant in different areas of the brain. Gonadaltems 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, locusstressful life events are interpreted and predicts the ceruleus (LC), midbrain raphe nuclei, pituitary glandresponse, which can lead to the development of and hypothalamus (Stomati et al., 1998). Estrogenmood disorders. The higher prevalence of mood receptors are located in the preoptic area anddisorders in women could be related to either an amygdala (McEwen, 1988) and the ventromedialincreased genetic predisposition, an increased vul- nucleus and arcuate nucleus of the hypothalamusnerability /exposure to stressful life events, modula- (Herbison et al., 1995).tion of the neuroendocrine system by fluctuating 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 increasetibility hypothesis to account for gender differences estrogen-binding sites in the female rat hypothalamusin the prevalence of mood disorders based on the (Lauber and Whalen, 1988). Estrogen, progesteroneidea that there is a disturbance in the interaction and glucocorticoid receptors can also be activated bybetween the HPG axis and other neuromodulators in insulin-like growth factor 1 (IGF-1), epidermalwomen (Steiner and Dunn, 1996; Dunn and Steiner, growth factor (EGF), transforming growth factor2000). 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 etvulnerable 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 bindingmenstrual dysphoric disorder (PMDD), depression of gonadal hormones in the central nervous systemwith 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. Theychanges 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 beenmate, GABA, acetylcholine (ACh), serotonin (5-HT), suggested that steroid hormone receptors function asdopamine (DA), noradrenaline (NA) and neuropep- general transcription factors to achieve integration oftides. 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 classicalbetween males and females, it is presumed that genomic mechanisms through intracellular receptorsgonadal steroid hormones are somehow involved. to modulate transcription and protein synthesis. ThisFor example, declining levels of estrogen in women mechanism involves the binding of the steroid to ahave 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 24this mechanism is of the order of several minutes, years of age) has been reported as 20.6% for femaleshours 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% anddirect 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 conflicting opinion regarding the age atonds 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 themembrane 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 adolescentssuch 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 innervous 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 fluidity thereby modifying ion The onset of puberty is heralded by a growthtransport or receptor function (Maggi and Perez, spurt, which begins with rapid growth in height and1985). 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 first signof current scientific attention. Estrogen has been of sexual maturation in girls is breast budding atdescribed as a 5-HT, NA and Ach agonist; it also about 10.5 years, followed by growth of pubic hairmodulates DA receptors. The implications to the which begins at about 11.5 years, growth of the2reproductive life cycle of women will be briefly uterus and vagina, and the enlargement of the labiareviewed. Specifically, the impact of hormonal fluc- and clitoris. Menstruation begins after these changestuations during menarche, premenstrually, during occur. Finally, axillary hair appears, hips broaden,pregnancy and postpartum, and perimenopausally and fat deposits increase. On average, these changeswill 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 since1850; 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 reachtwice 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 environmentalleast 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 assimilar 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 thefemale to male ratio (Kessler and Walters, 1998; timing of menarche. Girls who are blind with someLewinsohn et al., 1998). In the US general popula- perception of light reach menarche earlier thantion, 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 significantly related to a rapidgirls 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 wasamounts of daylight (fall and winter) (Bojlen and also associated with higher levels of testosterone andBentzen, 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 limitedexamined. Girls undergoing pubertal change are evidence of the involvement of the serotonergicthought to experience greater distress and to be more system in the etiology of depressive disorders invulnerable to stress than pre- or post-pubertal girls child and adolescent depression. In a comparative(Caspi and Moffitt, 1991). Two parameters of puber- study of psychiatric in-patients and normal controlstal change in particular have received much atten- (aged 7 to 17 years), levels of whole-blood 5-HTtion: pubertal status and pubertal timing. Pubertal were lowest in patients with mood disorders (Hughesstatus is defined as the current level of physical et al., 1996). There is some indication of thedevelopment of an adolescent relative to the overall responsiveness of children and adolescents with MDprocess 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, thetal (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 defined than the noradrenergic systems (Ryan and Varma,as the maturation of an adolescent relative to her 1998). Gonadal hormones effect the production ofpeers (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 receptorperiod in mid-puberty when girls become more subtypes brought on by changes in the hormonalvulnerable to depression than boys. In a recent report milieu at menarche may increase vulnerability toon 1073 US children, 9 to 13 years of age, the mood disorders.depression rates in girls rose significantly in mid- It is nevertheless still unclear how the dramaticpuberty, i.e., with the transition to Tanner stage III. changes in the hormonal milieu associated withIn 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 possibleFurther, 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 patternspredicted 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 depressiveand Girgus, 1994). episode in vulnerable individuals (Ehlers et al.,

Although changes in affect, mood, and behaviour 1988). Another complementary theory emphasizesare considered to be related to cyclic hormonal the neurobiology of stress and the dysregulation ofchanges, studies of female adolescents and premen- affect during female biological transitions such asstrual syndrome (PMS) are inconclusive with one menarche, a transition which may be associated withstudy reporting no relationship between menstrual changes in the reactivity of the stress system (Dorncycle phase and negative affect (Golub and Harrin- and Chrousos, 1997). The newly fluctuating levels ofgton, 1981) and others show that PMS is associated gonadal hormones as well as gonadotropins, whichwith other distress factors in this age group (Raja et mark the onset of menarche and the establishment ofal., 1992; Freeman et al., 1993). Notwithstanding, menstrual cycles, introduce a major change in therelationships between changes in pubertal hormones hormonal milieu to which the rest of the systemsand 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 thepsychosocial stressors, to sleep deprivation as well as elimination of premenstrual complaints with suppres-to the influences of nicotine, alcohol and other drugs, sion of ovarian activity (Schmidt et al., 1998) orresulting in a higher incidence of HPA axis dysregu- surgical menopause (Casson et al., 1990). Thelation 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 theother hormonal changes should be monitored pros- cyclic trigger for biochemical events within thepectively along with individual, genetic, constitution- central nervous system and other target tissues whichal, and psychological characteristics in our efforts to unleash premenstrual symptoms in vulnerablepredict the development of negative affect during women (Roca et al., 1996). This viewpoint ispuberty (Steiner et al., 2000). attractive in that it encourages investigation of the

neuroendocrine-modulated central neurotransmittersand the role of the hypothalamicpituitarygonadal

3 . Premenstrual dysphoria axis in PMDD. Notwithstanding, a surge of recentresearch has encompassed other etiological influ-

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, thetion, 1994a). Through the use of these criteria, ovarian axis is apparently functioning normally withPMDD can be differentiated from premenstrual normal hormone (estrogen and progesterone) levelssyndrome (PMS) which has milder physical symp- (Schmidt et al., 1998). Recently, attention has shiftedtoms, i.e. breast tenderness, bloating, headache and from a focus on estrogen and progesterone to the roleminor mood changes (World Health Organization, of androgens in premenstrual dysphoria.1996a). PMDD can also be differentiated from Early investigations of androgens have suggestedpremenstrual magnification (concurrent diagnoses of that women with PMS or PMDD have elevatedPMS or PMDD and a major psychiatric or an levels of serum testosterone in the luteal phaseunstable medical condition) and from premenstrual compared with controls (but still within the normalexacerbation 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 increasedmany as 75% of women with regular menstrual androgenicity is backed both by animal and humancycles 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 moodof women in this group (Johnson et al., 1988; (e.g. depression, and premenstrual irritability) andRamcharan et al., 1992; Angst et al., 2001), but it is impulsive behaviour (e.g. compulsions, and bingemore severe and exerts a much greater psychological eating). Enhanced serotonin availability (e.g. withtoll. These women report premenstrual symptoms the use of SSRIs), on the other hand, is associatedthat seriously interfere with their lifestyle and rela- with reduction in irritability, depression, impulsivetionships (Freeman et al., 1985; OBrien et al., behaviour, as well as reduced libido. An inverse1995). 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 premenstrualactivity (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 inincreased androgenicity (Rowe and Sasse, 1986; the pathogenesis of PMDD (Rapkin, 1992; Steiner etBurnet et al., 1991). Others, however, have not al., 1997). PMDD shares many features of otherobserved differences in plasma testosterone in com- mood and anxiety disorders linked to serotonergicparisons of women with or without PMS (Dougherty dysfunction. In addition, reduction in brain 5-HTet al., 1997), and one study has reported significantly neurotransmission is thought to lead to poor impulselower total and free testosterone plasma levels in a control, depressed mood, irritability, and increasedsample of 10 women with PMS (Bloch et al., 1998). carbohydrate cravingall mood and behavioralFurther 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 fluctuation inof 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 withthought 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, plateletxiolytic effect (Rapkin et al., 1997); quantitative uptake of 5-HT, and platelet tritiated imipraminedifferences in progesterone and allopregnanolone binding) and found altered 5-HT function during alllevels between PMS subjects and controls have been phases of the menstrual cycle (Ashby et al., 1988;examined. The findings to date in women are con- Rapkin, 1992; Steege et al., 1992). Other studies thattradictory (Rapkin et al., 1997; Schmidt et al., 1994; used challenge tests (with L-tryptophan, fenfluramine,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 womenmodel is more promising. In a progesterone-with- but differed in their findings as to whether thedrawal paradigm, designed to mimic PMS and response to 5-HT is blunted or heightened (Bancroftpostpartum depression in female rats, Smith et al. et al., 1991; Bancroft and Cook, 1995; FitzGerald ethave found that decreased levels of allopregnanolone al., 1997; Su et al., 1997; Steiner et al., 1999). Acutelead 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 significantly associated with exacerbationAGABA receptor to endogenous ligands, resulting in of premenstrual symptoms, in particular irritabilityAsymptoms 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 necessarilymone plasma levels in an attempt to discern the etiologic) of the serotonergic system has emergedetiology 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 reuptakewith various other forms of psychopathology. The inhibitors (SSRIs), are very effective in reducingmain advantage of this approach is its potential to premenstrual symptoms. These studies imply, at leasthelp further our understanding of PMDD as well as in part, a possible change in 5-HT receptor sen-1Aits relation to other psychiatric disorders. The current sitivity in women with premenstrual dysphorialiterature 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 ofstrual dysphoria may be behaviourally or biochemi- the postpartum mood disturbances; its prevalence hascally sub- or supersensitive to biological challenges been reported to be 2685%, depending on theof the serotonergic system. It is not yet clear whether diagnostic criteria used (Stein et al., 1981). Thethese women present with a trait or state marker symptoms of this syndrome typically begin within(alternatively, both conditions could be possible) of the first week following childbirth, peak on the fifthpremenstrual 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. Theidentified as the most plausible target for interven- mood disturbance characterizing postpartum blues istions. Thus, beyond the conservative treatment op- considered transient and insufficient in and of itselftions 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 theterm treatment with GnRH agonists, which is not initial postpartum period, leading to more seriousonly associated with the untoward effects of intro- PPD (Cox et al., 1993).ducing early menopause but may also increase Epidemiologic studies of the nature, prevalencedepressive symptoms; Warnock et al., 1998), the and course of an episode of major PPD have foundSSRIs are emerging as the most effective treatment that between 10 and 15% of women exhibit depres-options for this population. sive symptoms in the first weeks following delivery

Results from several randomized placebo-con- (Carothers and Murray, 1990; Pop et al., 1993), andtrolled trials in women with PMDD, with predomi- that the great majority of these depressive episodesnantly psychological symptoms of irritability, ten- resolve spontaneously within 3 to 6 months (Cox etsion, dysphoria and lability of mood, have clearly al., 1993; Cooper and Murray, 1995). The symptomdemonstrated that the SSRIs have excellent efficacy profile of PPD resembles that of a major depressiveand minimal side effects. More recently, several episode experienced at other times in life, but it isstudies indicate that intermittent (premenstrually unique in its timing and in that it always involves atonly) treatment with SSRIs is equally effective in least the motherbaby dyad and in most cases anthese 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 moretent (Steiner and Born, 2000). severe than either depression or the blues. It has a

prevalence of | 1 in 5001000 births, and a rapidonset within the first 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 specific link and the uniqueness of psychiatric of a manic-depressive illness, severely impairs thedisorders precipitated or triggered by pregnancy or affected womans ability to function. In the mostchildbirth have recently been acknowledged by the extreme cases, the risks of suicide or infanticide areAmerican 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-specific 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 changespostpartum mental disorders. Thus, major depressive in mood coincide with these profound changes indisorders, 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 specified) will have the qualifier 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) werebe divided into groups which define their proposed correlated with any of the maternal behavioursrole in maternal response: primersmost important measured (Fleming et al., 1987, 1995). These resultsduring 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 maternaloxytocin); and modifiersof oxytocin release (e.g. attitudes, which may then be expressed as emotionsbeta-endorphins, other neurotransmitters) (Keverne and/or behaviour.and Kendrick, 1994). There is, of course, a consider- Thyroid dysfunction has been implicated in moodable scope for interactions between these changes disorders and it has been suggested that transientand varying repertoires of maternal behaviour across thyroid dysfunction following childbirth is associateddifferent 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. Aaround the fifth day postpartum coincides with review of the literature in this area clearly indicatesextreme hormonal fluctuations that are a natural the possibility that a subgroup of women with PPDconsequence of parturition. These hormones act have a basis for the depressed mood in thyroidwithin the central nervous system at a variety of disorder. More specifically, in some women depres-limbic sites known to be involved in emotional sive symptoms are associated with positive thyroidresponses, arousal and reinforcement. Only a handful antibody status during the postpartum period (Harrisof studies attempted to measure these changes, et al., 1992). It is believed that 1% of all postpartumespecially in gonadal hormones and prolactin. To women will show a mood disorder associated withdate, the results do not seem to correlate strongly transient thyroid dysfunction and treatment of thewith 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 theterone showed a weak but significant relationship to postpartum withdrawal of some of the other majorthe 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-endorphinlated 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 estrogenet al., 1990; OHara et al., 1991). Preliminary results concentrations after delivery has been associatedsuggest that natural killer-cell activity is lower in with acute onset of postpartum psychosis (Wieck etpostpartum dysphorics and that this decrease is al., 1991). These changes are believed to be therelated to higher levels of cortisol (Pedersen et al., triggers to a cascade of changes at central and1993a). In contrast, negative or false-positive results peripheral monoamine centres. Very preliminary datawith 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 -adrenoceptor2(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 et1990; OHara et al., 1991). The HPA, rather than the al., 1992), but not in women with the blues (KatonaHPG 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 PPDpositive 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 thatgressively hyperactive throughout pregnancy, with postpartum withdrawal of gonadal hormones mayincreasing levels of circulating CRH of placental cause changes along the serotonergic cascade whichorigin and decreasing levels of CRH-binding protein. may lead to a mood disorder in vulnerable orBoth these phenomena, together with the elevated genetically predisposed women. (It should thereforelevels of estradiol of pregnancy which also stimulate be possible to treat the disturbance by adjusting thethe 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 onsource of placental CRH is removed, and together preventative interventions with lithium prophylaxiswith the postpartum estrogen withdrawal which is (Stewart et al., 1991; Cohen et al., 1995) and withfurther prolonged by breastfeeding (Kim et al., 2000) SSRIs (Stowe et al., 1995; Appleby et al., 1997) aremay lead to a prolonged state of HPA axis hypoac- very encouraging. Since mood disorders associatedtivity. Indeed, it has been demonstrated that in a with childbearing have different times of onset insubgroup of women with PPD, the suppression of the different women and are heterogenous in theirHPA axis was more severe and lasted longer than presentation, concomittant measurements of thethat of women who had no postpartum mood in- changes over time in gonadal hormones and thestability (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 ofPPD also appears to be a state of central CRH postpartum mood disorders comes from family anddysregulation. With the additional established evi- family history studies. A study of women withdence of direct estrogenic regulation of the CRH postpartum mood disturbances and their first-degreegene expression (Vamvakopoulos and Chrousos, relatives found that at least one family member met1993) it is therefore not surprising that estrogen has criteria for a past or present psychiatric disorder inbeen proposed as a treatment for PPD (Sichel et al., 71% of the cases for which the information was1995; Gregoire et al., 1996; Ahokas et al., 2001). In available. Positive histories for MD and alcoholismthe 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 significantly improved the clinical sis of these data revealed an interesting gendersymptoms of severely depressed women postpartum distribution of psychiatric disorders in the first-de-(Gregoire et al., 1996). Unfortunately further re- gree relatives of the postpartum women. Asearch on the role of estrogen therapy for PPD has female:male ratio greater than 2:1 was found innot yet emerged. Similarly, progesterone has been relatives with a past or present diagnosis of MD, inwidely used for the treatment of postnatal depression the case of alcoholism, a male:female ratio of 4:1but without controlled trials (OBrien and Pitt, was evident. This lifetime prevalence of mood-re-1994). lated disorders in the first-degree relatives of women

The role of hormone replacement therapy is of presenting with postpartum mood disorders is muchinterest beyond the realm of the postpartum period higher than in the population at large and mayand as discussed in the next section is of major indicate potential genetic or familial components ofrelevance 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 ingic system and gonadal hormones has not as yet been behavioral response between humans (as well asstudied 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 andpartum rats indicate that 5-HT receptor changes in nonprimates are mainly in the organization of socialthe limbic area are negatively correlated with proges- structures, the complex influences of the family unit,


and the constant exposure of all members of a group sometimes seems as if the only thing worse thanto the young. It is therefore easy to assume that, in being subjected to the raging hormonal influences ofhumans, even thinking about children may be suffi- the female cycle is to have those influences subsidecient to stimulate maternal responsiveness. The (Parlee, 1976). The notion of universal hormonepsychosocial literature to date has advanced several replacement for all menopausal women was sopsychological and social stress factors as potential rampant that the WHO convened a special sessionetiologic theories of primary nonpsychotic PPD. and eventually came out with a consensus statementThese factors include lack of social support, negative to counter the above which read: Menopause is partlife events, occupational instability, lack of prior the normal aging process which in itself does notexperience with children, unplanned pregnancy and require therapeutic intervention. The health status ofantenatal pessimism, dissatisfaction with the mari- women during this period is not recognized as beingtal relationship (or being unmarried), and a poor a simple endocrine-deficiency state which could orrelationship between the affected woman and her should be corrected by attempting to create for eachown mother (Paykel et al., 1980; Murray et al., woman a premenopausal normal environment1995). (World Health Organization, 1981).

In summarizing these studies, no unifying conclu- Changes most commonly associated with estrogension can be reached, and it is impossible at this stage depletion (and/or unpredictable fluctuations) includeto translate any of these results into predictive, vasomotor symptoms such as hot flushes and nightdiagnostic, therapeutic, prognostic or preventative sweats (Guthrie et al., 1996; Freedman, 2000),applications. It seems more likely that an intrinsic urogenital dryness /atrophy causing dyspareunia asabnormal reaction to some of the hormonal changes well as an increased risk over time of osteoporosisrather 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 dounderstanding of the etiology not only of PPD but not experience prominent symptoms of depressionalso of a wider range of psychiatric disorders might (epidemiologic data), but a higher than expectedbe enhanced. prevalence of depressive-like symptoms has been

observed in peri- and postmenopausal women attend-ing gynaecologic clinics (clinic-based surveys) (Avisand McKinlay, 1991; Schmidt and Rubinow, 1991).

5 . Perimenopause, menopause and beyond It is unclear as to whether there is decline in newonset 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 findingevent and is associated in many women with both not supported by data from the NCS. The role ofphysical and psychosocial symptoms. The term sociocultural factors and demographic differencesperimenopause describes the period immediately have been the focus of much study but the results arebefore 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 first year after Some cross-cultural differences are neverthelessmenopause (World Health Organization, 1996b). noteworthy: Japanese women experience very few

The physiologic hallmark of the transition into physical as well as emotional symptoms aroundmenopause is gradual estrogen depletion. In the menopause. It has been proposed that these findings1960s and 1970s depletion was equated with are indicative not only of cultural and demographicdeficiency and menopause, representing a state of differences but also reflect the influence of bio-estrogen deficiency, 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 specifically maintains verbal memory inThese symptoms have been linked to predictable women and may prevent or forestall the deteriorationfluctuations in estradiol, especially abrupt withdrawal in short- and long-term memory that occurs with agefrom 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 /deficiency and mood disorders in ment (Garcia-Segura et al., 2001). Estrogen has thevulnerable or predisposed women. Estrogen has properties of an antioxidant, can modify inflamma-direct effects on the CNS in areas which are not tory response, increases growth of ACh neurons, canstrictly relevant to reproduction. For example, es- affect amyloid precursor protein cleavage, inhibitstrogen regulates synaptogenesis, has a general ApoE levels, stimulates glucocorticoid levels, in-trophic effect on cholinergic neurons and stimulates creases glucose utilization and increases cerebrala significant increase in 5-HT binding sites in blood flow. Unfortunately the clinical data to date2Aareas which are involved in regulating both mood are somewhat mixed: the estimated risk of ADand cognition. It is therefore not surprising that decreases significantly in women who have been onestrogen 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 onlymenopausal women (Ditkoff et al., 1991; Palinkas 50% reduction in incidence (Waring et al., 1999),and Barrett-Connor, 1992) and that estrogen replace- with some benefit in early onset AD only and somement 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 beneficial effectestrogen to act as a 5HT agonist /modulator is of at all (Mulnard et al., 2000).particular significance. Estrogen not only increases The use of ERT continues to be controversial withthe number of 5HT receptor binding sites but also the risk of breast and endometrial cancer in long-2A

3increases 5HT synthesis, uptake and [ H]imipramine term users still looming. At the same time, the searchbinding; it decreases 5HT receptor binding sites and for the perfect selective estrogen receptor modulator15HT transporter mRNA and increases the prolactin (SERM) is ongoing. The ideal SERM would haveresponse to 5HT agonistsall in line with antide- negative receptor activity on breast and endometrialpressant-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 thatThompson et al., 1998). The clinical relevance of raloxifene is effective in preventing osteoporosis andthese effects to the pathophysiology of women-spe- has protective cardiovascular properties and alsocific mood and anxiety disorders remains to be seems to reduce the risk for breast cancer (Delmas etdetermined. 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 thecomes 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 thatand Suranyi-Cadotte, 1990). It is also encouraging to raloxifene plus estradiol induces neurite outgrowth tonote that several very preliminary studies seem to a greater extent than raloxifene or estradiol aloneindicate the beneficial effects of combining ERT (Nilsen et al., 1998).with SSRIs in the treatment of postmenopausal Progesterone, which in the past has been promoteddepressed women (Schneider et al., 1997). Prelimin- by some as an antidepressant, can by itself not onlyary evidence also indicates the efficacy of transder- cause depression but seems also to reverse themal 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 conflicts with parents around this timebrain excitability; they also increase the concen-may in part reflect this increased sensitivity. Thetration of monoamine oxidase, the enzyme thatconstant flux of estrogen and progesterone levelscatabolizes 5HT in the brain, whereas estrogencontinues throughout the reproductive years. Thedecreases the enzyme, thereby increasing the con-neurotransmitter systems are thus constantly beingcentration of 5HT (Luine et al., 1975; Sherwin,attenuated or amplified. PMS and PMDD may be the1999a).result of an altered activity (or sensitivity) of certainTestosterone is also an extremely important psy-neurotransmitter systems. Pregnancy and deliverychoactive compound and its relevance to womensproduce dramatic changes in estrogen and progester-well being is just beginning to be recognized (Tuitenone levels as well as significant suppression alonget al., 2000).the HPA axis, possibly increasing vulnerability toWhile we are awaiting results of the ongoingdepression. Finally, at menopause, estrogen levelslong-term prospective studies with ERT and SERM,decline while pituitary LH and FSH levels increase.it is important to recognize that depressive symptomsThe loss of modulating effects of estrogen andare a significant risk factor for mortality in olderprogesterone may underlie the development ofwomen (Whooley and Browner, 1998). Whetherperimenopausal mood disorders in vulnerabledepressive 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 onlyit seems safe to speculate that the development of

enhance the quality of life but may also reducemood disorders requires more than just fluctuating

mortality in this population. levels of hormones, but also a genetic predisposition.These genetic as yet unidentified defects probablyrelate to subtle alterations in number and function of6 . Conclusionvarious receptors and enzymes and to subtle structur-al and anatomical differences in the CNS. TheseThe complex integration of the neurotransmitter differences caused by genetic polymorphism, com-

and steroid hormone systems implies that circulating bined with the flux in the hormonal milieu determinesteroid hormones from peripheral endocrine glands how the system reacts to multiple environmentalcan directly regulate brain function and modulate

stresses and predicts the development of moodbehaviour. Regulation occurs through a variety of disorders. Further research into this complex systemmechanisms including, for example, direct interac- is needed to be able to identify specific genetiction with or up-regulation of specific receptors on markers which might help us better understand howneuronal 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 neurotransmittersystem. A cknowledgements

Steroid hormones also have direct effects onneuronal cell function by non-genomic mechanisms The authors would like to thank Janice Rogers andinfluencing the sensitivity and responsiveness of the Carol Ballantyne for their assistance in the prepara-neurons. tion of this manuscript.

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Hormones and mood: from menarche to menopause and beyondIntroductionMenarche and mood disorders in adolescencePremenstrual dysphoriaPostpartum depressionPerimenopause, menopause and beyondConclusionAcknowledgementsReferences

hormones and mood,from menarche to menopause and beyond.depresion2003

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