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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: ritus@igib.res.in
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
1394 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
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
1396 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
-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.
1398 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
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).
1400 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
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)
1402 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
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.
1404 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
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
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