KatCarney

Psychopharmacology Update
March, 2001

Reproductive effects found in men taking valproate.

Author/s:

In the last decade, several Finnish studies have indicated that valproate (Depakote, Depakene) may be linked to reproductive endocrine disorders such as polycystic ovary syndrome (PCOS) in young epileptic women. Now, a new study from the same investigators in Finland indicates valproate and two other antiepileptics -- carbamazepine (Tegretol) and oxcarbazepine (Trileptal) -- may have reproductive effects on men as well.

Although the study was conducted in epileptic men, the results may have implications for men with bipolar disorder or other psychiatric conditions who take valproate. In the study, reproductive endocrine function was evaluated in 90 men taking valproate, carbamazepine or oxcarbazepine as monotherapy for epilepsy and in 25 healthy control men.

Twelve of 21 men on valproate (57%) had increased serum androgen levels (such as serum testosterone), and mean serum levels of androstenedione were high as well. Men on valproate with high serum androgen concentrations were more obese than patients on valproate who had normal serum androgen levels.

The endocrine effects of carbamazepine and oxcarbazepine were different in that carbamazepine seems to decrease the bioactivity of androgens and oxcarbazepine does not. Serum levels of dehydroepiandrosterone sulfate (DHEAS) were low in men on carbamazepine, and sex hormone-binding globulin (SHBG) concentrations were high. In addition, 18 percent of men on carbamazepine reported decreased libido, impaired potency, or both. Low doses of oxcarbazepine did not have any effects on serum concentrations of reproductive hormones, but men taking higher doses of oxcarbazepine had increased serum testosterone, gonadotropins and SHBG levels.

Men in all three groups had significantly increased insulin levels as well, with men on vaiproate having the highest insulin levels

Effects on fertility were not evaluated in the study. However, sexual function was enhanced (increased libido, potency or increased satisfaction with erection and orgasm) in four men (19%) on valproate, three men (8%) on carbamazepine and one man on oxcarbazepine (3%). Sexual function was diminished in one man on valproate (5%), seven men on carbamazepine (18%) and five men on oxcarbazepine (17%). The majority of patients reported normal sexual function.

Similar effects in women

Michael Johnson, M.D., assistant professor of psychiatry at the Medical University of South Carolina in Charleston, says the study of men on vaiproate mimics earlier studies on reproductive effects in young women. These women had a high risk for developing PCOS due to higher levels of testosterone and changes in female sex hormones.

"I think this is fairly good data showing that valproic acid caused an increase in at least one of the male sex hormones, and ostendione," Johnson says. "For men, you can probably say that some sex hormone changes are likely to be expected."

However, he says it appears that the men didn't have any clinical problems, unlike women, who appearto be at risk of PCOS from valproate. He notes that some men on antiepileptics reported increased sexual function.




"The higher rate of male sex hormones may actually enhance sexuality," Johnson notes. "The numbers are too small to say definitively whether that is true, but it's certainly an interesting finding."

He says more studies need to be done on men on valproate and other antiepileptics to determine if there are detrimental clinical effects such as increased risk of prostate cancer from increased androgen levels.

"There is data accumulating that valproic acid has some very significant effects on sex hormones in men and women, but the clinical meaning is probably more serious and concerning in women," Johnson says. "It's unknown in men, and we need to look at it in men."

Prescribing valproate

Johnson says because of previous studies linking valproate and PCOS in women, he is reluctant to use it in female patients with bipolar disorder, especially younger women.

"I would certainly not use it firstline, and I use it only if other [drugs] are not effective," says Johnson. "I think there are enough data to be worried about it. There are other options. Old standbys like lithium have much fewer problems in my experience than valproic acid. I tend to use the newer agents such as lamotrigine [Lamictal] orgabapentin [Neurontin] more than I use valproic acid."

A previous study from Isojarvi et al found that hyperinsulinemia and obesity were reduced when women with PCOS on valproate were switched to lamotrigine.

The latest study in men also found increased insulin levels with all three antiepileptics, but particularly with valproate. Johnson says many psychotropic drugs affect insulin levels, such as fluoxetine (Prozac) and even some atypical antipsychotics.

"One way we see this as relevant is if you are treating a diabetic, it has an additive effect to their anti-insulin medication and they'll sometimes become hypoglycemic if you add a medication that affects [insulin levels]," he notes. "It mayjust be amatterof adjusting the dose, but there may be some people who have side effects from [valproate] that causes hyperinsulinemia that may then cause side effects that are blood-sugar related."

View latest study with caution

Gideon Koren, M.D., FRCPC, professor of pediatric pharmacology and medicine at the University of Toronto in Canada, has written a review on valproate use in psychiatry among young women. He says that the latest Finnish study in men should be viewed somewhat cautiously.

"This just shows again that chronic therapy has to be looked at very carefully, because it may affect other systems," he says. "But I think with any observational study, one has to be careful, and this has to repeated by other groups before one can draw conclusions. Valproic acid and carbamazepine are important drugs and very effective drugs. One should remember that every drug causes adverse effects. Everything has to be put into context."

Koren also says the laboratory changes found in the study may not be clinically significant.

"We do not treat numbers, we treat people," he says. "This [study] should clearly not be misinterpreted [to mean] the drugs should be discontinued. They are very crucial for people who have epilepsy and psychiatric conditions."




Jose Pimentel, Ph.D., a professor of neurology in the department of neurology at the Hospital de Santa Maria in Lisbon, Portugal, wrote a recent review on valproate use in epileptic women. He agrees with Koran.

"These findings should not preclude the use of valproate in men by psychiatrists or neurologists," he says. "Many other side effects of valproate such as tremor, increased weight, peripheral decreased blood count, etc., seem to be more frequent and more important than endocrinological ones."

References

Rattya J, Turkka J, Pakarinen AJ, et al.: Reproductive effects of vaiproate, carbamazepine, and oxcarbazepine in men with epilepsy. Neurology 2001; 56:31-36.

Isojarvi JI, Laatikainen TJ, Pakarinen AJ, et al.: Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. New England Journal of Medicine 1993; 329(19): 1383-1388.

Isojarvi JI, Laatikainen TJ, Knip M, et al.: Obesity and endocrine disorders in women taking valproate for epilepsy. Annals of Neurology 1996; 39:579-584.

Isojarvi JI, Rattya J, Myllyla VV, et al.: Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Annals of Neurology 1998; 43:446-451.

Kennedy D, Koren G: Valproic acid use in psychiatry: issues in treating women of reproductive age. Journal of Psychiatry and Neuroscience 1998; 23:223-228.

Pimentel J: Current issues on epileptic women. Current Pharmacology Design 2000; 6:865-872.

[Editor's note: For more information on PCOS, go to the Polycystic Ovary Syndrome Web site at Vanderbilt University http://www.mc.vanderbilt.edu/peds/pi...c/polcysov.htm]


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