oestrogen assignment
TRANSCRIPT
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The Relationship Between
Oestrogen Levels and MoodDisorders.
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Oestrogen
A gonadol hormone.
Responsible for sexual maturation, growth ofbreasts, development of fat deposits andgrowth of uterine lining in women.
Also has been identified as having a role in
depression as estrogen deficiency mayincrease the susceptibility for depression(Birkhauser, 2002).
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Mood Disorders
Bipolar Disorder (also known as manicdepression) - includes cyclical periods ofmania and depression.
Unipolar Depression - periods of depressionthat do not alternate with periods of mania.
29.2% of people with bipolar disorder and15.9% with unipolar depression attemptsuicide (Chen & Dilsaver, 1996).
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Role of Antidepressants
Three main types:
Monoamine oxidase inhibitors (MAOI) inhibits
monoamine oxidase which inactivates
norepinephrine, serotonin (5-HT) and dopamine.
Specific serotonin reuptake inhibitor (SSRI)
inhibits reuptake of serotonin. Trycyclic antidepressant inhibits reuptake of
serotonin and norepinephrine.
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Serotonin and Depression
5-hydroxyindoleacetic acid (5-HIAA) is a
metabolite formed when serotonin (5-HT) isdestroyed by monoamine oxidase (MAO).
People with suicidal depression have low
levels of 5-HIAA and therefore low levels of
5-HT (Roy, DeJong & Linnoila, 1989).
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Serotonin and Oestrogen 2
Oestrogen can modulate serotonergic function(Joffe & Cohen, 1998) which may contribute to the
greater risk for depression in women. Women have decreased whole brain 5-HT synthesis
(Nishizawa, Benkelfat, Young, Leyton, Mzengeza& de Montignuy, 1997) and increased 5-HIAA
levels (Agren, Mefford, Rudorfer, Linnoila &Potter, 1986).
Therefore oestrogen may affect risk of depressionby modulating serotonergic interactions.
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Oestrogen as an Antidepressant
Oestrogen may facilitate down-regulation of 5-HT2 receptors which also occurs with chronic (21
days) antidepressant treatment (Joffe & Cohen,1998).
As with antidepressants, oestrogen increases therelease of Nerve Growth Factors (NGFs) which
may help with maintenance of neurons as we age. Brain Derived Neurotrophic Factor (BDNF) has
been shown to have antidepressant effects uponanimal models of depression (Duman, Heninger &
Nestler, 1997).
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How Does Oestrogen Work?
Is oestrogen having antidepressant effects bymodulating serotonin receptors, increasing NGF
release, working as a free radical scavenger or is it acombination or all three factors?
Another aspect to consider is oestrogen as aprotective factor against depression which
commonly occurs co-morbidly with symptoms ofpsychiatric illness such as schizophrenia andAlzheimers Disease (AD).
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The Action of Oestrogen
Oestrogen binds to receptors.
These receptors are part of a large group of ligand-
activated transcription factors that combineresponses from the genome and modulate thetranscription of genes.
These genes encode proteins including enzymes for
neurotransmitters, neuropeptides, growth factorsand signal transduction.
Therefore oestrogen and other gonadal steroids caninfluence the actions of neurotransmitters.
(Rubinow, Schmidt & Roca, 1998).
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Gene Transcription versus Free
Radical Scavenger Oestrogen (17-oestradiol) has been shown to
protect cultured neurones from oxidative cell death
by acting as free radical scavengers (Green &Simpkins, 2000).
Oestrogen may facilitate down-regulation of 5-HT2 receptors (Joffe & Cohen, 1998) modulating
the transcription of genes which encode serotonin. Oestrogen can also increase the release of BDNF
which may aid as a protective factor.
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Studies Using Oestrogen as an
Antidepressant There are only six studies which used oestrogen as
a treatment for major depression.
2 used female psychiatric patients (Klaiber et.al.1979; Holsboer, Benkert & Demisch, 1983).
1 used females suffering from postpartumdepression (Gregoire et. al 1996).
3 used gynaecology patients selected for beingsymptomatic during peri and post menopausaltransition (Campbell & Whitehead, 1977; Schneideret. al. 1977; Coope, 1981).
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Results
In some of the studies, subjects treated with
oestrogen developed worse depressive or manic
symptoms.
Of the four studies which used a placebo control,
only Klaiber et al. (1979) and Gregoire et al. (1996)
demonstrated significant improvement in symptomsof participants taking oestrogen over those in the
placebo control group.
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Results 2
Oestrogen appeared less effective in the studiesexamining the peri and post menopausal transitional
period where no benefit was shown over placebogroups (Campbell & Whitehead, 1977; Schneider etal. 1977 and Coope, 1981).
However, in more recent studies, this has not been
the conclusion as Schmidt, Roca, Bloch & Rubinow(1997) found that oestrogen did offer greaterimprovement over placebo trials.
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When do Endogenous Levels of
Oestrogen Change
From puberty, levels of endogenous
oestrogen levels fluctuate during the
menstrual cycle and at critical reproductive
times:
During pregnancy and following childbirth.
During menopause.
Following menopause.
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What Happens to Oestrogen
Levels at These Times? Menstrual Changes.
Menstrual cycle is initiated by hormonal secretions
from the ovaries and pituitary gland.
First; Release of gonadotropins by anterior pituitary
gland thus stimulating growth of ovarian follicles.
Follicles mature, secrete estradiol which causes theuterus to increase lining. Usually leads to increase
of Luteinizing Hormone (LH) by anterior pituitary.
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Menstrual changes 2
This leads to ovulation where the follicle rupturesreleasing the ovum. The follicle becomes a corpus
luteum. If fertilization does not occur, estradiol and
progesterone levels fall as the corpus luteum stopsproducing.
At this point menstruation will occur.
Therefore, oestrogen levels fall dramatically at thepre-menstrual stage between the halt of estradioland progesterone production and the start of
menstruation.
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Menstrual Changes 3
However, in women with Premenstrual Dysphoria,oestrogen and progesterone levels were seen to be
normal (Schmidt, Neiman, Danaceau, Adams &Rubinow, 1998) and interest turned to the role ofandrogens.
Early investigations have shown that women
suffering from premenstrual syndrome (PMS) orpremenstrual dysphoria have higher levels of serumtestosterone in the luteal phase compared withcontrols (Ho, Olsson, Westberg, Melke & Eriksson,
2001).
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Oestrogen Levels During
Pregnancy and Post Partum? If fertilization does occur, progesterone promotes
gestation maintaining the thick lining of the uterus.
There is also an increase in endogenous levels ofoestrogen.
Women with a history of major depression have anincreased risk for postpartum depression (Kumar &
Robson, 1984).
Women with a history of bipolar disorder have agreatly increased risk for puerperal psychosis.
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Post Partum Disorders
It has been suggested that postpartum depressionmay be due to the dramatic decrease in oestrogen
following childbirth. There is also a high risk of postpartum mania and/or
psychosis for women with bipolar disorder resultingfrom this oestrogen decrease.
It has been proposed that this reduces theantidopaminergic effect and thus increasessensitivity of dopamine receptors (Wieck, Kumar,Hirst, Marks, Campbell & Checkley, 1991).
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Puerperal Psychosis
Puerperal psychosis has been observed in womenwith a familial history of psychotic episodes and is
believed to be presentation of a manic-depressiveillness.
Up to half of parous females with bipolar disorderwill develop puerperal psychosis within a few days
of childbirth (Coyle, Jones, Robertson, Lendon &Craddock, 2000).
Risks of suicide or infanticide are high in thosesuffering (Millis & Kornblith, 1992).
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Puerperal Psychosis 2
5-HT expression is influenced by oestrogen.
Study 97 women (mean age 40) who had
experienced at least one episode of puerperal
psychosis. 72 female controls (mean age 43).
Findings significant evidence (p
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Oestrogen Levels During and
Following Menopause. The perimenopausal period where transition occurs
is associated with a gradual but unstable decline of
endogenous oestrogen levels. And increase inLuteinizing Hormone (LH) and Follicle StimulatingHormone (FSH)
This has been suggested to be the time around
menopause most highly associated with an increasein depressive symptoms (Schmidt & Rubinow,1994).
Following menopause there are stable, low levels of
endogenous oestrogen.
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The Menopause and Depression
There is evidence of a link between oestrogendepletion during the menopause and mood
disorders in those who are predisposed todepression.
Oestrogen also effects the Central Nervous System(CNS) in areas not directly associated with
reproduction and leads to a significant increase in5-HT2A binding sites in areas involved with moodand cognition.
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The Menopause and Depression
Evidence. Studies have shown that in fact oestrogen also
improves psychological functioning and general
well being in non-depressed menopausal women(Ditkoff, Crary, Cristo & Lobo, 1991).
Estrogen Replacement Therapy (ERT) has alsobeen shown to improve mood (Zweiful & OBrien,
1997). This was the case in surgically menopausal women
(Sherwin & Suranyi-Cadotte, 1990).
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Depression Role of Hormone
Replacement. There is evidence for the efficacy of Hormone
Replacement Therapy (HRT) in surgical menopause
(Pearce & Hawton, 1996). However, there is no clear evidence of increased
cognitive functioning or improvement ofpsychological symptoms following HRT after a
natural menopause. ERT Study 6 women treated with ERT compared
with 6 controls. Showed significant decrease indepressive state P
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Role of Hormone Replacement
New findings suggest that oestrogen may improvethe effect of specific serotonin reuptake inhibitors
(Halbreich, 1997). Study - 358 women with perimenopausal
depression were given Fluoxetine (an SSRI). 72were also given ERT. Oestrogen group showed
40.1% increase on HAM-D-Tests compared to 17%in the control group (Schneider, Small, Hamilton,Bystritsky, Nemeroff & Meyers, 1997).
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Can Oestrogen Protect Against
Mood Disorders? It has been proposed that oestrogen has
neuroprotective properties which may help to
reduce the risk of developing Alzheimers diseaseor suffering from Schizophrenic episodes.
Therefore it is unlikely that oestrogen can protect
against mood disorders directly but that they couldhelp protect against psychiatric disorders which
have a high rate of co-morbidity with depression.
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Oestrogen as a
Neuroprotectant. Oestrogen has been associated with having an
antioxidant action (Behl & Holsboer, 1999) which
may act as a neuroprotectant. Activation of oestrogen receptors on genes can lead
to protection of brain neurones during aging(McEwen & Alves, 1999).
This could also help to explain the genderdifferences between the extent of neural damageoccurring during Transient Ischemic Attacks(TIAs).
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Oestrogen as a Neuroprotectant
2 Corticosteroid release is related to mood disorders
as they can lead to apoptosis of hippocampal
neurones (Haynes, Lendon, Barber & Mitchell,2003). Oestrogen is neuroprotective againstcorticiosteroid damage.
As an antioxidant, an oestrogen (17-oestradiol)
has also been shown to protect cultured neuronesfrom oxidative cell death by acting as a free radicalscavenger (Green & Simpkins, 2000).
Such cell death is associated with Alzheimers
Disease (AD) and Parkinsons Disease (PD).
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Oestrogen as a Neuroprotectant
3 Protective agent against the onset of schizophrenia?
Women have an increased vulnerability to first
episodes or reoccurrence of psychosis during thepostpartum period and during the menopause(Seeman, 1996).
Study 36 women with schizophrenia were chosen.
12 were given 50mcg oestrogen transdermally, 12were give 100mcg oestrogen and 12 were given aplacebo patch. 100mcg showed greatestimprovement followed by the 50mcg group and the
control (Kulkarni et al., 2001).
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Evaluation of Studies Using
Oestrogen as Treatment 2 Also, there are a large number of effective
treatments such as antidepressants, counselling and
in extreme cases Electro-Convulsive Therapy(ECT) for those suffering from mood disorders.
Posing the question of whether an oestrogen basedmedication is necessary or whether it may be more
useful to examine their use as part of a combinationtherapy with antidepressants (e.g. Schneider et. al.1997).
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Evaluation of Studies Using
Oestrogen as Treatment 3 However, as Coyle et. al. (2000) demonstrated,
there is significant evidence that serotonin
transporter gene variability can influence whetherwomen with bipolar disorder will be susceptible topuerperal psychosis.
As oestrogen can influence the transcription of such
genes, perhaps HRT could be used as post nataltreatment for women with bipolar disorder as aprotective agent. Further study is certainlywarranted and necessary.
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Conclusions
It is clear that oestrogen is an extremely powerfulgonadal steroid that can facilitate gene
transcription, BDNF release and that acts as a freeradical scavenger.
It appears that when endogenous oestrogen levelsfall, due to natural fluctuation, menopause or
childbirth, women with a predisposition to mooddisorders may have a higher risk of developingdepression or bipolar disorder.
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Conclusions 2
Treatment using ERT or HRT for depression couldbe possible but it may be more beneficial to
examine using oestrogen in combination with anti-depressants as a treatment for mood disorder.
Also, oestrogen therapy could provide preventativetreatment for women with mood disorders
following childbirth or during the menopause. However, further investigation into the possible
harmful effects of HRT is needed before it isconsidered as a long term treatment.