Table Of ContentW
Niels Bergemann
Anita Riecher-Rössler (eds.)
Estrogen Effects in
Psychiatric Disorders
SpringerWienNewYork
Dr. Dr. Niels Bergemann
Department of Psychiatry, University of Heidelberg, Germany
Prof. Dr. Anita Riecher-Rössler
Psychiatric Outpatient Department, University of Basel, Switzerland
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Contents
Introduction and Overview (N. Bergemann, A. Riecher-Rössler) ...................... VII
1 Estrogens in Neuropsychiatric Disorders: From Physiology to
Pathophysiology(H. Vedder, C. Behl)............................................................ 1
2 Estrogens and Schizophrenia (A. Riecher-Rössler) ........................................ 31
3 Gender Differences in Schizophrenia (H. Häfner) ......................................... 53
4 Puberty and Schizophrenia Onset(R. Z. Hayeems, M. V. Seeman) ............. 95
5 Clinical Estrogen Trials in Patients with Schizophrenia (J. Kulkarni) ......... 107
6 Hypoestrogenism and Estrogen Replacement Therapy in Women
Suffering from Schizophrenia (N. Bergemann, Ch. Mundt, P. Parzer,
B. Runnebaum, F. Resch) ................................................................................ 123
7 The Effect of Estrogens on Depression (L. S. Kahn, U. Halbreich) .............. 145
8 Estrogens and Other Hormones in the Treatment of Premenstrual
Syndromes(L. Born, M. Steiner) ..................................................................... 175
9 Estrogens and Perinatal Disorders (A. Gregoire)............................................ 191
10 Estrogen Therapy in Perimenopausal Affective Disorders
(G. Stoppe, M. Dören)...................................................................................... 207
11 The Effects of Estrogens on Cognition and Alzheimer’s Dementia
(T. Edwin, U. Halbreich) ................................................................................ 223
12 Effects of Hormone Therapy on Patterns of Brain Activation during
Cognitive Activity: A Review of Neuroimaging Studies (P. M. Maki,
S. M. Resnick) .................................................................................................. 239
13 Estrogens in Alzheimer’s Disease: A Clinical and Neurobiological
Perspective(P. Schönknecht, J. Pantel, A. Hunt, M. Henze,
T. Strowitzki, J. Schröder) ............................................................................... 253
14 Estrogen Therapy: Interface Between Gynecology and Psychiatry
(K. M. K. Ismail, G. V. Sunanda, P. M. S. O’Brien) ....................................... 271
List of Contributors ............................................................................................... 289
V
Introduction and Overview
N. Bergemann and A. Riecher-Rössler
The study of the effects of gonadal hormones in the brain was
focused mainly on reproductive actions for a long time. Meanwhile,
however, it is well known that gonadal hormones, in particular
estrogens, also have neuroprotective and psychoprotective pro-
perties. They can obviously modulate many actions in the brain such
as cognitive functions, pain regulation, motor coordination, epilepsy,
as well as affective and psychotic disorders, to name just a few. In
fact, during the past few years we have experienced a major change
in our understanding of the endocrinologic aspects of psychiatric
disorders. Endocrinologic irregularities in psychiatric patients are no
longer viewed as pure epiphenomena but rather discussed as part of
the pathomechanism of the disorders.
How exactly estrogens affect various disorders is a fascinating and
intriguing aspect of this emerging field of non-reproductive brain
actions of gonadal hormones. Among the estrogens, especially estra-
diol appears to play an important and multimodal role in the brain.
Which of estradiol’s many membrane, intracellular, and genomic ac-
tions matter most in psychiatric disorders, remains to be discovered.
The aim of this volume is to summarize the role estrogens play in
major psychiatric disorders, such as schizophrenia, depression, and
dementia, and to provide a state-of-the-art overview of current
knowledge but also of open questions. We hope that it will be a
useful resource for clinicians and readers who are interested in con-
temporary research developments in this field.
Helmut Vedder and Christian Behl (“Estrogens in Neuropsychia-
tric Disorders: From Physiology to Pathophysiology”) begin this
volume with a chapter on the basic mechanisms of estrogens, also
presenting an overview of the genomic and nongenomic effects of
estrogens and of the modulatory effects of estrogens on the various
neurotransmitter systems, particularly the glutaminergic, dopamin-
ergic, serotonergic, and cholinergic systems. Furthermore, the neu-
roprotective effects of estrogens and their immunological activation
in the central nervous system during neurodegeneration and aging
are discussed.
VII
N. Bergemann and A. Riecher-Rössler
The following twelve chapters are divided into three parts. The
first part focuses on the impact of estrogens in schizophrenia and
contains five chapters on the role of estrogens in the development
and course of schizophrenia. This section starts with chapter 2 by
Anita Riecher-Rösssler (“Estrogens and Schizophrenia”), which
gives an overview on the impact of estrogens in schizophrenia. She
first presents a historical view of this issue and then summarizes the
findings from various trials on the “estrogen protection hypothesis”
and the “hypoestrogenism hypothesis” in schizophrenia. She closes
her chapter with a discussion of the implications for therapy and pro-
phylaxis. In chapter 3, Heinz Häfner gives a detailed review on
“Gender Differences in Schizophrenia”, in particular concerning the
differences in diagnosis, subtypes and symptoms, lifetime risk and
age at onset, risk factors, illness behavior and illness-specific defi-
cits, and both course and outcome. In his review he refers to the fin-
dings of the ABC study, which he conducted together with Anita
Riecher-Rössler in a first-episode sample of schizophrenia. The data
presented here are of major importance for the “estrogen protection
hypothesis” in schizophrenia. Robin Z. Hayeems and Mary V. See-
man (chapter 4: “Puberty and Schizophrenia Onset”) then report on
a study showing the inverse relationship between onset of menarche
and schizophrenia onset in women. In chapter 5, Jayashri Kulkarni
and co-workers (“Clinical Estrogen Trials in Patients with Schizo-
phrenia”) present findings which show that add-on therapy with est-
radiol to the standard treatment of acute schizophrenia alleviates
symptoms and shortens the acute hospital stay. Niels Bergemann
and co-workers (chapter 6: “Hypoestrogenism and Estrogen Repla-
cement Therapy in Women Suffering from Schizophrenia”) report on
studies providing evidence for the “hypoestrogenism hypothesis”
that show menstrual irregularities and pathologically low estradiol
blood levels throughout the menstrual cycle as well as anovulation
in the majority of women suffering from schizophrenia. Furthermo-
re, the results of estrogen replacement as a prophylactic adjunct to
antipsychotics in women with schizophrenia are reported.
The second part of this book examines the role of estrogens in
depression. Uriel Halbreich and Linda S. Kahn open this section with
an overview on “The Effect of Estrogens on Depression.” They start
with a summary of the gender differences in the prevalence of de-
pression and regarding the response to psychotropic medication and
then outline the role of estrogens in the treatment of major depres-
VIII
Introduction and Overview
sion and reproduction-related disorders in women. In the following
chapter. 8, Leslie Born and Meir Steiner take a closer look at “Estro-
gens and Other Hormones in the Treatment of Premenstrual Syn-
dromes.” Alain Gregoire (chapter 9: “Estrogens and Perinatal Disor-
ders”) gives an overview of the evidence for antidepressive effects of
estrogens in postpartum disorders and summarizes the implications
this has for research and clinical practice. Gabriela Stoppe and Mar-
tina Dören (chapter 10) then critically discuss the current findings
regarding “Estrogen Therapy in Perimenopausal Affective Disor-
ders.”
The third part of the book focuses on the important association
between estrogens and cognition and/or Alzheimer’s disease. Tony
Edwin and Uriel Halbreich give a concise overview on “The Effects
of Estrogens on Cognition and Alzheimer’s Dementia” (chapter 11).
Pauline M. Maki and Susan M. Resnick follow with a review of
neuroimaging studies in this field (chapter 12: “Effects of Hormone
Therapy on Patterns of Brain Activation during Cognitive Activity:
A Review of Neuroimaging Studies”). They conclude that neuro-
imaging studies give evidence for a protective effect of estrogens on
age-related changes in cognition and Alzheimer’s disease. Findings
suggest that estrogens affect neural substrates of several cognitive
functions. Peter Schönknecht and co-workers (chapter 13: “Estro-
gens in Alzheimer’s Disease: A Clinical and Neurobiological Pers-
pective”) elaborate on the question of whether estrogen might have
a mediating effect on cerebral β-amyloid metabolism in Alzheimer’s
disease.
Finally, the last chapter of this book by Khaled M. K. Ismail, G.V.
Sunanda and P. M. Shaughn O’Brien deals with the “Interface bet-
ween Gynecology and Psychiatry” regarding estrogen therapy.
The present volume includes both reviews on the main topics and
also chapters providing more detailed information on individual stu-
dies. Thus, some overlap may occur and different views and inter-
pretations of empirical findings become evident. It is not intended to
rule out such discrepancies – on the contrary: different views may
stimulate the ongoing discussion.
Overall, it is obvious that interest is growing in this area and that
further research is required since clinical studies, especially inter-
vention studies, are still rare. Results of larger-scale, controlled stu-
dies are needed before recommendations for routine clinical appli-
cation of estrogens can be made for psychiatric patients. In addition,
IX
N. Bergemann and A. Riecher-Rössler: Introduction and Overviews
research needs to be undertaken on the best modality of hormone
(replacement) therapy in psychiatric patients. Clearly, any decision
for estrogen (replacement) therapy in women with psychiatric disor-
ders must be made on the basis of an individual risk-benefit-assess-
ment, evaluating the pros and cons. In this context, the results
of the “Women’s Health Initiative” need to be considered, which
should also include a critical evaluation of the study results and in-
terpretations (Notman and Nadelson 2002; Schneider 2002; Writing
Group for the Women’s Health Initiative Investigators 2002; Writing
Group of the International Menopause Society Executive Commit-
tee 2004; Turgeon et al. 2004).
We strongly believe that further research on the influence of
estrogens in schizophrenia, affective disorders, and dementia will
not only contribute to our understanding of the pathogenetic me-
chanisms underlying some aspects of psychiatric disorders, but will
also have direct therapeutic benefits for many women with these
disorders.
Many people have contributed to this volume. In particular, we
express our gratitude to our fellow authors. We also gratefully ack-
nowledge the expert tutelage, guidance, and patience of the staff at
SpringerWienNewYork, especially Raimund Petri-Wieder. Further-
more, we owe many thanks to Sherryl Sundell for editing the ma-
nuscripts.
Last but not least, the sponsoring of this volume by AstraZeneca-
GmbH, Pfizer GmbH, and Lilly Deutschland GmbH through unre-
stricted grants is greatly appreciated.
References
Notman MT, Nadelson CC (2002) The hormone replacement therapy controversy.
Arch Women Ment Health 5: 33-35
Schneider HPG (2002) The view of the International Menopause Society on the
Women’s Health Initiative. Climacteric 5: 211-216
Turgeon JL, McDonnel DP, Martin KA, Wise PM (2004) Hormone therapy: physio-
logical complexity belies therapeutic simplicity. Science 304: 1269-1273
Writing Group for the Women’s Health Initiative Investigators (2002) Risks and
benefits of estrogen plus progestin in healthy postmenopausal women. JAMA
288: 321-333
Writing Group of the International Menopause Society Executive Committee (2004)
Guidelines for the hormone treatment of women in the menopause transition
and beyond. Climacteric 7: 8-11
X
1
Estrogens in Neuropsychiatric Disorders:
From Physiology to Pathophysiology
Helmut Vedder and Christian Behl
Introduction:
The Role of Estrogens in Human Neuropsychiatric Diseases
A large number of studies, which often focus on the effects of estro-
gen replacement therapy (ERT) in women, have reported beneficial
actions of these hormones on various neurobiological and neuropa-
thological parameters in health and disease (Fig. 1). It is likely that
postmenopausal ERT helps reduce the risk of Alzheimer’s disease
(Kawas et al. 1997), improves cognitive and affective functions
(Schmidt et al. 1996), including postmenopausal depressive symp-
toms (Halbreich 1997), and affects the course of other illnesses such
as schizophrenia (Riecher-Rössler and Häfner 1993; Riecher-Rössler
et al. 1994) and probably also stroke (Toung et al. 1998; Yang et al.
2000) and Parkinson’s disease (Blanchet et al. 1999; Saunders-Pull-
man et al. 1999).
Unfortunately, these data have often not been clearly confirmed
by appropriately designed double-blind studies due to inherent prob-
lems such as the necessity for long-term evaluation and controlling
for confounding factors. Moreover, a recent treatment study under
rigorously controlled conditions failed to show positive effects of
estrogen treatment in patients already affected by Alzheimer’s dis-
ease (Mulnard et al. 2000).
In contrast, a large number of preclinical neurobiological studies
have unequivocally demonstrated neuroprotective effects of this
group of hormones during numerous toxic states and under various
different conditions (Behl and Holsboer 1999). Up to now, it is not at
all clear which of the various effects of estrogens on cells of different
systems (neuronal, vascular, immune, and others) contribute to
what extent to the neuroprotective effects of these hormones. It is
likely that several of these described actions represent similar cellu-
1
