The Relationship Between Oestrogen Levels and Mood Disorders.

Oestrogen
A gonadol hormone. Responsible for sexual maturation, growth of breasts, development of fat deposits and growth of uterine lining in women. Also has been identified as having a role in depression as estrogen deficiency may increase the susceptibility for depression (Birkhauser, 2002).

Mood Disorders
Bipolar Disorder (also known as manic depression) - includes cyclical periods of mania and depression. Unipolar Depression - periods of depression that do not alternate with periods of mania. 29.2% of people with bipolar disorder and 15.9% with unipolar depression attempt suicide (Chen & Dilsaver, 1996).

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.

Serotonin and Depression

5-hydroxyindoleacetic acid (5-HIAA) is a metabolite formed when serotonin (5-HT) is destroyed 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).

Serotonin and Oestrogen

Studies have examined effects of oestrogen on 5HT receptors. It has been found that oestrogen replacement therapy in postmenopausal women leads to significantly increased 5-HT2A receptor binding. (Kugaya, Epperson, Zoghbi, Van Dyck, Hou, Fujita, Staley, Garg, Seibyl & Innis, 2003). However, in this study, mood was not affected.

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 depression by modulating serotonergic interactions.

Oestrogen as an Antidepressant
Oestrogen may facilitate down-regulation of 5HT2 receptors which also occurs with chronic (21 days) antidepressant treatment (Joffe & Cohen, 1998). As with antidepressants, oestrogen increases the release 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 upon animal models of depression (Duman, Heninger & Nestler, 1997).

How Does Oestrogen Work?

Is oestrogen having antidepressant effects by modulating serotonin receptors, increasing NGF release, working as a free radical scavenger or is it a combination or all three factors? Another aspect to consider is oestrogen as a protective factor against depression which commonly occurs co-morbidly with symptoms of psychiatric illness such as schizophrenia and Alzheimers Disease (AD).

The Action of Oestrogen

Oestrogen binds to receptors. These receptors are part of a large group of ligandactivated transcription factors that combine responses from the genome and modulate the transcription of genes. These genes encode proteins including enzymes for neurotransmitters, neuropeptides, growth factors and signal transduction. Therefore oestrogen and other gonadal steroids can influence the actions of neurotransmitters. (Rubinow, Schmidt & Roca, 1998).

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 5HT2 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.

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 postpartum depression (Gregoire et. al 1996). 3 used gynaecology patients selected for being symptomatic during peri and post menopausal transition (Campbell & Whitehead, 1977; Schneider et. al. 1977; Coope, 1981).

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 symptoms of participants taking oestrogen over those in the placebo control group.

Results 2
Oestrogen appeared less effective in the studies examining the peri and post menopausal transitional period where no benefit was shown over placebo groups (Campbell & Whitehead, 1977; Schneider et al. 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 greater improvement over placebo trials.

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.

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 the uterus to increase lining. Usually leads to increase of Luteinizing Hormone (LH) by anterior pituitary.

Menstrual changes 2
This leads to ovulation where the follicle ruptures releasing the ovum. The follicle becomes a corpus luteum. If fertilization does not occur, estradiol and progesterone levels fall as the corpus luteum stops producing. At this point menstruation will occur. Therefore, oestrogen levels fall dramatically at the pre-menstrual stage between the halt of estradiol and progesterone production and the start of menstruation.

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 of androgens. Early investigations have shown that women suffering from premenstrual syndrome (PMS) or premenstrual dysphoria have higher levels of serum testosterone in the luteal phase compared with controls (Ho, Olsson, Westberg, Melke & Eriksson, 2001).

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 of oestrogen. Women with a history of major depression have an increased risk for postpartum depression (Kumar & Robson, 1984). Women with a history of bipolar disorder have a greatly increased risk for puerperal psychosis.

Post Partum Disorders

It has been suggested that postpartum depression may 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 resulting from this oestrogen decrease. It has been proposed that this reduces the antidopaminergic effect and thus increases sensitivity of dopamine receptors (Wieck, Kumar, Hirst, Marks, Campbell & Checkley, 1991).

Puerperal Psychosis
Puerperal psychosis has been observed in women with a familial history of psychotic episodes and is believed to be presentation of a manic-depressive illness. Up to half of parous females with bipolar disorder will develop puerperal psychosis within a few days of childbirth (Coyle, Jones, Robertson, Lendon & Craddock, 2000). Risks of suicide or infanticide are high in those suffering (Millis & Kornblith, 1992).

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<0.003) that variation in the serotonin transporter gene had an influence on susceptibility of having an episode of puerperal psychosis. (Coyle et. al. 2000)

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 in Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) This has been suggested to be the time around menopause most highly associated with an increase in depressive symptoms (Schmidt & Rubinow, 1994). Following menopause there are stable, low levels of endogenous oestrogen.

The Menopause and Depression

There is evidence of a link between oestrogen depletion during the menopause and mood disorders in those who are predisposed to depression. Oestrogen also effects the Central Nervous System (CNS) in areas not directly associated with reproduction and leads to a significant increase in 5-HT2A binding sites in areas involved with mood and cognition.

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 also been shown to improve mood (Zweiful & OBrien, 1997). This was the case in surgically menopausal women (Sherwin & Suranyi-Cadotte, 1990).

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 of psychological symptoms following HRT after a natural menopause. ERT Study 6 women treated with ERT compared with 6 controls. Showed significant decrease in depressive state P<0.03 (Carranza-Lira et.al, 1999).

Role of Hormone Replacement

New findings suggest that oestrogen may improve the effect of specific serotonin reuptake inhibitors (Halbreich, 1997). Study - 358 women with perimenopausal depression were given Fluoxetine (an SSRI). 72 were 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).

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 disease or suffering from Schizophrenic episodes. Therefore it is unlikely that oestrogen can protect against mood disorders directly but that they could help protect against psychiatric disorders which have a high rate of co-morbidity with depression.

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 gender differences between the extent of neural damage occurring during Transient Ischemic Attacks (TIAs).

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 against corticiosteroid damage. As an antioxidant, an oestrogen (17-oestradiol) has also been shown to protect cultured neurones from oxidative cell death by acting as a free radical scavenger (Green & Simpkins, 2000). Such cell death is associated with Alzheimers Disease (AD) and Parkinsons Disease (PD).

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 the postpartum period and during the menopause (Seeman, 1996). Study 36 women with schizophrenia were chosen. 12 were given 50mcg oestrogen transdermally, 12 were give 100mcg oestrogen and 12 were given a placebo patch. 100mcg showed greatest improvement followed by the 50mcg group and the control (Kulkarni et al., 2001).

Evaluation of Studies Using Oestrogen as Treatment.

Before the efficacy of oestrogen can be fully evaluated, it must be stated that use of HRT is being closely regulated due to the increase risk of developing breast cancers. In studies where oestrogen treatment was used, the findings varied: Kugaya et. al (2003) stated that oestrogen therapy increased 5-HT2A receptor binding but that mood was unchanged. Thus questioning whether risks associated with HRT would be worthwhile.

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 based medication is necessary or whether it may be more useful to examine their use as part of a combination therapy with antidepressants (e.g. Schneider et. al. 1997).

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 whether women with bipolar disorder will be susceptible to puerperal psychosis. As oestrogen can influence the transcription of such genes, perhaps HRT could be used as post natal treatment for women with bipolar disorder as a protective agent. Further study is certainly warranted and necessary.

Conclusions
It is clear that oestrogen is an extremely powerful gonadal steroid that can facilitate gene transcription, BDNF release and that acts as a free radical scavenger. It appears that when endogenous oestrogen levels fall, due to natural fluctuation, menopause or childbirth, women with a predisposition to mood disorders may have a higher risk of developing depression or bipolar disorder.

Conclusions 2
Treatment using ERT or HRT for depression could be possible but it may be more beneficial to examine using oestrogen in combination with antidepressants as a treatment for mood disorder. Also, oestrogen therapy could provide preventative treatment 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 is considered as a long term treatment.