Sex Hormones and Mood in the Perimenopause

GLUCOCORTICOIDS AND MOOD

Sex Hormones and Mood in thePerimenopause

Peter J. Schmidta and David R. Rubinowb

aBehavioral Endocrinology Branch, National Institute of Mental Health,Department of Health & Human Services, Bethesda, Maryland, USA

bDepartment of Psychiatry, University of North Carolina at Chapel Hill,Chapel Hill, North Carolina, USA

The focus of this chapter is the relationship between the onset of depression inwomen and the reproductive events of the menopause transition. Epidemiologic stud-ies have documented that the majority of women do not become depressed duringthe menopause transition. However, recent longitudinal studies suggest that in somewomen, the reproductive events related to the menopause transition could play a role inthe onset of depression. No abnormality of ovarian hormones has been identified thatdistinguishes women with depression from those who remain asymptomatic during themenopause transition. Nonetheless, several findings suggest a role of ovarian hormonesin the onset of these depressions. First, episodes of depression cluster during the stageof the menopause transition that is accompanied by estradiol withdrawal. Second, ran-domized controlled trials have documented the short-term (3–6 weeks) antidepressantefficacy of estradiol in depressed perimenopausal women. Third, experimentally in-duced estradiol withdrawal triggers mood symptoms in some women. Thus, althoughdepression is not a uniform accompaniment of the menopause transition, in somewomen, age-related changes in ovarian estrogen production may alter central nervoussystem function and predispose them to develop depression.

Key words: menopause transition; depression; estrogen

Introduction

The focus of this chapter is the potential re-lationship between the onset of affective dis-orders in women and the endocrinology ofthe menopause transition. First, we will re-view background information that is relevantto this relationship, including the endocrinol-ogy of the menopause transition and studies inboth lower animals and humans demonstrat-ing the widespread neuroregulatory effects ofovarian steroids. Second, we will review epi-demiologic studies reporting the risks of mooddisorders occurring during the menopausetransition. Finally, we will present studies exam-ining the role of ovarian steroids in the develop-

Address for correspondence: Peter J. Schmidt, Bldg. 10-CRC, Room65340, 10 Center Dr. MSC 1276, Bethesda, MD 20892-1276. Voice:301-496-6120; fax: 301-402-2588. [email protected]

ment of depression in women during the nat-ural menopause transition, as well as in thosewith pharmacologically induced menopause.

Endocrinology of the MenopauseTransition and the Postmenopause

The menopause is defined by the perma-nent cessation of menstruation for 12 monthssecondary to a loss of ovarian activity. Thepostmenopause is characterized endocrinolog-ically by tonically elevated gonadotropin (fol-licle stimulating hormone (FSH), luteinizinghormone (LH)) secretion, persistently low lev-els of ovarian steroids (estradiol, progesterone)and relatively low (50% decrease comparedto younger age groups) testosterone secre-tion.1 The menopause transition and the peri-menopause are the transitional periods from

Glucocorticoids and Mood: Ann. N.Y. Acad. Sci. 1179: 70–85 (2009).doi: 10.1111/j.1749-6632.2009.04982.x c© 2009 New York Academy of Sciences.

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Schmidt & Rubinow: Sex Hormones and Mood 71

reproductive to nonreproductive life.2 The av-erage duration of the menopause transition (de-fined by menstrual cycle irregularity) is esti-mated to be approximately 4 years, but there isconsiderable individual variation in the dura-tion of this phase of reproductive life, rang-ing from 0 to 11 years.3,4 During the earlystages of reproductive aging, the length of thefollicular phase of the menstrual cycle short-ens,5,6 early follicular phase plasma FSH lev-els increase and inhibin B levels decrease.7–9

As the menopause transition progresses, ovar-ian follicular depletion occurs, the ovarybecomes less sensitive to gonadotropin stimula-tion, and a state of relative hypoestrogenism oc-curs; gonadotropin secretion is elevated acrossthe menstrual cycle; ovulatory cycles are fewer;and menstrual cycle irregularity ensues. How-ever, in contrast to the postmenopause, episodic(not tonic) gonadotropin secretion is presentand both ovulation and normal premenopausal(or at times increased) estradiol secretion mayoccur.2,10–12 The late menopause transition ischaracterized endocrinologically by tonic ele-vations of plasma FSH and sustained menstrualcycle irregularity with more prolonged periodsof amenorrhea and hypoestrogenism. The lev-els of several other hormones decrease withaging and accompany these changes in repro-ductive function, including androgens (testos-terone, dehydroepiandrosterone (DHEA) andandrostenedione), which begin to decline in the20s and reach peak decline during the late 40sand 50s, as do insulin-like growth factors andbinding proteins.10,13–16

Role of Ovarian Steroids inModulating the Systems Involved

in Affective Adaptation

Neuroregulation

Results from animal studies demonstratethat ovarian steroids influence many of theneuroregulatory systems implicated in thepathophysiology of affective disorders.17–19 Pre-

clinical studies have documented the manifoldeffects of ovarian steroids on neurotransmittersystem activities, including regulation ofsynthetic and metabolic enzyme productionas well as receptor and transporter proteinactivity. For example, in some, but not all,(reviewed in Ref. 20) experimental paradigms,estradiol has been observed to inhibit serotonintransporter (SERT) mRNA,21 alter SERT pro-tein levels and binding,20–25 increase 5-HT2Areceptor binding26 and mRNA,27 and facili-tate imipramine-induced downregulation of5-HT2 receptors in the rat frontal cortex,an action seen to accompany antidepressantadministration.28 Although, 5HT1A receptorbinding is modulated by both estradiol29–35

and progesterone,25,36–38 estradiol has been re-ported to both decrease activity of the 5HT1A

receptor (downregulation and uncouplingfrom its G-protein)39,40 and increase the ex-pression of 5HT1A receptors. The latter actionoccurs by means of an interaction involvingnuclear factor-κB complexes, estrogen-receptor-α and a nonclassical estrogen responseelement.30

In humans, there are patterns of effects ofovarian steroids on the serotonin system similarto those observed in animals. Menstrual cyclephase effects on the concomitants of serotoner-gic stimulation include an increased prolactinsecretion during the luteal phase after adminis-tration of the serotonergic agents m-CPP41 andbuspirone42 compared with the early follicu-lar phase and a decreased prolactin responseafter L-tryptophan43 or d-fenfluramine44 dur-ing the luteal phase compared with mid-cycle.In asymptomatic women in whom a reversiblemenopause was induced by a GnRH-agonist,we observed that m-CPP-induced prolactinsecretion was increased during progesteronereplacement; however, no differences in anym-CPP–stimulated hormone measures wereobserved during estradiol replacement.45

Recent positron emission tomography (PET)studies in humans employing radioligands for5HT1A receptors report both decreased46–48

and increased49 binding in depression. Both

72 Annals of the New York Academy of Sciences

sex- and menstrual cycle phase-related differ-ences in 5HT1A binding (C11WAY) have beenobserved by PET, with women having bothgreater 5HT1A binding than men (in the an-terior cingulate, frontal and temporal cortices,insula, hippocampus and dorsal raphe) and de-creased binding (in the dorsal raphe) during thefollicular phase compared with the luteal phaseof the menstrual cycle.50,51 Finally, one uncon-trolled study reported an increase in 5-HT2Abinding (F18 altanserin) in the anterior cingu-late, dorsolateral prefrontal cortex and lateralorbital frontal cortex during combined estro-gen and progestin replacement (but not afterestradiol alone).52 Despite recent evidence sug-gesting the roles of 5HT1B and 5HT6 receptorsin depression, no studies in either animals orhumans have examined the potential role ofovarian steroids in the regulation of these 5HTreceptor subtypes.53,54

Several nonclassical neural signaling sys-tems also have been identified as potentialmediators of the therapeutic actions of an-tidepressant agents (e.g., cAMP response el-ement binding protein (CREB) and brain-derived neurotrophic factor (BDNF)).55 Thesecellular systems are modulated by a range oftherapies effective in depression (e.g., seroton-ergic and noradrenergic antidepressants andelectroconvulsive therapy (ECT)) and exhibit apattern of change in keeping with the latency totherapeutic efficacy for most antidepressants.56

For example, antidepressants increase the ex-pression and activity of CREB in certain brainregions (e.g., hippocampus)57 and regulate ac-tivity of genes with a cAMP response elementin a brain region–specific manner.56 Genes forBDNF and its receptor, trkB, have been pro-posed as potential targets for antidepressant-related changes in CREB activity.56 Estradiolhas been reported to influence many of thesesame cellular processes. Specifically, ovariec-tomy has been reported to decrease and estra-diol increase, BDNF levels in the forebrainand hippocampus.58 Estrogen also increasesCREB activity59 and trkA expression60 and de-creases glycogen synthase kinase-3 β activity

(Wnt pathway)61 in the rat brain, changes sim-ilar to those seen with mood stabilizer drugs.In contrast, an estradiol-induced decrease inBDNF has been reported to mediate estradiol’sregulation of dendritic spine formation in hip-pocampal neurons.62 Thus, the therapeutic po-tential of gonadal steroids in depression is sug-gested not only by their widespread actions onneurotransmitter systems, but also by certainneuroregulatory actions shared by both ovariansteroids and traditional therapies for depression(i.e., antidepressants, ECT).

Neurocircuitry

Neuroimaging techniques (i.e., PET andfunctional magnetic resonance imaging(fMRI)) have been employed to examinethe effects of ovarian steroids or the normalmenstrual cycle on regional cerebral bloodflow under conditions of brain activation.First, using PET (H2O15), Berman et al.63

employed the Wisconsin Card Sort Test, ameasure of executive function and cognitive setshifting and observed that during conditions ofGnRH agonist-induced ovarian suppression,both estradiol and progesterone upregulatedcortical activity in brain regions (prefrontal,parietal, and temporal cortices and hippocam-pus) that are also reported to be involved inthe regulation of mood. Similarly, Shaywitzet al.64 employed fMRI in women who wereseveral years postmenopause and showed thatestrogen therapy (but not placebo) significantlyincreased activation in the inferior parietallobule and right superior frontal gyrus duringverbal encoding and decreased activation inthe inferior parietal lobule during nonverbalcoding. These findings are consistent with arecent report by Craig et al.,65 who observedsignificantly decreased activation in the leftprefrontal cortex, right precentral gyrus,anterior cingulate and medial frontal gyrusduring verbal encoding in a group of womenwith GnRH agonist-induced “menopause”for the treatment of uterine fibroid tumors.Finally, MRI studies also have documented


menstrual cycle phase-related changes in theactivities of several brain regions involvedin the neurocircuitry of arousal, the stressresponse and reward processing, includingthe amygdala, orbitofrontal cortex, and stria-tum.66–68 Thus, although the brain regionspotentially regulated by estradiol remain tobe fully characterized, the activities in thefrontal cortex, amygdala, and hippocampus,areas subserving memory and the regulationof affect, appear to be regulated by ovariansteroids in women.

Stress Axis

Studies in animals demonstrate that repro-ductive steroids also regulate basal and stim-ulated hypothalamic-pituitary-adrenal (HPA)axis function. In general, low-dose, short-termadministration of estradiol inhibits HPA axis re-sponses in ovariectomized animals,69–72 whilehigher doses and longer treatment regimensenhance HPA axis reactivity to a variety ofstressors.73–75 Studies also indicate that es-trogen administration decreases glucocorticoidreceptor mRNA production in the thymus76

and the pituitary.76–79 Moreover, evidence fur-ther suggests that gonadal steroids influencethe serotonergic regulation of the HPAaxis by altering the function of the 5-HT1a and5-HT2 receptor systems in the cortex and hip-pocampus.80–82 Finally, interactions betweenglucocorticoid and estrogen response elementsand their receptors suggest additional ways bywhich gonadal steroids may modulate stress-related neural activity.83 For example, estro-gen and glucocorticoid receptors compete forCREB binding protein (CBP) and glucocorti-coid receptor interacting protein (GRIP), withthe relative amounts of these receptors increas-ing (estrogen) or decreasing (glucocorticoid re-ceptor) transcription at the AP-1 site.84,85

In women, the regulatory effects of changesin reproductive steroids on the HPA axis areless well studied. Although some studies us-ing psychological stressors identified increasedstimulated cortisol in the luteal phase,86,87

others using psychological88,89 or physiologi-cal (e.g., insulin-induced hypoglycemia, exer-cise)90,91 stressors failed to find changes inHPA axis activity across the menstrual cycle.Altemus et al.92 demonstrated that exercise-stimulated HPA responses were increased inthe mid-luteal compared with the follicularphase. However, in contrast to a large ani-mal literature documenting the ability of estra-diol to increase HPA axis secretion, Rocaet al.93 found that exogenously administeredprogesterone, but not estradiol, significantly in-creased exercise-stimulated vasopressin (AVP),adrenocorticotrophic hormone (ACTH), andcortisol secretion compared with a GnRHagonist-induced hypogonadal condition. Themechanism by which progesterone augmentsstimulated HPA axis activity is currently un-known but could include the following: mod-ulation of cortisol feedback restraint of theaxis69,94–97; neurosteroid-related downregula-tion of GABA receptors98; upregulation ofAVP (consistent with luteal phase reductionsin the threshold for AVP release)99; and en-hancement of oxytocin-induced corticotropin-releasing hormone (CRH) secretion.100 Over-all, it seems likely that multiple variables (e.g.,the nature and intensity of the stressor, the ex-act phase of the menstrual cycle) influence thedetection of reproductive steroid regulation ofHPA axis activity.

Behavior

Behavioral studies in lower animals havedocumented the antidepressant-like effects ofestradiol in the forced swim test.19,101 Addition-ally, existing evidence suggests that the anti-depressant effects of estradiol in the forcedswim test are mediated by estrogen recep-tor β102–104 and can be reversed by theco-administration of a 5HT1A receptor antago-nist.105,106 Selective agonists of estrogen recep-tor β also have anxiolytic effects on behaviortests of anxiety in rodents (e.g., open field orelevated plus maze) and decrease the HPA re-sponse to stress.104,107 Finally, estrogen receptor


β knock-out mice display an anxious phenotypein the female.35,108 Thus, behavioral studiesin lower animals confirm that ovarian steroidsmodulate central nervous system function andbehaviors relevant to affective adaptation andstress-responsivity.

Epidemiology of Depression duringthe Perimenopause

The majority of women do not developdepression during either the perimenopauseor the postmenopause. In fact, epidemiologicstudies have concluded that postmenopausalwomen are not at increased risk for develop-ing depression109–120; however, in four stud-ies,111,112,116,117 depressive symptoms were ob-served more frequently in perimenopausal thanpostmenopausal women. Indeed, in severalother longitudinal, community-based studies,the perimenopause (or the presence of men-strual cycle irregularity and hot flushes) wasassociated with an increased risk for depres-sion,121–126 consistent with studies of womenattending gynecology clinics.127–129 In the ini-tial cross-sectional survey from the Study ofWomen’s Health Across the Nation (SWAN),123

perimenopausal women reported significantlymore “psychological distress” than either pre-or postmenopausal women (defined by self-reported menstrual cycle status).123 In thisstudy, “psychological distress” was employedas a proxy for the syndrome of depressionby requiring that core depressive symptoms(sadness, anxiety, and irritability) persist for atleast 2 weeks (similar to the duration crite-rion employed in DSM-IV). The results of sev-eral studies published during the last 4 yearshave found similar results. First, in a longi-tudinal study, Freeman et al.126 found an in-creased risk for clinically significant depres-sion (defined by elevated CES-D scale scoresand the Primary Care Evaluation of MentalDisorders (PRIME-MD)130) during the peri-menopause compared with the pre- or post-menopause. In these studies, the relationship

between the menopause transition and the on-set of depression could have been confoundedby the presence of a past history of depressionin the women studied, since a prior episode ofdepression increases the risk for future recur-rences. Thus, two subsequent studies examinedthe risk of depression in women with no pasthistory of depression. Cohen et al.131 evaluatedthe risk of depression in 460 women who werefollowed prospectively for up to 7 years andwho had no past history of depression. Therisk of new onset depression (defined by Struc-tured Clinical Interview SCID-IV) in the peri-menopause was nearly twice that observed inthe premenopause (adjusted OR = 1.8). Sim-ilarly, Freeman et al.132 demonstrated a signifi-cantly increased (21/2 times greater) rate of newonset depression in women with no historyof depression during the late perimenopausecompared with women who remained pre-menopausal. Finally, two recent reports byBromberger et al.133,134 demonstrate an in-creased incidence of first-onset and recurrentmajor and minor depressive episodes duringthe late menopause transition and early post-menopause. These data notwithstanding, themajority of women in these studies remainedasymptomatic throughout the perimenopause.However, these data suggest that events occur-ring during the menopause transition and earlypostmenopause may predispose some womento develop clinically significant depressiveillness.

Endocrine Studies inPerimenopausal Depression

The stage of the menopause transition dur-ing which episodes of depression appear couldprovide clues to the physiologic events ac-companying the onset of depression. We haveexamined the temporal linkage between thestages of the menopause transition and de-pression in two studies. First, we prospec-tively examined asymptomatic premenopausalwomen with regular menstrual cycles to


determine whether the onsets of depres-sion clustered during a specific stage of themenopause transition. Women were followedwith behavioral and reproductive measures foran average of 5 years until 6 months to 1 yearafter the last menstrual period. In a prelim-inary analysis of 29 women, we documentednine episodes of major or minor depression ineight women, only two of whom had a priordepressive episode. These data documented aclustering of depressive episodes in women dur-ing the late menopause transition relative tothe premenopause.135 Second, we performeda cross-sectional study of 116 women present-ing to the NIMH midlife clinic for evaluationand treatment—all of whom met criteria forperimenopause-onset major or minor depres-sion. The majority of depressive episodes oc-curred during the late menopause transitionregardless of the presence of vasomotor symp-toms or a past history of depression.136 The latemenopause transition is characterized by estra-diol “withdrawal” relative to either the post-menopause or the early perimenopause.2,10

Thus, the temporal appearance of the depres-sions observed suggests an endocrine triggerrelated to the perimenopause (estradiol with-drawal and/or recent-onset of prolonged hy-pogonadism) in the onset of perimenopausaldepression.

Basal Hormone Studies

Several reports indirectly support a role forabnormalities of reproductive hormones dur-ing the perimenopause in depression: (1) lowergonadotropin levels are sometimes observed inpostmenopausal depressed women comparedwith asymptomatic comparison groups137–140;(2) perimenopausal women with depressivesymptoms are reported to have lower plasmaestrone levels141 than nondepressed peri-menopausal women; and (3) an associationhas been described between increased plasmaFSH levels and depression.142 In contrast, threestudies of perimenopausal and postmenopausalwomen observed either no diagnosis-related

differences in plasma estradiol and FSH,143

or no correlation between plasma levels ofestrogens or androgens and severity of de-pressive symptoms.144,145 Similarly, in a studyof 21 women with their first episode of de-pression occurring during the perimenopause,and 21 asymptomatic perimenopausal con-trols,146 we were unable to confirm previ-ous reports of lower basal plasma levels ofLH137–140 or estrone141 in perimenopausal andpostmenopausal women with depression. Ad-ditionally, we observed no diagnosis-related dif-ferences in basal plasma levels of FSH, estrone,testosterone, or free testosterone.

In addition to ovarian hormones, age-relateddifferences in the function of several other phys-iologic systems are observed in both animalsand humans. Some of these differences mayoccur coincidentally with the perimenopauseand, therefore, may potentially contribute tomood dysregulation at this time.

A role for the adrenal androgen DHEA andits sulfated metabolite (DHEA-S) in the regula-tion of mood state is suggested by both its effectson neural physiology147,148 and its reportedantidepressant-like actions in some,149–152 butnot all, clinical trials.153 DHEA’s potential rolein the onset of depression may be particularlyrelevant at midlife given the declining levelsof DHEA production that occur with agingand the accelerated decrease in DHEA lev-els reported in women, but not men, duringmidlife.154 It is possible, therefore, that de-clining secretion (or abnormally low secretion)of DHEA may interact with perimenopause-related changes in ovarian function to trig-ger the onset of depression in some women.Two studies146 (Rasgon et al., personal com-munication) measured plasma levels of DHEAand cortisol in samples of women with depres-sion during the perimenopause and in non-depressed women matched for age and re-productive status. Depressed perimenopausalwomen had significantly lower levels of plasmaDHEA, but not cortisol, compared with con-trols. These findings are consistent with sev-eral previous studies suggesting an association


between plasma DHEA levels and mood.First, plasma DHEA levels correlated with theseverity of depressive symptoms in a groupof postmenopausal women, with lower levelsof DHEA associated with higher depressionscores.144 In two other studies, a positive cor-relation between DHEA-S plasma levels andfeelings of well-being was observed in groupsof peri- and postmenopausal women,145 aswell as elderly depressed men and women.155

These differences in DHEA levels notwith-standing, there was considerable overlap inplasma DHEA levels between perimenopausalwomen with and without depression. Thus, atpresent, in addition to the limitations of basalhormonal measures, there is no consistent evi-dence that women who develop depression dur-ing the menopause transition have an ovarianor adrenal hormone-deficient state.

Longitudinal Studies

Daly et al.156 evaluated mood scores andplasma FSH levels serially over a 6-week screen-ing phase in women presenting to the NIMHmidlife clinic with perimenopausal depression.In the group of women (n = 18) whose CES-Dscores spontaneously decreased by ≥50%, weobserved an incremental decline in FSH levelsat each of the four clinic visits that paralleled theimprovements in CES-D scores.156 Increasedplasma FSH levels during the same 6-weekperiod were not consistently associated withworsening CES-D scores, nor were increasedCES-D scores associated with correspondingelevations in plasma FSH levels, whereas amore uniform relationship was observed be-tween mood and plasma FSH level when eithermeasure decreased. Thus, we identified a sub-group of women with perimenopausal depres-sion whose mood symptoms remitted sponta-neously in association with a significant declinein gonadotropin levels (and a suggested alter-ation in pituitary-ovarian function). Thus, al-though cross-sectional studies suggest that peri-menopausal depression is not associated withabnormalities of ovarian function, longitudinal

studies support a meaningful association be-tween alterations in pituitary-ovarian functionand mood symptoms in these women.

Effects of Estradiol “Replacement”Therapy

An association between the endocrine eventsrelated to the perimenopause and the on-set of depression is also implicated (albeit in-directly) by reports of the mood-enhancingeffects of estradiol in depressed hypogo-nadal women.157 Recently, three double-blind,placebo-controlled trials, which used similarmethodologies and identical preparations ofestradiol (i.e., 17 beta estradiol), have exam-ined the efficacy of estradiol in perimenopausaland postmenopausal women with major orminor depressions.158–160 First, the therapeu-tic efficacy of estradiol was examined in adouble-blind, placebo-controlled trial in 34perimenopausal women (late perimenopauseby STRAW criteria1) who also met standard-ized diagnostic criteria for major and minordepression.158 After 3 weeks of estradiol, de-pression rating scale scores were significantlydecreased compared with baseline scores andsignificantly lower than scores in the womenreceiving placebo. The therapeutic response toestradiol was observed in women regardless ofthe presence of major or minor depression, ahistory of non-perimenopause-related depres-sion, or the presence of hot flushes. Finally, nei-ther baseline nor post-treatment plasma estra-diol levels predicted the observed therapeuticresponse. In keeping with recent community-based cross-sectional surveys,123 these data sug-gest that estrogen’s effect on depression is notsolely a product of its ability to reduce the dis-tress of hot flushes. These findings also are con-sistent with data from Montgomery et al.161 andSaletu et al.,162 which document the beneficialeffects of estradiol on mood in perimenopausalwomen reporting depressive symptoms.

A second randomized, double-blind,placebo-controlled study by Soares et al.159


confirmed the observations of Schmidt et al.158

Soares et al. reported a significant and benefi-cial effect of estradiol replacement comparedto placebo in women with perimenopause-related major depression (as defined by thePRIME-MD)163 and, additionally, reportedthat baseline plasma estradiol levels did notpredict response to estrogen treatment.159

In contrast, a recent study using a similardesign to that employed in perimenopausalwomen158,159 failed to observe a significantantidepressant effect of estradiol relative toplacebo160 in depressed women who were5–10 years post natural menopause.

The evidence that younger perimenopausal,but not older postmenopausal, depressedwomen respond to short-term estradiol ther-apy suggests that the mood disorders occur-ring in perimenopausal women are caused bychanges in hormones (e.g., withdrawal or fluc-tuations) rather than prolonged ovarian steroiddeficiency.

Endocrine Manipulations: Induction ofEstradiol Withdrawal and

Hypogonadism

Several case series describe the onset ofdepressive symptoms after the induction ofhypogonadism by GnRH-agonists in gyne-cology clinic–based samples of women. Forexample, both Warnock164 and Steingold165

observed that 75% and 80% of women, respec-tively, experienced clinically significant depres-sive symptoms during GnRH agonist-inducedhypogonadism. These observations providefurther support for the potential role of the en-docrine events accompanying the menopausetransition in the onset of perimenopausaldepression.

We have examined the effects of estro-gen withdrawal and the recent onset of hy-pogonadism on mood symptoms using twostrategies. First, Harsh et al.166 administereda GnRH agonist for 2–3 months to 53 reg-ular cycling, premenopausal women. In con-

trast to previous reports from gynecology clinic-based samples, all women had the absence ofcurrent or past psychiatric illness confirmedby a structured psychiatric diagnostic inter-view and completed daily symptom ratingsfor 2 months prior to the study entry to con-firm the absence of significant mood or behav-ioral symptoms associated with their menstrualcycle. Additionally, all women had normalgynecologic and medical exams. Mood andbehavioral symptoms during GnRH-agonisttreatment were measured by the Beck Depres-sion Inventory (BDI) and a self-report symp-tom rating form completed on a daily ba-sis. Plasma hormone measures confirmed thatthe GnRH agonist suppressed the secretion ofboth ovarian steroids and gonadotropins. Onlythree women (5.7% of the sample) reportedBDI scores greater than seven (suggestive ofclinically significant symptoms of depression)and in only one of these women did the ele-vated BDI scores persist beyond 2 weeks’ du-ration. In contrast to the relative absence ofdepressive symptoms in these women, we didobserve the significant appearance of severalsymptoms, including both daytime and noc-turnal hot flushes, disturbed sleep, and dimin-ished libido. The latter finding is consistentwith a prior study performed in a smaller sub-sample of these women in whom significantreductions in libido (as measured by a modi-fied Derogatis Inventory of Sexual FunctioningScale167) were observed in approximately 30%of the sample.168 Thus, in otherwise healthywomen, the induction of neither hypogonadismnor hot flushes (with an accompanying sleepdisturbance) uniformly precipitated depressivesymptoms.

In a second ongoing study, we are evaluat-ing the effects of the acute withdrawal of estra-diol therapy in women with and without a pasthistory of perimenopausal depression. In thisstudy, asymptomatic, postmenopausal womenwith and without a past history of depressionduring the menopause transition are placed ona standard dose (100 mcg) of estradiol ther-apy and after 3 weeks are randomly assigned


under double-blind conditions to continue toreceive estradiol (maintenance of estradiol) orplacebo (estradiol withdrawal). Preliminary re-sults suggest that estradiol withdrawal inducesdepressive symptoms in women with a pasthistory of perimenopausal depression, but notin those without such a history. In women witha past history of depression during the peri-menopause, estradiol withdrawal is associatedwith a significant increase in depressive symp-toms (as measured by the CES-D scale169) com-pared with those women who were maintainedon estradiol therapy under double-blind con-ditions. Additionally, no significant depressivesymptoms emerged in the women lacking a his-tory of a past perimenopausal depression whowere either withdrawn or maintained on estra-diol therapy. Thus, in contrast to our findingswith GnRH agonist-induced hypogonadism inpremenopausal women with no past psychiatrichistory, estradiol withdrawal in women with apast history of perimenopausal depression trig-gers mood symptoms. Additionally, in thosewomen who developed depression during theperimenopause, preliminary evidence suggestsa direct relationship between declining estra-diol secretion, the onset of hypogonadism andthe development of clinically significant moodsymptoms. These data are consistent with thosefrom epidemiologic studies showing that, for asubgroup of women, the endocrine events of thelate menopause transition may represent im-portant triggers for mood destabilization andthe onset of depression. Both the markers ofthis risk and the mechanisms underlying estra-diol withdrawal-induced depressive symptomsremain to be identified.

In summary, endocrine studies of depressionduring the menopause transition suggest thefollowing:

1. Depression during the menopause transi-tion is not associated with a simple de-ficiency or excess of reproductive hor-mones, as is the case in other reproductiveendocrine-related mood disorders.

2. Pharmacologic induction of hypogo-nadism and estradiol withdrawal is notuniformly associated with depressivesymptoms, but in some women, estradiolwithdrawal appears to be an importantphysiologic trigger for the onset of mooddisturbance.

3. Similarly, based on the antidepressant ef-ficacy of estradiol therapy, declining estra-diol secretion may play a role in thepathophysiology of depression during themenopause transition (in contrast to de-pressions in the postmenopause).

Conclusions

Ovarian steroids regulate many of the signal-ing pathways, neurocircuits and behaviors thatare hypothesized to be abnormal in depres-sion. Recent evidence from prospective stud-ies suggests that for a subgroup of womenthe endocrine events during the menopausetransition play a role in the onset of depres-sion. Additionally, although perimenopausaldepression is not caused by abnormalities ofbasal ovarian hormone secretion, this disor-der, nonetheless, may be effectively treated withestradiol. The specificity of the relationship be-tween the endocrine events of the menopausetransition and depression in these women isfurther suggested by reports of the lack of an-tidepressant action of estradiol therapy in post-menopausal depressed women. Nonetheless,studies in which menopause is induced phar-macologically demonstrate that estradiol with-drawal and hypogonadism are sufficient to trig-ger depression in only a subgroup of women.Future studies need to identify the biochemi-cal factors and markers of risk underlying thedifferences between those women who remainasymptomatic during the menopause transi-tion and those who develop depression. Thebiological underpinning of this differential be-havioral phenotype also may serve to reconcileand/or predict differences in response to hor-mone therapies.


Conflicts of Interest

The authors declare no conflicts of interest.

References

1. Soules, M.R., S. Sherman, E. Parrott, et al. 2001.Executive summary: Stages of Reproductive Ag-ing Workshop (STRAW). Fertil. Steril. 76: 874–878.

2. Santoro, N., J.R. Brown, T. Adel, et al. 1996. Char-acterization of reproductive hormonal dynamics inthe perimenopause. J. Clin. Endocrinol. Metab. 81:1495–1501.

3. Treloar, A.E. 1981. Menstrual cyclicity and the pre-menopause. Maturitas 3: 249–264.

4. Richardson, S.J. 1993. The biological basis of themenopause Baillieres. Clin. Endocrinol. Metab. 7: 1–16.

5. Miro, F., S.W. Parker, L.J. Aspinall, et al. 2004. Rela-tionship between follicle-stimulating hormone lev-els at the beginning of the human menstrual cycle,length of the follicular phase and excreted estrogens:the FREEDOM study. J. Clin. Endocrinol. Metab. 89:3270–3275.

6. Klein, N.A., A.J. Harper, B.S. Houmard, et al. 2002.Is the short follicular phase in older women sec-ondary to advanced or accelerated dominant follicledevelopment? J. Clin. Endocrinol. Metab. 87: 5746–5750.

7. Hall, J.E. 2007. Neuroendocrine changes with re-productive aging in women. Semin. Repro. Med. 25:344–351.

8. Hall, J.E. 2004. Neuroendocrine physiology of theearly and late menopause. Endocrinol. Metab. Clin.

North Am. 33: 637–659.9. Welt, C.K., Y. Jimenez, P.M. Sluss, et al. 2006. Con-

trol of estradiol secretion in reproductive ageing.Hum. Reprod. 21: 2189–2193.

10. Burger, H.G., E.C. Dudley, J.L. Hopper, et al. 1995.The endocrinology of the menopausal transition: across-sectional study of a population-based sample.J. Clin. Endocrinol. Metab. 80: 3537–3545.

11. Hale, G.E., X. Zhao, C.L. Hughes, et al. 2007. En-docrine features of menstrual cycles in middle andlate reproductive age and the menopausal transitionclassified according to the staging of reproductiveaging workshop (STRAW) staging system. J. Clin.

Endocrinol. Metab. 92: 3060–3067.12. Freeman, E.W., M.D. Sammel, C.R. Gracia, et al.

2005. Follicular phase hormone levels and men-strual bleeding status in the approach to menopause.Fertil. Steril. 83: 383–392.

13. Couzinet, B., G. Meduri, M.G. Lecce, et al. 2001.

The postmenopausal ovary is not a major androgen-producing gland. J. Clin. Endocrinol. Metab. 86: 5060–5066.

14. Davison, S.L., S. Donath, J.G. Montalto, et al. 2005.Androgen levels in adult females: changes with age,menopause and oophorectomy. J. Clin. Endocrinol.

Metab. 90: 3847–3853.15. Fogle, R.H., F.Z. Stanczyk, X. Zhang, et al. 2007.

Ovarian androgen production in postmenopausalwomen. J. Clin. Endocrinol. Metab. 92: 3040–3043.

16. Chen, J., M.R. Sowers, F.M. Moran, et al. 2006.Circulating bioactive androgens in midlife women.J. Clin. Endocrinol. Metab. 91: 4387–4394.

17. Woolley, C.S. & P.A. Schwartzkroin. 1998. Hor-monal effects on the brain. Epilepsia 39: S2–S8.

18. McEwen, B.S., S.E. Alves, K. Bulloch, et al. 1997.Ovarian steroids and the brain: implications for cog-nition and aging. Neurology 48(Suppl 7): S8–S15.

19. Rachman, I.M., J.R. Unnerstall, D.W. Pfaff, et al.1998. Estrogen alters behavior and forebrain c-fos expression in ovariectomized rats subjected tothe forced swim test. Proc. Natl. Acad. Sci. USA 95:13941–13946.

20. Rubinow, D.R., P.J. Schmidt & C.A. Roca. 1998.Estrogen-serotonin interactions: implications for af-fective regulation. Biol. Psychiatry 44: 839–850.

21. Pecins-Thompson, M., N.A. Brown & C.L. Bethea.1998. Regulation of serotonin re-uptake transportermRNA expression by ovarian steroids in rhesusmacaques. Brain Res. Mol. Brain Res. 53: 120–129.

22. Sumner, B.E.H., K.E. Grant, R. Rosie, et al. 1999.Effects of tamoxifen on serotonin transporter and5-hydroxytryptamine2A receptor binding sites andmRNA levels in the brain of ovariectomized ratswith or without acute estradiol replacement. Mol.

Brain Res. 73: 119–128.23. Fink, G. & B.E.H. Sumner. 1996. Oestrogen and

mental state. Nature 383: 306.24. McQueen, J.K., H. Wilson, R.C. Dow, et al.

1996. Oestradiol-17β increases serotonin trans-porter (SERT) binding sites and SERT mRNA ex-pression in discrete regions of female rat brain. J.

Physiol. 495.P: 114P.25. Bethea, C.L., N.Z. Lu, C. Gundlah, et al. 2002.

Diverse actions of ovarian steroids in the serotoninneural system. Front. Neuroendocrinol. 23: 41–100.

26. Sumner, B.E.H. & G. Fink. 1995. Estrogen increasesthe density of 5-hydroxytryptamine2A receptors incerebral cortex and nucleus accumbens in the fe-male rat. J. Steroid Biochem. Mol. Biol. 54: 15–20.

27. Sumner, B.E.H. & G. Fink. 1993. Effects of acuteestradiol on 5-hydroxytryptamine and dopaminereceptor subtype mRNA expression in female ratbrain. Mol. Cell. Neurosci. 4: 83–92.


28. Kendall, D.A., G.M. Stancel & S.J. Enna. 1981.Imipramine: effect of ovarian steroids on modifi-cations in serotonin receptor binding. Science 211:1183–1185.

29. Le Saux, M. & Di Paolo. 2005. Changes in 5-HT1A

receptor binding and G-protein activation in therat brain after estrogen treatment: comparison withtamoxifen and raloxifene. J. Psychiatry Neurosci. 30:110–117.

30. Wissink, S., B. Van Der Burg, B.S. Katzenellen-bogen, et al. 2001. Synergistic activation of theserotonin-1A receptor by nuclear factor-kappaBand estrogen. Mol. Endocrinol. 15: 543–552.

31. Bethea, C.L., S.J. Mirkes, A. Su, et al. 2002. Ef-fects of oral estrogen, raloxifene and arzoxifene ongene expression in serotonin neurons of macaques.Psychoneuroendocrinology 27: 431–445.

32. Gundlah, C., M. Pecins-Thompson, W.E. Schutzer,et al. 1999. Ovarian steroid effects on serotonin 1A,2A and 2C receptor mRNA in macqaque hypotha-lamus. Mol. Brain Res. 63: 325–339.

33. McEwen, B.S. & S.E. Alves. 1999. Estrogen actionsin the central nervous system. Endocr. Rev. 20: 279–307.

34. Osterlund, M.K., C. Halldin & Y.L. Hurd. 2000. Ef-fects of chronic 17β-estradiol treatment on the sero-tonin 5-HT1A receptor mRNA and binding levelsin the rat brain. Synapse 35: 39–44.

35. Krezel, W., S. Dupont, A. Krust, et al. 2001. In-creased anxiety and synaptic plasticity in estrogenreceptor beta-deficient mice. Proc. Natl. Acad. Sci.

USA 98: 12278–12282.36. Lu, N.Z. & C.L. Bethea. 2002. Ovarian steroid reg-

ulation of 5-HT1A receptor binding and G proteinactivation in female monkeys. Neuropsychopharmacol-

ogy 27: 12–24.37. Hery, M., D. Becquet, A.M. Francois-Bellan, et al.

1995. Stimulatory effects of 5HT1A receptor ago-nists on luteinizing hormone-releasing hormone re-lease from cultured fetal rat hypothalamic cells: in-teractions with progesterone. Neuroendocrinology 61:11–18.

38. Maswood, S., G. Stewart & L. Uphouse. 1995. Gen-der and estrous cycle effects of the 5-HT1A agonist,8-OH-DPAT, on hypothalamic serotonin. Pharma-

col. Biochem. Behav. 51: 807–813.39. Clarke, W.P. & S. Maayani. 1990. Estrogen effects

on 5-HT1A receptors in hippocampal membranesfrom ovariectomized rats: functional and bindingstudies. Brain Res. 518: 287–291.

40. Thomas, M.L., D.A. Bland, C.H. Clarke, et al. 1997.Estrogen regulation of serotonin (5-HT) transporterand 5-HT1A receptor mRNA in female rat brain.Abstr. Soc. Neurosci. 23: 1501.

41. Su, T.-P., P.J. Schmidt, M. Danaceau, et al. 1997.

Effect of menstrual cycle phase on neuroendocrineand behavioral responses to the serotonin agonistm-chlorophenylpiperazine in women with premen-strual syndrome and controls. J. Clin. Endocrinol.

Metab. 82: 1220–1228.42. Dinan, T.G., S. Barry, L.N. Yatham, et al. 1990.

The reproducibility of the prolactin response to bus-pirone: relationship to the menstrual cycle. Int. Clin.

Psychopharmacol. 5: 119–123.43. Bancroft, J., A. Cook, D. Davidson, et al. 1991.

Blunting of neuroendocrine responses to infusion ofL-tryptophan in women with perimenstrual moodchange. Psychol. Med. 21: 305–312.

44. O’Keane, V., M. O’Hanlon, M. Webb, et al. 1991.d-Fenfluramine/prolactin response throughout themenstrual cycle: evidence for an oestrogen-inducedalteration. Clin. Endocrinol. 34: 289–292.

45. Schmidt, P.J., J. Raju, M. Danaceau, et al. 2002.The effects of gender and gonadal steroids on theneuroendocrine and temperature response to m-Chlorophenylpiperazine in leuprolide-induced hy-pogonadism in women and men. Neuropsychopharma-

cology 27: 800–812.46. Drevets, W.C. 1999. Prefrontal cortical-amygdalar

metabolism in major depression. Ann. N. Y. Acad. Sci.

877: 614–637.47. Drevets, W.C., M.E. Thase, E.L. Moses-Kolko, et al.

2007. Serotonin-1A receptor imaging in recurrentdepression: replication and literature review. Nucl.

Med. Biol. 34: 865–877.48. Sargent, P.A., K.H. Kjaer, C.J. Bench, et al. 2000.

Brain serotonin1A receptor binding measured bypositron emission tomography with [11C]WAY-100635: effects of depression and antidepressanttreatment. Arch. Gen. Psychiatry 57: 174–180.

49. Parsey, R.V., M.A. Oquendo, R.T. Ogden, et al.2006. Altered serotonin 1A binding in major depres-sion: a [carbonyl-C-11]WAY100635 positron emis-sion tomography study. Biol. Psychiatry 59: 106–113.

50. Jovanovic, H., J. Lundberg, P. Karlsson, et al. 2008.Sex differences in the serotonin 1A receptor andserotonin transporter binding in the human brainmeasured by PET. Neuroimage 39: 1408–1419.

51. Jovanovic, H., A. Cerin, P. Karlsson, et al. 2006. APET study of 5-HT1A receptors at different phasesof the menstrual cycle in women with premenstrualdysphoria. Psychiat. Res-Neuroim. 148: 185–193.

52. Moses, E.L., W.C. Drevets, G. Smith, et al. 2000.Effects of estradiol and progesterone administrationon human serotonin 2A receptor binding: a PETstudy. Biol. Psychiatry 48: 854–860.

53. Svenningsson, P., E.T. Tzavara, H. Qi, et al. 2007.Biochemical and behavioral evidence for anti-depressant-like effects of 5-HT6 receptor stimula-tion. J. Neurosci. 27: 4201–4209.


54. Svenningsson, P., K. Chergui, I. Rachleff, et al. 2006.Alterations in 5-HT1B receptor function by p11 indepression-like states. Science 311: 77–80.

55. Nestler, E.J., R.Z. Terwilliger & R.S. Duman. 1989.Chronic antidepressant administration alters thesubcellular distribution of cyclic AMP-dependentprotein kinase in rat frontal cortex. J. Neurochem. 53:1644–1647.

56. Duman, R.S., G.R. Heninger & E.J. Nestler. 1997.A molecular and cellular theory of depression. Arch.

Gen. Psychiatry 54: 597–606.57. Nibuya, M., E.J. Nestler & R.S. Duman. 1996.

Chronic antidepressant administration increasesthe expression of cAMP response element-bindingprotein (CREB) in rat hippocampus. J. Neurosci. 16:2365–2372.

58. Sohrabji, F., R.C. Miranda & C.D. Toran-Allerand.1994. Estrogen differentially regulates estrogen andnerve growth factor receptor mRNAs in adult sen-sory neurons. J. Neurosci. 14: 459–471.

59. Zhou, Y., J.J. Watters & D.M. Dorsa. 1996. Estrogenrapidly induces the phosphorylation of the cAMPresponse element binding protein in rat brain. En-

docrinology 137: 2163–2166.60. Sohrabji, F., L.A. Greene, R.C. Miranda, et al. 1994.

Reciprocal regulation of estrogen and NGF recep-tors by their ligands in PC12 cells. J. Neurobiol. 25:974–988.

61. Cardona-Gomez, P., M. Perez, J. Avila, et al. 2004.Estradiol inhibits GSK3 and regulates interaction ofestrogen receptors, GSK3 and beta-catenin in thehippocampus. Mol. Cell. Neurosci. 25: 363–373.

62. Murphy, D.D., N.B. Cole & M. Segal. 1998. Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocam-pal neurons. Proc. Natl. Acad. Sci. USA 95: 11412–11417.

63. Berman, K.F., P.J. Schmidt, D.R. Rubinow, et al.1997. Modulation of cognition-specific cortical ac-tivity by gonadal steroids: a positron-emission to-mography study in women. Proc. Natl. Acad. Sci. USA

94: 8836–8841.64. Shaywitz, S.E., B.A. Shaywitz, K.R. Pugh, et al.

1999. Effect of estrogen on brain activation patternsin postmenopausal women during working memorytasks. JAMA 281: 1197–1202.

65. Craig, M.C., P.C. Fletcher, E.M. Daly, et al. 2007.Gonadotropin hormone releasing hormone ago-nists alter prefrontal function during verbal en-coding in young women. Psychoneuroendocrinology 32:1116–1127.

66. Protopopescu, X., H. Pan, M. Altemus, et al. 2005.Orbitofrontal cortex activity related to emotionalprocessing changes across the menstrual cycle. Proc.

Natl. Acad. Sci. USA 102: 16060–16065.

67. Goldstein, J.M., M. Jerram, R. Poldrack, et al.2005. Hormonal cycle modulates arousal circuitryin women using functional magnetic resonanceimaging. J. Neurosci. 25: 9309–9316.

68. Dreher, J., P.J. Schmidt, P. Kohn, et al. 2007. Men-strual cycle phase modulates reward-related neuralfunction in women. Proc. Natl. Acad. Sci. USA 104:2465–2470.

69. Redei, E., L. Li, I. Halasz, et al. 1994. Fast glu-cocorticoid feedback inhibition of ACTH secretionin the ovariectomized rat: effect of chronic estro-gen and progesterone. Neuroendocrinology 60: 113–123.

70. Young, E.A., M. Altemus, V. Parkinson, et al. 2001.Effects of estrogen antagonists and agonists on theACTH response to restraint stress in female rats.Neuropsychopharmacology 25: 881–891.

71. Dayas, C.V., Y. Xu, K.M. Buller, et al. 2000. Effectsof chronic oestrogen replacement on stress-inducedactivation of hypothalamic-pituitary-adrenal axiscontrol pathways. J. Neuroendocrinol. 12: 784–794.

72. Komesaroff, P.A., M. Esler, I.J. Clarke, et al. 1998.Effects of estrogen and estrous cycle on glucocorti-coid and catecholamine responses to stress in sheep.Am. J. Physiol. 275: E671–E678.

73. Burgess, L.H. & R.J. Handa. 1992. Chronicestrogen-induced alterations in adrenocorticotropinand corticosterone secretion and glucocorticoidreceptor-mediated functions in female rats. En-

docrinology 131: 1261–1269.74. Carey, M.P., C.H. Deterd, J. de Koning, et al. 1995.

The influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in the female rat. J. En-

docrinol. 144: 311–321.75. Viau, V. & M.J. Meaney. 1991. Variations in the

hypothalamic-pituitary-adrenal response to stressduring the estrous cycle in the rat. Endocrinology 129:2503–2511.

76. Peiffer, A., M.C. Morale, N. Barden, et al. 1994.Modulation of glucocorticoid receptor gene expres-sion in the thymus by the sex steroid hormone milieuand correlation with sexual dimorphism of immuneresponse. Endocr. J. 2: 181–192.

77. Peiffer, A. & N. Barden. 1988. Glucocorticoid recep-tor gene expresion in rat pituitary gland intermedi-ate lobe following ovariectomy. Mol. Cell. Endocrinol.

55: 115–120.78. Pfeiffer, A. & N. Barden. 1987. Estrogen-induced

decrease of glucocorticoid receptor messenger ri-bonucleic acid concentration in rat anterior pitu-itary gland. Mol. Endocrinol. 1: 435–440.

79. Piroli, G., C. Grillo, M. Ferrini, et al. 1993. Restora-tion by bromocriptine of glucocorticoid receptorsand glucocorticoid negative feedback on prolactin


secretion in estrogen-induced pituitary tumors. Neu-

roendocrinology 58: 273–279.80. Biegon, A., A. Reches, L. Snyder, et al. 1983. Sero-

tonergic and noradrenergic receptors in the ratbrain: modulation by chronic exposure to ovarianhormones. Life Sci. 32: 2015–2021.

81. Clarke, W.P. & J. Goldfarb. 1989. Estrogen enhancesa 5-HT1A response in hippocampal slices from fe-male rats. Eur. J. Pharmacol. 160: 195–197.

82. Fuller, R.W. 1992. The involvement of serotoninin regulation of pituitary-adrenocortical function.Front. Neuroendocrinol. 13: 250–270.

83. Ankenbauer, W., U. Strahle & G. Schutz. 1988.Synergistic action of glucocorticoid and estradiolresponsive elements. Proc. Natl. Acad. Sci. USA 85:7526–7530.

84. Uht, R.M., C.M. Anderson, P. Webb, et al. 1997.Transcriptional activities of estrogen and glucocor-ticoid receptors are functionally integrated at theAP-1 response element. Endocrinology 138: 2900–2908.

85. Uht, R., C.M. Anderson, P. Webb, et al. 1998.Steroid hormone interactions at the AP-1 site. Ab-stracts of the 1998 American Neuroendocrine So-ciety 29.

86. Marinari, K.T., A.I. Leschner & M.P. Doyle. 1976.Menstrual cycle status and adrenocortical reactiv-ity to psychological stress. Psychoneuroendocrinology 1:213.

87. Kirschbaum, C., B.M. Kudielka, J. Gaab, et al.1999. Impact of gender, menstrual cycle phaseand oral contraceptives on the activity ofthe hypothalamic-pituitary-adrenal axis. Psychosom.

Med. 61: 154–162.88. Collins, A., P. Eneroth & B. Landgren. 1985. Psy-

choneuroendocrine stress responses and mood asrelated to the menstrual cycle. Psychosom. Med. 47:512–527.

89. Ablanalp, J.M., L. Livingston, R.M. Rose, et al.1977. Cortisol and growth hormone responses topsychological stress during the menstrual cycle. Psy-

chosom. Med. 39: 158–177.90. Long, T.D., V.L. Ellingrod, R.G. Kathol, et al. 2000.

Lack of menstrual cycle effects on hypothalamic-pituitary-adrenal axis response to insulin-inducedhypoglycaemia. Clin. Endocrinol. (Oxf.) 52: 781–787.

91. Galliven, E.A., A. Singh, D. Michelson, et al. 1997.Hormonal and metabolic responses to exerciseacross time of day and menstrual cycle phase. J.

Appl. Physiol. 83: 1822–1831.92. Altemus, M., C. Roca, E. Galliven, et al. 2001.

Increased vasopressin and adrenocorticotropin re-sponses to stress in the midluteal phase of the men-strual cycle. J. Clin. Endocrinol. Metab. 86: 2525–2530.

93. Roca, C.A., P.J. Schmidt, M. Altemus, et al.2003. Differential menstrual cycle regulation ofhypothalamic-pituitary-adrenal axis in women withpremenstrual syndrome and controls. J. Clin. En-

docrinol. Metab. 88: 3057–3063.94. Keller-Wood, M., J. Silbiger & C.E. Wood. 1988.

Progesterone attenuates the inhibition of adreno-corticotropin responses by cortisol in nonpregnantewes. Endocrinology 123: 647–651.

95. Turner, B.B. 1997. Influence of gonadal steroids onbrain corticosteriod receptors: a minireview. Neu-

rochem. Res. 22: 1375–1385.96. Patchev, V.K. & O.F.X. Almeida. 1996. Gonadal

steroids exert facilitating and “buffering” effects onglucocorticoid-mediated transcriptional regulationof corticotropin-releasing hormone and corticos-teroid receptor genes in rat brain. J. Neurosci. 16:7077–7084.

97. Young, E.A. 1995. The role of gonadal steroidsin hypothalamic-pituitary-adrenal axis regulation.Crit. Rev. Neurobiol. 9: 371–381.

98. Smith, S.S., Q.H. Gong, F.-C. Hsu, et al. 1998.GABAA receptor alpha-4 subunit suppression pre-vents withdrawal properties of an endogenoussteroid. Nature 392: 926–930.

99. Spruce, B.A., P.H. Baylis, J. Burd, et al. 1985. Varia-tion in osmoregulation of arginine vasopressin dur-ing the human menstrual cycle. Clin. Endocrinol. 22:37–42.

100. Ochedalski, T., S. Subburaju, P.C. Wynn, et al.2007. Interaction between oestrogen and oxytocinon hypothalamic-pituitary-adrenal axis activity. J.

Neuroendocrinol. 19: 189–197.101. Morgan, M.A. & D.W. Pfaff. 2002. Estrogen’s effects

on activity, anxiety and fear in two mouse strains.Behav. Brain Res. 132: 85–93.

102. Walf, A.A., M.E. Rhodes & C.A. Frye. 2004. An-tidepressant effects of ERβ-selective estrogen recep-tor modulators in the forced swim test. Pharmacol.

Biochem. Behav. 78: 523–529.103. Rocha, B.A., R. Fleischer, J.M. Schaeffer, et al. 2005.

17β-estradiol-induced antidepressant-like effect inthe forced swim test is absent in estrogen receptor-βknockout (BERKO) mice. Psychopharmacology 179:637–643.

104. Walf, A.A. & C.A. Frye. 2005. Antianxiety andantidepressive behavior produced by physiolog-ical estradiol regimen may be modulated byhypothalamic-pituitary-adrenal axis activity. Neu-

ropsychopharmacology 30: 1288–1301.105. Estrada-Camarena, E., A. Fernandez-Guasti & C.

Lopez-Rubalcava. 2006. Participation of the 5-HT1A receptor in the antidepressant-like effect of es-trogens in the forced swimming test. Neuropsychophar-

macology 31: 247–255.


106. Estrada-Camarena, E., C. Lopez-Rubalcava& A. Fernandez-Guasti. 2006. Facilitatingantidepressant-like actions of estrogens are medi-ated by 5-HT1A and estrogen receptors in the ratforced swimming test. Psychoneuroendocrinology 31:905–914.

107. Lund, T.D., T. Rovis, W.C.J. Chung, et al. 2005.Novel actions of estrogen receptor-β on anxiety-related behaviors. Endocrinology 146: 797–807.

108. Imwalle, D.B., J.-A. Gustafsson & E.F. Rissman.2005. Lack of functional estrogen receptor β in-fluences anxiety behavior and serotonin content infemale mice. Physiol. Behav. 84: 157–163.

109. McKinlay, J.B., S.M. McKinlay & D. Brambilla.1987. The relative contributions of endocrinechanges and social circumstances to depression inmid-aged women. J. Health Soc. Behav. 28: 345–363.

110. Kaufert, P.A., P. Gilbert & R. Tate. 1992. The Man-itoba project: a re-examination of the link betweenmenopause and depression. Maturitas 14: 143–155.

111. Avis, N.E., D. Brambilla, S.M. McKinlay, et al. 1994.A longitudinal analysis of the association betweenmenopause and depression: results from the Mas-sachusetts Women’s Health Study. Ann. Epidemiol. 4:214–220.

112. Matthews, K.A., R.R. Wing, L.H. Kuller, et al.1990. Influences of natural menopause on psycho-logical characteristics and symptoms of middle-agedhealthy women. J. Consult. Clin. Psychol. 58: 345–351.

113. Holte, A. 1992. Influences of natural menopauseon health complaints: a prospective study of healthyNorwegian women. Maturitas 14: 127–141.

114. Fugate Woods, N., A. Mariella & E. SullivanMitchell. 2002. Patterns of depressed mood acrossthe menopausal transition: approaches to studyingpatterns in longitudinal data. Acta Obstet. Gynecol.

Scand. 81: 623–632.115. Maartens, L.W., G.L. Leusink, J.A. Knottnerus, et al.

2001. Climacteric complaints in the community.Fam. Pract. 18: 189–194.

116. den Tonkelaar, I., F.J. Broekmans, E.J. de Boer, et al.2002. The stages of reproductive aging workshop.Letter to the Editor. Menopause 9: 463–464.

117. Hardy, R. & D. Kuh. 2002. Change in psycholog-ical and vasomotor symptom reporting during themenopause. Soc. Sci. Med. 55: 1975–1988.

118. Dennerstein, L., P. Lehert, H. Burger, et al. 1999.Mood and the menopausal transition. J. Nerv. Ment.

Dis. 187: 685–691.119. Weissman, M.M., P.J. Leaf, G.L. Tischler, et al. 1988.

Affective disorders in five United States communi-ties. Psychol. Med. 18: 141–153.

120. Kessler, R.C., K.A. McGonagle, M. Swartz, et al.1993. Sex and depression in the National Comor-

bidity Survey I: lifetime prevalence, chronicity andrecurrence. J. Affect. Disord. 29: 85–96.

121. Hunter, M. 1992. The South-East England longitu-dinal study of the climacteric and postmenopause.Maturitas 14: 117–126.

122. O’Connor, V.M., C.B. Del Mar, M. Sheehan, et al.1995. Do psycho-social factors contribute more tosymptom reporting by middle-aged women thanhormonal status? Maturitas 20: 63–69.

123. Bromberger, J.T., P.M. Meyer, H.M. Kravitz, et al.2001. Psychologic distress and natural menopause:a multiethnic community study. Am. J. Public Health

91: 1435–1442.124. Maartens, L.W.F., J.A. Knottnerus & V.J. Pop. 2002.

Menopausal transition and increased depressivesymptomatology: a community based prospectivestudy. Maturitas 42: 195–200.

125. Bromberger, J.T., S.F. Assmann, N.E. Avis, et al.2003. Persistent mood symptoms in a multieth-nic community cohort of pre- and perimenopausalwomen. Am. J. Epidemiol. 158: 347–356.

126. Freeman, E.W., M.D. Sammel, L. Liu, et al. 2004.Hormones and menopausal status as predictors ofdepression in women in transition to menopause.Arch. Gen. Psychiatry 61: 62–70.

127. Stewart, D.E., K. Boydell, C. Derzko, et al. 1992.Psychologic distress during the menopausal years inwomen attending a menopause clinic. Int. J. Psychi-

atry Med. 22: 213–220.128. Dennerstein, L., A.M.A. Smith, C. Morse, et al.

1993. Menopausal symptoms in Australian women.Med. J. Aust. 159: 232–236.

129. Hay, A.G., J. Bancroft & E.C. Johnstone. 1994. Af-fective symptoms in women attending a menopauseclinic. Br. J. Psychiatry 164: 513–516.

130. Spitzer, R.L., J.B.W. Williams, K. Kroenke, et al.1994. Utility of a new procedure for diagnosingmental disorders in primary care: the PRIME-MD1000 study. JAMA 272: 1749–1756.

131. Cohen, L.S., C.N. Soares, A.F. Vitonis, et al.2006. Risk for new onset of depression duringthe menopausal transition. The Harvard study ofmoods and cycles. Arch. Gen. Psychiatry 63: 385–390.

132. Freeman, E.W., M.D. Sammel, H. Lin, et al. 2006.Associations of hormones and menopausal statuswith depressed mood in women with no history ofdepression. Arch. Gen. Psychiatry 63: 375–382.

133. Bromberger, J.T., K.A. Matthews, L.L. Schott, et al.2007. Depressive symptoms during the menopausaltransition: the study of women’s health across thenation (SWAN). J. Affect. Disord. 103: 267–272.

134. Bromberger, J.T., H.M. Kravitz, K.A. Matthews,et al. 2007. Predictors of first episodes of clinical de-pression in midlife women. Abstr. APA 160th Ann.Meeting 121.


135. Schmidt, P.J., N.A. Haq & D.R. Rubinow. 2004. Alongitudinal evaluation of the relationship betweenreproductive status and mood in perimenopausalwomen. Am. J. Psychiatry 161: 2238–2244.

136. Steinberg, E.M., D.R. Rubinow, J.J. Bartko,et al. 2008. A cross sectional evaluation ofperimenopausal depression. J. Clin. Psychiatry 69:973–980.

137. Brambilla, F., M. Maggioni, E. Ferrari, et al. 1990.Tonic and dynamic gonadotropin secretion in de-pressive and normothymic phases of affective disor-ders. Psychiatry Res. 32: 229–239.

138. Amsterdam, J.D., A. Winokur, I. Lucki, et al.1983. Neuroendocrine regulation in depressed post-menopausal women and healthy subjects. Acta Psy-

chiatr. Scand. 67: 43–49.139. Altman, N., E.J. Sachar, P.H. Gruen, et al. 1975. Re-

duced plasma LH concentration in postmenopausaldepressed women. Psychosom. Med. 37: 274–276.

140. Guicheney, P., D. Leger, J. Barrat, et al. 1988.Platelet serotonin content and plasma tryptophan inperi- and postmenopausal women: variations withplasma oestrogen levels and depressive symptoms.Eur. J. Clin. Invest. 18: 297–304.

141. Ballinger, S. 1990. Stress as a factor in loweredestrogen-levels in the early postmenopause. Ann. N.

Y. Acad. Sci. 592: 95–113.142. Huerta, R., A. Mena, J.M. Malacara, et al. 1995.

Symptoms at perimenopausal period: its associa-tion with attitudes toward sexuality, life-style, familyfunction and FSH levels. Psychoneuroendocrinology 20:135–148.

143. Saletu, B., N. Brandstatter, M. Metka, et al. 1996.Hormonal, syndromal and EEG mapping studiesin menopausal syndrome patients with and withoutdepression as compared with controls. Maturitas 23:91–105.

144. Barrett-Connor, E., D. von Muhlen, G.A. Laughlin,et al. 1999. Endogenous levels of dehydroepiandros-terone sulfate, but not other sex hormones, are as-sociated with depressed mood in older women: theRancho Bernardo study. J. Am. Geriatr. Soc. 47: 685–691.

145. Cawood, E.H. & J. Bancroft. 1996. Steroid hor-mones, the menopause, sexuality and well-being ofwomen. Psychol. Med. 26: 925–936.

146. Schmidt, P.J., J.H. Murphy, N. Haq, et al. 2002.Basal plasma hormone levels in depressed per-imenopausal women. Psychoneuroendocrinology 27:907–920.

147. Majewska, M.D., S. Demirgoren, C.E. Spivak, et al.1990. The neurosteroid dehydroepiandrosteronesulfate is an allosteric antagonist of the GABAA re-ceptor. Brain Res. 526: 143–146.

148. Baulieu, E.-E. & P. Robel. 1998. Dehydroepiandros-terone (DHEA) and dehydroepiandrosterone sulfate(DHEAS) as neuroactive neurosteroids. Proc. Natl.

Acad. Sci. USA 95: 4089–4091.149. Morales, A.J., J.J. Nolan, J.C. Nelson, et al. 1994.

Effects of replacement dose of dehydroepiandros-terone in men and women of advancing age. J. Clin.

Endocrinol. Metab. 78: 1360–1367.150. Wolkowitz, O.M., V.I. Reus, A. Keebler, et al. 1999.

Double-blind treatment of major depression withdehydroepiandrosterone. Am. J. Psychiatry 156: 646–649.

151. Bloch, M., P.J. Schmidt, M.A. Danaceau, et al. 1999.Dehydroepiandrosterone treatment of mid-life dys-thymia. Biol. Psychiatry 45: 1533–1541.

152. Schmidt, P.J., R.C. Daly, M. Bloch, et al. 2005.Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch. Gen. Psychi-

atry 62: 154–162.153. Wolf, O.T., O. Neumann, D.H. Hellhammer, et al.

1997. Effects of a two-week physiological dehy-droepiandrosterone substitution on cognitive per-formance and well-being in healthy elderly womenand men. J. Clin. Endocrinol. Metab. 82: 2363–2367.

154. Laughlin, G.A. & E. Barrett-Connor. 2000. Sex-ual dimorphism in the influence of advanced agingon adrenal hormone levels: the Rancho Bernardostudy. J. Clin. Endocrinol. Metab. 85: 3561–3568.

155. Ferrari, E., M. Locatelli, A. Arcaini, et al. 1997.Chronobiological study of some neuroendocrinefeatures of major depression in elderly people. Abstr.79th Annu. Meeting Endocr. Soc.

156. Daly, R.C., M.A. Danaceau, D.R. Rubinow, et al.2003. Concordant restoration of ovarian functionand mood in perimenopausal depression. Am. J. Psy-

chiatry 160: 1842–1846.157. Zweifel, J.E. & W.H. O’Brien. 1997. A meta-analysis

of the effect of hormone replacement therapy upondepressed mood. Psychoneuroendocrinology 22: 189–212.

158. Schmidt, P.J., L. Nieman, M.A. Danaceau, et al.2000. Estrogen replacement in perimenopause-related depression: a preliminary report. Am. J. Ob-

stet. Gynecol. 183: 414–420.159. Soares, C.D., O.P. Almeida, H. Joffe, et al. 2001. Ef-

ficacy of estradiol for the treatment of depressive dis-orders in perimenopausal women: a double-blind,randomized, placebo-controlled trial. Arch. Gen. Psy-

chiatry 58: 529–534.160. Morrison, M.F., M.J. Kallan, T. Ten Have, et al.

2004. Lack of efficacy of estradiol for depression inpostmenopausal women: a randomized, controlledtrial. Biol. Psychiatry 55: 406–412.

161. Montgomery, J.C., M. Brincat, A. Tapp, et al. 1987.Effect of oestrogen and testosterone implants on


psychological disorders in the climacteric. Lancet

329: 297–299.162. Saletu, B., N. Brandstatter, M. Metka, et al.

1995. Double-blind, placebo-controlled, hormonal,syndromal and EEG mapping studies withtransdermal oestradiol therapy in menopausal de-pression. Psychopharmacology 122: 321–329.

163. Spitzer, R.L., K. Kroenke, M. Linzer, et al. 1995.Health-related quality of life in primary carepatients with mental disorders: results from thePRIME-MD 1000 study. JAMA 274: 1511–1517.

164. Warnock, J.K., J.C. Bundren & D.W. Morris. 1998.Sertraline in the treatment of depression associatedwith gonadotropin-releasing hormone agonist ther-apy. Biol. Psychiatry 43: 464–465.

165. Steingold, K.A., M. Cedars, J.K. Lu, et al. 1987.Treatment of endometriosis with a long-acting

gonadotropin-releasing hormone agonist. Obstet.

Gynecol. 69: 403–411.166. Harsh, V.L., P. Fortinsky, T.F. Gearhart, et al. 2008.

Effects of induced hypogonadism on mood and be-havior in healthy women. Abstr. 161st Ann. MeetingAPA.

167. Derogatis, L.R. 1997. The Derogatis interview forsexual functioning (DISF/DISF-SR): an introduc-tory report. J. Sex Marital Ther. 23: 291–304.

168. Schmidt, P.J., E.M. Steinberg, P. Palladino Ne-gro, et al. 2009. Pharmacologically-induced hy-pogonadism and sexual function in healthy youngwomen and men. Neuropsychopharmacology 34: 565–576.

169. Radloff, L.S. 1977. The CES-D scale: a self-reportdepression scale for research in the general popula-tion. Appl. Psychol. Meas. 1: 385–401.

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Sex Hormones and Mood in the Perimenopause