Depression, menopause and estrogens: is there a correlation?

Maturitas 41 Suppl. 1 (2002) S3 – S8 www.elsevier.com/locate/maturitas

Depression, menopause and estrogens: is there a correlation? Martin Birkha¨user Di6ision of Gynaecology and Endocrinology, Department of Obstetrics and Gynaecology, Uni6ersity of Berne, Uni6ersita¨ts-Frauenklinik, Inselspital, Schanzeneckstrasse 1, CH-3012 Bern, Switzerland

Abstract Women have a higher incidence of depression than men. The lifetime incidence of endogenous depression in women is twice the incidence in males. Because depression in the elderly is an important public health concern, an eventual correlation between menopause and depression is of practical importance. The relevant literature is reviewed. There are suggestive data that estrogen deficiency may increase the susceptibility for depression. Furthermore, here is suggestive evidence from observational studies and a limited number of randomized, controlled trials that estrogen therapy after menopause improves mood and cognition. However, the clinical relevance of estrogen administration is unproved. There are weak data that estrogens might be considered for mild depressive symptoms attributed to hot flushes, sleep disturbances, or other climacteric symptoms. No hard data exist to indicate whether estrogen could be used as adjunct therapy for other depressive disorders during the menopausal transition or postmenopausal period, but newer findings suggest that estrogens may improve the effect of serotonin reuptake inhibitors. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Depression; Menopause; Estrogens; Serotonin reuptake inhibitor; HRT

1. Introduction Women of all ages have a higher incidence of depression than men [1 – 4]. The lifetime incidence of endogenous depression in women is twice the incidence in males (Table 1). Because depression in the elderly is an important public health concern [5], an eventual correlation between menopause and depression is of practical importance. In the early 20th century, Manfred Bleuler had introduced the notion of ‘endocrine depression’: Bleuler had postulated a causal relationship between the endocrine system and psychiatric diseases. However, others claim that

depression and menopause are two different entities occurring independently in the same age group. In 1984, Osborn states [6]: ‘‘For the doctor confronted with an unhappy menopausal woman, who is weepy, irritable and sleeping badly, it is often difficult to decide whether these symptoms are a natural consequence of her endocrine status or due to social or psychological factors. Certainly, a link between depression and the menopause should not necessarily be assumed.’’ If the literature is contradictory concerning the correlation between depressive dysphoria and estrogens, it might be explained in part by the fact that the criteria used are not

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identical. Therefore, in 1998, Gath [7] postulates that for the tests to be used the following points have to be respected: the psychiatric criteria have to be fulfilled, the sensitivity, the ‘test – retest’ reliability and the usefulness have to be established.

Table 2 Incidence of different forms of depression in both sexes [12] f:m Unipolar depression One depressive episode bipolar I One depressive episode bipolar II No difference in: age at start, psychotic symptoms, tentamen, chronicity

4:1 2:1 1:1 1:1

2. Estrogen and depression Hot flushes and other climacteric symptoms may affect the quality of a woman’s life [8], but is there a correlation between estrogens and depression in women? The menopausal transition does not appear to represent a time of increased vulnerability to affective disorders [9]. Endogenous depressions are multifactorial. The Manitoba Project [10] explores the potential link between menopause and depression. Based on 477 interviews, the following main non-endocrine risk factors for depressive syndromes have been defined: ‘empty nest’, stress every day, health problems and death of a close friend or of family members. Other non-endocrine risk factors are age, the socio-economic situation, sexual abuse during childhood and recent periods of stress. These risk factors occur frequently in the age group between 45 and 55 years, the age of the menopausal transition. On the other hand, it is well known that physiologically unstable endocrine periods in life such as puberty, pregnancy, the postpartal period, the premenstrual phase or the climacteric are endocrine high-risk situations, independent of non-enTable 1 The comparison of 557 cases of unipolar and bipolar II depression in female and in male [1] —conclusions of the study Global: proportion of females to males = 2:1 In females/males there is no difference in Age at diagnosis Relapses Duration of the illness Psychosis Degree of severity Chronicity Age at diagnosis is significantly lower in women with bipolar than in unipolar depressions Atypical symptoms/comorbidity in women more frequent

docrine risk factors [11]. Clinical observations in women with premenstrual dysphoric disorders or with major depression beginning in the postpartal period point toward the importance of sex hormones as neuro-endocrine modulators. Perugi et al. [12] compared the incidence of depressions in 538 females and males. They confirm that, in general, more women suffer from depression than men. But they report differences between the sexes linked to the type of depression (Table 2): e.g. unipolar depressions are more frequent in females than in males, women suffering from depression are more often hospitalized and more women than men suffer from anxiety and from somatization. Therefore, endocrine factors might not only influence the incidence but also the expression of depression. Benazzi et al. [1,2] compared the incidence of depression and/or mania occurring before and after the age of 40 years. The study is based on the observation of 512 unipolar and bipolar I/II depressions. The results show that women older than 40 years suffer more often from unipolar and less from bipolar depressions. These facts point to a different biology of depression in women after menopause compared to premenopausal women and to males. Social factors modulate the female trend to suffer more often from depressions: GutierrezLobos et al. [13] study in 2599 persons the influence of partnership, occupation and profession on depression. Basically, they confirm that, in general, women suffer more often from depression than men. But the picture is more complex if partnership and occupation are taken into account. The sexual-endocrine component is superimposed by social factors:

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Relative incidence of depression Unmarried:married 2:1 Female:male (f:m) 1,7:1 Without occupation:regular work 1,7:1 Widowed with regular work, w:m 1:1,2

Therefore, the question is: is menopause itself linked to depression, or are some predisposing symptoms more frequent in the climacteric? Pearlstein et al. [14] do not observe a correlation between menopause and depression, but their findings suggest that dysphoria and anxiety are correlated to the climacteric. In the presence of a preexisting dysphoria or affective disorder, menopause may provoke a depressive state. Brace and McCauley state in 1997 [15] that underlying endocrinological changes may trigger emotional complaints in women who are vulnerable, and that the current data support a relationship between estrogen and psychological well being. Low estradiol levels contribute to a decreased vigilance at the neurophysiological level, which in turn is correlated with higher depressive and menopausal symptomatology at the behavioral level [36]. Furthermore, EEG data show that depression is correlated to a right frontal and left frontal hypoactivation [36].

3. Effects of treatment with hormones Should estrogens be a first-line treatment in menopausal depression? The reports on the positive effect of estrogens on mood are contradictory. In randomized, controlled trials in postmenopausal women without a diagnosis of depression, estrogen therapy has been reported both to reduce scores on measures of depressive symptoms [16– 18] and to have no effect on mood [19,20]. On the other hand, older postmenopausal women who use estrogens typically report fewer depressive symptoms than nonusers [21]. Several short-term studies indicate that estrogen therapy given during the perimenopausal or menopausal period can diminish anxiety or enhance mood and subjective sense of

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well being [16–18]. Apparent beneficial effects of estrogen on mood may be diminished by the concomitant administration of a progestin [22]. Already in 1990, Hunter [23] had reported that the positive mental effect of estrogens was counterbalanced by progestagens: Estrogens alone have a ‘mental tonic’ effect, whereas in a combined therapy by an estrogen and a progestagen, a comparable mental tonic effect is missing. Pearlstein et al. [14] recommend that, in discrete depressive states, estrogens should be given first, particularly in the presence of vasomotor symptoms, because their effect might be sufficient. Halbreich [30] reports that estrogens improve the cognitive function. Pearce and Hawton [24] write that there is a clear evidence for an improvement of psychological symptoms and an improvement of cognitive functions by HRT following surgical menopause, but that there is no clear evidence for improvement of psychological symptoms and the improvement of cognitive functions by HRT after natural menopause. They conclude that the improvement could be the consequence of a decrease of vasomotor symptoms. These symptoms are likely to be more pronounced after surgical menopause. Harlow et al. [25] compared the incidence of a medical treatment for depression in 344 women with early menopause (prior to the age of 40 years) to 344 controls without menopause. In 344 cases with early menopause, 14% had a medical treatment in the preceding year for depression, whereas in the controls, only 6% had a prior medical treatment. This difference was significant (relative risk= 1.9; 95% confidence interval 1.1–3.3). In a comparative study, six women are treated by 0.625 CEE (ERT-group) and compared to six female controls without treatment [26]. In spite of the small number, the ERT-group shows a significant (PB 0.03) decrease of the depressive state. It is concluded that the use of estrogens for depressive reaction may be helpful. Lack of concentration, fatigue, depressivity and sexual symptoms are improved by estrogens, i.e. by HRT [10]. de Lignie`res and Vincens [27] have studied the effect of estrogens on depressive symptoms in 56 women. They find a correlation between low E2values and depressive symptoms and conclude that estrogen administration has a positive effect

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in presence of low levels of endogenous estradiol. In a recent double-blind study, Schmidt et al. [28] had investigated the effect of estradiol versus placebo in perimenopausal depression. Group (A) (n = 16) received E2 during weeks 1– 3 and E2 during weeks 3–6, whereas group (B) (n =18) has been treated by Placebo during weeks 1– 3 and by E2 during weeks 3 – 6. The results show that the women of group (A) treated by estrogens have, after the first 3 weeks, a significant decrease of their depression. There is an 80% improvement in the E2-group, compared with a 22% improvement in the placebo-group. However, if CEE has been given to women with and without perimenopausal depression, the Beck depression inventory (BDI) shows no improvement in the estrogen-group with depression [28]. A meta-analysis of the effect of hormone replacement therapy upon depressed mood [22] concludes from the global data that estrogen significantly reduces depressed mood (ES =0.69). Progesterone, given alone or in combination with estrogens, is associated with smaller reductions in depressed mood (ES= 0.39 and 0.45, respectively), whereas androgen alone and in combination with estrogen is associated with greater reductions in depressed mood (ES=1.37 and 0.90, respectively). Also others have shown that androgens, given alone or in combination with estrogens, appear to be more potent than estrogens alone [10,22,38,39]. Loss of libido is often linked to subdepressive states. For Pierce and Hawton [24], there is sufficient evidence for improvement in the loss of libido and in the decrease of sexual activity by HRT after natural menopause, an opinion that is not uncontested. However, in the differential diagnosis of sexual problems after menopause, mainly dyspareunia due to vaginal dryness, stress, other diseases and a difficult partner relationship have to be respected.

4. Potentiation of antidepressants by estrogens Estrogens may decrease the susceptibility for depression [30]. They are known to influence noradrenalin and serotonin. A number of antidepressant drugs increase levels of noradrenaline and

serotonin in the central nervous system, supporting the importance of those monoaminergic neurotransmitter systems in regulating mood. Limited data suggest that severe depression in certain clinical populations can occasionally be improved by estrogen therapy. Recent clinical experimental studies of postpartum depression indicate that reproductive hormones can be involved in the development of this disorder [32] and that estrogen can be effective for a major depressive episode with postpartum onset [33,37]. For women with a major depressive disorder, an older randomized, placebocontrolled trial of high-dosage estrogen shows a significant amelioration of affective symptoms [34]. Dell and Stewart recommend in a recent review [29] that treatment with estrogens alone may improve mood in women with minor depressive symptoms, but that those unresponsive to estrogen and woman who have moderate to severe depression need antidepressant therapy. Estrogens may increase the serotonin-activity [30], and, therefore, estrogens may potentiate the effect of certain antidepressants. This hypothesis is confirmed by the work of Schneider et al. [31]. Fluoxetine (20 md/day) has been given to 358 women with perimenopausal depression. Seventytwo women received, in addition, CEE, whereas 286 received no estrogens. The estrogen-group showed an improvement of the HAM-D-Tests by 40.1%, the control group by only 17.0%. Therefore, estrogens may improve the effect of Fluoxetine. Among women with major depression treated with a selective serotonin reuptake inhibitor, however, retrospective analyses do not strongly suggest important additive effects of concomitant estrogen therapy [31,35]. In conclusion, there are suggestive data that estrogen deficiency may increase the susceptibility for depression. There is suggestive evidence, too, from observational studies and a limited number of randomized, controlled trials that estrogen therapy after menopause improves mood and cognition. However, the clinical relevance of estrogen administration in depression is unproved. There are weak data that estrogen might be considered for mild depressive symptoms attributed to hot flushes, sleep disturbances, or other climacteric symptoms. No hard data exist to indicate whether

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estrogen could be used as adjunct therapy for other depressive disorders during the menopausal transition or postmenopausal period, but newer data suggest that estrogens may improve the effect of serotonin reuptake inhibitors.

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