Estrogen in Psychiatry

You’d think psychiatry would know more about this. Everyone knows estrogen has something to do with mood, right? It’s amazing how little we know. While I’m trying to find research that might guide us clinicians in knowing what to do with estrogen in Psychiatry (measure it? ask OB-Gyn’s to start birth control or other forms of hormone replacement? learn how to do so safely ourselves?), here are some basics that seem relevant.

For basic information about estrogen therapy, from what appears to me to be a responsible organization, see Project Aware. Their volunteer, non-profit site is quite large, so remember when you’re done, if you’d like more on the research on estrogen use in Psychiatry (such as there is), come on back. Here is my collection of relevant research for a psychiatrist interested in mood and anxiety. When there is enough here to write an organized story, I’ll be back. At this point these are only “very suggestive” studies, not “tells you what to do” research, except for one conclusion at the bottom.

Estrogen effects on mood  are complex, not simple

In a recent review on of the brain chemistry of reproductive hormones in women,^Genazzani the following estrogen effects were described:

• an increase in brain norepinephrine levels;
• a decrease in dopamine release;
• multiple effects on serotonin, and even an effect on blood tryptophan levels (the amino acid from which serotonin is made);
• protective effects on acetycholine systems (possibly thereby protecting against Alzheimer’s disease);
• effects on the production of neurotrophic factors, the brain’s own cell fertilizers, now known to be very directly involved in the mechanism of depression;
• an increase in endorphin levels in the brain as well as the bloodstream;
• a possible relationship with melatonin, the sleep-regulating hormone (complex relationship, different in different animal species);
• promotion of the production of allopregnanolone, a “neurosteroid” with strong antianxiety effects; and
• a complex relationship, but clearly affecting the levels of DHEA, another neurosteroid with mood effects.

The moral of the story: there is no simple way to explain “here’s how estrogen affects mood”. While you will often see the implication “too little estrogen leads to depression”, and the related claim “estrogen can be a treatment for depression”, you should keep in mind that this is a dramatic simplification of a complex relationship, most of which we don’t understand.

Antidepressant effects, but sometimes anxiety

However, even though the effects of estrogen on the brain are clearly very complex, we psychiatrists are still faced with the fact that something about estrogen and progesterone clearly affects mood. For many women, the relationship is so obvious, they want to know if there isn’t some way to treat what appears to be the problem, namely their changing hormone levels. After all, if that’s the cause, why not treat the cause, rather than the symptoms?

Two studies have shown that estrogen can treat depression in perimenopausal women: first came a study from Harvard showing that an estrogen patch worked;^Soares and more recently smaller study from UCLA with similar results.^Morgan (There is also an “open trial”, meaning no control group, from Harvard^Cohen). However, as soon as you think about estrogen in this role, you have to think about the risks of estrogen.

But even something so seemingly simple as raising the estrogen levels we know are falling during perimenopause runs into some problems. One research team found that in women with severe mood/anxiety symptoms (so-called borderline personality disorder, an unfortunate term and very complex condition), there was in increase in symptoms when they went on birth control pills, though only if they already had a high level of estrogen.^DeSoto

Similarly, that UCLA study^Morgan included three women whose estrogen levels went up a lot when taking Premarin, and they actually got a little worse, including an increase in their anxiety scores in particular.

This is tricky. Move on if you’re not ready to dig into some graphs. The first shows an antidepressant effect from estrogen, but the second shows some increase in anxiety in a few women.

Note that zero, no change, is in the middle of these scales. So if increasing estrogen levels helped treat depression in these women, you’d expect that their diamonds would fall in the lower right side — right? Raise the estrogen, lower the depression score. As you can see, it wasn’t entirely that way, although there was enough of a result to be statistically significant. To me, the result that might be especially useful to Psychiatry right now, even though it was only two women, are the two diamonds in the upper right. These women had a large increase in their estrogen level, and their depression scores got worse.

In particular, what got worse was anxiety, as shown in the same kind of graph system for their anxiety subscale scores (part of the same depression scale that asks about anxiety):

Again you see that for the few women whose estrogen level went up quite a bit, their anxiety got worse. For now, then, here’s my conclusion about estrogen replacement, which is much simpler than trying to answer the question “does it work for depression?” or “is it worth the risk?”. Any woman with high anxiety who’s taking estrogen replacement needs her estrogen level checked.

If she’s taking Premarin, she should talk with her doctor about switching to estradiol so that her level can be checked (because you can’t do so on Premarin; here’s a description of that problem).

According to my OB-Gyn colleagues, in their experience “women seem to feel best when their estrogen level is between 50 and 100”. One said he tried to shoot for 75. For now, if anxiety is a problem and the level is higher than 150 or so (in one of my patients switched over to estradiol at what was thought to be an equivalent dose, it was 400), then you should talk to your doctors about trying a lower dose.

(reviewed 12/2014)