Science

Estrogen Replacement Therapy and Mood
ERT's effect on mood in menopausal women and the mechanics of this effect


ERT's effect on mood in menopausal women and the mechanics of this effect

Depression and Menopause:

Is depression a symptom of menopause?


Controversy is a central aspect of research in estrogen replacement therapy (ERT) for menopausal women and its affect on mood. One area of controversy is whether or not depression is a symptom of menopause. Depression is a low mood state characterized by significant levels of sadness, lack of energy, low self-worth, guilt, or related symptoms. This differs from the symptomology of major depression in which a person has at least five of the symptoms of depression not due to a normal reaction to a life event that last for two weeks or more.

Symptoms of Major Depression:

depressed mood most of the day, nearly every day
markedly diminished interest and pleasure in almost all daily activities
significant weight loss or gain, or a significant increase or decrease in appetite nearly every day
insomnia or hypersomnia nearly every day
psychomotor agitation or retardation nearly every day
fatigue or loss of energy nearly every day
feelings of worthlessness or excessive guilt nearly every day
reduced ability to think or concentrate nearly every day
recurrent thoughts of death or suicide, a suicide attempt, or a specific plan for committing suicide
Depressive mood has been linked to the activity of serotonin and norepinephrine in the brain. Serotonin and norepinephrine are neurotransmitters that, among other things, affect mood. Neurotransmitters are chemical messengers in the brain that are responsible for communication between different brain areas and the body. A higher level of serotonin and norepinephrine activity is associated with positive mood while decreased activity is associated with depressive mood.




During menopause, women experience hormonal and chemical changes. There is a decrease in a woman's level of estradiol, the principal estrogen of women. Also, some serotonin functioning decreases although it is unknown the extent to which serotonin and norepinephrine activity is affected by menopause. In one study, premenopausal women and menopausal women were given a drug that acts in much the same way that serotonin does in the brain, a kind of pseudo-serotonin used to study the activity of serotonin itself. The researchers found that serotonin activity was decreased in postmenopausal women and that this decrease was associated with decreased levels of estradiol in the blood. The premenopausal women did not show this decrease in activity.


Estrogen boosts the activity of serotonin. Women who experience a long duration of menopause or postmenopausal women who have not used ERT have a prolonged deficiency in estrogen. This prolonged estrogen deficiency may be associated with impairment in estradiol receptors in the brain. Estradiol receptors are the sites in the brain where estrogen connects to most readily and does its work. Estradiol receptors may be important in the faciliatory effect that estrogen has on the activity of serotonin and norepinephrine. When the receptors are impaired, estrogen does not work as well and is unable to facilitate the activity of serotonin.


With the above mentioned effects in mind, it may be that menopausal and postmenopausal women are more vulnerable to depression due to lower serotonin and norepinephrine activity. The Manitoba Project, an ongoing study of Canadian women, found that the stress of daily life, chronic disease, and family problems were most likely to trigger depression in menopausal women. Perhaps these triggers have a more powerful effect on menopausal women and postmenopausal women due to their lower serotonin and norepinephrine activity. One study by Weissman found that the occurrence of major depression may increase after menopause. Another study reported by J. Coope stated that depressive illness is not more common at menopause. However, "depressive illness" was not specified in that study. We do not know if they are talking about a person diagnosed with major depression or someone experiencing depressive mood states not severe enough to be classified as major depression. The data is not conclusive in regard to the occurrence or cause of menopausal or postmenopausal depression. However, the physiological effects of menopause may make a woman more vulnerable to other life aspects that may trigger depression.




Estrogen Replacement Therapy and Mood:

Does ERT help mood?

Does estrogen in combination with progestin help mood?



There is also some controversy about the effectiveness of ERT in alleviating depressive mood, however there is much evidence in support of its beneficial effects. A meta-analysis of 26 hormone replacement studies found that in a majority of these studies ERT helped significantly in the alleviation of depressed mood as rated by scales such as the Hamilton Scale of Depression and Beck Depression Inventory (BDI). These scales investigate the behavioral and bodily symptoms (Hamilton Scale) and the cognitive and mood symptoms (BDI). More recent studies have also shown support for the positive effects of ERT on mood as rated by scales similar to those mentioned above. However, J. Coope reported two studies that did not show these effects.



An interesting point to this controversy is the differences in report scales that have been used to measure depressed mood states. J. Zweifel and W. O'Brien report that the BDI yields smaller effect sizes, or the amount of change exhibited by the women of these studies compared to the effect sizes of the Hamilton Scale. Previous research also suggests that the BDI yields smaller effect sizes in comparison with other measures of depression. In other words, results from the BDI may not indicate as much change as another scale would. The BDI investigates cognition and feelings while the Hamilton Scale looks at behavioral and bodily symptoms. It may be that the BDI is less sensitive to the changes caused by ERT. Another difference in the scales is how they are taken. The BDI is a self-report measure whereas the Hamilton Scale utilizes a trained observer's ratings of symptoms. Women may be reluctant to endorse symptoms related to depression when they are doing the self-evaluation. Consequently, the BDI may not be an accurate measure of these symptoms.



Other evidence for the ERT's effectiveness in enhancing mood comes from it's effects on the chemistry of the brain. Estrogen enhances norepinephrine and serotonin activity, and inhibits production of monoamine oxidase. As mentioned earlier, serotonin and norepinephrine are involved in the regulation of depressive moods. Decreased activity of serotonin and norepinephrine are associated with increased depressive mood.

Estrogen's effects on serotonin:


estrogen increases the sensitivity of the receptors that receive serotonin (they are more likely to connect with serotonin)
increases the number of serotonin receptors which increases the activity level of serotonin
increases the reuptake of serotonin by the neuron it was released from in order that the serotonin may be made available once again in the synapse (the space between the neuron that releases the serotonin and the receptor that may connect with it)
increases the synthesis, or production, of serotonin
Estrogen's effects on norepinephrine
increases the binding rate of particular norepinephrine receptors (which increases norepinephrine activity)
increases "turnover" of norepinephrine, the rate at which it is "remade" available to be released into the synapse- this may be due to decreased metabolism or destruction of norepinephrine due to inhibition of MAO
Monoamine oxidase (MAO) is an enzyme that acts on other molecules, changing them in small ways that make the molecules more useful to the body. MAO acts on a variety of neurotransmitters, two of which are norepinephrine and serotonin. MAO destroys excessive amounts of norepinephrine and serotonin in healthy individuals. The activity level of MAO is used as an indicator of the activity level of serotonin and norepinephrine. If the activity level of MAO is high, the activity level of serotonin and norepinephrine is high. E. Klaiber and colleagues have demonstrated that increased levels of MAO platelet activity are indeed associated with lower levels of depression after two cycles of ERT.

Estrogen also acts as a MAO inhibitor by decreasing the production of MAO. The result is that there is less MAO to destroy serotonin and norepinephrine and hence, there is more of these two neurotransmitters available to be released into the synapse and their activity is increased. This action of estrogen is the same as MAO-inhibitors that are used as a therapy for depression. However, ERT alone may not be effective as an antidepressant but may be helpful as part of a larger regimen. The research for ERT as an antidepressant is not yet conclusive.



Estrogen Replacement Therapy and Progestin:

What are the effects of adding progestin to ERT?
Progestin is taken in combination with estrogen to diminish the risks of continual estrogen administration. One of the major risks of taking only estrogen is a significant increase in a woman's risk of endometrial cancer. Many studies however, have shown that the combination of estrogen and progestin has diminishes the positive effects that estrogen alone has on mood. However, not all women have such a negative reaction to the addition of progestin.




E. Klaiber and colleagues investigated the individual differences in women that may account for the differential reactions to the addition of progestin. They found that women who experienced an increase in positive mood during ERT and did not react adversely to the addition of progestin had the following characteristics:



short menopausal duration
high pretreatment estradiol levels in the blood
high pretreatment testosterone levels in the blood
low pretreatment levels of follicle stimulating hormone in the blood
****these above characteristics reflect early menopausal stages***

Women who had positive mood reaction to estrogen alone but experienced a reduction in the positive effect with the addition of progestin had the following characteristics:



long menopausal duration
low pretreatment estradiol level in the blood
low pretreatment testosterone level in the blood
high pretreatment follicle stimulating hormone in the blood
***these characteristics reflect the later stages of menopause***

Women whose benefits from estrogen were not completely countered by progestin had the following characteristics:

pretreatment adverse mood states
low pretreatment MAO activity (indicative of lower serotonin and norepinephrine activity)
older age (in an age span of 45-65 years)
The enhancing effect of estrogen on MAO activity (indicative of serotonin and norepinephrine activity) is diminished in some women by the addition of progestin. Women who did show an increase in MAO activity during ERT were woman who had short menopausal duration and high pretreatment levels of testosterone in their blood. These women showed a decline in MAO activity every time progestin was administered. An interesting occurrence is that the greater the rise in MAO activity during ERT, the less impairment there was in mood due to addition of progestin.



A paradox was found in the expected blood levels of estradiol in women with long menopausal duration. These women had higher levels of estradiol during ERT than did women with short menopausal duration but this raise in estradiol level did not counter the negative effects of progestin. They still experienced a reduction in the positive effects of estrogen. E. Klaiber and colleagues put forth an interesting hypothesis. Women with long duration of menopause also have experienced a prolonged deficiency in estrogen. The hypothesis is that the prolonged estrogen deficiency causes impairment of estradiol receptors in the brain which in turn causes a decrease in the use of estrogen resulting in more estradiol being left over in the brain (= high levels of estradiol in the blood). This impairment of estradiol receptors also impedes normal reactions to estrogen which means estrogen is not as able to have it's beneficial effects on the serotonin and norepinephrine activity.



However, women with long duration menopause do react positively to estrogen alone. S. Carranza and M. Valentino-Figueroa found that ERT was useful in alleviating depressive mood in postmenopausal women who had these depressive symptoms before ERT, but S. Girdler and colleagues found that it did not have a mood effect for women who did not have depression. It may be that in lieu of the already diminished number of healthy estradiol receptors, the progestin causes a further "down regulation" of estradiol receptors resulting in a lessening of the positive effects of estrogen. If this hypothesis of the impairment of estradiol receptors is true, it is not know if ERT can reverse it. If it can't, this is a strong argument for early intervention with ERT. However, this hypotheses have not been proven yet and further research needs to be done to investigate these probabilities.

Women with pretreatment adverse mood states and low MAO activity (indicative of low serotonin and norepinephrine activity) may already be vulnerable to depression before the onset of menopause. Their MAO level may already be low, and although estrogen may raise it, it may not be enough to protect against the effects of progestin.