Estrogens have cerebral effects in addition to the genuinely hormonal functions in the gonadal axis. In the past it could be demonstrated that estrogens have an influence on major neurotransmitter systems and brain regions affecting cognitive, emotional, and vegetative functions (e.g., Fink et al. 1996; 1998; Halbreich 1995; Morisette and DiPaolo 1993; DiPaolo 1994; Gordon et al. 1980). Estrogens also exert neurotrophic and neuroprotective effects which are mediated by non- genomic as well as by direct and indirect genomic pathways (for review, see McEwen and Alves 1999; Lee and McEwen 2001; Garcia- Segura 2001; Behl 2001). How estrogen influences the course of various diseases of the nervous system has been the focus of research in the neural sciences in the past few years. These diseases include stroke, Parkinson’s disease, Alzheimer’s disease, depression, and schizophrenia. Generally, gender differences in the incidence and in recovery from neurological damage and mental disorders were an important starting point of research in these fields.
In schizophrenia research, the estrogen protection hypothesis has been investigated over the last 20 years. It assumes a protective effect of estrogen in women vulnerable to schizophrenia. Evidence for this hypothesis is based on epidemiologic, neurochemical, ani- mal, and clinical data (cf. chap. 2 and 3 of this volume by Riecher- Rössler and/or Häfner; Seeman 1996).
As early as 1909, Kraepelin reported that first-time hospitaliza- tion in men with schizophrenia occurs earlier than in women.
However, the peak age of onset of schizophrenia is significantly later for women than for men, regardless of whether one investigates age at first hospitalization, first treatment, or age when psychotic symp- toms are first noted (DeLisi et al. 1989; Seeman 1982; 1985; Tsuang
Hypoestrogenism and Estrogen Replacement Therapy in Women Suffering
from Schizophrenia
Niels Bergemann, Christoph Mundt, Peter Parzer, Benno Runnebaum and Franz Resch
et al. 1976; Lewine 1981; Lewine et al. 1981; Forrest and Hay 1971;
Loranger 1984; Sartorius et al. 1986; Häfner et al. 1991, 1992, 1998;
for review see Angermeyer and Kühn 1988). In men, the age at onset is the mid-20s, and in women the late 20s. In contrast to men, the curve of age at onset in women shows not only a smaller peak in young age than in men, but also a second peak during the 40s (cf.
chap. 3 of this volume by Häfner). Thus, it seems plausible that the onset of schizophrenia is determined by changes in steroid hormone production that occur at different times in men and women. Between menarche and menopause women are more likely to have a higher vulnerability threshold to schizophrenia than men because of the protective effect of higher plasma concentrations of estradiol. Since within families men and women do not show differences in age at onset, a genetically determined vulnerability may antagonize the onset-delaying effect of estradiol in women and, to a slightly lesser extent, the degree of pre- and peri-natal brain injury (Albus and Maier 1995; Könnecke et al. 2000).
Other reports also indicate that women have a significantly less severe course of schizophrenia than men (Sartorius et al. 1978;
Solokangas 1983) which can be attributed to the fact that their pre- menopausal estrogen plasma level may modulate the illness course and serve as a partial endogenous antipsychotic agent. Thus, young women can be maintained on lower doses of antipsychotics than men, but after age 40, women require higher doses than men. This coincides with menopause and further suggests estrogen mediation (Seeman 1983; cf. DeLisi et al. 1989).
Several clinical studies, case reports, or case series show a corre- lation between low estrogen plasma concentrations and an increase in the risk for schizophrenic symptoms occurring in women: post- natally or after the menopause, physiologically low plasma concen- trations of estrogen prevail and, at the same time, there is an increased risk for the exacerbation of schizophrenia (Nott 1982;
Kendell et al. 1987; Brockington et al. 1988; Seeman 1997). Further studies have shown more severe psychotic symptoms and a higher risk for the exacerbation of schizophrenic symptoms or hospita- lization in low estradiol phases of the menstrual cycle than in high estradiol phases (e.g., Swanson et al. 1964; Glick and Stewart 1980;
Hallonquist et al. 1993; Riecher-Rössler et al. 1994; Hendrick et al.
1996; Harris 1997; for review see, e.g., Bergemann et al. 2002). Gattaz et al. (1994) showed a significant correlation between the estradiol
plasma concentration and the therapeutically required dose of anti- psychotics.
It is of particular interest, that the observation of a possible rela- tionship between phases of the menstrual cycle and psychotic disorders dates back many years and was discussed extensively as early as in the nineteenth century. In the second half of the nineteenth and the beginning of the twentieth century, a number of publications reported such a relationship (e.g., Häffner 1912; Mayer 1872; Ross 1909; Schroeter 1874; v. Krafft-Ebing 1878; Jolly 1915;
Schaefer 1894).
In our own study (Bergemann et al. 2002) the hypothesis of a perimenstrual increase in hospital admissions of women suffering from an exacerbation of schizophrenia was tested in two samples of premenopausal women (sample 1: n = 115; sample 2: n = 170). In both samples there was a significant increase in admissions in the perimenstrual phase – three days before and three days after the first day of the menses (sample 1: p = 0.002, sample 2: p = 0.028, binomial test). Of the patients 37.4% were admitted during the perimenstrual phase of the cycle in sample 1, 31.8% in sample 2. Regarding age, age at onset, and duration of illness, there was no difference between the group admitted to the hospital during the perimenstrual phase and the group admitted during the rest of the menstrual cycle in either of the samples.
Hypoestrogenism in Women with Schizophrenia
Although numerous investigations could prove that estrogen has a protective effect in schizophrenia, little work has been done to study the estrogen deficiency syndrome or the hypoestrogenism hypothesis in schizophrenia (Riecher-Rössler 2003; cf. chap. 2 of this volume by Riecher-Rössler), which postulates an association between schizo- phrenia and a chronic estrogen deficiency in schizophrenic women.
Low estrogen levels leading to an elevated rate of menstrual dysfunc- tion, such as amenorrhea and irregular menstruation, have been described in schizophrenic women.
Of particular interest are studies on hypoestrogenism carried out in the pre-antipsychotic era. They demonstrated different types of menstrual cycle disorders in schizophrenic psychoses, anomalies of secondary sexual features, and an increased rate of virilization (e.g.,
Häffner 1912; for review see Bleuler 1943, Reiss 1958, Diczfalusy and Lauritzen 1961). As early as 1869, Mayer described the interac- tionbetween gynecological disorders and/or menstrual cycle distur- bances and mental disorders in his frequently cited monograph „Die Beziehungen der krankhaften Zustände in den Sexualorganen des Weibes zu Geistesstörungen” [The relation between diseases of the sexual organs in women and mental illness]. Various menstrual cycle disturbances, anomalies of the genital organs, and masculi- nization were seen in conjunction with psychotic disorders; thus, genital abnormalities and menstrual cycle disturbances were consid- ered possible causes of psychoses (v. Krafft-Ebing 1903; König and Linzenmeier 1913). The terms uterine or amenorrheal insanity illus- trate the hypothesis that “insanity in some few cases actually results de novofrom this [amenorrhea] as an exciting or predisposing cause”
(Clouston 1906). Based on these assumptions, ovariectomies were even carried out as therapeutic interventions in women with schizo- phrenia (Hegar 1884; Battey 1877; for review see Wells 1886; Burger 1984). A dysfunction of the gonads was postulated to be the cause of psychotic disorders before the endocrine processes responsible for the menstrual cycle were discovered. Clinical observations led Kraepelin (1909), and Kretschmer (1921) to assume a relation between schizo- phrenia and a “disturbance in state of sexual hormones”, above all in the sense of a “hypofunction of the gonads” and/or a so-called
“hypoestrogenism.” Thus, in later years, a hypofunction of the gonads with subsequent hypoestrogenism was postulated in women with schizophrenia. It is of particular interest that the hypothesis of an estrogen deficiency syndrome was formulated before the intro- duction of antipsychotics (for review, see Diczfalusy and Lauritzen 1961). Since then, hypoestrogenism and subsequent, irregular menstrual cycles and amenorrhea have usually been attributed to antipsychotic-induced hyperprolactinemia, mediated by hypotha- lamic-pituitary-gonadal feedback mechanisms (Smith et al. 2002), although irregular menstruation had already been observed in schizo- phrenic women before antipsychotics were introduced in the therapy of patients suffering from psychoses. Diczfalusy and Lauritzen (1961) reviewed the few studies on estrogen plasma concentrations directly measured in urine and/or blood in schizophrenic women in the pre- neuroleptic era (between 1933 and 1955). In seven out of eight studies, low levels of estrogen were detected (Georgi and Fels 1933;
Saethre 1933; Oesterreicher 1934; Kafka 1935; Sears et al. 1937;
Nilsson 1939; Lansbury and Hughes 1939). Only one study showed increased estrogen levels (Sacerdoti and Carry 1955). However, these findings have to be interpreted carefully as the laboratory methods applied were are not comparable to currently available analytic methods. Furthermore, study samples of schizophrenic patients were small.
In a more recent study including 32 acutely ill premenopausal women with schizophrenia and a history of regular menstrual cycles, Riecher-Rössler et al. (1994) reported lower than normal estradiol plasma concentrations in the course of the menstrual cycle with narrow fluctuations. The estradiol values at admission ranged from 45 to 502 pmol/l (12–137 pg/ml) with a mean of 176.5 pmol/l (48 pg/ml), and only 4 patients reached the lower normal range of the preovulatory phase of 550 pmol/l (150 pg/ml) throughout the entire cycle. Interestingly, even these narrow fluctuations in the estradiol plasma levels correlated with psychopathology scores measured by various rating scales.
In addition, Choi et al. (2001) found extremely low serum estrogen levels in a study on premenstrual symptoms in 24 chronically ill patients suffering from schizophrenia in both the premenstrual and postmenstrual phases of the cycle. In these patients, the values did not reach the lower limit of normal levels in either of the phases, with a mean estrogen level of 13.2 pg/ml in the premenstrual phase and a level of 38.8 pg/ml in the postmenstrual phase.
Huber et al. (2001) compared the estradiol levels on admission of 32 patients with various psychotic disorders to a control group of 9 healthy controls and 11 patient controls with various psychiatric disorders, most of them with a diagnosis of affective disorder. About half of the patients were taking antipsychotics of some kind. Upon admission, the blood levels of estradiol in the study group ranged from < 7 pg/ml to 185.3 pg/ml (median 41.1 pg/ml); only one patient had an estradiol concentration above 150 pg/ml, indicated as the lower level of ovulation. Both control groups had higher median estradiol blood levels, with values of 67.7 pg/ml in the healthy controls and 55.2 pg/ml in the patient controls, but only the median of the healthy control group was statistically significantly higher (p = 0.017).
More recently, Canuso et al. (2002) reported a study on 16 preme- nopausal women with schizophrenia and schizoaffective disorder treated with an antipsychotic with either a prolactin-elevating or
prolactin-sparing potential. Similar rates of menstrual dysfunction and ovarian hormone values were observed between hyperprolac- tinemic and normoprolactinemic subjects, and, irrespective of anti- psychotic type or prolactin status, most subjects had peak estradiol levels below normal reference values for the periovulatory phase of the menstrual cycle; 11 subjects had peak estradiol levels beneath the lower limit of normal for this phase.
Hoff et al. (2001) conducted a study including 22 women with schizophrenia and investigated the association between blood levels of estrogen and neuropsychological performance. In this sample of inpatients the authors found not only a correlation between average estrogen level and cognitive function but also, and more relevant for the present context, abnormally low estrogen levels compared to reference values: only one patient showed a value over 550 pmol/l (150 pg/ml).
In our own study (Bergemann et al. 2004a; cf. Bergemann et al.
1996) the serum levels of 17β-estradiol, prolactin, luteinizing hor- mone (LH), follicle-stimulating hormone (FSH), progesterone, and testosterone were investigated during the entire course of the men- strual cycle. In 75 premenopausal, menstruating women with schizo- phrenia diagnosed according to DSM-IV and ICD-10 and consecu- tively admitted to the psychiatric unit at the Department of Psy- chiatry at the University of Heidelberg, hormone levels were assess- ed three times during the first menstrual cycle after admission to the hospital: at the follicular (proliferative) phase at day 2–4 (t1), at the periovulatory phase at day 10–12 (t2), and at the luteal phase at day 20–22 (t3). This regimen was chosen because a single measurement of hormone levels at any point during the menstrual cycle would not have provided any evidence – for example, results from one blood analysis at admission would be questionable because most schizo- phrenic women are hospitalized perimenstrually, i.e., during a phase of the cycle in which estradiol levels are very low anyway (Berge- mann et al. 2002; Huber et al. 2001) and this value cannot be consid- ered indicative of overall estradiol levels throughout the entire cycle.
The results were compared to normal reference values by the Department of Obstetrics and Gynecology at the University of Hei- delberg (Rabe and Runnebaum 1994; Klinga 1994). All participants were Caucasian. The mean age was 32.9±6.8 years (range: 18–46 years), and the mean duration of illness was 7.5±7.0 years.
The levels of the hormones investigated in this study during the
three phases of the menstrual cycle are shown in Fig.1. The results are presented as box plots (Tukey 1977) showing the median, inter- quartile range (“boxes”), and the total deviation of the values;
extreme values are shown separately.
estradiol pg/ml
day of menstrual cycle 0
100 200 300
2-4 10-12 20-22
LH mE/ml
day of menstrual cycle 0
20 40 60 80
2-4 10-12 20-22
Fig. 1. Course of 17β-estradiol, LH, progesterone, prolactin, FSH, and testosterone during the phases of the menstrual cycle in women with schizophrenia (n = 75; box plots, extreme values as circles) (cf. Bergemann et al. 2004a)
We could show that the serum levels of estradiol were generally reduced during the entire menstrual cycle although there were signif- icant changes in the estradiol serum levels between the three phases
Fig. 1. (continued)
of the menstrual cycle investigated (analysis of variance for repeated measurements with Huyhn-Feldt correction). In accordance with the normal reference range one would expect estradiol plasma levels of
Fig. 1. (continued)
between 40 pg/ml and a maximum of 100 pg/ml in the follicular phase (cycle day 2–4) and values of above at least 150 pg/ml and up to 350 pg/ml during the periovulatory phase (cycle day 10–12).
The levels of LH were also low throughout the entire cycle. As would be expected, no significant increase in LH could be seen dur- ing the periovulatory phase. With a mean progesterone level of 1.56 ± 3.10 ng/ml (normal reference value: >10 ng/ml) in the luteal phase, it was assumed that ovulation had not occurred and/or that the follicles had not matured sufficiently. The prolactin levels were significantly elevated throughout the entire menstrual cycle, as could be expected under medication with predominantly conven- tional antipsychotics, and no difference between the mean values and deviation between the three phases could be detected (Bergemann et al. 2004a).
Estradiol values of < 100 pg/ml during the periovulatory phase (day 10–12 of the menstrual cycle) and < 30 pg/ml during the follicular phase (day 2–4) were considered hypoestrogenemic. In accordance with this strict definition we found hypoestrogenism in 57.3% of the patients.
To rule out a possible effect of hyperprolactinemia on the gonadal axis and the subsequent effect on the estrogen level due to the intake of conventional antipsychotics, serum levels of estradiol in women treated with atypical antipsychotics known to induce only a mild or no increase in prolactin were compared to those in women treated with conventional antipsychotics.
For this additional analysis, subgroups of patients were selected from the sample described above who had been treated continuously for at least 12 weeks with clozapine (n = 11) or olanzapine (n = 7).
These subgroups were compared to 31 patients treated continuously for at least 12 weeks with one conventional antipsychotic. For each group the hormone values of the periovulatory phase (cycle day 10–12) were taken for comparison.
As expected, the mean prolactin serum level in patients receiving conventional antipsychotics (M ± SD: 1,600 ± 1,278 mU/l) was much higher than the upper range of the normal reference values of 410 mU/l. As expected, there is a statistically significant difference in prolactin serum levels between the group receiving conventional antipsychotics and patients receiving the atypical antipsychotic clozapine (M±SD: 467 ± 170 mU/l; p < 0.001) or olanzapine (M ± SD:
654 ± 456 mU/l; p = 0.005). The difference between the prolactin
levels in the patients who received clozapine vs. olanzapine was not statistically significant. However, in contrast to the results for prolactin, the mean serum estradiol levels were far below 100 pg/ml in all three groups (Bergemann et al. 2004a).
Thus, there is some evidence for a sex hormone dysregulation and hypoestrogenism in schizophrenia. Furthermore, the fact that hypo- estrogenism in schizophrenic women occurs with and without anti- psychotic-induced hyperprolactinemia supports the hypothesis of primary hypoestrogenism.
Estrogen Replacement Therapy in Women with Schizophrenia
The results presented here are not only of particular interest from a theoretical point of view, but also for their therapeutic implica- tions. As already reported, empirical evidence was found in previous studies for a protective effect of estrogen in schizophrenia, which also suggests its use in treatment and prophylaxis. An estrogen repla- cement therapy could be particularly effective in those women with schizophrenia suffering from hypoestrogenemia. However, only very few studies addressing an estrogen medication in schizophrenia at all have been conducted to date.
Mall (1958; 1960) was the first to apply estrogen treatment in women suffering from schizophrenia. He distinguished between pre- menstrually and post-menstrually admitted patients and describes different psychopathological types of illness. On the basis of quan- titative analyses of estrogen in the urine, he also distinguished between “hypofollicular” and “hyperfollicular” psychoses, where most of the “post-menstrual psychoses” belong to the group of
“hypofollicular” psychoses. For this group he recommends estrogen replacement therapy. Unfortunately, the author gives only little information on the results of his study.
In recent times Kulkarni (1996; 2001, cf. chap. 5 of this volume) showed a beneficial effect of estradiol on the course of illness in the acute phase in various experimental trials. Lindamer et al. (2001) showed in a post hoc analysis that hormone replacement therapy with estrogen in conjunction with antipsychotic medication in postmenopausal women with schizophrenia helped to reduce ne- gative symptoms. In addition, the users of estrogen replacement
therapy required a lower dose of antipsychotic medication than con- trols.
Our own study (Bergemann et al. 2004b) was the first clinical inter- vention trial to empirically investigate the validity of the estrogen hypothesis in the context of relapse prevention in schizophrenic women.
The expected therapeutic effect of estrogen in the treatment of schizophrenia was tested under real-life conditions in order to obtain further clinical evidence for the estrogen hypothesis in schizophrenia and to evaluate the practical importance of an adjuvant estrogen re- placement therapy in hypoestrogenemic women with schizophrenia.
In particular, the question was addressed as to whether antipsy- chotics plus estrogen (and/or a combination of estrogen and gestagen) is superior to antipsychotic monotherapy in preventing relapse. A more favorable course of illness or a lower antipsychotic drug requi- rement as well as a better tolerance were expected from an adjuvant therapy with estrogen versus a antipsychotic monotherapy (Berge- mann et al. 2004b).
A multi-center, randomized, placebo-controlled, double-blind, cross-over study based on an A-B-A-B- (and/or B-A-B-A) design was applied (Fig. 2, Bergemann et al. 2004b).
Forty-six schizophrenic women with hypoestrogenism hospital- ized for the first time or repeatedly were included in the study. Their average age was 37.9 (SD = 9.8, range 21–60 years) and they had been suffering from schizophrenia for 8.4 years (SD = 7.4 years; ICD-10 F20.0, F20.1, F20.5). Here, too, hypoestrogenism was defined as estradiol serum level < 30 pg/ml on day 2-4 of the menstrual cycle and estradiol serum level < 100 pg/ml on day 10–12. Women with relevant co-morbidity or who were pregnant or lactating were excluded from the trial (cf. Bergemann et al. 2004b).
The estrogen replacement was administered as an adjuvant to routine relapse prevention with antipsychotics. A three-phase estrogen-gestagen combination was used (17β-estradiol 4 mg in the follicular phase, plus norethisteroneacetate 1 mg in the periovulatory phase and 17β-estradiol 1 mg in the luteal phase; Trisequens forte®).
If any side effects developed, the dose could be halved to 2 mg in the follicular and periovulatory phase. In addition, a placebo of the same appearance and feel was administered. For a basic relapse prevention, various antipsychotics were given without predefining the drug or dose. For 8 months the patients alternately received, in addition to
the various antipsychotics, estradiol or placebo for 2 months each according to the randomization schedule for the study groups A-B-A-B or B-A-B-A (cf. Fig. 2).
The endocrinological parameters were calculated separately for the age groups 21–45 and 45+ so as to take potential age effects into account. As defined as inclusion criteria the age group 21–45 showed hypoestrogenism at baseline. The age group 45+ displayed a meno- pausal hormone profile at baseline, with low estradiol levels along with elevated gonadotropins, as expected.
A significant effect of the adjuvant hormone replacement therapy on the estradiol levels could be observed in both groups, and high and low levels of estradiol prevailed in the verum and placebo phases, respectively. During the 2-month replacement therapy phases the estradiol levels corresponded more or less to normal; in the placebo phases the levels were considerably below the norm.
We did not find any relevant difference either in the psychopa- thology scales (Brief Psychiatric Rating Scale, BPRS, Overall and Gorham 1962; Positive and Negative Symptom Scale, PANSS, Kay et al. 1986; Beck Depression Inventory, BDI, Beck et al. 1987, German version by Hautzinger et al. 1995; Clinical Global Impression, CGI, Guy 1976; 100 mm analoque scale) or in defined relapse events (BPRS-Score 3: “Thought disorder” 3 points lower; CGI: deteriora- tion to score 7 or 8; 100-mm-scale: 20% lower score) between the
Fig. 2. Study design of a multi-center, randomized, placebo-controlled, double-blind, cross-over study based on an A-B-A-B- (and/or B-A-B-A) design
(Bergemann et al. 2004b)
verum (estradiol replacement) and placebo phase. Neither the re- quired antipsychotic doses (haloperidol equivalence) nor the data on side effects differed between the two phases. Thus, the results of our study could not confirm the hypothesis that a combined estradiol- antipsychotic therapy is superior to relapse prevention with anti- psychotic monotherapy. Furthermore, the results could not provide evidence for the hypothesis of an estrogen effect especially on the negative symptomsas via an effect on the serotonergic transmission described by Fink et al. (1996) and as concluded by Lindamer et al.
(2001).
These results were critically reviewed with respect to the litera- ture and regarding the methodology. One objection might be that the phases of verum and placebo treatment were too short. In response to this concern, we refer to Riecher-Rössler et al. (1994), who showed changes in psychopathology based on physiological fluctuations that were much smaller than the estradiol values in the present study.
Furthermore, the women included in the study of Riecher-Rössler et al. – as well as in the studies by Kulkarni et al. (1996; 2001;
cf. chap. 5 in this volume) – were in the acute phase of schizophrenia, which differs from the women investigated in our study. It is remark- able that in the open intervention trial by Kulkarni et al. (1996) the superiority of a combined treatment also wanes after 3 weeks.
Given these results, it could be assumed that estradiol has an antipsychotic-like effect in the acute phase, in particular before the antipsychotics administered have displayed their antidopaminergic effect. After this period a “ceiling effect” could occur, which means that the potential effect of estradiol is outperformed by the effect of antipsychotics. In this context, studies analyzing low-dose antipsy- chotic treatment might be more sensible – they could serve as an alternative to trails, in which estrogens in monotherapy versus placebo are tested. The latter of course could present an ethical problem.
Summary and Conclusions
Following the work of several authors at the end of the nineteenth and the beginning of the twentieth century a few recent studies provided evidence for primary hypoestrogenism in women suffering from schizophrenia independent of hypoestrogenism secondary to
hyperprolactinemia induced by some antipsychotics. This estrogen deficiency could indicate a disturbance in the hypothalamic- pituitary-gonadal axis in those patients. The underlying pathogenetic process for this disturbance has not been clarified yet, however, some assumptions relating to this topic have been put forward (Bergemann et al. 2004a).
In this context, a highly interesting issue to be addressed in further studies is whether schizophrenic women are suffering from long-term hypoestrogenism. An answer to this imminent question is of particular value as somatic problems secondary to hypoestroge- nemia in schizophrenic women might require specific therapy. In clinical routine, taking of the patient history should include ques- tions regarding the consequences of hypostrogenism such as mens- trual irregularities and amenorrhea or galactorrhea. As hypoestro- genism could also occur in women with schizophrenia reporting regular menstrual cycles, it would be important to know the serum levels of estrodial and prolactin, and potentially of other relevant hormones. Furthermore, the different endocrinological effects of various antipsychotics have to be taken into consideration.
From a clinical point of view, the findings that indicate hypo- estrogenism in schizophrenic women are of major interest for the estrogen hypothesis in schizophrenia, which postulates a protective effect of estradiol. Estrogen replacement therapy in these patients is considered to be of high value. For this reason, we conducted a prospective randomized, placebo-controlled, double-blind, cross- over study in women suffering from schizophrenia (Bergemann et al.
2004b). In this study, we could not find an advantage of the estrogen replacement as an adjuvant to routine relapse prevention with antip- sychotics in our patients, which was contrary to our hypothesis.
Although an additional effect of estrogen could not be proven, these results still cannot be regarded as refuting the estrogen protection hypothesis. Further studies should consider and overcome the limita- tions of our study.
Assuming that the influence of hormones is different in different groups of patients, as the results of Albus and Maier (1995) as well as Könecke et al. (2000) indicate, the group of women falling ill in the perimenopause represents a particularly interesting subject for fur- ther intervention studies. In this group, estrogens could have played a decisive role in suppressing the symptoms until the onset of schizo- phrenia; the physiological decrease in estrogen serum levels might
play a key role in the etiopathogenesis of schizophrenia in these women. To verify these assumptions, further clinical research into the estrogen protection hypothesis in the form of intervention studies of perimenopausal women hospitalized for the first time could provide further insights. However, gynecological indications may prevail in particular in the patient group in question because of perimenopausal complaints. Estrogen replacement therapy has also been recommended in perimenopausal women, for example, as osteoporosis prevention treatment.
In general, more interventional trials should be carried out, ideally with a double-blinded and placebo-controlled design and that take the estrogen status of the patients into consideration. However, due to potential side effects and contraindications the individual risk and benefit of such estrogen treatment should be assessed and taken into account (cf. Notman and Nadelson 2002; Schneider 2002; Writing Group for the Women’s Health Initiative Investigators 2002; Writing Group of the International Menopause Society Executive Committee 2004; Turgeon et al. 2004).
Within this framework, the use of compounds with more specific and/or potent estrogenic activity in the brain than in other tissues should be the target of further research (Riecher-Rössler 2002; 2003;
Halbreich 2002; Cyr et al. 2002). The application of selective estrogen receptor modulators (SERMS), but also of other estrogenic com- pounds such as phyto-estrogens, xeno-estrogens and dihydroepiand- rosterone, should be investigated as they could minimize the side effects of estrogen therapy.
Further research in this area should focus on both the potential therapeutic effects of estrogen and/or other estrogenic compounds in schizophrenia and on studies providing more insight into the currently poorly understood relationship between hypoestrogenism and/or disturbances of the hypothalamic-pituitary-gonadal axis and schizophrenia. For example, further endocrinological studies in schizophrenic patients should contribute to understanding the hor- monal status of these patients and also provide results on the inter- dependency of the various hormones relevant in this context and their role in the pathogenesis of schizophrenia. Furthermore, studies on the effects of estrogens on cognition in the therapy of schizo- phrenia may be of major interest (Bergemann et al. 2001; Hoff et al.
2001). Here, brain-imaging studies might shed light on the relati- onship between estrogen, cognitive function, and psychopathology
(cf. Resnick et al. 2001; chap. 12 of this volume). Further research regarding the role of estrogen in schizophrenia would contribute to our understanding of the development and the course of schizo- phrenia to the benefit of patients suffering from this disease.
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