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have biochemical evidence of hyperandrogenaemia than those who had taken carbamazepine
or lamotrigine31. However, others have not been able to replicate their results, reporting that
the occurrence of polycystic ovaries in women taking AEDs is not higher than the general
population32. The occurrence of polycystic ovarian syndrome (PCOS), which is associated
with menstrual disturbance, has also been shown to be similar for women with epilepsy taking
either carbamazepine or valproate, and similar to women with epilepsy on no treatment33.
Furthermore a subsequent study performed in monkeys did not indicate that exposure to
valproate for 1215 months induced hormonal or morphological ovarian abnormalities or
characteristics of PCOS34. Morrell et al conducted a recent prospective, randomised,
longitudinal evaluation for the impact of valproate on the development of PCOS. Women
with epilepsy and regular menstrual cycles were randomised to treatment with valproate or
lamotrigine and followed up for 12 months. Women taking valproate were significantly more
likely to develop PCOS than those taking lamotrigine (9% vs 2% respectively, P = 0.007)35.
These observations, together with data showing that valproate associated changes are
reversible when valproate is discontinued36,37 suggest that a reasonable treatment option in
women who develop PCOS and/or ovulatory dysfunction while taking valproate is to
consider discontinuation of the drug and treatment with an alternative AED, if possible.

Contraception

The AEDs phenobarbital, primidone, phenytoin, carbamazepine38, topiramate39 and
eslicarbazepine acetate are inducers of the hepatic P450 microsomal isoenzyme CYP3A4
which is responsible for the metabolism of oestrogens and progestogens. This results in an
increased metabolism of the combined oral contraceptive pill (OCP), which may lead to a
higher rate of breakthrough bleeding and contraceptive failure. Sodium valproate and the
newer AEDs, vigabatrin, gabapentin, tiagabine, pregabalin, levetiracetam and zonisamide do
not induce hepatic enzymes and hence do not react with the OCP. Oxcarbazepine is
considered a weak enzyme-inducing agent40. The situation for lamotrigine is less clear. While
initially not thought to interfere with the OCP, there is one report in which lamotrigine was
associated with a small decrease in the levels of the progestin used in this study,
levonorgestrel, with the AUC reduced by 19% and maximal concentration by 12%41. As a
result of this data, the manufacturer of lamotrigine released new guidance and the Summary
of Product Characteristics (SPC) now comments that ‘the possibility of reduced contraceptive
effectiveness cannot be excluded’. It suggests that ‘the use of alternative non-hormonal
methods should be encouraged’ and, ‘a hormonal contraceptive should only be used as a sole
method of contraception if there is no other alternative’. A statement regarding this change
was issued by the Faculty of Family Planning and Reproductive Healthcare Clinical
Effectiveness Unit, concluding that there was ‘no evidence that lamotrigine reduces the
effectiveness of hormonal contraceptives’ and that ‘there is no good evidence to suggest that
non-hormonal methods should be used in favour of hormonal methods’42. Further studies in
larger numbers of women are needed to clarify this possible effect.

The manufacturers of the new AED perampanel state that it is not a strong inducer or inhibitor
of cytochrome P450. However there is evidence that concomitant use of the OCP with doses
of perampanel 12 mg per day result in reduction in levonorgestrel exposure (AUC and mean
peak serum concentration both reduced by 40%), and an 18% reduction in the mean peak
serum concentration of ethinyl oestradiol, which may result in reduced efficacy of
progesterone-containing oral contraceptives. No such effect was seen at lower doses43.

It is recommended that women taking enzyme-inducing AEDs increase their ethinyl
oestradiol dose from 2035 µg to 50 µg. If breakthrough bleeding occurs ethinyl oestradiol
dosages may need to be increased to 75 or 100 µg or the 50 µg pill may be tricycled (three
packets taken continuously, then a four-day break). Women also need counselling that even