Hormones Affect Anxiety and Depression

Trish Morse

01/29/02

The good news is, it's not all in your head! The bad news is, it's hard to get people to understand that when even as good a source of information as WebMD can say "most of the menopause 'blues' women experience are rooted in the psychological fear of aging and the stress of menopausal symptoms such as hot flashes. If you're taking HRT because you think it will cure any depression you're experiencing, you're mistaken. ... Often depression seems to just 'vanish' once hrt or ert is started. This vanishing act has nothing to do with estrogen; it has to do with time and the positive psychological placebo effect estrogen therapy often has." (46)

Well, of course stress and lack of sleep and personal fears have all kinds of effects and hormones do not explain everything, but they explain a lot--and they have a LOT to do with getting that heavenly good night's sleep!

As researcher come to understand other times of extreme hormone change, maybe they will understand menopause better too. They're finally admitting that girls at puberty are at risk for mood disorders as hormones arrive (27) (maybe all the researchers should just hang out in a middle school for awhile!). And they are realizing that there are women with unusually strong reactions to the loss of hormones after the birth of a baby.(25) So, I predict that soon there will be more agreement that losing hormones at menopause affects our moods too. However, there's no doubt that the situation is very complex so it might be a long time before they know exactly what does which to whom.

Hormones have receptors throughout the brain, including the parts that respond with the pounding heart of panic and the flush of anger.(37) Hormones also have a large effect on neurotransmitters--the chemicals that "thoughts" pass through to get from one brain cell to another. Neurotransmitters "color" our thoughts. But they aren't straightforward, like serotonin = crayon yellow. Right now, the exact same chemical seems to produce a huge range of colors in different women. This might be a sign of genetic differences in how we process these chemicals--but this part of the Jungle is Terra Incognita now!

So, I'm going to look at some of the pieces of the puzzle, then at anxiety and depression, which seem to affect so many in the Hormone Jungle, and some things that might help.

PIECES OF THE PUZZLE--NEUROTRANSMITTERS

Norepinephrine

Norepinephrine is a neurotransmitter that has a lot to do with the flight or fight response--which is a response that makes sense if you are a lizard or a mouse, but humans often don't fight or run away. They just stay put!

Norepinephrine is found mostly in that old lizard and mouse part of the brain.(35) In the amygdala, which is a central processing unit for anxiety, there are 12,000 neurons that are sensitive to norepinephrine.(10) Norepinephrine helps with emergencies: it tells the stress hormones to appear, raises blood pressure, speeds up the metabolism, raises body temperature, affects the lungs, and makes us alert and focused. It helps with memory and learning.(16) All of these things are good if we're in danger. But when we just stay put every day in stress, these responses cause wear and tear on the body and we can run out of norepinephrine--and that's not good.

In humans, if norepinephrine levels stay high or spike, they feel irritability, fear, anxiety, and even panic.(36) So high norepinephrine can bring on the symptoms of a panic attack--which seemingly comes out of the blue.(10) Our heartbeat speeds up, our skin constricts, blood pressure increases, we're breathless and dizzy, and our digestive system shuts down. We can even have visual disturbances.(10)

We want norepinephrine to help us be awake and alert, but if the levels of norepinephrine don't drop down at night, we can't get restful rapid-eye-movement (REM) sleep.(16) Lack of REM sleep can have disastrous long-term consequences on mood and our whole body, even leading to fibromyalgia.(47)

Norepinephrine plays a role in hot flashes and night sweats too. They don't have all the answers to hot flashes, but they know that luteinizing hormone (a hormone that signals the ovaries) surges (probably trying to get the missing or sleeping ovaries to DO something, ANYthing). With the surge, norepinephrine in the hypothalamus rises.(6) The hypothalamus is trying to regulate the body's temperature and sleep.(29) So, one of the awful things that they think might be happening is that it's the actual act of entering REM sleep--which we NEED--that triggers the hot flash.(29) Without REM sleep, we feel tired, foggy, and depressed.(29) So high norepinephrine can seem like depression as well as anxiety.

However, if norepinephrine levels are low, we're even more likely to be depressed.(16) Tricyclic antidepressants work by maintaining higher levels of norepinephrine.(16) Mice who can't process norepinephrine don't respond to antidepressants at all.(15)

The presence of estrogen, especially estradiol, has a mixed effect on norepinephrine levels (6) so the effect of HRT on anxiety is unpredictable. But it's clear that the lack of estrogen has a huge effect. Six days after ovaries are removed from mice, there is a measurable loss in connections in the brain that use norepinephrine. HRT stops the loss. (32) The adrenal glands also produce norepinephrine, so adrenal health is important too in helping out.(16)

Serotonin

Serotonin is probably the most famous neurotransmitter because of the antidepressants that boost it up. Receptors for serotonin show up in the intestines (it makes food move through faster), blood vessels (increases constriction--and blood pressure and migraines), and of course the central nervous system. High serotonin levels lower appetite.(36)

When levels of serotonin are low, our ability to sleep is disturbed and we can't feel pleasure in anything. (36) We crave carbohydrates.(36) Low levels are linked to depression, obsessive compulsive disorder, violence, aggression, and suicide.(16) And low levels of serotonin are linked to panic disorder.(10) Weirdly, low levels of serotonin may also lead to urinary frequency, hyperactive bladder, and urge incontinence.(46) In the past they knew that women with bladder problems were depressed, but they thought the bladder problems caused the depression. Now, however, it looks as though both could be caused by low serotonin levels.

GABA

GABA is gamma amino butyric acid--the anti-stress, anti-anxiety, anti-panic, anti-pain neurotransmitter.(10) GABA helps us fall asleep. In fact, barbiturates and the anti-anxiety drugs Valium, Librium, Ativan, and Xanax all interact with GABA receptors. Enough of it and we feel calm. Too little and we feel anxious and can't fall asleep. It interacts with 25% to 40% of brain synapses so it's busy up there.(5)

Dopamine

Dopamine, like all of these neurotransmitters, controls the whole body--digestion, heart, muscle control, ovulation, thyroid health (and through thyroid--depression), water retention, and milk production. Low levels of dopamine are connected to schizophrenia and incoherent thoughts,(35) Parkinson's disease, and depression. High levels are connected with increased anger and aggression.(36) But dopamine in balance leaves you feeling alert, relaxed, and happy--it's the pleasure neurotransmitter! In fact, a lot of addictive things, like nicotine, trigger dopamine release. And it prevents sodium and water retention, which always puts me in a better mood right there.(36)

Acetylcholine

Acetylcholine isn't one of the main mood neurotransmitters like the other four, but it is high during the fight or flight response (10), helps with alertness (20), and is released during REM sleep (16), so it probably plays a role in mood that they haven't figured out yet. Estrogen has a big effect on maintaining its levels.(7)

PIECES OF THE PUZZLE--HORMONES

Estrogen

Low estrogen is probably a risk for depression, though estrogen out of balance is probably a risk for anxiety. But it can get confusing! Estrogen affects all the big neurotransmitters.

The most straightforward connection is with serotonin. Estrogen boosts serotonin (6, 36) by both making more of it (17) and keeping it around after it's made.(27) So that's likely to be the reason that estrogen--for most people--helps fight depression and helps with sleep.

Estrogen has a mixed effect on norepinephrine (6) but probably boosts it in most women, which for most would mean feeling better, more alert. But for some, high norepinephrine might be the cause of the anxiety and panic attacks that estrogen seems to produce in some women.

Estrogen probably lowers dopamine (6) more than it boosts it.(23, 27) Since low dopamine can be depressing, this might be one of the reasons that some women feel more depressed on estrogen. Estrogen definitely boosts acetylcholine.(6) And high acetylcholine has been linked with depression, so there's another possibility.

However, most of the evidence is that estrogen improves mood (11) for many. And estrogen may in particular give a sense of well-being to women in surgical menopause who aren't depressed to begin with.(27)

Estrogen has receptors all through the "mouse" and "lizard" parts of the brain that control physical responses to emotions and moods.(17) In particular, the hippocampus in this "old" part of the brain connects emotions and memory--we're more likely to remember something with an emotion attached to it.(5) The hippocampus shrinks in severe depression and schizophrenia, but estrogen boosts the health of the hippocampus so it may have a very direct benefit when we are depressed.(5)

Some of the mixed reports on estrogen's effects on mood (27) might be caused by the kind of estrogen used in the study. The reports of doctors on their own practices seem to show that women who take conjugated equine estrogen (CEE, aka Premarin) are more likely to feel depressed, irritable, or anxious than women on other forms.(6)

In one test, they found that women were much happier when using esterified estrogen (a synthetic form but with few side effects) than when using conjugated equine estrogen (CEE; aka Premarin). The two different kinds of estrogen caused blood to flow to different parts of the brain.(28) They've just discovered that there are two different kinds of estrogen receptors--alpha and beta. It's possible that CEE and esterified estrogen hook up with those receptors differently.(28) Eventually they might be able to "design" estrogens to have specific effects, but for right now it makes sense to avoid CEE if depression is an issue.

In one test of estradiol in a patch versus a placebo, the depressed women on the patch did much better than women on the placebo.(1) It's possible that the delivery system makes a difference, with a patch being better.(27) Of course, patches are estradiol, not CEE, so that could be the difference as well.

So, if you are feeling anxious, estrogen out of balance might be to blame. To balance estrogen, you can try increasing progesterone or taking the supplements that help the liver metabolize estrogen: magnesium, folic acid, vitamin B6, and zinc. If you're feeling depressed while taking HRT, you can try switching to bio-identical estrogen and transdermal delivery, as well as try the supplements. But you can have unusual reactions because of all the neurotransmitters involved. Trial and error is the only way to go for now.

Progesterone

Progesterone may be even more unpredictable than estrogen.(18) It can convert to estrogen and testosterone, and no one's quite sure what the progesterone receptors scattered throughout the brain are doing.(18) And it can be turned into different chemicals (metabolites). One metabolite (allopregnanolone) is very depressing and another (pregnenolone) is just the opposite.(27)

It's clear though that progesterone helps with anxiety, (10) probably because it helps with GABA.(18) Its metabolites bind with the GABA receptors (which are also throughout the brain). Progesterone binds with them even better than barbiturates or alcohol. It's probably this GABA connection that gives progesterone its antiepileptic effect.(18) But it's not clear whether progesterone helps with depression. Some people feel more depressed when GABA is high because it's a sedative, but some people are less depressed when it's high.(27)

It's possible that progesterone cream might help with depression by helping with dopamine levels (the pleasure neurotransmitter). In one small preliminary test, progesterone cream was more effective than a placebo in boosting low self-image and decreasing feelings of guilt.(27) Another form that might be good for depression is vaginal gel, which is more available outside the U.S.(18)

However, oral progesterone may not be a good idea for people with a personal or family history of depression.(27) Oral progesterone can convert into the bad metabolite. The worst forms for depression are definitely the oral progestins (synthetic imitations that don't break down). They are notorious for bringing on irritability, anxiety, depression, and crying.(18)

There is another way that progesterone may have a good effect on mood. Progesterone helps create that desperately needed REM sleep. Women with high levels of serum progesterone spent longer periods in restful REM sleep and roused from deep sleep less often. They also had more positive emotions than women with low progesterone. (45)

As always, the ratio of progesterone to estrogen may be crucial.(27) So, if you're depressed and using progesterone, try creams instead of oral and lower the dose. If you're anxious, a bit more of progesterone, or even switching from cream to an oral form, might be better.

Testosterone

Almost nothing is really known about testosterone and mood. There are receptors throughout the brain. It probably increases a sense of more energy and well-being for someone who is depressed.(18) But some think that the main effect of testosterone even in men may be that it converts to estrogen.(6) Testosterone may increase anger and aggression.

ANXIETY

Panic attacks and chronic anxiety come from the "primitive" parts of the brain over-reacting to stress. That's a problem, though we know that there's an excellent way to help manage stress by tricking the old mouse brain into thinking that we're being sensible and running away (aerobic exercise) or fighting (weight lifting). In other words, the best thing for anxiety is exercise.

Panic disorders, however, are not really a response to a specific stress--or at best the are a totally out of proportion response.(49) Central to this exaggerated response is the release of norepinephrine, with all the symptoms that can bring.(49) Probably panic disorders also reflect an absence of serotonin and GABA, which calm anxiety and panic. So boosting serotonin and GABA are good things to do.

There are two aspects that have to be considered as well--genetics and personal history. We're all wired differently so the same chemicals can produce different reactions in different people. And if we've experienced trauma, both panic and depression can be "hard-wired" into the brain and will need stronger treatment.

Post-traumatic stress disorder rewires the fear center in the amygdala to respond with panic.(49) And parts of the hippocampus--which deals with emotions and memories--die away after trauma (perhaps to protect us from them?)(49).

So, though hormonal balance may be enough for some, other people might need more help. If panic and/or depression showed up after the hysterectomy and never did before, then there's a better chance that tinkering with hormones might solve the problem.

If balancing progesterone and estrogen through HRT isn't an option (or even if it is), there are other things that can help. Cognitive therapy can help to rewire the brain as can breathing exercise and massage.(49, 50) Exercise of any kind always helps. Since stress uses up neurotransmitters, a healthy diet with enough protein to supply the building blocks is a good idea. There are supplements that might help (particularly if you are taking estrogen). Magnesium helps with insomnia, nervousness, restlessness, anxiety, and blood pressure. Vitamin B6 is involved with helping serotonin, GABA, and dopamine (a balanced B complex is best). People who get panic attacks might be extra sensitive to caffeine, so it's good to avoid it.(10) Anything that will help you relax (except alcohol, which really messes with hormone balance) is probably a good thing.

There are prescriptions of course--all the things that react with GABA like Xanax, Ativan, and Valium. Effexor seems to be good for anxiety and palpitations and hot flashes, though it targets both serotonin and norepinephrine apparently, so some people might find it makes anxiety worse.(43) And some of the SSRIs may fight anxiety problems as well. Paxil in particular has been approved for anxiety.

DEPRESSION

If anyone tells you that there's no connection to hormones, point out that women are two times more likely than men to have depression from ages 20-45, but they are four time more likely than men to develop major depression in the years just before menopause.(27) This means that depression is more likely when hormone levels are bouncing around than after menopause when levels are steady, so some mood problems in the Hormone Jungle might be helped by finding a balance and sticking with it.(27)

However, make an appointment with your doctor RIGHT AWAY if 5 or more of the following symptoms have hung around for a month or more and at least one of the symptoms is (1) depressed mood (sometimes shows up as irritability) or (2) loss of interest or pleasure in life.

The other symptoms are

(3) significant change in appetite (up or down),

(4) can't sleep or always sleep,

(5) fatigue or loss of energy,

(6) feelings of worthlessness or inappropriate excessive guilt,

(7) diminished ability to think or becoming indecisive,

(8) and the biggy--thoughts of death and suicide. (49)

Obviously some of these symptoms might be simple post-op recovery, but if it's a whole pattern, especially with the thoughts of death and suicide and the worthlessness/guilt, then don't put up with it. Go get help! It's not weakness--it's brain chemistry!

If you had depression or dysthmia (prolonged greyness as opposed to deep darkness) before surgery, then you're more likely to need extra help after surgery. HRT alone might not be enough.

In addition, there are things that can mimic depression--stroke, hypothyroidism (a real problem in the Jungle), Cushing's disease, side effects from medication--especially blood pressure medicine. All of these can be treated or adjusted. So again, don't put up with it. Talk to your doctor!

Low serotonin, dopamine, and norepinephrine are the most important neurotransmitters for depression, though high acetylcholine (boosted by estrogen) can be depressing too. So in general, estrogen helps. One psychiatrist is recommending a very low dose patch as a treatment for depression.(5)

An interesting thing is that half of all depressed people have high levels of cortisol, the stress hormone pumped out by the adrenal glands. So depression and anxiety are often linked reactions to stress or trauma.(27) People who are not depressed release cortisol at 8 am and 4 pm and then levels drop at night. Depressed people don't cycle. Their levels stay high.(27) So lowering stress and cortisol through exercise, meditation, and massage might help depression.

Obviously, antidepressants help--though different ones affect different neurotransmitters so some experimentation might be needed to put the right puzzle pieces together. Women using a combination of SSRIs (Prozac, Celexa, etc.) and estrogen did better than either estrogen alone or SSRIs alone.(11) If you can't take estrogen, then SSRIs are a great way to go since so many of them also fight hot flashes (better sleep) and may help with heart disease too. Effexor boosts norepinephrine and serotonin.(43) while Wellbutrin/Zyban boosts dopamine and maybe norepinephrine. So, if you are having an odd reaction to high serotonin, one of these others might be just the thing for you.

The best thing for depression is exercise. It's as effective as drugs, works much faster, and of course has no bad side effects.(36) Just 30 minutes three times a week can make a difference in depression.

Bananas and plums are rumored to help serotonin levels (hey! You never know), and some supplements might help. Magnesium helps with depression and insomnia, while vitamin B6 is a workhorse with mood--it increases serotonin, GABA, and dopamine levels and balances norepinephrine. It's best though to take a balanced B complex (100% of RDAs) than vitamin B6 alone--especially at high levels.

And don't dismiss therapy. It can help you get your feet under you while you work your way toward balance. Sometimes it's terribly important to get that floor under your feet as you are sliding down into the tiger trap covered with vines. If you had periods of depression before surgery, then it's all the more likely that therapy--in addition to finding chemical balance--may really help you. Therapy is a mirror that will help you see what you can do to help yourself. In addition, psychiatrists are often the people most trained in dealing with the nuances of brain chemistry. They might be more help in finding the right balance than a general practitioner or gynecologist.

Most of all, don't put up with a mood disorder. It steals your life away and there IS help.

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