Oestrogen Assignment

8/4/2019 Oestrogen Assignment

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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.

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Oestrogen Assignment