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