Perimenopause and Affective Disorders
A role of estrogen in the regulation of mood has been postulated since extracts of animal ovarian tissue were administered to oophorecto- mized women at the end of the 1990s to alleviate psychological symptoms thought to be related to the removal of the ovaries (Note- lovitz 1999). Today, however, the exact role of endogenous estrogen and its deficiency in depressive disorders and mood changes still needs to be defined.
In this review, menopause is defined as the last episode of men- strual bleeding generated by endogenous ovarian function. This is a definition which only applies to women with an intact uterus and can only be established retrospectively. Postmenopause is the subse- quent period in a woman’s remaining life span. The term “perimen- opause” is less well defined; this interval includes the time of change of ovarian function associated with estrogen deficiency symptoms such as bleeding irregularities and vasomotor symptoms. By defi- nition, the term perimenopause includes both the immediate end of the reproductive potential at the time before menopause and the very beginning of the time after menopause. This is a somewhat arbitrary definition; however, it serves the purpose of highlighting a period which, for many women, is marked by a health-related impairment of quality of life due to symptoms that are thought to be predominantly related to estrogen deficiency, such as vasomotor complaints.
This chapter focuses on depression, because this disorder, and not mania or anxiety, has been discussed in the context of hormonal changes and therapy. Gynecologists and psychiatrists usually see other types of patients and are confronted with presumably other types and patterns of complaints. Therefore, it seems important to
Estrogen Therapy in
Perimenopausal Affective Disorders
Gabriela Stoppe and Martina Dören
distinguish between mood changes and complaints (e.g., depressive symptoms) and depressive disorders using operationalized criteria, for example, those in DSM-IV or ICD-10 (American Psychiatric Association 1994; World Health Organization 1991). According to these criteria, „major depression” is defined as a reduction of mood, performance, and drive along with hopelessness usually accom- panied by feelings of reduced self-esteem, guilt, suicidal tendency and changes in appetite, weight, libido, psychomotor activity, and sleep, generally lasting at least 2 weeks. To define an episode as “depres- sion”, these symptoms must represent a significant change compared to the patient’s previous state. There is still ongoing debate on whether only major or also minor and other unspecified forms of depression are of clinical relevance, because the physical and socio- economic impacts of the different forms of depression do not vary substantially (Simon et al. 1995). Numerous epidemiological studies revealed an approximately twofold prevalence rate of depression and dysthymia in women – with less difference in childhood and ad- vanced old age and a female:male ratio of 3–4:1 during reproductive years (Weissman et al. 1988; Wells et al. 1989; Parry 1989; Leon et al.
1993). This difference has been attributed to biological reasons (Wilhelm and Parker 1989; Gater et al. 1989; Harris et al. 1991;
Hamilton and Halbreich 1993) as well as more extraindividual parameters such as the social role of women (Aro 1994; Silverstein and Perlick 1991; Jorm 1987; Lalive d’Epinay 1985). However, there were also discussions regarding the relevance of comorbidity (Breslau et al. 1995) and epidemiological methods (e.g., the symptom thres- hold, definition of case, selection of instruments), factors which may contribute toward higher rates of depression in women than in men (Wilhelm and Parker 1989; Young et al. 1990; Stommel et al. 1993;
Angst and Dobler-Mikola 1984). Finally, there are reports about
gender-type patient behavior, with women reporting more and re-
membering better any depressive symptoms (Angst and Dobler-
Mikola 1984; Wilhelm and Parker 1994). It has been shown that
female patients complain more often about depressed mood, seek
their physicians’ help more frequently, and are more likely to receive
adequate treatment than men (Williams et al. 1995). According to our
own investigations, identical complaining would lead to a signifi-
cantly higher recognition rate in women, which might be the result
of probabilistic behavior and/or of role stereotypes on the part of the
physicians (Stoppe et al. 1999).
Community-based studies providing data on self-reported depres- sive symptoms suggest that most peri- and postmenopausal women do not experience symptoms of major depression (Kaufert et al. 1992;
Avis et al. 1994; Matthews et al. 1994; Matthews 1992), but rather symptoms of mild depression (Avis et al. 1994; Hunter 1990; Hay et al. 1994). However, many studies conducted to date simply asked about mental and emotional states without sufficiently investing in the selection or development of appropriate questionnaires. Further- more, by announcing to undertake “menopause research,” many studies introduced a bias toward attribution of symptoms to this female life event. There appear to be substantial differences regarding a variety of symptoms reported by perimenopausal women from various cultures including symptoms of depression. European and North American women seem to report similar frequencies of menopausal symptoms, the prevalence of which appears to be lower in Asian countries (Makhlouf Obermeyer 2000). Social factors commonly related to mental health also vary between these areas:
In Europe and the USA, menopausal symptoms are more frequent in lower socioeconomic groups, whereas the opposite is true in Asia (Dennerstein 1996; Neri et al. 1997; Polit and LaRocco 1982; Kuh et al. 1997).
Regarding the range of symptoms, irritability, suggested to con- stitute a female-specific mood disorder by some authors (Born and Steiner 1999), seems to be more common in women with hormonal changes including the perimenopause and was, for example, reported as often as hot flushes in a representative cross-sectional nationwide survey of 1,038 German women aged 50–70 years (Schultz-Zehden 1998). Some authors found that the extent of previous premenstrual symptoms – such as irritability, anxiety and panic, fatigue, sleep disturbances, depression and cognitive dysfunction – is related to the occurrence of similar symptoms during perimenopause (including postpartum blues and depression as well as oral contraceptive dysphoria), implying a common physiological denominator (Abra- ham et al. 1994; Stewart and Boydell 1993; Arpels 1996; Holte and Mikkelsen 1982; Hunter 1990; Avis and McKinlay 1991; Greene and Visser 1992; Dennerstein 1996).
The menopause itself has not been identified as a major cause of depressive symptoms (Nicol-Smith 1996); signs of mild depression/
mood changes were observed in perimenopausal women in some
prospective population-based studies (Bungay et al. 1980; Ballinger
1975; Hunter 1992) including women with surgical menopause (McKinlay et al. 1987), but did not increase in other longitudinal investigations that included women with surgical menopause, too (Neugarten and Kraines 1965; Hallström et al. 1985; Busch et al.
1994). According to recent, large, population-based longitudinal stud- ies, more than 50% of the variance for the development of depression in the menopausal transition is explained by previous depression as well as cognitive and social factors such as poor social support and/or poor marital relationship (Hunter 1990; Avis et al. 1994; Greene and Visser 1992; Kaufert et al. 1992; Pearlstein et al. 1997).
Cross-sectional studies failed to show a higher prevalence of depression in the perimenopausal period. If serum hormone levels were obtained concomitantly, there was no direct correlation to the severity of depression (Coope 1981; Ballinger et al. 1987; Hunter 1990; Wilbur et al. 1995; Holte 1992). Only four studies, largely with considerable methodological problems, reported associations be- tween well-being (not further specified) or depression and serum levels of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S) (Morales et al. 1994; Cawood and Bancroft 1996;
Barrett-Connor et al. 1999), or follicle-stimulating hormone FSH (Huerta et al. 1995).
However, among women attending (gynecology) outpatient cli- nics, the prevalence of depression including major depression may be considerably higher (Anderson et al. 1987; Montgomery et al. 1987;
Stewart et al. 1992; Dennerstein et al. 1993; Hay et al. 1994). Women with previous use of gynecological services and resources, e.g., hys- terectomy and/or ovariectomy and use of contraceptives, are much more prevalent in a (gynecological outpatient) clinic. It is the same group of women, however, who complain significantly more often about menopausal symptoms including depression and also show a much higher rate of hormone (replacement) therapy (Topo et al. 1995;
Schultz-Zehden 1998; Barrett-Connor et al. 1999; Li et al. 2000). It is noteworthy that perimenopausal women utilizing health care ser- vices differ from women who do not. The former may embrace medical treatments including hormone therapy (HT) in the hope of solving an existing, not necessarily medical, problem (Morse et al.
1994). This could be one reason that clinicians may develop opinions
regarding the symptomatology of the menopause which might not
be applicable to more representative population samples including
women not seeking medical attention.
The end of the reproductive life span does not cause problems in a majority of women, which contradicts an often-expressed opinion that menopausal women suffer due to the loss of their social role.
About 75% of women in the postmenopause feel well (again), some- times even happier and healthier than in previous life spans with a trend to an increasingly “positive” and accepting attitude toward the menopause (von Sydow and Reimer 1995; Wilbur et al. 1995; Denner- stein et al. 1994; Kaufert et al. 1998; Schultz-Zehden 1998). This opinion is consistent with a Dutch investigation that did not demonstrate any gender difference for a variety of psychological and emotional complaints in women and men in their midlife (van Hall et al. 1994).
A German study on a representative sample of men older than 40 years revealed mild to moderate somato-vegetative symptoms in about 50% (Heinemann et al. 1999).
Whether depression can trigger an early onset of menopause or whether the specific pharmacological treatment is responsible for the premature termination of cyclic ovarian function was only recently identified as an area for future research (Harlow and Signorello 2000). An earlier onset of menopause was found in women at risk for dementia in later life (van Duijn 1997).
Impact of Hormone (Replacement) Therapy on (Signs and Symptoms of) Depression
When using the term “hormone replacement therapy”, one should consider that “replacement” implies the correction of “ovarian fail- ure” and a deficiency state. Since all women experience sinking hormonal levels during the menopausal transition, this could lead to the assumption that all women are somewhat “defective” (i.e., ill) after the end of the reproductive cycle. The term “hormone treat- ment” could be more neutral and therefore better for this discussion (Stoppe et al. 2000).
Today, it is still difficult to describe precisely the specific effects
of various compounds in common clinical use. The findings of many
early studies are difficult to interpret because of their methodological
shortcomings regarding design and patient selection. Several, but
not all, prospective, randomized, double-blind, placebo-controlled,
short-term clinical trials suggest a role for various natural oral and parenteral estrogens in enhancing depressive mood (Dören 1999).
Only a few of the published studies fulfill basic methodological quality requirements (see above; von Sydow and Reimer 1995;
Greendale et al. 1999). A review of 111 studies revealed no consistent effect of HT on depression in patients with natural menopause and some effects in women with surgical menopause (Pearce et al. 1995).
The Cochrane Library – based on a meta-analysis of Zweifel and O’Brien (1997; 2000) of no more than 26 studies with sample sizes of 10–110 which used at least one method to quantify depression – concluded that overall, there seems to be a moderate effect of estrogens (mostly conjugated equine estrogens 0.625 mg or 1.25 mg).
However, the authors rated the quality of data as too poor to allow for general recommendations. Only 18 studies were randomized, a third of all studies included no control group. Three studies included women without any menopausal symptoms, seven other studies did not comment on this topic. Most patients were recruited from special menopause clinics with the above-mentioned high proportion of women with surgical menopause. In addition, most women included in the studies were not depressed or only mildly depressed!
There seems to be no proven efficacy of estrogens in moderate and severe depression. However, estrogens appear to exert positive effects on well-being, which has been described as a “tonic” effect by Utian (1972). Recent studies found an increase of vigilance measured with electroencephalography (Saletu et al. 1995). A corresponding survey finding could be that women who depend on their cognitive skills show a more positive attitude to HT (Collins and Landgren 1997; for review, Stoppe et al. 2000).
This view is now supported by the results of the Women’s Health Initiative (WHI) study, which assigned 16.608 postmenopausal women (50–79 years) with an intact uterus to HT (0.625 mg con- jugated equine estrogen plus 2.5 mg medroxyprogesterone acetate).
There were no significant effects on general health, vitality, mental
health, depressive symptoms, or sexual satisfaction. After one, but
not after three years HT resulted in statistically significant however
small and clinically not meaningful benefit in terms of sleep distur-
bances and physical functioning (Hays et al. 2003). The authors
discussed that women with a “positive” view on HT might have been
reluctant to accept randomization, pointing again to the selection
problem discussed above.
The efficacy of estrogens seems to be demonstrated in surgically menopausal women. These women can be treated with unopposed estrogens, without coadministration of a progestogen, which may be a reason for this finding. In the WHI study the estrogen-only treatment is still ongoing. Results are expected by the year 2005.
However, some authors stress the importance of the acuteness of hormonal changes for the occurrence of symptoms and therapy (Rubinow and Schmidt 1995). In addition, the relative depletion of androgens in ovarectomized women should be discussed (Khastgir and Studd 1998). According to representative studies, the percentage of surgical menopausal women varies between 3% (Japan), 14%
(Great Britain), 19.7% (Sweden), 26% (Germany) and 34% (USA), and about every fifth hysterectomized woman is also ovarectomized (Stoppe et al. 2000; Khastgir and Studd 1998).
Progestins appear to reduce the effects on the central nervous system when combined with estrogens (Archer 1999; Zweifel and O’Brien 1997). Data are insufficient to distinguish between the two major types of progestins: compounds derived from hydroxyproge- sterone and nortestosterone. Androgens may be at least of similar effectiveness as estrogens. Most data are available for longer-acting parenteral testosterone preparations such as implants and injec- tables. However, due to a paucity of studies that directly compare various treatment modalities – estrogen versus estrogen plus pro- gestin, estrogen versus estrogen plus androgen – great caution is warranted in qualifying any form of hormone therapy according to its ability to influence depressed mood. In addition, the schedule/
timing of use – continuous versus sequential – and the dosage should be considered (Halbreich 1997). A completely unresolved question is the issue of any potential, optimal combination of (the type of) antidepressants and hormones, because there are at least some studies suggesting a role for estrogens as adjunct in the treatment of depression. However, this is a controversial debate (Sherwin 1991;
Schneider et al. 1997; Stahl 1998; Snow et al. 2000).
New data add to the complexity of this topic showing that the selective serotonin reupteka inhibitor and anti-depressant paroxe- tine is effective in the treatment of vasomotor symptoms (Stearns et al. 2003).
DHEA, thought to be a neurosteroid because it is possibly synthe-
sized in the central nervous system of humans (Lacroix et al. 1987),
has been suggested for treatment of major depression on the basis of
a few small-scale preliminary studies (for review, see Wolf et al.
1999). Recent studies looking at the sense of well-being including mood in pre- and postmenopausal women yielded different findings.
Placebo-controlled trials suggested a small positive effect (Morales et al. 1994) or no effect at all (Wolf et al. 1997; Barnhart et al. 1999).
Whether DHEA may act synergistically with HT (Stomati et al. 1999) has not been adequately studied.
Pathophysiological Mechanisms
Unfortunately, the above mentioned meta-analysis does not appear to address the so-called domino effect, which denotes the observation that the alleviation of vasomotor symptoms and sleep disturbances may lead to an improvement of depressed mood (Campbell and Whitehead 1977). The majority of studies included for the meta- analysis investigated women with vasomotor symptoms; thus, it is quite possible that the alleviation of these most common symptoms of the menopause contributed to the observed impact on symptoms of depressed mood. The selection of studies using validated instru- ments to assess depressive symptoms does not exclude this possi- bility.
According to representative surveys, the number of women re- porting sleep complaints increases during the menopausal transition (Porter et al. 1996; Kuh et al. 1997; Ledésert et al. 1995; Hunter 1990).
Many authors underlined the importance of a body mass index
between 20 and 30 for better sleep (Adam 1987; Owens and Matthews
1998; Polo-Kantola et al. 1999). As a consistent finding, women tak-
ing HT reported favorable effects on sleep quality (Asplund and Aberg
1995; Wiklund et al. 1992; Polo-Kantola et al. 1998). Estrogens are
involved in the regulation of sleep, particular rapid eye movement
(REM) sleep (Thomson and Oswald 1977; Schiff et al. 1979; Purdie et
al. 1995). Progesterone affects primarily non-REM sleep. It may have
a sedative effect at high doses and may change sleep architecture,
similar to benzodiazepines, including shortening the sleep onset and
reducing wakefulness after sleep onset (Halbreich 1997). While most
studies have limited value for methodological reasons (only self
report, small number etc.), one recent study (n = 62) tested trans-
dermal HT versus placebo in a crossover design. While subjective
sleep quality increased, the number of nocturnal arousals decreased
(Polo-Kantola et al. 1999). Another recent study suggests that trans-
dermal estradiol restores the normal sleep electroencephalogram pattern (Antonijevic et al. 2000). Thus, improvements of sleep quality may positively influence mood and substantially contribute to the
“tonic” effect by enhancement of daytime vigilance and everyday performance (see above).
As reported in other chapters in this book, estrogens are thought to modulate neurotransmitter activities in several ways, e.g., in- cluding the synthesis of serotonin, serotonin uptake, serotonin re- ceptor transcription and receptor density, and the response to sero- tonin stimulation (Gallo et al. 1999; Archer 1999). Regarding menopause, earlier animal studies showed that the receptor dysfun- ction increases with the duration of hormone deficiency (Clark et al.
1981). However, the question of whether, and after which time span, these dysfunctions are reversible by exogenous hormones is still un- resolved, both in animals and in humans, and may be significant in menopausal research (Klaiber et al. 1997; Barrett-Connor et al. 1999).
Conclusion
The occurrence of depressive symptoms in the perimenopause is associated with a variety of factors. A previous history of either depression and/or premenstrual syndrome as well as cognitive factors (e.g., attitude to menopause) explain most of the variance.
There are no consistent findings of a correlation between any serum hormone level and severity or presence of mood symptoms. Neuro- biological studies show promising effects of estradiol – with regard to an antidepressant effect – on serotonergic, noradrenergic, cholin- ergic, dopaminergic, and GABAergic functions. Progestogens seem to oppose some of these effects. The role of androgenic hormones and DHEA(-S) is less clear. Clinical trials showed, in general, a modest effect on symptoms of depression. However, the predominantly poor methodological quality does not allow generalization and recom- mendations. A “tonic” effect on well-being in non- or mildly depres- sed women should not be regarded as a true antidepressant effect.
Results from studies of surgically menopausal women may not be
applicable to women with natural menopause. There is a great poten-
tial for exploring various types, doses, and routes of administration
of both antidepressants and sex hormones. With regard to the domino
theory, future studies should also focus on the mediation of treat- ment effects through alleviation of vasomotor symptoms or sleep disturbances. These conclusions are supported by the large Women’s Health Initiative (WHI) study, which revealed no benefit of combined estrogen-progestin treatment in terms of mental health and depres- sive symptoms, and only small positive effects on sleep disturbances.
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