Polycystic Ovarian Syndrome
PCOS has something to do with psychiatry? Indeed it appears so, in two ways: first, it may be caused by at least one of the medications we routinely use (Depakote), though this is not certain. Second, PCOS may worsen mood and anxiety symptoms, although this is not certain either. [Update 2008: Here is another connection. A recent article found that women with PCOS were far more likely then women without PCOS to have mood and anxiety symptoms; and seven times more likely to make a suicide attemptMansson]
Here's a basic introduction to PCOS. For information on how it might affect mood symptoms, please follow the link to "metabolic syndrome", which is where I'll be putting information on that aspect of PCOS. Metabolic syndrome may be the broader definition of this problem, whereas PCOS focuses on ovarian/reproductive aspects; if you really want to know which is which and how they relate, try this summary.
[Update 2009: "opiate" receptors have been implicated in the mechanism of PCOS (you know about these receptors; they're the ones that heroin and morphine connect with, but which are found in all of us and which respond to our own natural opiate-like molecules). Medications that affect these receptors can actually improve some aspects of PCOS (naltrexone).
Now, on to the issue of whether PCOS is caused by valproate (U.S. trade name version, Depakote) (updated 9/2009).
PCOS and Depakote
Update 2009: Because divalproex (Depakote) was widely used in the treatment of bipolar disorder, the possibility that it might cause PCOS was of great concern when this began to surface as an issue. There was resistance to admit that the medication might indeed be a cause. But the evidence slowly became more solid (e.g. Morrell 2008), and now there is little debate -- although articles on this subject almost always emphasize the connection between bipolar disorder and PCOS. In other words, bipolar disorder itself can cause PCOS; then medications like divalproex (Depakote) just increase the risk that PCOS will develop (e.g. Jiang 2009) .
The only reason to read any further is to see some of the older articles in this previous debate.
Currently there is considerable debate in psychiatry as to whether valproate might cause PCOS. It's tricky because it looks like the things we treat with Depakote, at least epilepsy and possibly bipolar disorder itself, can cause PCOS with no valproate around. However, it may be that Depakote adds to that risk.
Update 2/2006: The debate continues. This is the second update on this topic this month! However, this newest study may just about clinch a causal connection between valproate and PCOS. Mind you, this doesn't mean that you should stop your valproate if you're doing well on it, not gaining weight, and having normal menstrual cycles. And if one of those wasn't true for you, you would talk to your doctor, not just stop it, right? You must have a plan for this kind of thing.
The newest study, from HarvardJoffe 1/2006 looked at women starting valproate, versus those starting some other mood stabilizer in the "anticonvulsant" category (anti-seizure medications, originally, before we psychiatrists started using them for bipolar disorder: lamotrigine, topiramate, carbamazepine, gabapentin, oxcarbazepine), or lithium. Ten percent of the group starting valproate showed signs of PCOS within a year, versus 1% of the women taking any of those others.
directly investigating this issue again found that insulin resistance, obesity, and high levels of androgens (male hormones, which occur in small amounts in normal women) are extremely common in women with bipolar disorder. For example, 80% of these women had high insulin levels; two thirds were overweight, and a quarter were obese (BMI > 30). So one of the problems with research on this question (Does valproate cause PCOS?) is that so many women already have the biochemical changes associated with PCOS, it's hard to find women who don't have them and then put them on valproate and watch what happens.
In another recent study by Dr. Rasgon and colleaguesRasgon 12/2005, the investigators found a small increase in androgens over time in all the women studied, but a slightly larger increase in those on Depakote. The study was very small, with less than 20 women completing the follow-up lab test, so their report is "preliminary".
Neither the Joffe nor the Rasgon study was a randomized trial, where women were randomly assigned to get valproate, or some other mood stabilizer, and then observed. These are "naturalistic" studies, where the researchers just look at what happens to women who are being treated by other doctors. So there might be something different about those women who were placed on valproate which might explain why they develop PCOS signs more than the other women -- some reason other than the valproate (Depakote).
But until such a randomized trial is done, these studies, particularly the newer Joffe study, seem very close to establishing that Depakote does indeed raise the rate of women getting PCOS over the already-elevated rate they have from their bipolar disorder alone. However, a colleague requested that his somewhat opposing view be added here for fair consideration: "This finding may mean that Depakote should not be the best choice in young women, teenagers and girls, particularly since there are other treatments available. However, clearly the disagreements about it mean that it is not that common. If Depakote is already working well, or better than other treatments, and PCOS has not developed my view would be to continue it and watch closely for PCOS. But you should ask your own doctor and try to arrive at the best plan for you." -- Dr. Simon Sobo.
Below you'll find much of the research that's been done on this question. It's pretty thick reading, even just my simple summaries. Here's a different, well-referenced point of view, but notice the publication date: 2001. Many of the most suggestive studies have come along since then. I think there is a slight change in tone in the author's more recent summary, though that is online only in abstract.Rasgon2004
You will probably only want to read on only if you are very interested in the research on this debate.
[Update 7/2004: Investigating Depakote and PCOS, a research group showed recently that Depakote does cause ovaries to change their steroid hormone secretion, in the direction that would be predicted by the "Depakote does cause PCOS" theory.Nelson-DeGrave This doesn't clinch the relationship either, but adds one more bit of evidence, this time at the biochemical level.]
The same gene-activity changes in ovarian cells have been found in women with PCOS and those treated with Depakote. (Wood, December 2004). Now we have some basis for understanding how a known effect of Depakote, a trophic effect if you know that literature, might be involved in the basis of PCOS.
A recent review concluded that the evidence was suggestive but not conclusiveChappell. The size of the supposed Depakote effect was small in the studies reviewed, compared to the data of the researcher who raised the issue in the first place.Isojarvi [Update 4/2004: Isojarvi has just published two more studies ( one in men, one more in women) which continue to suggest that Depakote causes hormone abnormalities more than epilepsy alone does , and more than other anti-epileptic medications, though almost all of the anti-seizure medications his research group studied caused some sort of problem with hormone systems. (At this point one exception appears to be lamotrigine). However, the design of these most recent studies still does not allow a firm conclusion on the issue of Depakote and PCOS.]
Here are some of the other studies on this issue (or you may skip to a summary of another point of view, followed by "Do I have it?" ):
A recent comparison of PCOS signs and symptoms in women taking valproate, versus women taking lithium, showed no difference in the two groups. None had indications of PCOS, though almost all had evidence of some kind of hormone imbalanceRasgon, as I have seen in my practice also. This was a small sample, and the fact that none of the women had PCOS findings makes the results hard to interpret. A commentary in the same journal issuePiontek called for much more caution about this PCOS risk. Those authors cite the recent follow-up study by IsojarviIsojarvi(c) in which women who had PCOS markers showed a substantial reduction in those signs and lab abnormalities when switched from valproate to lamotrigine. [Update 2004: a group in Britain has now published a comparison study of women with epilepsy on valproate, versus women on other antiseizure medications, versus women who don't have epilepsy. Their results show an association between valproate and PCOS, but not carbamazepine or lamotrigine. Betts]
It used to be thought that weight gain might be the thing that causes PCOS with valproateIsojarvi et al(b), Piontek, if the medication does indeed cause PCOS at all. But now the Finnish group that raised much of the alarm on this subject has reported changes in hormones which could lead toward PCOS without any weight gain, within a month of having started Depakote.Rattya
By 2002, more data began to emerge on this weight/hormone issue. In April, Dr. O'Donovan and colleagues published new data on this question.O'Donovan The study was fairly small, 32 women with bipolar disorder, 22 controls. Here are their simplified results and conclusions:
|On valproate (Depakote)||Bipolar but not on valproate|
|Polycystic ovarian syndrome||41%|
|Menstrual cycle abnormalities||47%||13%
(A similar small study by Rasgon did not find this difference)
Since then 2 more studies have appeared. First came Dr. Morrell (a neurologist who is very concerned about this issue) and colleagues.Morrell. Studying women with epilepsy, they found:
|Valproate within 3 years||Epilepsy but no valproate in 3 yrs|
|Menstrual cycle abnormalities||38%||11%|
In February 2003 a Canadian group reported similar findings from another group of women with bipolar disorder:
|On valproate (18 women)||On lithium (20 women)|
|Menstrual cycle abnormalities||50%||15%|
They specifically noted the presence of "metabolic syndrome" as more common in women receiving Depakote.McIntyre For more data from this study, if you aren't lost already in the numbers, try this additional page including estrogen levels more than twice those of women on lithium.
However, notice that all of these studies are "snapshots in time" comparing women who might have ended up on these different medication treatments for specific reasons -- reasons that might influence the rate of menstrual cycle abnormalities! This is the problem with these so-called "cross-sectional" studies. The preferred study design is "longitudinal": following a group of women, all presumably at the same risk of menstrual problems to start with, as they go onto and stay on Depakote. That's why the above 12/2005 study by Rasgon and colleagues, though small, is so important: it's a start at such a way of looking at this issue. Another study gets pretty close: The Finnish group did follow women as they went off Depakote and onto lamotrigine, with improvement, as noted above.Isojarvi(c)
(This issue of PCOS, especially it's relationship to Depakote, is still pretty controversial. For an even fuller picture, here is a review of the topic from another source. You'll see most of the articles above are referenced. The emphasis comes out a little differently, less clearly convinced we have a problem. The article appears on a website which has been strongly supported by the makers of Depakote. I'll let you be the judge of the difference in emphasis.)
Do I have it? Lab tests for PCOS
An "official" definition for metabolic syndrome is easier to specify, as you'll see in that essay. By contrast, there are multiple different definitions for PCOS. There is no current standard set of tests to order. I like a simple approach. If it seems plausible that you have PCOS or metabolic syndrome on the basis of your symptoms; and if those symptoms are severe enough to warrant taking a treatment with some risks; then the question of what you should do next has more to do with the risks of the treatment than "diagnosis" as such. In this case, metformin has some but not extensive risks. Take the link above (metformin) to read about them.
However, if you want an offical list of labs that have been suggested, here's one: TSH; prolactin; total testosterone; androstenedione; LH; and FSH for LH/FSH ratio]. Other endocrine specialists might include other tests. Doing an ultrasound exam of your ovaries, looking for cysts, will not really clinch things one way or another: some women with PCOS do not have ovarian cysts (despite the title of the syndrome); and some women with no PCOS symptoms have cystic ovaries! In my view, metabolic syndrome is the more important of the two conditions (PCOS versus metabolic -- there's that link on the difference again), and that definition is a little easier.
Oh, before you go, take a look at your hands. Is your second finger (counting your thumb as #1) shorter than your fourth finger? A recent article wonders whether women for whom the answer is "yes" might have a greater risk of getting this PCOS thing.Cattrell Well, the difference was very subtle, you probably wouldn't be able to conclude anything from looking at your own hand; but it's an interesting idea and I stuck it down here so I can find it when looking at my own patients' hands!