Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge?

doi:10.1016/S0006-3223(98)00169-3

Biological Psychiatry

Volume 44, Issue 9, 1 November 1998, Pages 798-811

https://doi.org/10.1016/S0006-3223(98)00169-3 Get rights and content

Abstract

A growing body of literature describes the effects of estrogen and other gonadal steroids on the central nervous system. The ability of estrogen to modulate serotonergic function, in particular, raises the possibility that sex steroids may play a role in the mechanisms associated with depression and its treatment. This review will focus on those aspects of the estrogen–serotonin interaction that relate to possible increased vulnerability to affective disorders and on hormonal treatments that may be clinically applicable to women. After a discussion of the potential relationship between estrogen and mood disorders across the female life cycle, a model is proposed in which differential sensitivity to mood disorders explains the differential response by some women to periods of normal hormonal changes. Possible serotonin receptor-mediated and intracellular mechanisms by which estrogen may exert its effects on mood are also reviewed. These are compared to putative mechanisms of standard antidepressant effect. Lastly, treatment studies in which estrogen has been used as 1) monotherapy for depression, 2) an augmentation strategy, or 3) a prophylactic intervention against recurrence of depression are reviewed.

Introduction

The precise relationship between estrogen and serotonergic function has yet to be fully delineated. Nonetheless, many investigators have suggested that the neuromodulatory effects of estrogen may contribute to a greater risk for depression in women and might point the way to effective hormonal treatments for mood disorders in female patients. The increasing evidence of a neuromodulatory role of estrogen on the serotonergic system, in particular, raises the possibility that estrogen might alter risk for depression through its effects on serotonergic function.

In the first section of this paper, we will briefly review the epidemiologic associations between mood disorders and the reproductive years in women. The extent to which a change in estrogen status may mediate serotonergic function and the increased risk of depression for women will be reviewed. Specific reproductive endocrine-associated mood syndromes including premenstrual dysphoric disorder, postpartum mood disorders, and perimenopausal depressive symptoms will be discussed. These reproductive-related mood syndromes will be used as models for the proposed differential vulnerability of subpopulations of women to normal changes in hormonal levels during the premenstrual, postpartum, and perimenopausal periods. The latter section of this paper will outline the molecular mechanism by which antidepressants may exert their effects, and a comparison will be made to what is known about the intracellular and serotonergic effects of estrogen. Studies in which estrogen has been used as 1) monotherapy for the treatment of depression, 2) an augmentation strategy, or 3) a prophylactic intervention against recurrence of depression will also be reviewed.

Section snippets

Neurobiology of estrogen and serotonin

The neuroendocrine system has been described as a “window to the brain,” providing information about the central nervous system (CNS) and the potential pathophysiology of depression. The association of endocrinopathies with mood disturbance has led to studies in which dysregulation of hypothalamic–pituitary axes affecting adrenal, thyroid, and gonadal function have been examined as potential predictors of mood disturbance. The hypothalamic–pituitary–gonadal (HPG) axis has been of particular

Mechanism of antidepressant action: the role of estrogen

The ability of antidepressants to alter serotonergic and noradrenergic function has been implicated with respect to efficacy of these agents in the treatment of depression. The development of selective serotonin reuptake inhibitors (SSRIs) has focused attention on specific changes in 5-HT receptors that may contribute to their antidepressant effect. For example, chronic antidepressant treatment (21 days) causes down-regulation of 5-HT₂ receptors, a finding that has been linked to the mechanism

Conclusions

Estrogen has multiple neuromodulating effects, including direct intracellular effects and those mediated by its effects on the serotonergic system. It is likely that these effects together manifest an antidepressant benefit in certain groups of women, although in others who have differential sensitivity to normal hormonal changes, the CNS effects of estrogen may confer added risk for mood disorders. The temporal context of these effects (i.e., the extent to which they play a role at different

Acknowledgements

This work was presented at the Neuroscience Discussion Forum “A Decade of Serotonin Research” held at Amelia Island, Florida in November 1997. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.

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We investigated the association between vasomotor symptoms (VMSs) and the onset of depressive symptoms among premenopausal women.
This cross-sectional study included 4376 premenopausal women aged 42–52 years, and the cohort study included 2832 women without clinically relevant depressive symptoms at baseline. VMSs included the symptoms of hot flashes and night sweats. Depressive symptoms were evaluated using the Center for Epidemiological Studies Depression Scale; a score of ≥16 was considered to define clinically relevant depressive symptoms.
Premenopausal Women with VMSs at baseline exhibited a higher prevalence of depressive symptoms compared with women without VMSs at baseline (multivariable-adjusted prevalence ratio 1.76, 95 % confidence interval [CI] 1.47–2.11). Among the 2832 women followed up (median, 6.1 years), 406 developed clinically relevant depressive symptoms. Women with versus without VMSs had a significantly higher risk of developing clinically relevant depressive symptoms (multivariable-adjusted hazard ratio, 1.72; 95 % CI 1.39–2.14). VMS severity exhibited a dose-response relationship with depressive symptoms (P for trend <0.05).
Self-reported questionnaires were only used to obtain VMSs and depressive symptoms, which could have led to misclassification. We also could not directly measure sex hormone levels.
Even in the premenopausal stage, women who experience hot flashes or night sweats have an increased risk of present and developed clinically relevant depressive symptoms. It is important to conduct mental health screenings and provide appropriate support to middle-aged women who experience early-onset VMSs.
Estradiol attenuates chronic restraint stress-induced dendrite and dendritic spine loss and cofilin1 activation in ovariectomized mice
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Ovarian hormone deprivation is associated with mood disorders, such as depression, and estradiol therapy is significantly more effective than placebos in treating major depression associated with menopause onset. However, the effect of estradiol on neuronal plasticity and its mechanisms remain to be further elucidated. In this study, behavioral assessments were used to examine the antidepressant effect of estradiol in ovariectomized (OVX) B6.Cg-TgN (Thy-YFP-H)-2Jrs transgenic mice on chronic restraint stress (CRS)-induced dendrite and dendritic spine loss; Yellow fluorescent protein (YFP) is characteristically expressed in excitatory neurons in transgenic mice, and its three-dimensional images were used to evaluate the effect of estradiol on the density of different types of dendritic spines. Quantification and distribution of cofilin1 and p-cofilin1 were determined by qPCR, Western blots, and immunohistochemistry, respectively. The results revealed that treatment with estradiol or clomipramine significantly improved depression-like behaviors. Estradiol treatment also significantly upregulated the dendritic density in all areas examined and increased the density of filopodia-type, thin-type and mushroom-type spines in the hippocampal CA1 and elevated the thin-type and mushroom-type spine density in the PFC. Consistent with these changes, estradiol treatment significantly increased the density of p-cofilin1 immunopositive dendritic spines. Thus, these data reveal a possible estradiol antidepressant mechanism, in that estradiol promoted the phosphorylation of cofilin1 and reduced the loss of dendrites and dendritic spines, which of these dendritic spines include not only immature spines such as filopodia-type, but also mature spines such as mushroom-type, and attenuated the depression-like behavior.
Neonatal treatment with clomipramine modifies the expression of estrogen receptors in brain areas of male adult rats
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The participation of estrogens in depression has been well recognized. To exert its effects, estradiol binds mainly to estrogen receptors ESR1 and ESR2 (α and β, respectively), expressed in brain regions including the hippocampus, limbic regions and hypothalamic nuclei. In rodents, modified estrogen receptors expression in brain areas have been implicated in different signs similar to those observed in depressive patients. Neonatal clomipramine (CMI) treatment is a pharmacological manipulation that generates behavioral and neurochemical changes that persist throughout adulthood and resemble human depression.
The aim of this study was to analyze whether CMI neonatal treatment modifies the expression of nuclear ESR1 and ESR2 in the hippocampus, amygdala basolateral (BLA), amygdala medial (MeA), hypothalamic medial preoptic area (mPOA) and raphe nucleus in male rats. Our results indicate that CMI treatment significantly induced an mRNA increase of ESR1 in the hypothalamus, additionally produce a reduction in the mRNA ESR2 expression in raphe accompanied of an increase in hypothalamus and amygdala. CMI treated rats show more immunorreactive cells to ESR1 (ESR1-ir) in mPOA, BLA, MeA, together with a reduction of these cells in the hippocampal CA1 region. Moreover, an increase in the number of immunorreactive cells to ESR2 (ESR2-ir), in BLA and MeA, was observed in CMI treated rats. Additionally, the hippocampal CA2 region and raphe nucleus showed a decrease in these cells. Also, neonatal CMI treatment induced a decrease in the number of cells of the pyramidal layer in CA1. Overall, the results suggest that neonatal CMI treatment in rats (during brain development) induces changes in estrogen receptors in different brain areas involved with the regulation of depressive-like behaviors.
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Citation Excerpt :
There is also evidence regarding the neuro-modulatory effects of estrogen and progesterone on the serotonergic system (Leibenluft et al., 1994; Linnoila et al., 1993; Malone et al., 1996; Rubinow et al., 1998). Estrogen and progesterone receptors have been found in different regions of the brain including serotonergic, dopaminergic, and noradrenergic neurons that could play a significant role in depression and suicide (Joffe and Cohen, 1998; Young et al., 2000). Although initial theories have emphasized on dysregulations in sexual steroids in PMS, further studies did not confirm any differences between progesterone levels in women with and without PMS (Walsh et al., 2015).
Women likely attempt suicide more than men and sex hormones or menstrual cycle may be associated with female suicide attempts. There are debates regarding the correlation of premenstrual dysphoric disorder (PMDD) and suicidal behaviors. The objective of this study was to examine if PMDD was associated with suicidal attempts as sex hormones are contributed in its pathogenesis.
As a case-control study 120 fertile woman with regular menstrual cycles attempting suicide and admitted to a general hospital were compared with a matched control group of 120 women selected among those accompanying other patients in other wards. Psychiatric interview based on DSM-5 criteria was conducted for diagnosing PMDD.
There was a significantly higher frequency of PMDD in suicide attempters than in the controls (P = 0.001); while no remarkable difference was seen in frequency of premenstrual syndrome (PMS) between the two groups (P = 0.294) and attempting suicide was not related to the menstrual cycle (P = 0.52).
This study suggests that PMDD may be associated with suicidal attempts, however it is not related to menstrual cycle. No relationship was found between PMS and suicidal acts.
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A Decade of Serotonin Research: Regulation of Affect and Eating BehaviorEstrogen, serotonin, and mood disturbance: where is the therapeutic bridge?

Abstract

Introduction

Section snippets

Neurobiology of estrogen and serotonin

Mechanism of antidepressant action: the role of estrogen

Conclusions

Acknowledgements

J Psychiatr Res

Ann Epidemiol

Brain Res

Neurosci Lett

Psychiatry Res

Lancet

Clin Obstet Gynaecol

Prog Neuropsychopharmacol Biol Psychiatry

J Affect Disord

Maturitas

J Affect Disord

Neuropsychopharmacology

Lancet

Maturitas

J Affect Disord

Am J Obstet Gynecol

Trends Pharmacol Sci

Lancet

Am J Obstet Gynecol

Am J Med

Am J Obstet Gynecol

Biol Psychiatry

Am J Geriatr Psychiatry

Biol Psychiatry

Psychoneuroendocrinology

Reduced plasma LH concentration in postmenopausal depressed women

Psychosom Med

An investigation into the observed sex difference in prevalence of unipolar depression

J Abnorm Psychol

Neuroendocrine regulation in depressed postmenopausal women and healthy subjects

Acta Psychiatr Scand

Plasma tryptophan levels and mental depression in post-menopausal subjectsEffects of oral piperazine oestrone sulfate

Int Res Commun Syst

Modulation by estradiol of serotonin1 receptors in brain

J Neurosci

The psychiatric evaluation and treatment of premenstrual dysphoric disorder

Efficacy of depot leuprolide in premenstrual syndromeEffect of symptom severity and type in a controlled trial

Obstet Gynecol

Estrogen-progesterone combinationAnother mood stabilizer?

Am J Psychiatry

Is oestrogen therapy effective in the treatment of menopausal depression?

J R Coll Gen Pract

Predictors of relapse into major depressive disorder in a nonclinical population

Am J Psychiatry

Major depression in a nonclinical sampleDemographic and clinical risk factors for first onset

Arch Gen Psychiatry

Is puerperal psychosis the same as bipolar manic-depressive disorder? A family study

Psychol Med

Estrogen improves psychological function in asymptomatic postmenopausal women

Obstet Gynecol

A molecular and cellular theory of depression

Arch Gen Psychiatry

Organo-therapeutic in mental disease

Br Med J

The Zurich Study XIISex differences in depression: Evidence from longitudinal epidemiological data

Eur Arch Psychiatry Clin Neurosci

A window for the study of prenatal sex hormone influences on postnatal development

J Genet Psychol

Estrogen control of central neurotransmissionEffect on mood, mental state, and memory

Cell Mol Neurobiol

Variations in the concentrations of monoamines and their metabolites in eight regions of rat brain during the oestrus cycleA basis for interactions between hormones and psychotropic drugs

J Pharm Pharmacol

Pregnancy-related affective episodes among women with recurrent depression

Am J Psychiatry

Sex differences in recurrent depressionAre there any that are significant?

Am J Psychiatry

Three-year outcomes for maintenance therapies in recurrent depression

Arch Gen Psychiatry

The effect of estrogen therapy on somatic and psychical symptoms in postmenopausal women

Acta Obstet Gynecol Scand

Platelet serotonin content and plasma tryptophan in peri- and postmenopausal womenVariations with plasma oestrogen levels and depressive symptoms

Eur J Clin Invest

A Decade of Serotonin Research: Regulation of Affect and Eating Behavior
Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge?

Modulation by estradiol of serotonin₁ receptors in brain