Introduction
There is increasing evidence from both clinical and epidemiological as well as basic research that estrogens exert protective effects in schizophrenia. A brief overview of these protective effects will be provided in this chapter and potential therapeutic implications will be discussed. If these effects are confirmed, it could have important consequences for prophylaxis and therapy. For instance, considera- tion would need to be given to estrogen replacement therapy in peri- and postmenopausal women with schizophrenia, adjunct estrogen therapy in women with estrogen deficiency syndromes, cycle-modu- lated neuroleptic therapy in women with frequent perimenstrual relapses, and/or emphasis on prolactin-sparing atypical neuroleptics in women with hypoestrogenism. Further research is urgently needed since direct therapeutic benefits for women might result.
Estrogens and Schizophrenia: Historical Evidence The interest for the association between female sex hormones and mental diseases is not new. Particularly concerning psychosis, al- ready at the beginning of the twentieth century psychiatrists con- sidered a possible association of schizophrenia with estrogens:
Early clinicians, such as Kraepelin (1909) or Kretschmer (1921), reported that many schizophrenic women show physical signs and other anatomical abnormalities indicating “insufficient functioning of the sexual glands” with “hypoestrogenism”. In the 1930s, studies analyzing estrogen levels in the blood and urine confirmed these observations. Researchers found decreased blood levels of estrogens in most of the schizophrenic inpatients they examined (for reviews see Diczfalusy and Lauritzen 1961; Riecher-Rössler and Häfner
Estrogens and Schizophrenia
Anita Riecher-Rössler
1993). As at this time neuroleptic therapy had not been introduced, the observed abnormalities cannot be interpreted as side effects of drug treatment.
In later decades, studies showed that the gonadotrophins follicle- stimulating hormone (FSH) and luteinizing hormone (LH) are low in women with schizophrenia as compared to controls. Many authors also reported irregular cycles in these women (for review see Riecher-Rössler and Häfner 1993). All these disturbances can pos- sibly be attributed to a gonadal dysfunction with insufficient estrogen production from the ovaries.
Furthermore, there have always been observations indicating a possible influence of estrogens on psychotic symptomatology.
Krafft-Ebing (1896) was among the first to describe how some wo- men became psychotic mainly before or during menstruation, i.e., when estrogen blood levels are relatively low. Kraepelin (1909) even created a separate diagnostic category, “menstrual psychosis”.
Kretschmer (1921) reported on patients in whom the outbreak of schizophrenia was in temporal relation with “surgery of ovaries, pregnancy, delivery and puerperium.” Finally, Manfred Bleuler (1943) noted that late-onset schizophrenia with onset after age 40 years was much more frequent in women than in men, which he associated with the “loss of ovarian function” starting at around the same age.
Further evidence comes from early intervention studies. As early as in the 1940s, Manfred Bleuer (1943) reported the first unsystem- atic trials using a combination of ovarian and pituitary hormones.
Mall (1959, 1960), a German psychiatrist in charge of a large hospital, examined 167 women suffering from schizophrenia with respect to estrogen excretion in a 24-h urine sample, basal temperature, and vaginal cytology. Based on his findings, he divided the psychoses into two groups: hypofollicular and hyperfollicular. In the former group, he replaced estrogens and found that “hypofollicular psycho- sis can be healed relatively easily by this substitution therapy”. Un- fortunately, Mall does not give many details about these interesting studies.
Two hypotheses can be derived from these early observations (Riecher-Rössler and Häfner 1993):
(1) The hypothesis of hypoestrogenism
Some schizophrenic women suffer from chronic gonadal hypo- function and hypoestrogenism.
(2) The estrogen protection hypothesis
Estrogens have a protective effect in schizophrenia.
Recently, research has shown a renewed interest in this topic. In fact, there is a growing body of evidence in the meantime for both hypotheses. However, there is still need for more research. Especial- ly as regards the causal explanation of the first finding – the gonadal hypofunction and hypoestrogenism in schizophrenic wo- men –, data are still very limited.
The Estrogen Protection Hypothesis Research in the Past Few Decades
Research in the last decades has confirmed many of the histori- cal findings concerning a protective effect of estrogens in schizo- phrenia. Clinically, psychotic symptomatology has been shown to be exacerbated pre- or perimenstrually, i.e., in the low estrogen phase of the cycle (Endo et al. 1978; Glick and Stewart 1980; Gerada and Re- veley 1988; Riecher-Rössler et al. 1994a, b). During pregnancy, when estradiol levels are about 200-fold higher than normal, chronic psy- choses seem to improve (Chang and Renshaw 1986), but there is a 20-fold excess of psychosis after delivery (Kendell et al. 1987), when estrogen levels suddenly drop to normal. Psychoses associated with other forms of estrogen withdrawal have also been described (Mahé and Dumaine 2001). Furthermore, Seeman (1983) noted that schizo- phrenic women in the fertile age group of 20–40 years, i.e., the time of the highest ovarian estradiol production, require lower doses of neuroleptics than older women or men of the same age group – even when controlled for body weight. The same group has recently shown that early puberty is associated with a late onset of schizo- phrenia (Cohen et al. 1999). That means physiological estrogens might delay the outbreak of the disease.
In the early 1980s, it was also observed that the effect of estrogens in laboratory animals is in some respects similar to that of neuro- leptics. Estrogens can, for example, enhance neuroleptic-induced catalepsy and reduce amphetamine- and apomorphine-induced be- havioral changes such as stereotypies (Gordon et al. 1980; Hruska and Silbergeld 1980; Di Paolo et al. 1981; Nicoletti et al. 1983). It has also been shown that estrogens can modulate the sensitivity and
number of dopamine receptors (Koller et al. 1980; Gordon and Dia- mond 1981; Bédard et al. 1984). The identification of estrogen recep- tors in the limbic system further supported the assumption that estrogens not only play a role in the modulation of endocrine func- tions, but also have a “neuromodulating function” (for review see Riecher-Rössler and Häfner 1993).
Today we know that estrogens produce many other effects. They do not only improve cerebral blood flow and glucose metabolism (Rasgon et al. 2001), but also promote neuronal sprouting and are re- garded as neuroprotective. Their modes of action are not only clas- sical genomic ones, but also involve nongenomic, rapid interactions, which explains the different latency of effects. They modulate mo- noaminergic neurotransmission and appear to have specific and sig- nificant effects not only on dopamine, but also on serotonin and GABA (Stahl 2001a, b; De Battista et al. 1999; Garcia-Segura et al.
2001; Kuhl 2001) to such a degree that they have even been called
“nature’s psychoprotectant” (Fink et al. 1996).
Own Studies
In an epidemiological study on a representative sample of 392 first- time admitted patients with schizophrenia, the ABC Study, we found that schizophrenic women have a later peak of illness onset in comparison with schizophrenic men (Riecher et al. 1990; Häfner et al. 1991a, b; Häfner see this volume). They also exhibit an addition- al, smaller peak after age 45. We postulated that estrogens raise the vulnerability threshold for the outbreak of the disease. According to this hypothesis, women would be protected against schizophrenia between puberty and menopause to some extent by their relatively high gonadal estrogen production during this time. Then, around age 45, several years before menopause sets in at a mean age of 51.4 years, estrogen production begins to fall (Labhart 1978). Thus, wo- men would lose the protection estrogens give, which could account for their second peak of illness onset after age 45.
Based on these findings and on the aforementioned results from basic research which pointed to antidopaminergic properties of es- trogens, Häfner together with Gattaz examined the neurohormonal effects of estradiol, the main component of estrogens, by means of animal experiments. They found evidence that chronic estradiol
treatment reduces the sensitivity of dopamine-D2 receptors (Häfner et al. 1991c; Gattaz et al. 1992).
We also tried to examine the influence of estrogens on schizo- phrenic symptomatology in a clinical study (Riecher-Rössler et al.
1994a, b). We chose the female menstrual cycle as a “natural expe- riment” and tested the hypothesis that schizophrenic symptomato- logy varies with estradiol blood levels throughout the menstrual cycle. We examined 32 acutely admitted female schizophrenics, who gave a history of regular menstrual cycles. We saw a significant ex- cess of admissions during the perimenstrual low-estrogen phase of the cycle (p < .005). During the hospital stay of the 32 women, a sig- nificant association emerged between estradiol levels, on the one hand, and psychopathology scores, on the other: Psychopathology seemed to improve when estradiol levels rose and vice versa. This was not only true for the total score of the Brief Psychiatric Rating Scale (BPRS, Overall and Gorham 1962) and for almost all the sub- scores of this scale, including anergia, thought disturbance, activa- tion, and hostile suspiciousness, but also for general behavior on the ward as rated by the nurses (NOSIE, Honigfeld et al. 1976) and for ge- neral well-being and paranoid feelings as rated by the patients them- selves (BfS and paranoid subscore of PDS, both by von Zerssen and Koeller 1976). The only exceptions were the anxiety/depression sco- re of the BPRS and self-rated depression (depression score of PDS), which did not show this association. We interpreted this finding as further evidence for a protective effect of estradiol in schizophrenia.
Our findings, however, rose various questions, especially con- cerning their specificity for schizophrenia: Is the observed estradiol- dependent fluctuation of the symptoms specific for schizophrenia or can it also be found in other mental diseases?
We therefore tested the specificity of our results for schizophre- nia by examining a control group of 29 acutely admitted females with psychiatric disorders other than schizophrenia and comparing them to the 32 schizophrenic women described above (Riecher-Röss- ler et al. 1998).
In the control group, consisting mainly of women with depressive disorders, symptoms were not correlated with estradiol blood levels (Table 1). Based on the observations made on depressive symptoms in the schizophrenic women, these results were hardly surprising.
The only exception in the control group was general behavior on the ward as assessed by the nursing staff. It was obviously positively
Table 1.Correlations between psychopathology scores and estradiol serum levels throughout hospital stay of schizophrenic and nonschizophrenic womena Schizophrenics (n= 32)Non-schizophrenics (n= 29) Parametersnbmean(SD)pnbmean(SD)p BPRS-total score31–0.25(0.41)<0.01290.03(0.55)n.s. BPRS subscores Anxiety/depression31–0.10(0.52)n.s.290.00(0.52)n.s. Anergia31–0.15(0.42)<0.1028–0.04(0.53)n.s. Thought disturbance31–0.28(0.44)<0.0115–0.13(0.55)n.s. Activation31–0.27(0.41)<0.0129–0.06(0.49)n.s. Hostile–suspiciousness31–0.19(0.47)<0.1022–0.13(0.45)n.s. NOSIE-total scorec320.25(0.49)<0.01290.22(0.43)<0.01 BfS-total score32–0.20(0.43)<0.0529–0.02(0.56)n.s. PDS-paranoid subscore32–0.17(0.42)<0.05270.06(0.51)n.s. PDS-depression subscore32–0.10(0.52)n.s.290.01(0.56)n.s. HAMD-total score– not evaluated –290.03(0.53)n.s. aShown as means of individual correlation coefficient, i.e., cross-correlations (Jenkins and Watts 1968). bThe slightly varying numbers are partly due to missing data, partly due to exclusions: patients who never showed symptoms of a certain score or never showed variability in a certain score were excluded from analysis concerning the respective score (14 con- trols concerning “thought disturbance”, 6 controls concerning “hostile-suspiciousness” and 2 controls concerning “PDS-paranoid subscore”). cContrary to the other scores, in the total NOSIE score a highervalue means lesspsychopathology. Source: Riecher-Rössler A, Häfner H, Dütsch-Strobel A, Stumbaum M (1998) Gonadal function and its influence on psychopathol- ogy – A comparison of schizophrenic and non-schizophrenic female inpatients. Arch Women Ment Health 1: 15-26
associated with estradiol levels in the control group as well. If only the control patients with major depressive disorders were taken into account, the results remained essentially unchanged.
Thus, the clinical effect of estrogens seems to resemble that of neuroleptics: They appear to ameliorate psychotic symptoms and general behavior, but not depressive symptoms as much (Riecher- Rössler et al. 1998).
We have also looked in more detail into our epidemiological ABC sample – with a special focus on late onset cases and the second peak of onsets after age 45 in women. This second peak reflects what has been described by many psychiatrists for a long time, namely, the fact that the incidence of late onset schizophrenia is about twice as high in women as in men (Bleuler 1943).
We could almost exactly confirm this finding. First admission for schizophrenia after age 40 occurs in only 10% of all schizophrenic men, but in about 21% of all schizophrenic women. Incidence in wo- men over 40 is 8.9 per 100,000, whereas it is only 4.2 per 100,000 in men (Riecher-Rössler et al. 1997).
Furthermore, we had a very interesting new finding as regards the symptoms and disease course of these late-onset women. As for symptoms, we saw hardly any differences between late- and early- onset patients when we compared these age groups without separa- tion of the two sexes. Late-onset patients just showed slightly fewer nonspecific symptoms than early-onset patients. However, if we looked at the two genders separately, it was only the late onset men who had distinctly milder symptoms – not the late-onset women!
Late-onset women obviously suffer from distinctly more severe sym- ptoms than late-onset men – their symptoms are as severe as those of early onset women and men (Riecher-Rössler et al. 1997).
The results concerning the course of the disease (based on Danish case register data) were very similar: Late-onset and also very late onset patients generally had a distinctly better institutional course than early-onset patients. For example, they spent significantly fewer days in the hospital than early-onset patients. Again, this was mainly due to the over 40-year-old men, who spent the shortest time in hospital, whereas women over 40 spent almost as much time in the hospital as the early-onset women (Riecher-Rössler et al. 1997).
Thus, we have found that the over-40-year-old men have dis- tinctly milder symptoms and a better institutional course than early-onset patients, whereas the over 40-year-old women not only
Table 2. Psychopathology scores with significant differences between early- and late-onset schizophrenia cases (ICD-9: 295) by gender (ABC Study). MenaWomenbTotalc M(SD)p(t)M(SD)p(t)M(SD)p(t) TOT <40 years42.5(16.4)**41.9(16.1)n.s.42.2(16.2)° ≥40 years24.6(14.8)39.5(14.5)35.9(15.7) NSN <40 years16.1(7.3)**15.1(6.1)n.s.15.6(6.8)** ≥40 years8.3(5.4)12.9(6.1)11.8(6.2) DAH <40 years10.6(7.3)**11.4(7.7)n.s.11.0(7.5)n.s. ≥40 years5.3(3.3)11.7(7.8)10.1(7.5) Psychotic symptoms <40 years10.7(5.5)°11.3(4.8)n.s.11.0(5.2)n.s. ≥40 years7.1(3.9)11.1(4.8)10.2(4.8) First-rank symptoms <40 years2.2(2.0)°2.3(1.9)n.s.2.2(2.0)n.s. ≥40 years0.7(1.3)2.0(1.8)1.7(1.8) n.s. not significant; °p< 0.1; ** p< 0.01TOTtotal score of PSE (Wing et al. 1973; 1974) an< 40 years: 106; n≥40 years: 7NSNnon-specific neurotic syndromes, subscore of PSE bn< 40 years: 99; n≥40 years: 22DAHdelusions and hallucinations, subscore of PSE cn< 40 years: 205; n≥40 years: 29 Source: Riecher-Rössler A, Löffler W, Munk-Jorgensen P (1997) What do we really know about late-onset schizophrenia? Eur Arch Psychiatry Clin Neurosci 247: 195-208
fall ill twice as often as elderly men, they obviously also suffer from a disease almost as severe as young patients.
One explanation for this could again be the estrogen effect: if ill- ness onset of women with a relatively high underlying vulnerability is delayed by estrogens, this high vulnerability is “unmasked” by the loss of this protective factor around menopause. These women then not only fall ill more frequently, but the disease is more severe as regards symptoms and course.
The Hypoestrogenism Hypothesis
We and several other authors in the meantime also found a disturbed gonadal function and/or hypoestrogenism in schizophrenic women (Riecher-Rössler et al. 1994a, 1998; Kulkarni et al. 1996; Bergemann et al. 1996; 2002, see also this volume; Choi et al. 2001; Hoff et al.
2001; Huber 2001; Huber et al. 2001; Canuso et al. 2002; Smith et al.
2002; Zhang and Seeman 2002; for review see Riecher-Rössler 2003).
Findings are menstrual irregularities and pathologically low estra- diol and progesterone blood levels throughout the menstrual cycle as well as anovulation in the majority of women with schizophrenia.
Reduced fertility rates have also been described in the past and recently confirmed (Hutchinson et al. 1999).
In our own study on 32 acutely admitted schizophrenic women (see above), we had interesting results regarding this hypothesis. To start with, many schizophrenic women failed to qualify for our study because of considerable menstrual irregularities. However, even the 32 women who gave a history of regular menstrual cycles and were therefore included in our study showed many hints of a severely disturbed gonadal function (Riecher-Rössler et al. 1998). As compared to the 29 controls, they not only had greater variation in their cycle length observed on ward, but they also had significantly lower estradiol and progesterone blood levels throughout their men- strual cycle.
Of these women, 56% presumably suffered from anovulation, which is a much higher proportion than in the control patients with depressive disorders, where anovulation had to be suspected in only 19% of those assessed (Riecher-Rössler et al. 1998).
Furthermore, these abnormalities were obviously not (solely) due to neuroleptics. Thus, we could not, for example, find any associa-
Table 3.Menstrual and hormonal status of the schizophrenic group and the control group with depression Schizophrenic patientsControlsp(t) (n= 32a/n= 27b)(n= 29) MeanRangeMeanRange Length of menstrual cycle (days) Before admission(n= 32)a27.1(23.0-31.5)27.6(16.5-35.0)n.s. (As stated by patient)(n= 27)b27.1(23.0-31.5)n.s. During hospital stay(n= 32)a28.4(11.0-66.0)28.4(20.0-41.0)n.s. (As observed)(n= 27)b29.2(11.0-66.0)n.s. Hormonal status Mean values throughout observation: Estradiol(n= 32)a158.6(40.0-824.0)282.3(15-1258)<0.001 [pmol/l](n= 27)b172.5(45.0-824.0)<0.001 Progesterone(n= 32)a3.1(0.1-37.2)6.5(0.1-63.3)<0.01 [nmol/l)(n= 27)b3.5(0.1-37.2)<0.05 On admission: Prolactin(n= 32)a43.1(4.8-99.9)9.9(1.9-40.8)<0.001 [ng/ml](n= 27)b42.0(4.8-99.9)<0.001 Testosterone(n= 32)a1.8(0.8-4.8)1.6(0.6-3.1)n.s. [nmol/l](n= 27)b2.0(0.8-4.8)<0.1 Estradiol(n= 32)a176.5(45.0-502.0)271.7(63-1165)<0.1 [pmol/l](n= 27)b196.7(45.0-502.0)n.s. Progesterone(n= 32)a4.3(0.1-37.2)2.8(0.1-26.2)n.s. [nmol/l](n= 27)b4.9(0.1-37.2)n.s. aAll schizophrenic women investigated (n= 32) bOnly the schizophrenic women which had not taken oral contraceptives in the months preceeding admission (n= 27) Source: Riecher-Rössler A, Häfner H, Dütsch-Strobel A, Stumbaum M (1998) Gonadal function and its influence on psychopathol- ogy – A comparison of schizophrenic and non-schizophrenic female inpatients. Arch Women Ment Health 1: 15–26
tion between neuroleptic dosage (in chlorpromazine equivalents) and estradiol serum levels or ovulation (Riecher-Rössler et al. 1998).
For theoretical reasons and also historically, the most interesting question was whether gonadal dysfunction with estrogen deficiency was just a state or rather a trait marker. We could not answer this from our clinical study sample as these women had been selected:
Only women with a history of regular menstrual cycles had been in- cluded.
Regarding this question we, therefore, investigated the women aged 18–45 of our representative ABC sample of first-time admitted schizophrenia patients. Forty-four women took part and were com- pared to 33 age-matched healthy women regarding potential indica- tors of preexisting chronic gonadal dysfunction with estrogen defi- ciency such as age at menarche, irregular cycles, midcycle bleeding, infertility, abortions, signs of relative hypoestrogenism or hyper- androgenism (Schepp 1997). The results were most interesting: Wo- men with schizophrenia could be distinguished from the controls by several factors: Their menarche had been later and they had suffered more often from loss of hair, midcycle bleeding, mild bleeding, and hirsutism. There was also a tendency to more infertility in the patients.
Discussion
Although closely connected, the two hypotheses shall be discussed separately. Firstly concerning the hypoestrogenism hypothesis we must discuss the causes for the menstrual irregularities and hormon- al disturbances actually observed. Several explanations are feasible:
The disturbances could – at least partly – be a secondary pheno- menon due to general mental “stress,” which patients experience during an acute psychiatric episode. It is well known that stress can induce hyperprolactinemia, and hyperprolactinemia can suppress gonadal function (Scriba and von Werder 1976; Maguire 2002).
However, if this was the main cause of the disturbances, they should be seen not only in schizophrenia but in other acute psychiatric conditions as well. Thus, the fact that the irregularities were mainly seen in schizophrenic women and only very rarely in the control group both in our study and in other studies (e.g., Huber 2001; Huber et al. 2001) speaks more against this explanation – at least against it being the main cause.
Another explanation to be considered is the influence of neuro- leptics.Although this explanation is often given, a critical review of the literature showed that it is not at all clear whether the distur- bances observed are solely a side effect of neuroleptic treatment (Riecher-Rössler et al. 1998; Riecher-Rössler 2003). Thus, there are several studies showing no association between dosage of typical neuroleptics on the one hand and either estradiol serum levels or irregularity of menstrual cycle on the other hand (Carter et al. 1982;
Riecher-Rössler et al. 1998; Canuso et al. 2002). Furthermore, hypo- oestrogenism and menstrual irregularities were also present in wo- men on atypical prolactin-sparing neuroleptics (Bergemann et al.
2002; Zhang and Seeman 2002).
Finally, gonadal hypofunction and “hypoestrogenism” in schizo- phrenic women had already been observed and reported a long time before the introduction of neuroleptics (Kretschmer 1921; Ripley and Papanicolaou 1942; Bleuler 1943). Thus, even if we suspect that neu- roleptics are partly responsible for the hypoestrogenism observed, we must be careful not to overlook (additional) endocrine disturban- ces associated with the disease itself.
Therefore, we have finally to consider the possibility that the menstrual and/or hormonal abnormalities observed in our schizo- phrenic patients are – at least partly – directly associated with the disease itself. In principle, such an association is conceivable in two ways: Either the pathological processes of schizophrenia can lead to the observed abnormalities or – the other way around – gonadal dys- function and estrogen deficiency of other origin can enhance the vul- nerability for schizophrenia or trigger the outbreak of the disease.
Both possibilities are theoretically feasible either acutely (as a state) or chronically (as a trait). In our studies we could find hints of both acute and of chronic gonadal hypofunction with physical signs of hypoestrogenism in schizophrenia.
Regarding chronic hypoestrogenism, we found long-standing ab- normalities in our patients as described by Kretschmer and other psychiatrists at the beginning of the last century. Although we could only examine a small group of 44 first-episode patients, they showed significant differences to the healthy control women as regards var- ious indicators of a relative estrogen deficiency, such as delayed menarche, mid-cycle bleeding, weak bleeding, loss of hair, and hir- sutism. The finding of a later menarche in schizophrenic women as compared to healthy controls is well in line with the finding of
Cohen et al. (1999) concerning the association of an earlier onset of schizophrenia in women with later puberty. A later physiological rise in serum estrogen levels might be associated with a higher risk of developing psychosis and an earlier onset. These results could also be explained by the hypoestrogenism hypothesis: There might be a subgroup of schizophrenic women with a chronic and even preexis- ting estrogen-deficiency state. This chronic state might have en- hanced their vulnerability for the psychosis.
We could also show that during acute schizophrenia most women suffer from marked menstrual irregularities and decreased estradiol and progesterone levels and many even from anovulation. Just like in chronic hypoestrogenism, we cannot identify the direction, let alone the cause of the association between this acute estrogen defi- ciency state and the psychotic episodes. However, as there is strong evidence that estrogens influence the dopaminergic system, it is intriguing to speculate that some schizophrenic episodes of women predisposed to schizophrenia are induced by acute gonadal dysfunc- tion with decreased estrogen production. The causes for the latter might be manifold, ranging from premenstrual to postnatal and (pre-)menopausal drop in estrogen levels and even to surgical loss of ovaries or pharmacological suppression of physiological estrogen production. The resulting decrease in estradiol serum levels would, in this case, mean the loss of a protective factor and could thereby – in women predisposed to schizophrenia – lead to the outbreak of schizophrenic symptoms.
As regards the estrogen protection hypothesis, well in line with our findings, Hallonquist et al. (1993) observed lower psychopathol- ogy scores in schizophrenic women during the mid-luteal phase than in the early follicular phase of the menstrual cycle. They concluded that estrogens may act as “endogenous neuroleptics”. Together with Gattaz et al. (1994), in a further study we found a better therapeutic response in schizophrenic inpatients admitted during their peri- menstruum, i.e., the low-estrogen phase of their cycle. These pa- tients required lower doses of neuroleptics and a shorter treatment to reach the same degree of remission as the patients admitted dur- ing their intermenstruum, i.e., their high-estrogen phase. We specu- lated that the better therapeutic response of the low-estrogen admis- sion group may be related to the increasing levels of circulating estradiol just after admission.
In the meantime several investigators have reported promising in-
itial results using estrogens as a therapeutic agent. Thus, Kulkarni et al. (1996, 2001) found that schizophrenic women receiving estra- diol as an adjunct to neuroleptic treatment showed more rapid im- provement in psychotic symptoms compared with the group recei- ving neuroleptics only. Similar effects were reported by Lindamer et al. (1997) in a case report on a postmenopausal women. Recently, Lindamer et al. (2001) reported on a community-dwelling sample of women with schizophrenia. Twenty-four women received hormone replacement therapy (HRT), and 28 women had never received such therapy. Interestingly, the users of HRT required a lower average dose of antipsychotic medication and suffered from less severe ne- gative symptoms. Jeste et al. (2001) report on “encouraging” results using estrogen “augmentation” of antipsychotics in an ongoing study in postmenopausal women with schizophrenia. Ahokas et al.
(2000) could show positive effects of estrogen substitution in two women with postpartum psychosis.
The results of our studies further imply that the effects of estro- gens are not restricted to schizophrenia and psychotic symptoms, but that they can also influence general behavior. This could reflect a generally stabilizing effect of estrogens in addition to their presu- med antipsychotic properties. Such an effect might also play a role in otherwise healthy women, who suffer from estrogen deficiency around and after menopause. Estrogen substitution in these cases not only seems to ameliorate physical complaints, but also the women’s mental state. Furthermore, this unspecific effect might be relevant in the pathogenesis of premenstrual syndrome.
Well in line with this are the results of another study which we conducted in a consecutive sample of 88 female patients admitted to an emergency service of a general hospital because of a suicide attempt (Riecher-Rössler 1994). We found a significant excess of suicide attempts in the perimenstrual low-estrogen phase of the cycle as compared to the high-estrogen phase (p < .005).
Choi et al. (2001) found only affective and somatic symptoms to correlate with estradiol levels in women with chronic schizophre- nia, not psychotic symptoms. However, as the authors themselves state, their 24 patients were not in an acute psychotic episode, but had been treated with antipsychotics for at least 6 months. The va- riation in psychotic symptoms, thus, was possibly not sufficiently high to find significant statistical correlations. Furthermore, there was no self-rating of paranoid symptoms in this study.
Also regarding the potential effect of estrogens on depression there have been findings that are at odds with ours. Thus, Klaiber et al. (1979), and Holsboer (1983) reported on positive effects. Particular- ly in postpartum depression (Sichel et al. 1995; Gregoire et al. 1996;
Ahokas et al. 1998) or in postmenopausal depression (Zweifel and O’Brien 1997; Schmidt et al. 2000; de Noaves Soares et al. 2001), po- sitive effects of estrogens could be shown. Postpartum and postme- nopausal disorders, however, might be partly due to the sudden drop or even a sustained lack of estrogens. Furthermore, the effects may depend on the severity of the depression and the estrogen state of the women, i.e., estrogens might only be helpful if there is a deficiency.
Implications for Therapy and Prophylaxis
Further research on the potentially protective effect of estrogens in psychoses is urgently needed, as if this effect could be confirmed, it would have interesting consequences for prophylaxis and therapy of these disorders.
First intervention trials in schizophrenia indicate that estradiol should be used as an augmentation compound, an adjunct to neuro- leptic medication. Replications of these results in larger controlled studies are needed though before recommendations for broad clinical application can be made.
Hormonal replacement with estrogens might be even more pro- mising for women with schizophrenia during and after perimen- opause, as estrogens in other disorders such as depression have proven to be especially helpful when there a hormone deficiency is substituted. Estrogen replacement therapy definitely ameliorates pe- rimenopausal complaints, which can act as stressors and theore- tically provoke relapses. HRT has also been recommended for other reasons, e.g., for prophylaxis of osteoporosis and possibly also Alz- heimer’s disease. Schizophrenia might represent an additional indi- cation to be studied.
As there is growing evidence that many even younger women are in an estrogen-deficiency state, estrogens and the gonadal axis should, in the future, be more seriously considered in the treatment of women with schizophrenia. Psychiatric history taking should always include questions regarding menstrual irregularities, amen- orrhea, galactorrhoea, etc. Prolactin and estrogen serum levels should be tested, if necessary.
Even in menstruating women gonadal dysfunction and hypoes- trogenic states can often be found (Riecher-Rössler et al. 1994a, 1998;
Smith et al. 2002). In addition, hyperprolactinaemia is obviously un- derdiagnosed (Maguire 2002). Some authors therefore suggest routi- ne laboratory tests (e.g., Smith et al. 2002).
Most neuroleptics can cause hyperprolactinaemia and can – espe- cially if taken over years – theoretically induce “iatrogenic early me- nopause” via suppression of physiological estradiol production. The risks of that are not only short-term effects such as hot flushes and sexual dysfunction, but also long-term consequences such as osteo- porosis and potentially also cardiovascular disease or cognitive dete- rioration (Maguire 2002; Oesterlund 2002). In schizophrenia patients these risks are further increased by additional risk factors such as smoking, poor diet, and reduced exercise (Smith et al. 2002).
Furthermore, the menopause complaints might lead to compliance problems.
In hyperprolactinemia with secondary estrogen deficiency, pro- lactin-sparing neuroleptics (e.g., clozapine, quetiapine, or olanza- pine – Maguire 2002) should therefore be preferred. If a switch to these neuroleptics is not possible for clinical reasons or if hypo- estrogenism persists in spite of switching, estrogens should be sub- stituted.
The question of contraception needs to be taken into account in these cases as, when switching to prolactin-sparing neuroleptics, the menstrual cycle often normalizes and fertility is regained, with a high risk of unplanned pregnancy (Neumann and Frasch 2001).
In women suffering from frequent perimenstrual psychotic relap- ses, “cycle-modulated” neuroleptic therapy or – if contraception is required at the same time – continuous use of oral contraceptives without hormone-free intervals might represent strategies worth being researched (Braendle et al. 2001; Riecher-Rössler 2002).
Research should also be conducted on the best mode of HRT for psychiatric patients. Progestogens are usually added to estrogens to prevent endometrial cancer, but can antagonize the positive effects of estrogens with respect to mental state (Braendle et al. 2001; Cyr et al. 2002). Furthermore, we have to consider other risks of hormone therapy, including breast cancer or cardiovascular disease for certain combinations (Barrett-Connor and Stuenkel 2001; Writing Group for Women’s Mental Health 2002).
As an alternative to conventional HRT, compounds with more
specific and potent estrogenic activity in the brain as opposed to other tissues should be searched for (Halbreich 2002; Riecher-Röss- ler 2002). This would not only minimize the side effects of hormonal therapy, but may also allow new therapeutic strategies in men.
Possible candidates are the selective estrogen receptor modula- tors (SERMS), whose agonist or antagonist properties depend on the target tissue. The effects of the so far existing SERMS on the brain, however, remain to be clarified. Raloxifene, e.g., seems to exert its main effects on the bone, although there are recent data suggesting that it also acts on different brain receptors (Cyr et al. 2002). The syn- thetic steroid tibolone also seems to cause less endometrial prolif- eration, but its effects on the central nervous system are still not clear, apart from the fact that it seems to have an androgenic effect and increase β-endorphin levels with improvement of mood and libido (Davis 2002). Further studies on the brain effects of SERMS and other estrogenic compounds (e.g., phytoestrogens, xenoestro- gens, DHEA) are urgently needed.
In summary, there are emerging hopes that estrogens as neuro- and psychoprotective adjunctive therapy may complement the tra- ditional drug therapies in schizophrenia in the future. However, it must be emphasized that most strategies are still being researched.
Especially before using estrogens as an adjunct therapy in younger women without proven estrogen deficiency, the results of larger con- trolled studies are needed.
Other strategies, however, should even now be part of standard clinical care (Grigoriadis and Seeman 2002). These include exami- nation of the gonadal axis and to draw therapeutic consequences, if indicated. Regarding estrogen substitution and replacement therapy, it has to be stressed that the decision must always be made on the basis of an individual risk-benefit assessment (NAMS 2000; Writing Group for Women’s Mental Health 2002) and in close cooperation with a gynecologist.
For future research, many questions arise, not only regarding new therapeutic strategies and compounds, but also regarding some so far not well explained disturbances of estrogens and the HPG axis in women with schizophrenia. Further research into this area could hopefully even contribute to better understanding the pathogenesis of this disease, at least in a subgroup of women.
Acknowledgement
Shorter, preliminary versions of this article were previously pub- lished in the “Archives of Women’s Mental Health” (2002; 5:
111–118) and in the “Nervenarzt” in 2003.
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