Estrogen Review_Grover Et Al 2010

REVIEW ARTICLE

Genetic Variability in Estrogen Disposition:Potential Clinical Implications for NeuropsychiatricDisordersSandeep Grover,1 Puneet Talwar,1 Ruchi Baghel,1 Harpreet Kaur,1 Meenal Gupta,1

Mandaville Gourie-Devi,2 Kiran Bala,2 Sangeeta Sharma,2 and Ritushree Kukreti1*1Council of Scientific and Industrial Research (CSIR), Institute of Genomics and Integrative Biology (IGIB), Delhi, India2Institute of Human Behavior & Allied Sciences (IHBAS), Delhi, India

Received 19 April 2010; Accepted 3 August 2010

Variability in the physiological levels of neuroactive estrogens is

widely believed to play a role in predisposition to several dis-

orders of the central nervous system. Local biosynthesis of

estrogens in the brain as well as their circulating serum levels

are known to contribute to this pool of neuroactive steroids. It

has been well accepted that estrogens modulate neuronal func-

tions by affecting genesis, differentiation, excitability, and de-

generation of nerve cells. These actions of estrogens appear to be

more prominent in females with higher concentrations and

marked variability of circulating serum levels occurring over a

woman’s lifetime. However, our knowledge regarding the vari-

ability of neuroactive steroid levels is very limited. Furthermore,

several studies have recently reported differences in the synchro-

nization of circulating and neuronal levels of estradiol. In the

absence of reliable circulating steroid levels, knowledge of ge-

netic variability in estrogen disposition may play a determining

factor in predicting altered susceptibility or severity of neuro-

psychiatric disorders in women. Over the past decade, several

genetic variants have been linked to both differential serum

estrogen levels and predisposition to diverse types of neuropsy-

chiatric disorders in women. Polymorphisms in genes encoding

estrogen-metabolizing enzymes as well as estrogen receptors

may account for this phenotypic variability. In this review, we

attempt to show the contribution of genetics in determining

estrogenicity in females with a particular emphasis on the central

nervous system. This knowledge will further provide a driving

force for unearthing the novel field of ‘‘Estrogen

Pharmacogenomics.’’ � 2010 Wiley-Liss, Inc.

Key words: sex steroids; 17b estradiol (E2); sex hormones; single

nucleotide polymorphism (SNP); menstrual cycle; menopause

INTRODUCTION

Estrogens have been traditionally viewed as female sex hormones

secreted by ovaries which help in the development of secondary sex

characters and regulation of reproductive life in females [Kane et al.,

1969]. Estrogens are also secreted in males but in significantly lower

quantities and may influence spermatogenesis [Luconi et al., 2002].

However, in the last two decades, burgeoning number of articles

has documented non-reproductive functional relevance of estro-

gens with emphasis upon their relationship with the central nervous

system (CNS) [McEwen, 2002; Wihlback et al., 2006; Cosimo and

Garcia-Segura, 2010] (Fig. 1). Furthermore, it is now becoming

increasingly evident that estrogens play a central role in maintaining

health of a female brain [King, 2008]. Their role in neurophysiology

is further corroborated by several recent reports demonstrating

local biosynthesis of sex steroids and existence of complete

machinery of estrogen metabolizing enzymes in neurons

[Mellon and Deschepper, 1993; Dutheil et al., 2008].

Besides their higher concentration, estrogens assume greater

significance in a female’s life span with fluctuating serum levels

contributing to a wide array of functions. The surge or decline in

estrogen levels can be attributed to change associated with the

menstrual cycle [Farage et al., 2009], pregnancy [Venners et al.,

2006], and menopause [Burger et al., 2008; Nelson, 2008] (Fig. 2).

These changes might play a significant role in altering the

homeostasis of the nervous system with increased vulnerability to

*Correspondence to:

Dr. Ritushree Kukreti, Genomics and Molecular Medicine, Institute of

Genomics and Integrative Biology (IGIB), Council of Scienctific and

Industrial Research (CSIR), Mall Road, Delhi 110 007, India.

E-mail: [email protected]

Published online 30 September 2010 in Wiley Online Library

(wileyonlinelibrary.com)

DOI 10.1002/ajmg.b.31119

How to Cite this Article:Grover S, Talwar P, Baghel R, Kaur H, Gupta

M, Gourie-Devi M, Bala K, Sharma S, Kukreti

R. 2010. Genetic Variability in Estrogen

Disposition: Potential Clinical Implications

for Neuropsychiatric Disorders.

Am J Med Genet Part B 153B:1391–1410.

� 2010 Wiley-Liss, Inc. 1391

Neuropsychiatric Genetics

neuropsychiatric disorders and decreased sensitivity to pharmaco-

logical agents.

In addition, some women are more predisposed to these

vulnerabilities with an early age of onset and increased severity

of symptoms than others. Further, treatment of symptoms with

drugs and exogenous steroids has received mixed success [Riecher-

Rossler and de Geyter, 2007]. Variability in serum estrogen levels

in women may contribute to this differential predisposition,

and response to medications. However, studies correlating

serum estradiol (E2) levels with disease susceptibility and severity

of symptoms have yielded conflicting results. These discrepancies

might be attributed to limitations imposed in measuring neuro-

active steroid levels.

Thus, studying genetic variations might be a better alternative to

overcome this limitation as functional polymorphisms may have

similar consequences irrespective of their sites of expression, on the

activity of proteins involved in estrogen metabolism, transport, or

action. The purpose of this review was to highlight the significance

of estrogens in women with a focus on its relationship with the CNS.

In addition, the primary goal of this article was to provide com-

prehensive overview on the current knowledge regarding the role of

genetic variants in altering the susceptibility to neuropsychiatric

disorders by influencing estrogenicity.

ROLE OF ESTROGENS IN THE PATHOGENESIS OF CNSDISORDERS

It has been established that E2 alters the activity of cholinergic

[Gibbs and Aggarwal, 1998], serotonergic [Lasiuk and Hegadoren,

2007], dopaminergic [Dluzen and Horstink, 2003], glutamatergic

[Zamani et al., 2004], and GABAergic [Wojtowicz et al., 2008]

neurons (Fig. 1). Hence, any alteration in normal physiological

levels of neuroactive E2 could lead to a wide range of medical

symptoms including cognitive deficits, psychiatric symptoms, mo-

tor problems, or seizure recurrence. There have been considerable

studies showing the role of estrogens in the pathogenesis of neuro-

psychiatric disorders namely epilepsy [Hamed, 2008], Alzheimer’s

diseases (AD) [Pike et al., 2009], Parkinson’s disease (PD) [Bourque

et al., 2009]; multiple sclerosis (MS) [Kipp and Beyer, 2009];

migraine [MacGregor, 2005]; mood disorders [Deecher et al.,

2008]; and schizophrenia (SCZ) [Mortimer, 2007]. Preliminary

evidence from epidemiological studies suggests gender differences

in prevalence and incidence of these disorders. Furthermore, several

studies have suggested gender specific age of onset and severity

of these diseases. The females, in particular, exhibit risk pattern

peculiar to their hormonal milieu that varies with the phase of

menstrual cycle and menopausal status. In addition, gender also

influences the range of symptoms with regional specificity of brain

reported by some studies. This has necessitated gender-specific

drug treatment with differential dosages of drugs and exogenous

hormonal requirements for optimal response and undesirable side

effects.

Prevalence and IncidenceNon-reproductive actions of estrogens in the brain are more

pronounced in women as compared to men. This could be due

to higher concentration of circulating estrogens in women. Further,

a woman exhibits fluctuations in estrogen levels in her life and any

slight deviation from homeostasis in hormonal milieu could act

as a trigger for an increased risk to estrogen-related diseases. This

gender-specific effect of estrogens is highlighted in the manifesta-

tion of differential prevalence and incidence of common neuro-

psychiatric disorders between men and women, irrespective of their

ethnic backgrounds.

On the basis of most replicated findings, higher prevalence

and incidence has been observed in women afflicted with AD

[Jorm et al., 1987; Gao et al., 1998], MS [Noonan et al., 2002;

Orton et al., 2006], migraine [Cucurachi et al., 2006; Queiroz et al.,

2009], and mood disorders [Kessler et al., 1994; Alonso et al., 2004].

However, a reverse trend has been observed for predisposition

to PD [Baldereschi et al., 2000; Schrag et al., 2000]. In addition,

prevalence of epilepsy [Radhakrishnan et al., 2000; Christensen

et al., 2007] is slightly higher in men and a comparable cumulative

risk for both the genders has been reported in predisposition to SCZ

[Hafner, 2003].

However, when age is taken into account, estimates of these

prevalence rates might show marked inconsistencies. Although

greater prevalence with increase in age is observed for both the

genders, a higher increase in risk is observed in postmenopausal

women for most of the neuropsychiatric disorders. This could be

attributed to precipitous decline in estrogen levels in postmeno-

pausal women, indicative of neuroprotective actions of estrogen at

an earlier age. In summary, women in their lifetime are more likely

to be effected by imbalances in the neurotransmission, largely due

to gender-specific influence of estrogens.

FIG. 1. Role of estrogens in the pathogenesis of CNS disorders.

Estrogens are known to influence cholinergic, serotonergic,

dopaminergic, glutamatergic, and GABAergic neurons. This could

result in gender-specific age of onset, prevalence, and incidence,

drug response, and differential severity and types of symptoms

for estrogen-dependent neuropsychiatric disorders.

1392 AMERICAN JOURNAL OF MEDICAL GENETICS PART B

Age of Onset and SeverityA delay in the onset of symptoms is often gender related for majority

of brain diseases. Further, a patient with delayed onset may experi-

ence less severe symptoms. Women with AD are associated with

more severe symptoms as compared to men and are associated with

poor cognitive scores with memory impairment and reduced visuo-

spatial ability [Barnes et al., 2005]. In contrast, women with PD

show a higher mean age of onset with less severity and slow

progression as compared to men [Lyons et al., 1998; Haaxma

et al., 2007]. Similarly, women show a 3–4 years higher mean age

of onset for SCZ than men [Leung and Chue, 2000]. Women

afflicted with MS show mild symptoms and take a longer time to

reach the period of irreversible disability [Confavreux et al., 2003].

Although peak age of onset of headache symptoms in migraine

could be as early as 5 years of age in males, however in females, age of

onset is closely associated with the beginning of first menstrual cycle

(menarche) [Stewart et al., 1991]. Therefore, increased production

of female hormones might be one of the several factors which lead to

an increase in the incidence of migraine in the postpubertal period.

No gender specific inference could be drawn on published literature

regarding the age of onset of first depressive symptoms, with

indications of an earlier onset in women by some [Fava et al.,

1996] and absence of any significant difference by others [Perugi

et al., 1990]. Nevertheless, majority of studies have observed greater

severity of depressive symptoms in women with more frequent

recurrence [Fava et al., 1996; Bracke, 1998]. Information about

differential age of onset and severity in seizure disorder is very

scant to reach any conclusive evidence for role of estrogens in

seizure susceptibility.

In summary, while severity of disease might correlate with

estrogen levels, women often show a delay in the age of onset with

comparatively mild symptoms. This further supports the idea that

the estrogens might play a role in modulating both the expression as

well as progression of clinical symptoms in women.

Types of SymptomsThere is consensus in research articles with regard to gender being

an important variable in contributing to the differential symptom

profiles in men and women, diagnosed with disturbances in the

functioning of nervous system. For instance, men are more prone to

progressive neuronal damage associated with repetitive seizures

[Briellmann et al., 2000]. On other hand, epilepsy is considered as

one of the most common reproductive endocrine disorders in

women with reports of increased risk of spontaneous abortions

[Schupf and Ottman, 1997]. Women with PD are more likely

to experience impairment of postural stability and depressive

FIG. 2. Role of genetic variability in disposition of estrogens. Menstrual cycle, pregnancy, perimenopausal, and postmenopausal phases and

exogenous hormonal therapy are associated with variability in estrogen levels in women’s life. Genetic variants from estrogen metabolizing

enzymes could influence the state of hormonal homeostasis during any of these phases. In addition, genetic polymorphisms in estrogen receptors

could also alter the functional effect of endogenous as well as exogenous estrogens.

GROVER ET AL. 1393

symptoms [Lyons et al., 1998; Rojo et al., 2003; Haaxma et al., 2007].

In contrast, men tend to exhibit sleeping disturbances such as rapid

eye movement behavior disorders with wandering and violent

intentions [Scaglione et al., 2005]. While symptoms in men afflicted

with SCZ include hyperactivity, attention deficit, aggression, and

antisocial behavior, women are more commonly associated with

anxiety, depression, and affective symptoms [Goldstein and Link,

1988; Hafner, 2003]. Men with MS are frequently associated with

motor symptoms and cognitive deficits as compared to women

[Hawkins and McDonnell, 1999; Savettieri et al., 2004]. Weight loss

appears to be more common in men with depression than woman

who tend to gain weight characterized by an increased appetite.

Increase anxiety, anger, and sleep disturbances are few other

symptoms which are more often associated with depressed women

[Frank et al., 1988; Perugi et al., 1990]. Women with migraine

experience nausea and photophobia symptoms lasting for several

hours more often than men, in whom migraines with aura are more

prevalent [Rasmussen and Olesen, 1992]. Data on gender-specific

symptoms are relatively scarce for AD. In summary, although there

are clearly defined gender-based differences in symptomatology of

CNS disorders, a deeper understanding is required for potential

explanations on direct or indirect actions of female sex hormones.

Menstrual CycleReproductive life of females between puberty and menopause is

governed by cyclical changes in circulating estrogen and progester-

one (Pg) levels during the menstrual cycle. Menstrual cycle begins

with a menstrual phase characterized by shedding of endometrium

with low E2 levels. This is followed by a follicular phase with build-

up of endometrium along with synthesis of E2 by ovarian follicles.

Follicular phase ends with ovulation immediately after attaining

steep peak in E2 levels. The final stage is the luteal phase during

which E2 shows a slight rise in its levels and begins to fall shortly

before the onset of menstrual flow. These cyclical variations in

E2 levels during menstrual cycle have been linked to the onset or

worsening of symptoms associated with diseases of CNS. There are

incontrovertible epidemiological and neuropathological evidences

which implicate low estrogen levels, that is, hypoestrogenecity

during premenstrual and menstrual periods in providing trigger

for increased vulnerability to diseased mental state. For instance,

Quinn and Marsden [1986] reported deterioration in Parkinsonian

features during the onset of menstrual flow coinciding with the

decline in the levels of estrogens. Few studies have also shown

exacerbation of MS in the premenstrual period [Smith and Studd,

1992; Zorgdrager and De Keyser, 2002]. Withdrawal of estrogens

during menstruation might also lead to an increase in headache

symptoms in the migraine patients [Granella et al., 1993]. Premen-

strual syndrome (PMS), which affects 80% of women is character-

ized by recurrent physical and emotional symptoms and is further

accompanied with symptoms of irritability and depressed mood

during the late luteal phase [Halbreich, 2003]. Riecher-Rossler and

Hafner [2000] reported an increased probability in hospitalization

of schizophrenic patients during the late luteal phase of menstrual

cycle when estrogen levels are low. This increased severity of

symptoms is followed by a sudden remission with an elevation of

E2 levels during postmenstrual period in majority of these neuro-

logical diseases. In contrast to other disorders, a higher frequency of

seizures is associated with hyperestrogenic state during periovula-

tory period in women with catamenial epilepsy, a pattern of

epilepsy seen in more than 30% of women epilepsy patients

[Herzog, 2008]. We could not trace any study attempting to

correlate AD propensity with menstrual cycle which might be

attributed to relatively late onset of symptoms, after the cessation

of menstrual cycle in majority of patients. To sum up, rapid

fluctuating levels of estrogen during menstrual cycle in women

might contribute to increased sensitivity towards CNS dysregula-

tion in women as compared to men.

PregnancyPregnancy is characterized by several folds increase in the circulat-

ing levels of estrogens including E2. Sustained period of high

E2 levels is followed by postpartum period when a precipitous

fall in E2 levels restores it back to its prepregnancy baseline levels.

Both onset of pregnancy and postpartum period are considered as

important milestones for women’s mental health. During these

periods, changing E2 levels might predispose women towards onset

of neuropsychiatric disorders or it may result in either deterioration

or improvement of symptoms associated with pre-existing brain

disease. Lower rates of relapse with onset of pregnancy have been

observed in patients with MS with a reversal to baseline levels after

delivery [Confavreux et al., 1998]. E2 might also exert its neuro-

protective role in reducing the migraine frequency during preg-

nancy with most of published articles showing improvement in

headache particularly in patients diagnosed for migraine without

aura before pregnancy [Chen and Leviton, 1994; Sances et al., 2003].

Several studies have observed an increase in the rate of postpartum

(or puerperal) psychoses within first few months after childbirth

as confirmed by referral or hospitalization records [Nott, 1982;

Kendell et al., 1987]. About 14–18% of women experience

moderate-to-severe depressive symptoms during the last trimester

of pregnancy or in the early postpartum period [Kumar and

Robson, 1984; Josefsson et al., 2001]. Pregnancy might even alter

the seizure threshold as compared to prepregnancy period with up

to 45% of women with epilepsy reporting an increase in seizure

frequency [Knight and Rhind, 1975; Otani, 1985]. However, such

results should be interpreted with caution as many patients stop

taking medication due to conventionally known risk of teratoto-

genecity associated with some of the AEDs [Otani, 1985]. Chances

of a Parkinson’s or an Alzheimer’s patient getting pregnant is

extremely rare as late age of onset is observed in majority of patients

after the permanent cessation of menstrual cycle. Nonetheless, there

have been several case reports showing exacerbation of symptoms

with pregnancy in young onset PD [Routiot et al., 2000; Mucchiut

et al., 2004]. In summary, influence of hormonal associated changes

during pregnancy and postpartum period on neuronal activity is

clearly evident. However, a deeper understanding of this phenom-

enology is required for the development of suitable therapeutic

choices.

MenopauseMenopause refers to a complete loss of reproductive functions in

women as a result of menstrual cycle cessation. It is a part of normal


aging process which follows a series of complex physiological

changes in a female’s body and culminates with a precipitous

depletion of ovarian follicles. There is as much as 90% fall in

estrogen levels during period of transition leading to menopause

(perimenopausal period) compared to levels in the premenopausal

period. Both perimenopausal and postmenopausal period have

potential influence on neuronal activity with considerable epide-

miological evidence showing a surge in risk factor for vulnerability

to plethora of neuropsychiatric disorders. This period of low

estrogen levels which also results in an increase in severity of

symptoms suggests a neuroprotective role of estrogens in premen-

opausal women. Support for neuroprotective action of estrogens

also comes from numerous in vitro cell culture and in vivo animal

models studies [Woolley, 2007]. However, several studies have

indicated perimenopausal period as a more crucial period for an

increased vulnerability as compared to postmenopausal period.

Moreover, improvement in the symptoms has been reported by few

studies for several neurological disorders during the postmeno-

pausal period. The plausible scientific reason for these differential

risks has been debated over the last several years, although low

estrogen levels have been observed during both the periods. It is

hypothesized that fluctuating estrogen levels during perimen-

opausal period could act as a trigger for the development of the

nervous system disorders. In addition, duration for transition to

menopausal period could also be a crucial factor in determining the

risk factors. An observational study by Bonomo et al. [2009]

reported a higher incidence and prevalence of AD in postmeno-

pausal women as compared to age-matched men. The study also

identified period of menopausal transition as a crucial factor for

predisposition to neurodegeneration in women. Recent studies by

Freeman et al. [2004, 2006] reported greater than twofold increase

in depressive symptoms in women undergoing menopausal tran-

sition as compared to premenopausal stage. The author also

observed an improvement in the depressive symptoms after this

transitional period, further supporting the hypothesis of fluctuat-

ing estrogen levels as a risk factor rather than low estrogen levels.

A study of schizophrenic women observed a sudden increase in

incidence of SCZ at 45–50 years of age around the premenopausal

period [Riecher-Rossler and Hafner, 2000]. On other hand,

improvement in migraine symptoms has been replicated in several

studies, during both the periods of menopausal transition as well as

postmenopausal phase [Neri et al., 1993; Freeman et al., 2008]. So

far, there have been very limited studies investigating changes in risk

factors associated with menopausal transition in women diagnosed

with young onset PD and MS. To conclude, while fluctuating

estrogen levels appear to be more prominent in determining the

onset and course of several brain disorders, sustained low levels of

estrogens could have neuroprotective effect as well as pathological

consequences.

Drug ResponseGender-specific effects of estrogens may also get reflected in

differential dose requirement, response time, and predisposition

to adverse drug reactions (ADRs) to commonly prescribed med-

ications for the treatment of brain diseases. In addition, a woman

may respond differently according to her hormonal status during

different phases of menstrual cycle, pregnancy, postpartum period,

perimenopausal transition, and postmenopausal stage.

Wong et al. [1999] observed a higher risk of lamotrigine-related

skin rash in women as compared to men diagnosed with epilepsy. In

addition, men with epilepsy are more prone to vigabatrin-induced

visual changes [Wild et al., 1999]. Levodopa is one of most

commonly prescribed dopaminergic agonists for the treatment of

Parkinsonian symptoms. Although women on levodopa showed a

marked improvement in motor symptoms than men, they were

more prone to drug-induced dyskinesia [Arabia et al., 2002; Zappia

and Quattrone, 2002]. While MacGowan et al. [1998] observed

better response to acetylcholinesterase therapy for the treatment of

AD in men; no gender differences were observed for treatment with

tacrine by Rigaud et al. [2000]. Absence of gender differences was

also observed in migraine patients treated with antiepileptic drugs

(AEDs) including topiramate [Rothrock et al., 2005] and valproate

[Stillman et al., 2004]. Recently, a study by Dodick et al. [2008]

observed that the use of eletripan resulted in a reduced incidence of

headache recurrence in women aged 35 or above with a history of

severe headache. Similarly, pharmacological response to different

categories of antidepressants exhibits gender bias. While women are

known to respond better to selective serotonin uptake inhibitors

(SSRI), men respond best to tricyclic antidepressants (TCA)

[Glassman et al., 1977; Khan et al., 2005; Berlanga and Flores-

Ramos, 2006; Young et al., 2009]. Few studies have also reported

absence of gender differences towards drug responsiveness in

patients diagnosed with depression [Parker et al., 2003; Wohlfarth

et al., 2004; Thiels et al., 2005]. In general, female schizophrenic

patients respond faster to antipsychotics with a greater improve-

ment in overall clinical symptoms than male counterparts

[Salokangas, 1995; Robinson et al., 1999; Goldstein et al., 2002;

Usall et al., 2007]. However, these gender differences might get

eliminated with age in postmenopausal women with some inves-

tigations even reporting higher dose requirement of antipsychotics

[Seeman, 1983; Dworkin and Adams, 1984]. Moreover, gender-

specific influence is not consistent with regard to antipsychotic

treatment with few studies reporting absence of differential drug

response [Perry et al., 1991; Labelle et al., 2001]. In summary,

considering clinical implications of female hormones on drug

response, there are relatively few studies which have addressed the

biochemical and molecular basis of these gender differences. Over-

all, ADRs are more common to women than men possibly due to

influence of female sex hormones on inducibility of drug metabo-

lizing enzymes (DME). Moreover, estrogens are known to influence

neurotransmission and may influence sensitivity of drug targets.

Hormone Replacement TherapyAs postmenopausal women with low levels of circulating estrogen

might be associated with vulnerability to spectrum of diseased

states, estrogen replacement therapy for the treatment of health-

related problems has been in practice for last several decades.

However, in patients with epilepsy, estrogens being proconvulsant,

estrogen therapy might enhance the seizure frequency [Harden

et al., 2006]. A series of findings by Women’s Health Initiative

Memory Study (WHIMS) suggested lack of efficacy in the treat-

ment of cognitive decline or dementia with exogenous estrogens as

GROVER ET AL. 1395

well as combination therapy [Rapp et al., 2003; Shumaker et al.,

2003, 2004; Espeland et al., 2004]. On the other hand, the study also

observed that hormonal therapy was associated with increased risk

of stroke and breast cancer. Similar results indicating lack of efficacy

were confirmed by numerous other reports [Haskell et al., 1997].

On the contrary, several other publications showed a reduced AD

risk in women with history of hormonal therapy [Tang et al., 1996;

Kawas et al., 1997; Waring et al., 1999]. An improvement in motor

symptoms in Parkinsonian postmenopausal women was observed

with estrogen therapy in several clinical studies [Saunders-Pullman

et al., 1999; Tsang et al., 2000]. Neuroprotection exerted by estro-

gens is also evident in the treatment of MS with estriol (E3), which is

also known to be a protective factor against MS during pregnancy

[Sicotte et al., 2002]. Maintenance of stable levels of endogenous

estrogens after menopause is hypothesized to play a role in im-

proving the clinical symptoms for some of the neuropsychiatric

disorders. Similarly, several studies have shown that transdermal

estrogen therapy is more effective than oral therapy, which could be

attributed to more stable estrogen milieu achieved with non-oral

therapy. In contrast, oral delivery could even worsen the clinical

symptoms in migraineurs with an increase in headache frequency

[Nappi et al., 2001]. On the other hand, transdermal estrogen

therapy, although ineffective, did not deteriorate the prevailing

symptoms in such patients. Estrogen therapy for the treatment of

mood disorders is also well documented with reports of significant

amelioration of mood, immediately after childbirth (puerperal),

premenstrual, perimenopausal, and postmenopausal periods in

women diagnosed with severe depression or mood disorders

[Zweifel and O’Brien, 1997; Soares et al., 2003]. Improvement in

negative symptoms with estrogen therapy besides neuroleptic

treatment has also been reported in schizophrenic women with a

rapid remission from psychotic symptoms [Kulkarni et al., 1996;

Lindamer et al., 2001]. Although, use of hormonal replacement

therapy has proved beneficial for the treatment of neuropsychiatric

disorders in more than half of the clinical trials, many observational

studies have failed to reach any significant conclusion [Haskell et al.,

1997; Rapp et al., 2003; Morrison et al., 2004]. This might be

attributed to differential dose requirement and optimal duration of

therapy specific for each patient [Warren, 2007]. Furthermore, age

at the time of initiation of treatment and route of estrogen delivery

could also play a major role in influencing the response [Shumaker

et al., 2003; Kuhl, 2005]. In addition, some clinical trials have also

indicated harmful effects with risks of clotting and stroke particu-

larly in women on long-term therapy [Bushnell, 2005]. Hence, a

clinician must weigh the risk and benefits of the therapy before

prescribing an optimum dose for an appropriate duration for

medical treatment of neurological and psychiatric diseases.

ROLE OF GENETIC VARIABILITY IN ESTROGENDISPOSITION

Besides age, gender, and environmental factors, genetic variability

may also influence hormonal milieu by altering metabolism of

estrogens. Over the last decade, complex network of enzymes

involved in the estrogen metabolism has been well characterized.

Considerable evidence has emerged in recent years implicating

genetic polymorphisms in estrogen metabolizing enzymes in con-

tributing to the risk of hormone-related diseases. Polymorphisms

in the genes encoding phase I estrogen metabolizing enzymes

mainly cytochrome P450 enzymes and phase II estrogen metabo-

lizing enzymes including sulfo and catechol transferases have been

extensively studied in this regard. In addition, genetic variability in

estrogen receptors could alter the sensitivity of neuronal cells to

estrogens. Further, corroborating role of genetic polymorphisms in

modulating disease susceptibility also comes from several reports

showing role of genetic variants in modulating circulating estrogen

levels. Based on the available literature, comprehensive schematic

pathway of estrogen synthesis and degradation has been shown in

Figure 3.

PHASE I ESTROGEN METABOLIZING ENZYMES

Phase I metabolism involves oxidation and reduction reactions

that are primarily catalyzed by members of cytochrome P450

(CYP) superfamily of enzymes. Several genetic variants from

genes encoding phase I estrogen metabolizing enzymes such as

CYP1A1, CYP1A2, CYP1B1, CYP17A1, and CYP19A1 have been

well studied with respect to estrogen metabolism and estrogen-

dependent disorders (Fig. 3).

CYP1A1 (Cytochrome P450, Family 1, Subfamily A,Polypeptide 1)CYP1A1 is expressed predominantly in extrahepatic tissues includ-

ing nervous tissue in the brain [McFayden et al., 1998]. It is one

of the major cytochrome P450 (CYP) isoforms involved in the

hydroxylation of estrone (E1) and E2 into their respective catechol-

estrogens (CEs): 2-OH-E1 and 2-OH-E2, resulting in lowered

estrogenicity [Lee et al., 2003]. It also plays a minor role in the

generation of 4- and 16a-hydroxylated derivatives of E1 and E2

[Badawi et al., 2001; Lee et al., 2003].

In recent years, SWAN (the Study of Women’s health Across

Nations) group, engaged in a multiethnic longitudinal study has

extensively studied genetic variants in CYP1A1 for predisposition

towards estrogen-related neuropsychiatric disorders. The group

reported significant association of IVS1þ 606 (C/A) with depres-

sive symptoms in premenopausal and perimenopausal women

[Kravitz et al., 2006a]. The study indicated CC and AC genotypes

in Caucasians and CC genotype in African Americans as risk factors

for showing depressive traits [Kravitz et al., 2006a]. The ethnic

variability in estrogen metabolism was further reflected in circu-

lating serum E2 levels measured during the same study [Sowers

et al., 2006a]. Of all the ethnic groups studied, only Japanese women

were associated with markedly lower E2 levels with CC genotype as

compared to AC and AA genotype. Significantly lower E2 levels in

Japanese women might be indicative of a higher catalytic efficiency

of CYP1A1 with CC genotype. The Chinese women, on the other

hand, showed an association of CC genotype with 2-OH-E1.

Further, African American women with CC genotype had

elevated 16a-OH-E1 levels. A recent study by our group also

suggested functional significance of the variant, with an altered

drug response in Indian women with epilepsy. We observed an over


-representation of the ‘‘A’’ allele and AA genotype in women

patients with recurrent seizures on adequate AED treatment, as

compared to patients showing excellent control over seizures

[Grover et al., 2010]. However, so far, there has been no report

of in vitro studies demonstrating the influence of IVS1þ 606 (C/A)

in altering enzymatic activity.

In addition, few other genetic variants have been well character-

ized for their influence on enzymatic activity. An increase in E2

metabolism by several folds resulting in a lower free E2 index (total

E2: SHBG) and elevated mean urinary levels of estrogen metabolites

have been observed in women with Thr461Asn variant [Napoli

et al., 2005]. In the same year, Kisselev et al. [2005] reported a higher

catalytic efficiency of CYP1A1 with Ile462Val substitution for

generation of 2-OH derivatives of estrogens in reconstituted CY-

P1A1 systems. Hence, both these genetic variants from CYP1A1

may confer differential vulnerability to diseases of CNS by modu-

lating estrogen catabolism.

CYP1A2 (Cytochrome P450, Family 1, Subfamily A,Polypeptide 2)CYP1A2 plays a major role in the generation of hydroxylated

derivatives of E1 and E2, mainly hydroxylated at II or IV carbon

positions of the aromatic ring [Yamazaki et al., 1998]. However, at

higher estrogen concentration, other CYPs such as CYP2C19,

CYP3A4 and to a lesser extent CYP2C9 might exert predominant

influence in its metabolism [Zhu and Lee, 2005; Cribb et al., 2006].

There has been paucity of literature on the role of genetic

variants from CYP1A2 on estrogen metabolism. A report by Lurie

et al. [2005] reported a significant association of �163C>A

(CYP1A2*1F) polymorphism in the promoter region of CYP1A2

with lower E2 levels. The study observed an association of CC

genotype with lower serum E2 levels and AC genotype with lower

urinary 2-OHE1/16a-OHE1 during the luteal phase in premeno-

pausal women. Hence, CYP1A2*1F may be a susceptible allele for

neurotransmitter imbalance, exerting its influence through altered

estrogen metabolism.

CYP1B1 (Cytochrome P450, Family 1, Subfamily B,Polypeptide 1)CYP1B1 is expressed primarily in the extrahepatic steroidogenic

tissues including brain [Rieder et al., 1998]. It plays an important

role in the metabolism of estrogens, catalyzing the oxidation of

E1 and E2 to their respective 2- and 4-hydroxy CEs and further

to semiquinones and quinones [Hayes et al., 1996; Belous et al.,

2007]. In addition, CYP1B1 also contributes to estrogen toxicity

by catalyzing hydroxylation of E2 to 16a-E2 having carcinogenic

FIG. 3. Pathway of estrogen metabolism. Me, Methoxy; S, sulfate; G, glucoronide; Q, quinone.

GROVER ET AL. 1397

potency. Using a yeast expression system, Hayes et al. [1996]

demonstrated that CYP1B1 exhibits a higher specific activity to-

wards 4-hydroxylation than 2-hydroxylation of E2. Furthermore,

Hanna et al. [2000] observed that genetic variants from CYP1B1

displays a higher fold increase in catalytic efficiency towards 4-

hydroxylation reaction than 2-hydroxylation and 16a-hydroxyl-

ation reactions, respectively.

Functional genetic variants from CYP1B1 have also been associ-

ated with variable estrogen levels in both postmenopausal and

premenopausal women. Napoli et al. [2009] in a study on post-

menopausal women and Garcia-Closas et al. [2002] on premeno-

pausal women independently reported a decline in the rate of

estrogen catabolism in carriers of leu432Val variant, as indicated

by decreased urinary E2 metabolites and increased serum E2 levels,

respectively. In contrast, De Vivo et al. [2002] observed an increase

in estrogen catabolism with leu432Val variant compared to wild-

type form. Significantly raised serum E2 levels were also observed

with Asn453Ser polymorphism [Garcia-Closas et al., 2002]. On the

other hand, in vitro studies by Hanna et al. [2000] showed that these

variants and Ala119Ser display a higher catalytic efficiency with a

corresponding increase in 2-, 4-, and 16a-hydroxylated forms of E2.

Hence, both in vitro and in vivo studies have yielded conflicting

results with leu432Val as well as Asn453Ser. Further, a study by

Aklillu et al. [2002] demonstrated that neither of these missense

mutations on its own could explain activity of enzyme, showing the

role of haplotypic combinations of the genetic variants for better

prediction of altered enzymatic activity.

CYP17A1 (Cytochrome P450, Family 17,Subfamily A, Polypeptide 1)CYP17A1 catalyzes conversion of pregnenolone and progesterone

(Pg) to dehydroepiandosterone (DHEA) and androstenediol (A),

respectively [Zwain and Yen, 1999; Kristensen and Borresen-Dale,

2000]. Relatively, few functional variants from CYP17A1 gene have

been studied for testing associations with steroid levels and altered

disease vulnerability in women. Among them, a promoter poly-

morphism (�34T>C; A1>A2), which also generates a MspAI

restriction enzyme recognition site, has shown an association with

estrogen metabolism irrespective of menopausal status in women.

Its significant association with elevated serum E2 and Pg levels were

first reported by Feigelson et al. [1998] in premenopausal women.

Later, role of this variant in influencing estrogen metabolism was

also replicated in postmenopausal women with A2/A2 genotype

resulting in raised E1 levels as compared to women with A1/A1

genotype [Haiman et al., 1999].

CYP19A1 (Cytochrome P450, Family 19,Subfamily A, Polypeptide 1)CYP19A1 (CYP19; aromatase) catalyzes the final step in the bio-

genesis of estrogens by converting C19 androgens, androstenediol

(A) and testosterone (T), into C18 estrogens, E1 and E2, respectively,

with little modifications to follow in the downstream pathway of

estrogen metabolism [Stoffel-Wagner et al., 1999]. Being a rate-

limiting step in the synthesis of estrogens, expression and activity of

CYP19A1 could play a major role in determining hormonal milieu

in women [Mendelson et al., 1990]. Consistent with its functional

significance, several polymorphic variants have been reported for

their association with altered steroid levels as well as estrogen-

dependent neuropsychiatric disorders. Recently, studies have dem-

onstrated that the variants from brain aromatase gene may modify

the risk of AD [Livonen et al., 2004; Huang and Poduslo, 2006] and

depressive symptoms [Kravitz et al., 2006a]. In addition, role of

these polymorphic variants might be of considerable significance in

females with reports demonstrating a large reduction of aromatase

levels in the brain of women AD patients [Yue et al., 2005].

As CYP19 catalyzes conversion of T into E2 and ‘‘A’’ into E1,

hence any alteration of T:E2 or A:E1 baseline levels might be

indicative of its catalytic activity. For instance, an elevation in

serum E2 levels or a fall in serum T or T:E2 levels could all be the

consequence of higher enzymatic activity of CYP19. A significantly

lower serum T:E2 was reported by Sowers et al. [2006b] in pre-

menopausal or perimenopausal African American women with TT

genotype for IVS2þ 36415C>T (rs936306) variant. In the same

study, author also observed markedly lower serum T levels in

Japanese women with AA genotype as compared to AG genotype

for IVS2� 23584G>A (rs749292) polymorphism. TT genotype

for rs936306 was further reported by Kravitz et al. [2006a] with a

considerable increased risk for showing depressive symptoms in

premenopausal or perimenopausal women. The author also ob-

served differences in cognitive functioning with the same variant in

various ethnic populations. In a study by Somner et al. [2004], a

synonymous variant with G to A transition (rs700518) in post-

menopausal women was significantly associated with higher serum

E2 levels. On the contrary, another study reported reduced serum E2

levels and elevated serum T:E2 levels in postmenopausal women

with T to C transversion for rs10046 present in 30 untranslated

region [Dunning et al., 2004]. Similar results were also observed

with silent [(TCT)þ/�] (rs11575899) polymorphism in the IVS4 of

CYP19 gene by the same group. A study by Paynter et al. [2005] in

postmenopausal women showed an increase in aromatase activity

for several intronic allelic variants (rs4775936, rs11636639,

rs767199) on the basis of serum E1, E2, ‘‘E1:A,’’ or E2:T levels. A

tetranucleotide repeat polymorphism (TTTA)n has also been ex-

tensively studied for its influence on hormonal milieu in women. A

significant increase in E1:A was observed by Haiman et al. [2000] in

women homozygous for eight repeats of (TTTA) when compared

with women with different number of repeats. On the other hand,

Tworoger et al. [2004] observed an increase in E1 and E2 in women

carrying (TTTA)8 in homozygous as well as heterozygous condi-

tion. The importance of this repeat polymorphism was further

realized with a recent article reporting its association with AD in

women having longer repeats (8–13) as compared to women

homozygous for seven repeats of the polymorphism [Butler

et al., 2009]. A significant association of AD was also observed

with several other allelic variants including insertion/deletion

polymorphism (rs11575899) and intronic variants (rs1065778,

rs727479, rs767199) [Livonen et al., 2004; Butler et al., 2009]. In

summary, genetic variants from CYP19 appear to play a major role

in disease susceptibility with large number of polymorphisms

showing notable associations with altered sex steroid levels in

women.


PHASE II ESTROGEN METABOLIZING ENZYMES

Phase II metabolism involves conjugation of glucoronic, glutathi-

one, methyl, and sulfate moieties to estrogens and their metabolites

(Fig. 3). This makes them more hydrophilic as compared to their

parent substrates and facilitates renal excretion. Several genetic

variants in the genes encoding phase II enzymes mainly COMT

and SULT1A1 are known to influence estrogen metabolism, which

might modulate predisposition to common neuropsychiatric

disorders.

COMT (Catechol-O-Methyltransferase)Catechol-O-methyltransferase (COMT) is a ubiquitously

expressed key phase II metabolizing enzyme involved in the inacti-

vation of estrogen metabolites. After the conversion of E1 and

E2 into 2- and 4-CEs by CYP1A1 and CYP1B1, COMT catalyzes

O-methylation of these CEs into respective methoxy metabolites

[Ball et al., 1972]. The methoxy conjugates exhibit markedly

reduced or no affinity for estrogen receptors as compared to their

parent substrates and could act as temporary reservoirs for the

release of active estrogens. Further, CEs can also be competitively

oxidized by CYP1B1 and NADPH quinone oxidoreductase

(NOQ1) to corresponding 3,4-semiquinones and quinones, which

may act as potent carcinogens by forming depurinated DNA

adducts [Belous et al., 2007; Singh et al., 2009] Thus, COMT also

plays a role of an intrinsic detoxifying agent by shifting the balance

of estrogen metabolic pathway towards the generation of methyl-

ated derivatives.

Estrogens are known to alter activity and expression of COMT by

regulating its transcription, mediated via their binding to estrogen

response elements in the COMT gene. Estrogen response elements,

which are located in the proximal and distal promoter regions,

further regulate the relative expression of two known isoforms of

COMT—membrane bound form (MB-COMT) and cytosolic or

soluble isoform (S-COMT), previous isoform being expressed

predominantly in the CNS [Tenhunen et al., 1994; Hong et al.,

1998; Xie et al., 1999]. Further, COMT could also influence

neuronal activity by altering the degradation of catecholamines

as dopamine and noradrenaline neurotransmitters are primarily

inactivated by COMT [Hamilton et al., 2002].

COMT, being a major inactivation enzyme for the metabolism of

estrogens and neurotransmitters, could serve as a candidate gene

for influencing estrogen levels and vulnerability to prevalent neu-

ropsychiatric disorders. Female gender characterized by higher

estrogen levels with considerable variability might be at greater

risk for predisposition to brain diseases. Further, some studies

have highlighted lower COMT activity in women as compared

to men, making women more vulnerable to diseases with even a

slight alteration in its activity [Fahndrich et al., 1980; Boudikova

et al., 1990].

Several epidemiological studies have shown that alteration in

COMT expression and activity could have a major impact on

women’s mental health. In this regard, substantial evidence has

emerged in last few years showing influence of functionally char-

acterized genetic variants in altering, circulating E2 levels as well as

prevalence of neuropsychiatric disorders in women. The most

extensively studied functional polymorphism is valine (val) to

methionine (met) substitution, corresponding to codon 158 in the

MB-form. The met variant has been linked to a 40% reduction in the

methylation activity of the enzyme as demonstrated by Chen et al.

[2004] using postmortem human prefrontal cortex tissue. The

functional effect of val to met transition was also evident in

significantly higher urinary levels of 16a-OH-E1 with Met/Met

genotype as compared to Val/Val genotype in postmenopausal

women from non-Hispanic white ethnicity [Tworoger et al., 2004].

However, the study failed to observe any association with circulat-

ing E1 or E2 levels. In another report by Worda et al. [2003], it was

observed that postmenopausal women on exogenous E2 prepara-

tion, with Met allele in homozygous as well as heterozygous

conditions, had significantly higher serum E2 levels as compared

to wild-type Val/Val genotype. So far, investigations of polymor-

phic variants from COMT gene with disease vulnerability in female

gender have yielded mixed results with several studies failing to

observe gender specificity. Few studies have observed association of

intermediate phenotypes of anxiety mainly harm avoidance [Enoch

et al., 2003], low extraversion, and high neuroticism [Eley et al.,

2003; Stein et al., 2005] in women with low activity Met allele. In

contrast, women with phobic anxiety [McGrath et al., 2004] and

panic disorder [Rothe et al., 2006] showed significant over-repre-

sentation of Val allele. Women specific influence of COMT gene

variation has also been reported for other loci in the gene. Female

gender with GG genotype for rs165599 displayed a significant

association with schizophrenic symptoms in a case control study

[Shifman et al., 2002]. Another variant, IVS1þ 701A>rs737865

(AA) was significantly over-represented in women showing low

extraversion trait [Stein et al., 2005]. In conclusion, due to the

influence of COMT on nervous system via different pathways, it

might be difficult to attribute gender-specific associations with

steroid levels and could be one main reason for inconclusive genetic

associations with CNS disorders.

SULTs: SULT1A1 (Sulfotransferase Family,Cytosolic, 1A, Phenol-Preferring, Member 1) andSULT1E1 (Sulfotransferase Family, Cytosolic, 1E,Phenol-Preferring, Member 1)Sulfotransferases (SULTs) are members of a superfamily of soluble

cytosolic proteins that preferentially catalyze estrogen sulfonation

through transfer of the sulfo group to nucleophilic sites of estrogens

forming water-soluble and biologically inactive estrogen sulfates

[Adjei and Weinshilboum, 2002]. These conjugates are excreted

into the bile or urine, resulting in reduced levels of estrogen

exposure in the target tissues. SULT1A1 is considered as a predomi-

nant type of SULT among SULT1E1, SULT1A1, and SULT2A1 due

to its extensive tissue distribution, abundance, and broad substrate

specificity for estrogens including CEs [Coughtrie, 2002].

SULT gene is highly polymorphic with three commonly known

allozymes (SULT1A1*1, SULT1A1*2, and SULT1A1*3)

[Raftogianis et al., 1999; Carlini et al., 2001]. Several recent studies

have reported association of SULT1A1*2 allele, defined by

Arg213His (638G>A) polymorphism, with a lower enzyme

activity and reduced estrogen sulfation ability than the wild-type

GROVER ET AL. 1399

variant [Adjei and Weinshilboum, 2002; Coughtrie, 2002; Shata-

lova et al., 2005; Yang et al., 2005; Nagar et al., 2006]. Yang et al.

[2005] demonstrated that women carrying ‘‘His’’ allele show

significantly decreased levels of plasma E1-S and DHEA-S. So far,

none of the genetic variants in SULT has been characterized for their

possible association with neuropsychiatric diseases.

ESTROGEN RECEPTORS

Estrogens exert their action by binding to estrogen receptors, which

are widely distributed throughout the human brain (Fig. 3). These

receptors are members of the nuclear receptor superfamily of

ligand-activated transcription factors.

ERs: ERa (Estrogen Receptor a) and ERb(Estrogen Receptor b)Estrogen receptor proteins, ERa and ERb, are transcription factors

encoded by estrogen receptor genes, ESR1 and ESR2, which exert

their influence by binding to estrogen responsive elements (ERE) in

the regulatory regions of multiple genes such as COMT, CYP19,

APOE, and HLA. Owing to their binding to numerous genes, these

proteins could account for pleiotropic effects of estrogens in the

nervous tissue by regulating transcription of their respective target

genes. ERa and ERb being structurally and functionally distinct,

it is the relative proportion of both the receptors that regulate

estrogenicity in the brain in spatial as well as temporal dependent

fashion. Consistent with their functional significance, several stud-

ies have demonstrated an alteration in expression levels of these

receptor proteins in pathophysiology of neurological diseases with

gender specificity observed in some studies. Common genetic

variants including functionally important polymorphisms have

been implicated in migraine, SCZ, AD, PD, and mood disorders.

Intronic PvuII (rs2234693), XbaI (rs9340799), and variable number

tandem repeat (VNTR) polymorphisms are the most extensively

studied ERa genetic variations for their role in modulating disease

risk, possibly by altering the expression level of estrogen receptors

and serum E2 levels.

Schuit et al. [2005] demonstrated a 22% reduction in E2 levels in

postmenopausal women carrying PvuII–Xba1 haplotype (T–A) in

homozygous condition as compared to non-carriers. The author

attributed the significant association to modulated expression of

estrogen metabolizing enzyme, CYP19 or 17b HSD. This could be

due to the influence of altered ESR1 transcription through E2 in

homozygous carriers. Lower circulating E2 levels were even ob-

served by Sowers et al. [2006c] in African American women

harboring ESR1 rs3798577 CC genotype and Japanese women with

ESR2 rs1255998 GC genotype. Estrogens may also influence tran-

scription of APOE, known to be a risk factor for predisposition to

AD, thereby modulating synaptic sprouting and b amyloid metab-

olism in cholinergic neurons. Further, support for the interaction

between estrogens and APOE also comes from a study by Porrello

et al. [2006] in which carriers of ERa—T allele (PvuII) or ‘‘A’’ allele

(XbaI) in combination with APOE e4 allele were at significantly

increased risk for developing sporadic AD in women as compared

to individuals who had neither of the alleles. Estrogens are known to

influence prevalence of migraine in women; functional genetic

variants in ESR1 might alter this prevalence by modulating E2

levels [Oterino et al., 2008]. In a recent study in North Indian cohort

of female patients, T allele and TT genotype of PvuII polymorphism

were significantly over-represented in migraineurs [Joshi et al.,

2009]. In another study, carriers of 594A (rs2228480) allele were

significantly associated with increased risk for developing Migraine

with aura in women as compared to control group [Colson et al.,

2004]. Several studies have suggested gender associated increased

risk of cognitive impairment with genetic variants from ESR1 gene,

specifically in elderly women. While Yaffe et al. [2002] observed

increased likelihood of impaired cognition with PvuII as well as

XbaI polymorphisms, a borderline association of XbaI with cogni-

tion in elderly postmenopausal women was observed by Olsen et al.

[2006].

Similar to ESR1, several genetic variants from ESR2 confer

increased risk to neurological diseases in a gender-dependent

manner. A report with genetic analysis of ESR2 polymorphisms

in AD patients and normal controls revealed significant allelic

and genotypic associations with disease risk for women carrying

IVS3� 1880C>T (rs1271573) and IVS4þ 1231C>T (rs1256043),

respectively [Pirskanen et al., 2005]. In another study, G1082A

polymorphism in heterozygous condition showed a strong associ-

ation with susceptibility to anorexia nervosa in women [Eastwood

et al., 2002]. A study by Geng et al. [2007] indicated the role of

shorter alleles of microsatellite repeats in the ESR2 gene in influ-

encing age of onset of major depressive disorder (MDD) in female

adolescents. Role of genetic variants from estrogen receptors in

diagnosis of MDD in women was also observed by Tsai et al. [2003].

The author reported allelic as well as genotypic associations of PvuII

polymorphism from ESR1 gene with susceptibility to MDD as

compared to healthy controls. Significant alterations in cognitive

functioning with rs9340799, rs22634693, and rs728524 were ob-

served by SWAN group. However, these associations were not

consistent across different ethnic groups in the same study

[Kravitz et al., 2006b].

Hence, it is clearly evident that genetic variants from estrogen

receptors might alter vulnerability to neuropsychiatric symptoms

particularly those associated with neurodegenerative disorders,

possibly by modulating, binding affinity of estrogens to their

respective receptors. Summing up, genetic polymorphisms

from estrogen receptors might mask neuroprotective effect of

estrogens.

SUMMARY

The clinical findings presented in the current review strongly

suggest influence of female sex hormones on phenotypic manifes-

tations of CNS imbalances. Besides, genetic polymorphisms from

several candidate genes appear to influence levels of circulating

estrogens and modulate risk factors for showing neuropsychiatric

symptoms (Table I). In addition, the existence of complete ma-

chinery of estrogen metabolizing enzymes as well as various pre-

cursors and intermediate metabolites of estrogens in the brain

tissues further demonstrate significance of estrogens in functioning

of neurons (Table I).


TAB

LEI.

List

ofAs

soci

ated

Vari

ants

From

Gen

esEn

codi

ng

Estr

ogen

Met

abol

izin

gEn

zym

esan

dR

ecep

tors

Gen

eR

eact

ion

cata

lyze

dEx

pres

sion

inbr

ain

tiss

uedb

SNP

ID(a

llele

)G

ene

loca

tion

Subs

titu

tion

sE

nzy

me

acti

vity

Asso

ciat

ion

(gen

otyp

e/al

lele

)in

fem

ales

Nuc

leot

ide

Amin

oac

idIn

vitr

oIn

vivo

Ster

oid

leve

lsN

euro

psyc

hiat

ric

dise

ase

Phas

eI

ster

oid

met

abol

izin

gen

zym

esCY

P1A1

(cyt

ochr

ome

P45

0,

fam

ily1

,su

bfam

ilyA,

poly

pept

ide

1)

2-h

ydro

xyla

tion

ofE

1an

dE

2

[Lee

etal

.,2

00

3]

4-

and

16

a-h

ydro

xyla

tion

ofE

1an

dE

2

[Bad

awi

etal

.,2

00

1;

Lee

etal

.,2

00

3]

Yes

[McF

ayde

net

al.,

19

98

]rs

26

06

34

5In

tron

1IV

S1þ

60

6C>

A?

Dec

reas

ed[S

ower

set

al.,

20

06

a]

Dec

reas

edse

rum

E2

(CC)

[Sow

ers

etal

.,2

00

6a]

Incr

ease

dur

inar

y2

-OH

-E1

(CC)

[Sow

ers

etal

.,2

00

6a]

Incr

ease

dur

inar

y1

6a

-OH

-E1

(CC)

[Sow

ers

etal

.,2

00

6a]

Dep

ress

ive

sym

ptom

s(C

C)[K

ravi

tzet

al.,

20

06

a]Ep

ileps

y(A

A)[G

rove

ret

al.,

20

10

]

rs1

79

98

14

(m4

,*4

)Ex

on7

c.1

38

2C>

ATh

r46

1As

n?

Incr

ease

d[N

apol

iet

al.,

20

05

]

Incr

ease

dur

inar

y2

-OH

-E1

and

16

a-O

H-E

1

(CAþ

AA)

[Nap

oli

etal

.,2

00

5]

?

Dec

reas

edse

rum

E2

:SH

BG

(CAþ

AA)

[Nap

oli

etal

.,2

00

5]

rs1

04

89

43

(m2

,*2

C)Ex

on7

c.1

38

4A>

GIle

46

2Va

lIn

crea

sed

[Kis

sele

vet

al.,

20

05

]

?In

crea

sed

invi

tro

2-O

H-E

1an

d2

-OH

-E2

(G)

[Kis

sele

vet

al.,

20

05

]

?

Incr

ease

d2

-OH

-E1

:16

-OH

-E1

(A)

[Tai

oli

etal

.,1

99

9]

CYP1

A2(c

ytoc

hrom

eP4

50

,fa

mily

1,

subf

amily

A,po

lype

ptid

e2

)

2-

and

4-h

ydro

xyla

tion

ofE

1an

dE

2

[Yam

azak

iet

al.,

19

98

]

Yes

[McF

ayde

net

al.,

19

98

]rs

76

25

51

(*1

F)In

tron

1c.�

16

3C>

A?

Incr

ease

d[L

urie

etal

.,2

00

5]

Dec

reas

edse

rum

E2

(CC)

[Lur

ieet

al.,

20

05

]

?

Dec

reas

edur

inar

y2

-OH

-E1

:16

a-O

H-E

1

(CCþ

AC)

[Lur

ieet

al.,

20

05

]

CYP1

B1

(cyt

ochr

ome

P45

0,

fam

ily1

,su

bfam

ilyB

,po

lype

ptid

e1

)

2an

d4

-hyd

roxy

lati

onof

E1

and

E2

[Hay

eset

al.,

19

96

]2

-OH

-E1

/E2

to

Yes

[Rie

der

etal

.,1

99

8]

rs1

05

68

27

Exon

2c.

35

5G>

TAl

a11

9Se

rIn

crea

sed

[Han

na

etal

.,2

00

0]

?In

crea

sed

invi

tro

2-,

4-,

and

16

a-O

H-E

2(T

)[H

ann

aet

al.,

20

00

]

?

sem

iqui

non

esan

dqu

inon

es[B

elou

set

al.,

20

07

]rs

10

56

83

6(m

1,

*3)

Exon

3c.

12

94

C>

GLe

u43

2Va

lIn

crea

sed

[Han

na

etal

.,2

00

0]

Incr

ease

d[D

eVi

voet

al.,

20

02

]D

ecre

ased

[Gar

cia-

Clos

aset

al.,

20

02

;N

apol

iet

al.,

20

09

].

Dec

reas

edse

rum

E2

(GG

)[D

eVi

voet

al.,

20

02

]D

ecre

ased

urin

ary

(2-O

H-E

1þ

2-M

eO-E

1þ

16

a-O

H-E

1þ

E3

)(G

G)

[Nap

oli

etal

.,2

00

9]

? (Con

tinu

ed)

GROVER ET AL. 1401

TAB

LEI.

(Con

tin

ued)

Gen

eR

eact

ion

cata

lyze

dEx

pres

sion

inbr

ain

tiss

uedb

SNP

ID(a

llele

)G

ene

loca

tion

Subs

titu

tion

sE

nzy

me

acti

vity

Asso

ciat

ion

(gen

otyp

e/al

lele

)in

fem

ales

Nuc

leot

ide

Amin

oac

idIn

vitr

oIn

vivo

Ster

oid

leve

lsN

euro

psyc

hiat

ric

dise

ase

rs1

80

04

40

(m2

,*4

)Ex

on3

c.1

35

8A>

GAs

n4

53

Ser

Incr

ease

d[H

ann

aet

al.,

20

00

]

Dec

reas

ed[D

eVi

voet

al.,

20

02

;

Incr

ease

din

vitr

o2

-,4

-,an

d1

6a

-OH

-E2

(G)

[Han

na

etal

.,2

00

0]

?

Gar

cia-

Clos

aset

al.,

20

02

]In

crea

sed

seru

mE

2(G

G+

AG)

[De

Vivo

etal

.,2

00

2;

Gar

cia-

Clos

aset

al.,

20

02

]

CYP1

7A1

(cyt

ochr

ome

P45

0,

fam

ily1

7,

subf

amily

A,po

lype

ptid

e1

)

Preg

nen

olon

ean

dPg

toD

HEA

and

AZw

ain

and

Yen

[19

99

]an

dK

rist

ense

nan

dB

orre

sen

-Dal

e[2

00

0]

Yes

[Zw

ain

and

Yen

,1

99

9;

Kri

sten

sen

and

Bor

rese

n-D

ale,

20

00

]

rs7

43

57

2(M

spAI

)Ex

on1

(5’U

TR)

c.�

34

T>

C?

Incr

ease

d[F

eige

lson

etal

.,1

99

8;

Hai

man

etal

.,1

99

9]

Incr

ease

dse

rum

E2

and

Pg(C

Cþ

CT)

[Fei

gels

onet

al.,

19

98

]In

crea

sed

seru

mE

1(C

C)[H

aim

anet

al.,

19

99

]

?

CYP1

9A1

(cyt

ochr

ome

P45

0,

fam

ily1

9,

subf

amily

A,po

lype

ptid

e1

)

Aan

dT

into

E1

and

E2

[Sto

ffel

-Wag

ner

etal

.,1

99

9]

Yes

[Sas

ano

etal

.,1

99

8;

Stof

fel-W

agn

eret

al.,

19

99

;Ya

gue

etal

.,2

00

6]

rs9

36

30

6In

tron

2IV

S2þ

36

41

5C>

T?

Incr

ease

d[S

ower

set

al.,

20

06

b]

Incr

ease

dse

rum

E2

:T(T

T)[S

ower

set

al.,

20

06

b]D

epre

ssiv

esy

mpt

oms

(TT)

[Kra

vitz

etal

.,2

00

6a]

rs1

16

36

63

9In

tron

2c.�

27

98

3G>

T?

Incr

ease

d[P

ayn

ter

etal

.,2

00

5]

Incr

ease

dse

rum

E2

(GTþ

TT)

[Pay

nte

ret

al.,

20

05

]In

crea

sed

seru

mE

2:T

(GTþ

TT)

[Pay

nte

ret

al.,

20

05

]

?

rs7

49

29

2In

tron

2IV

S2�

23

58

4G>

A?

Incr

ease

d[S

ower

set

al.,

20

06

b]

Dec

reas

edse

rum

T(A

A)[S

ower

set

al.,

20

06

b]?

rs7

67

19

9In

tron

2(5

0fl

ank)

c.�

52

78

G>

A?

Incr

ease

d[P

ayn

ter

etal

.,2

00

5]

Incr

ease

dse

rum

E2

:T(A

Aþ

AG)

[Pay

nte

ret

al.,

20

05

]

Alzh

eim

er’s

dise

ase

(GGþ

AG)

[Liv

onen

etal

.,2

00

4]

rs4

77

59

36

Intr

on2

c.�

91

3G>

A?

Incr

ease

d[P

ayn

ter

etal

.,2

00

5]

Incr

ease

dse

rum

E2

:T(A

Aþ

AG)

[Pay

nte

ret

al.,

20

05

]

?

rs7

27

47

9In

tron

3c.

56

3T>

G?

??

Alzh

eim

er’s

dise

ase

(GGþ

GT)

[Liv

onen

etal

.,2

00

4]

rs7

00

51

8Ex

on4

c.2

40

G>

AVa

l80

Val

?In

crea

sed

[Som

ner

etal

.,2

00

4]

Incr

ease

dse

rum

E2

(AA)

[Som

ner

etal

.,2

00

4]

?

rs1

06

57

78

Intr

on3

IVS4

�7

6A>

G?

??

Alzh

eim

er’s

dise

ase

(GGþ

AG)

[But

ler

etal

.,2

00

9]

Alzh

eim

er’s

dise

ase

(GGþ

AG)

[Liv

onen

etal

.,2

00

4]

rs1

15

75

89

9In

tron

5IV

S4þ

26

_IVS4

þ2

7In

s3?

Dec

reas

ed[D

unn

ing

etal

.,2

00

4]

Dec

reas

edse

rum

E1

and

E2

([TC

T]þ

/�)

[Dun

nin

get

al.,

20

04

]

Alzh

eim

er’s

dise

ase

(TCT

/TCT

)[B

utle

ret

al.,

20

09

]D

ecre

ased

seru

mE

2:T

([TC

T]þ

/�)

[Dun

nin

get

al.,

20

04

]

(Con

tinu

ed)


TAB

LEI.

(Con

tin

ued

)

Gen

eR

eact

ion

cata

lyze

dEx

pres

sion

inbr

ain

tiss

uedb

SNP

ID(a

llele

)G

ene

loca

tion

Subs

titu

tion

sEn

zym

eac

tivi

ty

Asso

ciat

ion

(gen

otyp

e/al

lele

)in

fem

ales

Nuc

leot

ide

Amin

oac

idIn

vitr

oIn

vivo

Ster

oid

leve

lsN

euro

psyc

hiat

ric

dise

ase

rs6

02

71

53

4In

tron

5((

TTTA

) 7(�

3))

?D

ecre

ased

[Tw

orog

eret

al.,

20

04

]

Dec

reas

edE

1an

dE

2

inw

omen

carr

yin

gat

leas

t2

copi

esof

((TT

TA) 7

(�3

))vs

.n

on-c

arri

ers

[Tw

orog

eret

al.,

20

04

]

Alzh

eim

er’s

dis

ease

(hom

ozyg

ous

(TTT

A)8–

13

and

hete

rozy

gous

wit

h(T

TTA)

7)

vs.

hom

ozyg

ous

(TTT

A)7

[But

ler

etal

.,2

00

9]

Intr

on5

((TT

TA) 8

)?

Incr

ease

d[H

aim

anet

al.,

20

00

;Tw

orog

eret

al.,

20

04

]

Incr

ease

dse

rum

E1

:Ain

wom

enh

omoz

ygou

sfo

r(T

TTA)

8vs

.w

omen

wit

hn

on-(

TTTA

) 8re

peat

s[H

aim

anet

al.,

20

00

]In

crea

sed

seru

mE

1an

dE

2

inw

omen

carr

yin

gat

leas

t1

copy

of(T

TTA)

8

[Tw

orog

eret

al.,

20

04

]

rs1

00

46

Exon

11

(3’U

TR)

c.*1

9T>

C?

Dec

reas

ed[D

un

nin

get

al.,

20

04

]

Dec

reas

edse

rum

E1

and

E2

(CCþ

CT)

[Dun

nin

get

al.,

20

04

]

Alzh

eim

er’s

dis

ease

(TTþ

CT)

[But

ler

etal

.,2

00

9]

Incr

ease

d[P

ayn

ter

etal

.,2

00

5]

Dec

reas

edse

rum

E2

:T(C

Cþ

CT)

[Dun

nin

get

al.,

20

04

]

Dec

reas

edse

rum

E1

:A(C

Cþ

CT)

[Dun

nin

get

al.,

20

04

]In

crea

sed

seru

mE

1:A

;E

2:T

(CCþ

CT)

[Pay

nte

ret

al.,

20

05

]Ph

ase

IIst

eroi

dm

etab

oliz

ing

enzy

mes

COM

T(c

atec

hol-

O-

met

hylt

ran

sfer

ase)

Cate

chol

estr

ogen

sto

resp

ecti

vem

etho

xym

etab

olit

es

Yes

[Hon

get

al.,

19

98

]rs

73

78

65

Intr

on1

IVS1

þ7

01

A>

G?

??

Low

extr

aver

sion

(AA)

[Ste

inet

al.,

20

05

]

[Bal

let

al.,

19

72

]rs

46

80

Exon

4c.

47

2G>

AVa

l15

8M

etD

ecre

ased

[Che

net

al.,

20

04

]D

ecre

ased

[Tw

orog

eret

al.,

20

04

;W

ord

aet

al.

20

03

]

Incr

ease

dur

inar

y2

-OH

-E1

and

16

-a-O

H-E

1(A

A)[T

wor

oger

etal

.,2

00

4]

Incr

ease

dse

rum

E2

Low

extr

aver

sion

and

high

neu

roti

cism

(AA)

[Ele

yet

al.,

20

03

;St

ein

etal

.,2

00

5]

Phob

ican

xiet

y(G

G)

(AAþ

AG)

[Wor

daet

al.,

20

03

][M

cGra

thet

al.,

20

04

]Pa

nic

dis

orde

r(G

Gþ

AG)

[Rot

heet

al.,

20

06

]H

arm

avoi

dan

ce(A

A)[E

noc

het

al.,

20

03

]rs

16

55

99

Exon

6(3

’UTR

)c.

*52

2G>

A?

??

Schi

zoph

ren

ia(G

G)

[Shi

fman

etal

.,2

00

2]

SULT

1A1

(sul

fotr

ansf

eras

efa

mily

,cy

toso

lic,

1A,

phen

ol-p

refe

rrin

g,m

embe

r1

)

Sulfo

nat

ion

of2

-an

d4

-OH

Estr

ogen

s(E

1an

dE

2)

[Adj

eian

dW

ein

shilb

oum

,2

00

2]

Yes

[Sal

man

etal

.,2

00

9]

rs9

28

28

61

(*2

)Ex

on5

c.6

38

G>

AAr

g21

3H

isD

ecre

ased

[Nag

aret

al.,

20

06

]

Dec

reas

ed[Y

ang

etal

.,2

00

5]

Dec

reas

edin

vitr

oE

2-S

(A)

[Nag

aret

al.,

20

06

]D

ecre

ased

seru

mE

1-S

and

DH

EA-S

(AAþ

AG)

[Yan

get

al.,

20

05

]In

crea

sed

seru

mT

(AA)

[Spa

rks

etal

.,2

00

4]

? (Con

tinu

ed)

GROVER ET AL. 1403

TAB

LEI.

(Con

tin

ued)

Gen

eR

eact

ion

cata

lyze

dEx

pres

sion

inbr

ain

tiss

uedb

SNP

ID(a

llele

)G

ene

loca

tion

Subs

titu

tion

sE

nzy

me

acti

vity

Asso

ciat

ion

(gen

otyp

e/al

lele

)in

fem

ales

Nuc

leot

ide

Amin

oac

idIn

vitr

oIn

vivo

Ster

oid

leve

lsN

euro

psyc

hiat

ric

dise

ase

SULT

1E 1

(sul

fotr

ansf

eras

efa

mily

,cy

toso

lic,

1E,

phen

ol-p

refe

rrin

g,m

emb

er1

)

Sulfo

nat

ion

ofE

1,

E2

,ca

tech

oles

trog

ens,

and

met

hoxy

-E2

[Adj

eian

dW

ein

shilb

oum

,2

00

2]

?rs

11

56

97

05

Exon

2c.

64

G>

TAs

p22

Tyr

Dec

reas

ed[A

djei

and

Wei

nsh

ilbou

m,

20

02

]

??

?

rs3

45

47

14

8Ex

on2

c.9

5C>

TAl

a32

Val

Dec

reas

ed[A

djei

and

Wei

nsh

ilbou

m,

20

02

]

??

?

Estr

ogen

ster

oid

rece

ptor

sES

R1

(est

roge

nre

cept

or1

)R

ecep

tor

for

estr

ogen

s[G

reen

etal

.,1

98

6]

Yes

[Car

roll

etal

.,1

99

9]

rs2

23

46

93

(Pvu

II)In

tron

1IV

S1�

39

7T>

C?

?D

ecre

ased

seru

mE

2(T

)[S

chui

tet

al.,

20

05

]M

igra

ine

(TT)

[Jos

hiet

al.,

20

09

]Al

zhei

mer

’sd

isea

se(C

)[L

inet

al.,

20

03

]Al

zhei

mer

’sdi

seas

e(T

inco

mbi

nat

ion

wit

hAP

OE

«4

alle

le)

[Por

rello

etal

.,2

00

6]

Schi

zoph

ren

ia(C

C)[W

eick

ert

etal

.,2

00

8]

rs9

34

07

99

(Xba

I)In

tron

1IV

S1�

35

1A>

G?

?D

ecre

ased

seru

mE

2(A

)[S

chui

tet

al.,

20

05

]

Alzh

eim

er’s

dise

ase

(G)

[Iso

e-W

ada

etal

.,1

99

9;

Lin

etal

.,2

00

3]

Alzh

eim

er’s

dise

ase

(Ain

com

bin

atio

nw

ith

APO

E«

4al

lele

)[P

orre

lloet

al.,

20

06

]

rs1

80

11

32

Exon

1c.

97

5C>

GP

ro3

25

Pro

??

?M

igra

ine

(C)

[Ote

rin

oet

al.,

20

08

]

rs2

22

84

80

Exon

8c.

17

82

G>

ATh

r59

4Th

r?

??

Mig

rain

e(A

)[C

olso

net

al.,

20

04

]

rs3

79

85

77

Exon

1(3

0U

TR)

c.*1

02

9T>

C?

?D

ecre

ased

seru

mE

2(C

C)[S

ower

set

al.,

20

06

c]?

ESR

2(e

stro

gen

rece

ptor

2)

Rec

epto

rfo

res

trog

ens

[Ost

erlu

nd

and

Hur

d,2

00

1]

Yes

[Car

roll

etal

.,1

99

9]

rs1

27

15

73

Intr

on3

IVS3

�1

88

0C>

T?

??

Alzh

eim

er’s

dis

ease

(TT)

[Pir

skan

enet

al.,

20

05

]rs

12

56

04

3In

tron

4IV

S4þ

12

31

C>

T?

??

Alzh

eim

er’s

dis

ease

(TT)

[Pir

skan

enet

al.,

20

05

]

rs1

25

60

49

Exon

6c.

98

4G>

AVa

l32

8Va

l?

??

Anor

exia

ner

vosa

(AG

)[E

astw

ood

etal

.,2

00

2]

rs4

98

69

38

Intr

on8

17

30

G>

A?

??

Park

inso

n’s

dis

ease

[Wes

tber

get

al.,

20

04

]

rs1

25

59

98

Exon

9(3

’UTR

)c.

*38

0C>

G?

?D

ecre

ased

seru

mE

2(G

C)[S

ower

set

al.,

20

06

c]

?

?in

dica

tes

lack

ofsc

ien

tifi

cev

iden

ce.


Post Human Genome Project, with the arrival of high through-

put genotyping chips, genetic studies of complex human diseases

have garnered enormous attention. Such studies are increasingly

being used to identify genetic variants that may influence predis-

position to various neuropsychiatric disorders and their treatment.

Prominent among these sequence variants are millions of SNPs that

have emerged as strong candidates for investigating association

with disease susceptibility and drug response. Availability of such an

enormous wealth of data has fuelled the genetic epidemiological

studies. However, such studies often come under the scanner owing

to lack of reproducibility of results. There are several key issues in

this regard that need to be adequately addressed to ensure the

validity, accuracy, and reliability of findings, before coming to

scientifically relevant conclusions. These issues of concern could

include population stratification bias, small sample size, inconsis-

tency in the phenotypic definitions across different studies, highly

heterogeneous clinical symptoms in a specific study design, and

unaccountability of environmental variables. Further, stratification

according to age is crucial for conducting epidemiological studies

related to gender as hormonal profile shows marked variability at

various stages of women’s life span. Basal metabolic ratio (BMR),

waist hip ratio (WHR), and sex hormone binding globulin (SHBG)

levels are known to influence circulating estrogen levels, and should

be taken into account before conducting any statistical analysis. In

addition, nature and regimen of drug therapy, brand of the drug

administered, hormonal therapy, and duration of treatment could

all have a major affect on improvement in clinical symptoms or

phenotype under observation, during the study. Lastly, selection

and prioritization of candidate genes and SNPs, and use of appro-

priate statistical tools could also play an important role in detecting

true positive associations.

Hence, there is an urgent necessitation of conducting large-scale

genetic epidemiological studies with consistency in study designs

and accountability of different environmental and genetic variables.

The advent of high-throughput genomic technologies coupled with

the use of strong bioinformatics and biostatistical tools would

further enhance the chances of discovering genetic markers or

their combinations with high predictability for determining altered

estrogenicity in a woman’s lifespan. When validated and replicated

in populations from different ethnic backgrounds, these markers

could aid in predicting age-specific physiological changes that

could result from hypoestrogenicity and hyperestrogenicity or

fluctuations between these two stages. Further, by using an inter-

disciplinary approach, these studies might be helpful in designing

drugs targeting specific genes involved in estrogen metabolism.

Besides neuropsychiatric disorders, an alteration in estrogen

levels could lead to reproductive disorders and various types

of cancer, particularly in postmenopausal women. Hence, such

genetic association studies could help in development of individu-

alized pharmacogenetic therapies with appropriate dose and

duration of exogenous estrogen therapy, or drug treatment target-

ing estrogen metabolism. In all, such comprehensive integration of

literature on clinical evidence, and genetic variants associated

with estrogen disposition and vulnerability to neuropsychiatric

disorders might divert the attention of scientific community

towards this unexplored but biologically highly relevant field of

‘‘Estrogen Pharmacogenomics.’’

ACKNOWLEDGMENTS

The authors are grateful to Prof. Samir K. Brahmachari for intel-

lectual inputs. The authors Sandeep Grover and Meenal Gupta are

also grateful to CSIR for senior research fellowship.

REFERENCES

Adjei AA, Weinshilboum RM. 2002. Catecholestrogen sulfation: Possiblerole in carcinogenesis. Biochem Biophys Res Commun 292:402–408.

Aklillu E, Oscarson M, Hidestrand M, Leidvik B, et al. 2002. Functionalanalysis of six different polymorphic CYP1B1 enzyme variants found inan Ethiopian population. Mol Pharmacol 61:586–594.

Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, et al. 2004. Prevalence ofmental disorders in Europe: Results from the European Study of theEpidemiology of Mental Disorders ESEMeD project. Acta PsychiatrScand Suppl 420:21–27.

Arabia G, Zappia M, Bosco D, Crescibene L, et al. 2002. Body weight,levodopa pharmacokinetics and dyskinesia in Parkinson’s disease. Neu-rol Sci 23(Suppl2): S53–S54.

Badawi AF, Cavalieri EL, Rogan EG. 2001. Role of human cytochrome P4501A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol. Metabolism 50:1001–1003.

Baldereschi M, Di Carlo A, Rocca WA, Vanni P. 2000. Parkinson’s diseaseand Parkinsonism in a longitudinal study: Two-fold higher incidence inmen. ILSA Working Group. Italian Longitudinal Study on Aging.Neurology 55:1358–1363.

Ball P, Knuppen R, Haupt M, Breuer H. 1972. Interactions betweenestrogens and catechol amines. 3. Studies on the methylation of catecholestrogens, catechol amines and other catechols by the ctechol-O-meth-yltransferases of human liver. J Clin Endocrinol Metab 34:736–746.

Barnes LL, Wilson RS, Bienias JL, Schneider JA, et al. 2005. Sex differencesin the clinical manifestations of Alzheimer disease pathology. Arch GenPsychiatry 62:685–691.

Belous AR, Hachey DL, Dawling S, Roodi N, et al. 2007. Cytochrome P4501B1-mediated estrogen metabolism results in estrogen-deoxyribonu-cleoside adduct formation. Cancer Res 67:812–817.

Berlanga C, Flores-Ramos M. 2006. Different gender response to seroto-nergic and noradrenergic antidepressants. A comparative study of theefficacy of citalopram and reboxetine. J Affect Disord 95:119–123.

Bonomo SM, Rigamonti AE, Giunta M, Galimberti D, et al. 2009. Meno-pausal transition: A possible risk factor for brain pathologic events.Neurobiol Aging 30:71–80.

Boudikova B, Szumlanski C, Maidak B, Weinshilboum R. 1990. Humanliver catechol-O-methyltransferase pharmacogenetics. Clin PharmacolTherap 48:381–389.

Bourque M, Dluzen DE, Di Paolo T. 2009. Neuroprotective actions of sexsteroids in Parkinson’s disease. Front Neuroendocrinol 30:142–157.

Bracke P. 1998. Sex differences in the course of depression: Evidence from alongitudinal study of a representative sample of the Belgian population.Soc Psychiatry Psychiatr Epidemiol 33:420–429.

Briellmann RS, Berkovic SF, Jackson GD. 2000. Men may be morevulnerable to seizure-associated brain damage. Neurology 55:1479–1485.

Burger HG, Hale GE, Dennerstein L, Robertson DM. 2008. Cycle andhormone changes during perimenopause: The key role of ovarianfunction. Menopause 15:603–612.

Bushnell CD. 2005. Oestrogen and stroke in women: Assessment of risk.Lancet Neurol 4:743–751.

GROVER ET AL. 1405

Butler HT, Warden DR, Hogervorst E, Ragoussis J, et al. 2009. Associationof the aromatase gene with Alzheimer’s disease in women. Neurosci Lett468:202–206.

Carlini EJ, Raftogianis RB, Wood TC, Jin F, et al. 2001. Sulfation pharma-cogenetics: SULT1A1 and SULT1A2 allele frequencies in Caucasian,Chinese and African-American subjects. Pharmacogenetics 11:57–68.

Carroll RS, Zhang J, Black PM. 1999. Expression of estrogen receptors alphaand beta in human meningiomas. J Neuro-Oncol 42:109–116.

Chen TC, Leviton A. 1994. Headache recurrence in pregnant women withmigraine. Headache 34:107–110.

Chen J, Lipska BK, Halim N, Ma QD, et al. 2004. Functional analysis ofgenetic variation in catechol-O-methyltransferase COMT: Effects onmRNA, protein, and enzyme activity in postmortem human brain. AmJ Hum Genet 75:807–821.

Christensen J, Vestergaard M, Pedersen MG, Pedersen CB, et al. 2007.Incidence and prevalence of epilepsy in Denmark. Epilepsy Res 76:60–65.

Colson NJ, Lea RA, Quinlan S, MacMillan J, et al. 2004. The estrogenreceptor 1 G594A polymorphism is associated with migraine suscepti-bility in two independent case/control groups. Neurogenetics 5:129–133.

Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, et al.1998. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancyin Multiple Sclerosis Group. N Engl J Med 339:285–291.

Confavreux C, Vukusic S, Adeleine P. 2003. Early clinical predictors andprogression of irreversible disability in multiple sclerosis: an amnesicprocess. Brain 126:770–782.

Cosimo MR, Garcia-Segura LM. 2010. Sex-specific therapeutic strategiesbased on neuroactive steroids: In search for innovative tools for neuro-protection. Horm Behav 57:2–11.

Coughtrie MW. 2002. Sulfation through the looking glass—Recent ad-vances in sulfotransferase research for the curious. Pharmacogenomics J2:297–308.

Cribb AE, Knight MJ, Dryer D, Guernsey J, et al. 2006. Role of polymorphichuman cytochrome P450 enzymes in estrone oxidation. Cancer Epide-miol Biomarkers Prev 15:551–558.

Cucurachi L, Devetak M, Torelli P, Lambru G, et al. 2006. Gender ratio ofmigraine without aura: Observations over time. Neurol Sci 27:47–50.

De Vivo I, Hankinson SE, Li L, Colditz GA, et al. 2002. Association ofCYP1B1 polymorphisms and breast cancer risk. Cancer EpidemiolBiomarkers Prev 11:489–492.

Deecher D, Andree TH, Sloan D, Schechter LE. 2008. From menarche tomenopause: Exploring the underlying biology of depression in womenexperiencing hormonal changes. Psychoneuroendocrinology 33:3–17.

Dluzen D, Horstink M. 2003. Estrogen as neuroprotectant of nigrostriataldopaminergic system: Laboratory and clinical studies. Endocrine21:67–75.

Dodick DW, Lipton RB, Goadsby PJ, Tfelt-Hansen P, et al. 2008. Predictorsof migraine headache recurrence: A pooled analysis from the eletriptandatabase. Headache 48:184–193.

Dunning AM, Dowsett M, Healey CS, Tee L, et al. 2004. Polymorphismsassociated with circulating sex hormone levels in postmenopausal wom-en. J Natl Cancer Inst 96:936–945.

Dutheil F, Beaune P, Loriot MA. 2008. Xenobiotic metabolizingenzymes in the central nervous system: Contribution of cytochromeP450 enzymes in normal and pathological human brain. Biochimie 90:426–436.

Dworkin RJ, Adams GL. 1984. Pharmacotherapy of the chronic patient:Gender and diagnostic factors. Community Mental Health J 20:253–261.

Eastwood H, Brown KM, Markovic D, Pieri LF. 2002. Variation in the ESR1and ESR2 genes and genetic susceptibility to anorexia nervosa. MolPsychiatry 7:86–89.

Eley TC, Tahir E, Angleitner A, Harriss K, et al. 2003. Association analysis ofMAOA and COMT with neuroticism assessed by peers. Am J Med GenetPart B 120B:90–96.

Enoch MA, Xu K, Ferro E, Harris CR, et al. 2003. Genetic origins of anxietyin women: A role for a functional catechol-O-methyltransferase poly-morphism. Psychiatr Genet 13:33–41.

Espeland MA, Rapp SR, Shumaker SA, Brunner R, et al. 2004. Conjugatedequine estrogens and global cognitive function in postmenopausalwomen: Women’s Health Initiative Memory Study. J Am Med Assoc291:2959–2968.

Fahndrich E, Coper H, Christ W, Helmchen H, et al. 1980. ErythrocyteCOMT-activity in patients with affective disorders. Acta Psychiatr Scand61:427–437.

Farage MA, Neill S, MacLean AB. 2009. Physiological changes asso-ciated with the menstrual cycle: A review. Obstet Gynecol Surv 64:58–72.

Fava M, Abraham M, Alpert J, Nierenberg AA, et al. 1996. Gender differ-ences in Axis I comorbidity among depressed outpatients. J Affect Disord38:129–133.

Feigelson HS, Shames LS, Pike MC, Coetzee GA, et al. 1998. CytochromeP450c17alpha gene CYP17 polymorphism is associated with serumestrogen and progesterone concentrations. Cancer Res 58:585–587.

Frank E, Carpenter LL, Kupfer DJ. 1988. Sex differences in recurrentdepression: Are there any that are significant? Am J Psychiatry 145:41–45.

Freeman EW, Sammel MD, Liu L, Gracia CR, et al. 2004. Hormones andmenopausal status as predictors of depression in women in transition tomenopause. Arch Gen Psychiatry 61:62–70.

Freeman EW, Sammel MD, Lin H, Nelson DB. 2006. Associations ofhormones and menopausal status with depressed mood in women withno history of depression. Arch Gen Psychiatry 63:375–382.

Freeman EW, Sammel MD, Lin H, Gracia CR, et al. 2008. Symptoms inthe menopausal transition: Hormone and behavioral correlates. ObstetGynecol 111:127–136.

Gao S, Hendrie HC, Hall KS, Hui S. 1998. The relationships between age,sex, and the incidence of dementia and Alzheimer disease: A meta-analysis. Arch Gen Psychiatry 55:809–815.

Garcia-Closas M, Herbstman J, Schiffman M, Glass A, et al. 2002. Rela-tionship between serum hormone concentrations, reproductive history,alcohol consumption and genetic polymorphisms in pre-menopausalwomen. Int J Cancer 102:172–178.

Geng YG, Su QR, Su LY, Chen Q, et al. 2007. Comparison of the poly-morphisms of androgen receptor gene and estrogen alpha and beta genebetween adolescent females with first-onset major depressive disorderand controls. Int J Neurosci 117:539–547.

Gibbs RB, Aggarwal P. 1998. Estrogen and basal forebrain cholinergicneurons: Implications for brain aging and Alzheimer’s disease-relatedcognitive decline. Horm Behav 34:98–111.

Glassman AH, Perel JM, Shostak M, Kantor SJ, et al. 1977. Clinicalimplications of imipramine plasma levels for depressive illness. ArchGen Psychiatry 34:197–204.

Goldstein JM, Link BG. 1988. Gender and the expression of schizophrenia.J Psychiatr Res 22:141–155.

Goldstein JM, Cohen LS, Horton NJ, Lee H, et al. 2002. Sex differences inclinical response to olanzapine compared with haloperidol. PsychiatryRes 110:27–37.


Granella F, Sances G, Zanferrari C, Costa A, et al. 1993. Migraine withoutaura and reproductive life events: A clinical epidemiological study in 1300women. Headache 33:385–389.

Green S, Walter P, Kumar V, Krust A, et al. 1986. Human oestrogenreceptor cDNA: Sequence, expression and homology to v-erb-A. Nature320:134–139.

Grover S, Talwar P, Gourie-Devi M, Gupta M, et al. 2010. Geneticpolymorphism in sex hormone metabolizing genes and drug responsein women with epilepsy. Pharmacogenomics (in press).

Haaxma CA, Bloem BR, Borm GF, Oyen WJ, et al. 2007. Genderdifferences in Parkinson’s disease. J Neurol Neurosurg Psychiatry78:819–824.

Hafner H. 2003. Gender differences in schizophrenia. Psychoneuroendoc-rinology 28(Suppl2): 17–54.

Haiman CA, Hankinson SE, Spiegelman D, Colditz GA, et al. 1999. Therelationship between a polymorphism in CYP17 with plasma hormonelevels and breast cancer. Cancer Res 59:1015–1020.

Haiman CA, Hankinson SE, Spiegelman D, De Vivo I, et al. 2000. Atetranucleotide repeat polymorphism in CYP19 and breast cancer risk.Int J Cancer 87:204–210.

Halbreich U. 2003. The etiology, biology, and evolving pathology ofpremenstrual syndromes. Psychoneuroendocrinology 28(Suppl3):55–99.

Hamed SA. 2008. Neuroendocrine hormonal conditions in epilepsy:Relationship to reproductive and sexual functions. Neurologist14:157–169.

Hamilton SP, Slager SL, Heiman GA, Deng Z, et al. 2002. Evidence for asusceptibility locus for panic disorder near the catechol-O-methyltrans-ferase gene on chromosome 22. Biol Psychiatry 51:591–601.

Hanna IH, Dawling S, Roodi N, Guengerich FP, et al. 2000. CytochromeP450 1B1 CYP1B1 pharmacogenetics: Association of polymorphismswith functional differences in estrogen hydroxylation activity. Cancer Res60:3440–3444.

Harden CL, Herzog AG, Nikolov BG, Koppel BS, et al. 2006. Hormonereplacement therapy in women with epilepsy: A randomized, double-blind, placebo-controlled study. Epilepsia 47:1447–1451.

Haskell SG, Richardson ED, Horwitz RI. 1997. The effect of estrogenreplacement therapy on cognitive function in women: A critical review ofthe literature. J Clin Epidemiol 50:1249–1264.

Hawkins SA, McDonnell GV. 1999. Benign multiple sclerosis? Clinicalcourse, long term follow up, and assessment of prognostic factors. JNeurol Neurosurg Psychiatry 67:148–152.

Hayes CL, Spink DC, Spink BC, Cao JQ, et al. 1996. 17 Beta-estradiolhydroxylation catalyzed by human cytochrome P450 1B1. Proc Natl AcadSci USA 93:9776–9781.

Herzog AG. 2008. Catamenial epilepsy: Definition, prevalence pathophys-iology and treatment. Seizure 17:151–159.

Hong J, Shu-Leong H, Tao X, Lap-Ping Y. 1998. Distribution of catechol-O-methyltransferase expression in human central nervous system. Neuro-report 9:2861–2864.

Huang R, Poduslo SE. 2006. CYP19 haplotypes increase risk for Alzheimer’sdisease. J Med Genet 43:e42.

Isoe-Wada K, Maeda M, Yong J, Adachi Y, et al. 1999. Positive associationbetween an estrogen receptor gene polymorphism and Parkinson’sdisease with dementia. Eur J Neurol 6:431–435.

Jorm AF, Korten AE, Henderson AS. 1987. The prevalence of dementia: Aquantitative integration of the literature. Acta Psychiatr Scand76:465–479.

Josefsson A, Berg G, Nordin C, Sydsjo G. 2001. Prevalence of depressivesymptoms in late pregnancy and postpartum. Acta Obstet Gynecol Scand80:251–255.

Joshi G, Pradhan S, Mittal B. 2009. Role of the oestrogen receptor ESR1PvuII and ESR1 325 C–>G and progesterone receptor PROGINS poly-morphisms in genetic susceptibility to migraine in a North Indianpopulation. Cephalalgia 30:311–320.

Kane FJ Jr, Lipton MA, Ewing JA. 1969. Hormonal influences in femalesexual response. Arch Gen Psychiatry 20:202–209.

Kawas C, Resnick S, Morrison A, Brookmeyer R, et al. 1997. A prospectivestudy of estrogen replacement therapy and the risk of developingAlzheimer’s disease: The Baltimore Longitudinal Study of Aging. Neu-rology 48:1517–1521.

Kendell RE, Chalmers JC, Platz C. 1987. Epidemiology of puerperalpsychoses. Br J Psychiatry 150:662–673.

Kessler RC, McGonagle KA, Zhao S, Nelson CB, et al. 1994. Lifetime and12-month prevalence of DSM-III-R psychiatric disorders in the UnitedStates. Results from the National Comorbidity Survey. Arch GenPsychiatry 51:8–19.

Khan A, Brodhead AE, Schwartz KA, Kolts RL, et al. 2005. Sex differences inantidepressant response in recent antidepressant clinical trials. J ClinPsychopharmacol 25:318–324.

King SR. 2008. Emerging roles for neurosteroids in sexual behavior andfunction. J Androl 29:524–533.

Kipp M, Beyer C. 2009. Impact of sex steroids on neuroinflammatoryprocesses and experimental multiple sclerosis. Front Neuroendocrinol30:188–200.

Kisselev P, Schunck WH, Roots I, Schwarz D. 2005. Association of CYP1A1polymorphisms with differential metabolic activation of 17beta-estradioland estrone. Cancer Res 65:2972–2978.

Knight AH, Rhind EG. 1975. Epilepsy and pregnancy: A study of 153pregnancies in 59 patients. Epilepsia 16:99–110.

Kravitz HM, Janssen I, Lotrich FE, Kado DM, et al. 2006a. Sex steroidhormone gene polymorphisms and depressive symptoms in women atmidlife. Am J Med 119:S87–S93.

Kravitz HM, Meyer PM, Seeman TE, Greendale GA, et al. 2006b. Cognitivefunctioning and sex steroid hormone gene polymorphisms in women atmidlife. Am J Med 119:S94–S102.

Kristensen VN, Borresen-Dale AL. 2000. Molecular epidemiology of breastcancer: Genetic variation in steroid hormone metabolism. Mut Res462:323–333.

Kuhl H. 2005. Pharmacology of estrogens and progestogens: Influence ofdifferent routes of administration. Climacteric 8(Suppl1): 3–63.

Kulkarni J, de Castella A, Smith D, Taffe J, et al. 1996. A clinical trial of theeffects of estrogen in acutely psychotic women. Schizophr Res 20:247–252.

Kumar R, Robson KM. 1984. A prospective study of emotional disorders inchildbearing women. Br J Psychiatry 144:35–47.

Labelle A, Light M, Dunbar F. 2001. Risperidone treatment of outpatientswith schizophrenia: No evidence of sex differences in treatment response.Can J Psychiatry 46:534–541.

Lasiuk GC, Hegadoren KM. 2007. The effects of estradiol on centralserotonergic systems and its relationship to mood in women. Biol ResNurs 9:147–160.

Lee AJ, Cai MX, Thomas PE, Conney AH, et al. 2003. Characterization ofthe oxidative metabolites of 17beta-estradiol and estrone formed by 15selectively expressed human cytochrome p450 isoforms. Endocrinology144:3382–3398.

GROVER ET AL. 1407

Leung A, Chue P. 2000. Sex differences in schizophrenia, a review of theliterature. Acta Psychiatr Scand Suppl 401:3–38.

Lin GF, Ma QW, Zhang DS, Zha YL, et al. 2003. Polymorphism ofalpha-estrogen receptor and aryl hydrocarbon receptor genes indementia patients in Shanghai suburb. Acta Pharmacol Sin 24:651–656.

Lindamer LA, Buse DC, Lohr JB, Jeste DV. 2001. Hormone replacementtherapy in postmenopausal women with schizophrenia: Positive effect onnegative symptoms? Biol Psychiatry 49:47–51.

Livonen S, Corder E, Lehtovirta M, Helisalmi S, et al. 2004. Polymorphismsin the CYP19 gene confer increased risk for Alzheimer disease. Neurology62:1170–1176.

Luconi M, Forti G, Baldi E. 2002. Genomic and nongenomic effects ofestrogens: Molecular mechanisms of action and clinical implications formale reproduction. J Steroid Biochem Mol Biol 80:369–381.

Lurie G, Maskarinec G, Kaaks R, Stanczyk FZ, et al. 2005. Association ofgenetic polymorphisms with serum estrogens measured multiple timesduring a 2-year period in premenopausal women. Cancer EpidemiolBiomarkers Prev 14:1521–1527.

Lyons KE, Hubble JP, Troster AI, Pahwa R, et al. 1998. Gender differences inParkinson’s disease. Clin Neuropharmacol 21:118–121.

MacGowan SH, Wilcock GK, Scott M. 1998. Effect of gender and apolipo-protein E genotype on response to anticholinesterase therapy inAlzheimer’s disease. Int J Geriatr Psychiatry 13:625–630.

MacGregor EA. 2005. Female sex hormones and migraine. Rev Neurol Paris161:677–678.

McEwen B. 2002. Estrogen actions throughout the brain. Recent ProgHorm Res 57:357–384.

McFayden MC, Melvin WT, Murray GI. 1998. Regional distribution ofindividual forms of cytochrome P450 mRNA in normal adult humanbrain. Biochem Pharmacol 55:825–830.

McGrath M, Kawachi I, Ascherio A, Colditz GA, et al. 2004. Associationbetween catechol-O-methyltransferase and phobic anxiety. Am J Psychi-atry 161:1703–1705.

Mellon SH, Deschepper CF. 1993. Neurosteroid biosynthesis: Genes foradrenal steroidogenic enzymes are expressed in the brain. Brain Res629:283–292.

Mendelson CR, Means GD, Mahendroo MS, Corbin CJ, et al. 1990. Use ofmolecular probes to study regulation of aromatase cytochrome P-450.Biol Reprod 42:1–10.

Morrison MF, Kallan MJ, Ten Have T, Katz I, et al. 2004. Lack of efficacy ofestradiol for depression in postmenopausal women: A randomized,controlled trial. Biol Psychiatry 55:406–412.

Mortimer AM. 2007. Relationship between estrogen and schizophrenia.Expert Rev Neurotherap 7:45–55.

Mucchiut M, Belgrado E, Cutuli D, Antonini A, et al. 2004. Pramipexole-treated Parkinson’s disease during pregnancy. Movement Disord 19:1114–1115.

Nagar S, Walther S, Blanchard RL. 2006. Sulfotransferase SULT 1A1polymorphic variants *1, *2, and *3 are associated with altered enzymaticactivity, cellular phenotype, and protein degradation. Mol Pharmacol69:2084–2092.

Napoli N, Villareal DT, Mumm S, Halstead L, et al. 2005. Effect of CYP1A1gene polymorphisms on estrogen metabolism and bone density. J BoneMiner Res 20:232–239.

Napoli N, Rini GB, Serber D, Giri T, et al. 2009. The Val432Leu polymor-phism of the CYP1B1 gene is associated with differences in estrogenmetabolism and bone density. Bone 44:442–448.

Nappi RE, Cagnacci A, Granella F, Piccinini F, et al. 2001. Course of primaryheadaches during hormone replacement therapy. Maturitas 38:157–163.

Nelson HD. 2008. Menopause. Lancet 371:760–770.

Neri I, Granella F, Nappi R, Manzoni GC, et al. 1993. Characteristics ofheadache at menopause: A clinico-epidemiologic study. Maturitas17:31–37.

Noonan CW, Kathman SJ, White MC. 2002. Prevalence estimates for MS inthe United States and evidence of an increasing trend for women.Neurology 58:136–138.

Nott PN. 1982. Psychiatric illness following childbirth in Southampton: Acase register study. Psychol Med 12:557–561.

Olsen L, Rasmussen HB, Hansen T, Bagger YZ, et al. 2006. Estrogenreceptor alpha and risk for cognitive impairment in postmenopausalwomen. Psychiatr Genet 16:85–88.

Orton SM, Herrera BM, Yee IM, Valdar W, et al. 2006. Sex ratio of multiplesclerosis in Canada: A longitudinal study. Lancet Neurol 5:932–936.

Osterlund MK, Hurd YL. 2001. Estrogen receptors in the human forebrainand the relation to neuropsychiatric disorders. Prog Neurobiol64:251–267.

Otani K. 1985. Risk factors for the increased seizure frequency duringpregnancy and puerperium. Folia Psychiatr Neurol Jpn 39:33–41.

Oterino A, Toriello M, Cayon A, Castillo J, et al. 2008. Multilocus analysesreveal involvement of the ESR1, ESR2, and FSHR genes in migraine.Headache 48:1438–1450.

Parker G, Parker K, Austin MP, Mitchell P, et al. 2003. Gender differences inresponse to differing antidepressant drug classes: Two negative studies.Psychol Med 33:1473–1477.

Paynter RA, Hankinson SE, Colditz GA, Kraft P, et al. 2005. CYP19aromatase haplotypes and endometrial cancer risk. Int J Cancer116:267–274.

Perry PJ, Miller DD, Arndt SV, Cadoret RJ. 1991. Clozapine and norclo-zapine plasma concentrations and clinical response of treatment-refrac-tory schizophrenic patients. Am J Psychiatry 148:231–235.

Perugi G, Musetti L, Simonini E, Piagentini F, et al. 1990. Gender-mediatedclinical features of depressive illness. The importance of temperamentaldifferences. Br J Psychiatry 157:835–841.

Pike CJ, Carroll JC, Rosario ER, Barron AM. 2009. Protective actions of sexsteroid hormones in Alzheimer’s disease. Front Neuroendocrinol30:239–258.

Pirskanen M, Hiltunen M, Mannermaa A, Helisalmi S, et al. 2005.Estrogen receptor beta gene variants are associated with increasedrisk of Alzheimer’s disease in women. Eur J Hum Genet 13:1000–1006.

Porrello E, Monti MC, Sinforiani E, Cairati M., et al. 2006. Estrogenreceptor alpha and APOEepsilon4 polymorphisms interact to increaserisk for sporadic AD in Italian females. Eur J Neurol 13:639–644.

Queiroz LP, Peres MF, Piovesan EJ, Kowacs F, et al. 2009. A nationwidepopulation-based study of migraine in Brazil. Cephalalgia 29:642–649.

Quinn NP, Marsden CD. 1986. Menstrual-related fluctuations inParkinson’s disease. Movement Disord 1:85–87.

Radhakrishnan K, Pandian JD, Santhoshkumar T, Thomas SV, et al. 2000.Prevalence, knowledge, attitude, and practice of epilepsy in Kerala, SouthIndia. Epilepsia 41:1027–1035.

Raftogianis RB, Wood TC, Weinshilboum RM. 1999. Human phenolsulfotransferases SULT1A2 and SULT1A1: Genetic polymorphisms,allozyme properties, and human liver genotype–phenotype correlations.Biochem Pharmacol 58:605–616.


Rapp SR, Espeland MA, Shumaker SA, Henderson VW, et al. 2003. Effect ofestrogen plus progestin on global cognitive function in postmenopausalwomen: The Women’s Health Initiative Memory Study: A randomizedcontrolled trial. J Am Med Assoc 289:2663–2672.

Rasmussen BK, Olesen J. 1992. Migraine with aura and migraine withoutaura: An epidemiological study. Cephalalgia 12:221–228.

Riecher-Rossler A, de Geyter C. 2007. The forthcoming role of treatmentwith oestrogens in mental health. Swiss Med Wkly 137:565–572.

Riecher-Rossler A, Hafner H. 2000. Gender aspects in schizophrenia:Bridging the border between social and biological psychiatry. ActaPsychiatr Scand Suppl 407:58–62.

Rieder CR, Ramsden DB, Williams AC. 1998. Cytochrome P450 1B1mRNA in the human central nervous system. Mol Pathol 51:138–142.

Rigaud AS, Traykov L, Caputo L, Guelfi MC, et al. 2000. The apolipoproteinE epsilon4 allele and the response to tacrine therapy in Alzheimer’sdisease. Eur J Neurol 7:255–258.

Robinson DG, Woerner MG, Alvir JM, Geisler S, et al. 1999. Predictors oftreatment response from a first episode of schizophrenia or schizoaffec-tive disorder. Am J Psychiatry 156:544–549.

Rojo A, Aguilar M, Garolera MT, Cubo E, et al. 2003. Depression inParkinson’s disease: Clinical correlates and outcome. Parkinsonism RelatDisord 10:23–28.

Rothe C, Koszycki D, Bradwejn J, King N, et al. 2006. Association of theVal158Met catechol O-methyltransferase genetic polymorphism withpanic disorder. Neuropsychopharmacology 31:2237–2242.

Rothrock JF, Parada VA, Drinkard R, Zweifler RM, et al. 2005. Predictors ofa negative response to topiramate therapy in patients with chronicmigraine. Headache 45:932–935.

Routiot T, Lurel S, Denis E, Barbarino-Monnier P. 2000. Parkinson’sdisease and pregnancy: Case report and literature review. J Gyn�ecolObst�et Biol Reprod 29:454–457.

Salman ED, Kadlubar SA, Falany CN. 2009. Expression and localization ofcytosolic sulfotransferase SULT 1A1 and SULT1A3 in normal humanbrain. Drug Metab Dispos 37:706–709.

Salokangas RK. 1995. Gender and the use of neuroleptics in schizophrenia.Further testing of the oestrogen hypothesis. Schizophr Res 16:7–16.

Sances G, Granella F, Nappi RE, Fignon A, et al. 2003. Course of migraineduring pregnancy and postpartum: A prospective study. Cephalalgia23:197–205.

Sasano H, Takashashi K, Satoh F, Nagura H, et al. 1998. Aromatasein the human central nervous system. Clin Endocrinol (Oxf) 48:325–329.

Saunders-Pullman R, Gordon-Elliott J, Parides M, Fahn S, et al. 1999. Theeffect of estrogen replacement on early Parkinson’s disease. Neurology52:1417–1421.

Savettieri G, Messina D, Andreoli V, Bonavita S, et al. 2004. Gender-relatedeffect of clinical and genetic variables on the cognitive impairment inmultiple sclerosis. J Neurol 251:1208–1214.

Scaglione C, Vignatelli L, Plazzi G, Marchese R, et al. 2005. REM sleepbehaviour disorder in Parkinson’s disease: A questionnaire-based study.Neurol Sci 25:316–321.

Schrag A, Ben-Shlomo Y, Quinn NP. 2000. Cross sectional prevalencesurvey of idiopathic Parkinson’s disease and Parkinsonism in London.BMJ 321:21–22.

Schuit SC, de Jong FH, Stolk L, Koek WN, et al. 2005. Estrogen receptoralpha gene polymorphisms are associated with estradiol levels in post-menopausal women. Eur J Endocrinol 153:327–334.

Schupf N, Ottman R. 1997. Reproduction among individuals withidiopathic/cryptogenic epilepsy: Risk factors for spontaneous abortion.Epilepsia 38:824–829.

Seeman MV. 1983. Interaction of sex, age, and neuroleptic dose. ComprPsychiatry 24:125–128.

Shatalova EG, Walther SE, Favorova OO, Rebbeck TR, et al. 2005. Geneticpolymorphisms in human SULT1A1 and UGT1A1 genes associate withbreast tumor characteristics: A case-series study. Breast Cancer Res7:R909–R921.

Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, et al. 2002. Ahighly significant association between a COMT haplotype and schizo-phrenia. Am J Hum Genet 71:1296–1302.

Shumaker SA, Legault C, Rapp SR, Thal L, et al. 2003. Estrogen plusprogestin and the incidence of dementia and mild cognitive impairmentin postmenopausal women: The Women’s Health Initiative MemoryStudy: A randomized controlled trial. J Am Med Assoc 289:2651–2662.

Shumaker SA, Legault C, Kuller L, Rapp SR, et al. 2004. Conjugated equineestrogens and incidence of probable dementia and mild cognitive im-pairment in postmenopausal women: Women’s Health InitiativeMemory Study. J Am Med Assoc 291:2947–2958.

Sicotte NL, Liva SM, Klutch R, Pfeiffer P. 2002. Treatment of multiplesclerosis with the pregnancy hormone estriol. Ann Neurol 52:421–428.

Singh S, Zahid M, Saeed M, Gaikwad NW, et al. 2009. NADPH:quinoneoxidoreductase 1 Arg139Trp and Pro187Ser polymorphisms imbalanceestrogen metabolism towards DNA adduct formation in human mam-mary epithelial cells. J Steroid Biochem Mol Biol 117:56–66.

Smith R, Studd JW. 1992. A pilot study of the effect upon multiple sclerosisof the menopause, hormone replacement therapy and the menstrualcycle. J R Soc Med 85:612–613.

Soares CN, Poitras JR, Prouty J. 2003. Effect of reproductive hormones andselective estrogen receptor modulators on mood during menopause.Drugs Aging 20:85–100.

Somner J, McLellan S, Cheung J, Mak YT. 2004. Polymorphisms in theP450 c17 17-hydroxylase/17,20-lyase and P450 c19 aromatase genes:Association with serum sex steroid concentrations and bone mineraldensity in postmenopausal women. J Clin Endocrinol Metab 89:344–351.

Sowers MR, Wilson AL, Kardia SR, Chu J, et al. 2006a. CYP1A1 andCYP1B1 polymorphisms and their association with estradiol and estro-gen metabolites in women who are premenopausal and perimenopausal.Am J Med 119:(9 Suppl 1): S44–S51.

Sowers MR, Wilson AL, Kardia SR, Chu J, et al. 2006b. Aromatase geneCYP19 polymorphisms and endogenous androgen concentrations in amultiracial/multiethnic, multisite study of women at midlife. Am J Med119:S23–S30.

Sowers MR, Jannausch ML, McConnell DS, Kardia SR, et al. 2006c.Endogenous estradiol and its association with estrogen receptor genepolymorphisms. Am J Med 119:S16–S22.

Sparks R, Ulrich CM, Bigler J, Tworoger SS, et al. 2004. UDP-glucurono-syltransferase and sulfotransferase polymorphisms, sex hormone con-centrations, and tumor receptor status in breast cancer patients. BreastCancer Res 6:488–498.

Stein MB, Fallin MD, Schork NJ, Gelernter J. 2005. COMT polymorphismsand anxiety-related personality traits. Neuropsychopharmacology30:2092–2102.

Stewart WF, Linet MS, Celentano DD, Van NM, et al. 1991. Age- and sex-specific incidence rates of migraine with and without visual aura. Am JEpidemiol 134:1111–1120.

GROVER ET AL. 1409

Stillman MJ, Zajac D, Rybicki LA. 2004. Treatment of primary headachedisorders with intravenous valproate: Initial outpatient experience.Headache 44:65–69.

Stoffel-Wagner B, Watzka M, Schramm J, Bidlingmaier F, et al. 1999.Expression of CYP19 aromatase mRNA in different areas of the humanbrain. J Steroid Biochem Mol Biol 70:237–241.

Taioli E, Bradlow HL, Garbers SV, Sepkovic DW, et al. 1999. Role ofestradiol metabolism and CYP1A1 polymorphisms in breast cancer risk.Cancer Detect Prev 23:232–237.

Tang MX, Jacobs D, Stern Y, Marder K, et al. 1996. Effect of oestrogenduring menopause on risk and age at onset of Alzheimer’s disease. Lancet348:429–432.

Tenhunen J, Salminen M, Lundstrom K, Kiviluoto T, et al. 1994. Genomicorganization of the human catechol O-methyltransferase gene and itsexpression from two distinct promoters. Eur J Biochem 223:1049–1059.

Thiels C, Linden M, Grieger F, Leonard J. 2005. Gender differences inroutine treatment of depressed outpatients with the selective serotoninreuptake inhibitor sertraline. Int Clin Psychopharmacol 20:1–7.

Tsai SJ, Wang YC, Hong CJ, Chiu HJ. 2003. Association study of oestrogenreceptor alpha gene polymorphism and suicidal behaviours in majordepressive disorder. Psychiatr Genet 13:19–22.

Tsang KL, Ho SL, Lo SK. 2000. Estrogen improves motor disability inParkinsonian postmenopausal women with motor fluctuations. Neurol-ogy 54:2292–2298.

Tworoger SS, Chubak J, Aiello EJ, Ulrich CM, et al. 2004. Association ofCYP17, CYP19, CYP1B1, and COMT polymorphisms with serum andurinary sex hormone concentrations in postmenopausal women. CancerEpidemiol Biomarkers Prev 13:94–101.

Usall J, Suarez D, Haro JM. 2007. Gender differences in response toantipsychotic treatment in outpatients with schizophrenia. PsychiatryRes 153:225–231.

Venners SA, Liu X, Perry MJ, Korrick SA, et al. 2006. Urinary estrogen andprogesterone metabolite concentrations in menstrual cycles of fertilewomen with non-conception, early pregnancy loss or clinical pregnancy.Hum Reprod 21:2272–2280.

Waring SC, Rocca WA, Petersen RC, O’Brien PC, et al. 1999. Postmeno-pausal estrogen replacement therapy and risk of AD: A population-basedstudy. Neurology 52:965–970.

Warren MP. 2007. Historical perspectives in postmenopausal hormonetherapy: Defining the right dose and duration. Mayo Clin Proc82:219–226.

Weickert CS, Miranda-Angulo AL, Wong J, Perlman WR, et al. 2008.Variants in the estrogen receptor alpha gene and its mRNA contribute torisk for schizophrenia. Hum Mol Genet 17:2293–2309.

Westberg L, Ha�kansson A, Melke J, Shahabi HN, et al. 2004. Association

between the estrogen receptor beta gene and age of onset of Parkinson’sdisease. Psychoneuroendocrinology 29:993–998.

Wihlback AC, Sundstrom-Poromaa I, Backstrom T. 2006. Action by andsensitivity to neuroactive steroids in menstrual cycle related CNS dis-orders. Psychopharmacology (Berl) 186:388–401.

Wild JM, Martinez C, Reinshagen G, Harding GF. 1999. Characteristicsof a unique visual field defect attributed to vigabatrin. Epilepsia 40:1784–1794.

Wohlfarth T, Storosum JG, Elferink AJ, van Zwieten BJ, et al. 2004.Response to tricyclic antidepressants: Independent of gender? Am JPsychiatry 161:370–372.

Wojtowicz T, Lebida K, Mozrzymas JW. 2008. 17beta-estradiol affectsGABAergic transmission in developing hippocampus. Brain Res1241:7–17.

Wong IC, Mawer GE, Sander JW. 1999. Factors influencing theincidence of lamotrigine-related skin rash. Ann Pharmacother 33:1037–1042.

Woolley CS. 2007. Acute effects of estrogen on neuronal physiology. AnnuRev Pharmacol Toxicol 47:657–680.

Worda C, Sator MO, Schneeberger C, Jantschev T, et al. 2003. Influence ofthe catechol-O-methyltransferase COMT codon 158 polymorphism onestrogen levels in women. Hum Reprod 18:262–266.

Xie T, Ho SL, Ramsden D. 1999. Characterization and implications ofestrogenic down-regulation of human catechol-O-methyltransferasegene transcription. Mol Pharmacol 56:31–38.

Yaffe K, Lui LY, Grady D, Stone K, et al. 2002. Estrogen receptor 1polymorphisms and risk of cognitive impairment in older women. BiolPsychiatry 51:677–682.

Yague JG, Munoz A, de Monasterio-Schrader P, Defelipe J, et al. 2006.Aromatase expression in the human temporal cortex. Neuroscience138:389–401.

Yamazaki H, Shaw PM, Guengerich FP, Shimada T. 1998. Roles ofcytochromes P450 1A2 and 3A4 in the oxidation of estradiol and estronein human liver microsomes. Chem Res Toxicol 11:659–665.

Yang G, Gao YT, Cai QY, Shu XO, et al. 2005. Modifying effects ofsulfotransferase 1A1 gene polymorphism on the association of breastcancer risk with body mass index or endogenous steroid hormones.Breast Cancer Res Treat 94:63–70.

Young EA, Kornstein SG, Marcus SM, Harvey AT, et al. 2009. Sex differ-ences in response to citalopram: A STAR*D report. J Psychiatr Res43:503–511.

Yue X, Lu M, Lancaster T, Cao P, et al. 2005. Brain estrogen deficiencyaccelerates Abeta plaque formation in an Alzheimer’s disease animalmodel. Proc Natl Acad Sci USA 102:19198–19203.

Zamani MR, Levy WB, Desmond NL. 2004. Estradiol increases delayed, N-methyl-D-aspartate receptor-mediated excitation in the hippocampalCA1 region. Neuroscience 129:243–254.

Zappia M, Quattrone A. 2002. Gender and pramipexole effects onlevodopa pharmacokinetics and pharmacodynamics. Neurology 59:2010.

Zhu BT, Lee AJ. 2005. NADPH-dependent metabolism of 17beta-estradioland estrone to polar and nonpolar metabolites by human tissues andcytochrome P450 isoforms. Steroids 70:225–244.

Zorgdrager A, De Keyser J. 2002. The premenstrual period and exacer-bations in multiple sclerosis. Eur Neurol 48:204–206.

Zwain IH, Yen SS. 1999. Dehydroepiandrosterone: Biosynthesis andmetabolism in the brain. Endocrinology 140:880–887.

Zweifel JE, O’Brien WH. 1997. A meta-analysis of the effect of hormonereplacement therapy upon depressed mood. Psychoneuroendocrinology22:189–212.


Estrogen Review_Grover Et Al 2010

Documents

related skin rash

medical genetics part

ivs2 23584g

ivs2 36415c

db snp id

central nervous system

altered enzymatic activity

estrogen metabolizing enzymes