**4. Contraception and epilepsy**

58 Novel Aspects on Epilepsy

POF is characterized by amenorrhea, cessation of ovarian function, and elevated gonadotropin levels before 35 years of age and younger. Ovarian failure due to POF may not be absolute; hence, this condition needs to be differentiated from premature menopause

Indeed, women with POF often continue to have some residual ovarian function for many years after diagnosis (Kodaman, 2010, Kalantaridou&Nelson 2000). Both sporadic ovulation and occasional pregnancy are possible with POF; (Nelson et al, 1994, Alper et al, 1986) in fact; up to half of women affected by POF have intermittent follicular development, 25% may occasionally ovulate, and 5 to 10% will conceive and deliver (Nelson et al, 1994, Rebar&Connolly, 1990, Rebar, 2009). The term menopause thus should be avoided in the context of counseling these patients, and more recently, the term POF has also fallen into disfavor because it implies nality and gives a further negative connotation to an already devastating diagnosis for a young woman to come to terms with. POF, the term rst coined by the endocrinologist Fuller Albright almost 70 years ago, is now the preferred nomenclature for this entity. (Albright et al, 1942, Welt, 2008, Nelson, 2009) The incidence of POF increases with age, affecting 0.01%, 0.1%, and 1% of women <20, 30, and 40 years of age, respectively (Coulam, 1986). Given the association of chemoradiation therapy with subsequent ovarian insufciency and the increasing successes with childhood and early adulthood malignancy treatments, it has been predicted that the number of cases of POF will increase signicantly in the future (Sklar, 2006, Panay&Fenton, 2008). Etiologies for POF are heterogeneous and, for the most part, poorly understood. The etiology for up to 90% of

POF occurs more commonly in women with epilepsy. Klein et al (2001) evaluated the incidence of POF in 50 women with epilepsy, aged 38 to 64, compared with control women. Premature menopause was defined as amenorrhea for greater than 1 year with elevated day 3 FSH levels in women younger than 42 years. Premature perimenopause was defined by the presence of perimenopausal symptoms. Of the women with epilepsy, 14% had premature perimenopause or menopause, compared with only 3.7% of the control women (P = 0.042). They did not find an association with epilepsy duration, seizure severity, or AEDs; although women with premature menopause were more likely to have had catamenial exacerbation of their seizures than women without POF (P = 0.02). Harden et al (2003) also found in their multicentric cohort study that premature menopause was associated with epilepsy. In another study, the median age at menopause in the group of women with epilepsy was 47 years, compared with the median age of 51.4 years in the general US population (Gold, et al, 2001). When the investigators divided the patients into low, intermediate, and high seizure frequency groups, there was an increasingly lower age at menopause with a negative correlation between the age at menopause and seizure group based on estimated lifetime seizures (P = 0.014). They also found no influence of enzymeinducing AEDs. The authors concluded that the association of lifetime number of seizures with the timing of cessation of reproductive cycling may occur as a result of direct

Women with epilepsy have an increased risk of experiencing an early onset of perimenopausal symptoms. Some studies draw attention to the increased frequency of POF in women with epilepsy. However, no association has been detected so far between the POF and epilepsy duration, seizure severity, or use of enzyme-inducing AEDs. POF may occur as

**3. Epilepsy and premature ovarian failure** 

cases of POF remains elusive (Kodaman, 2010).

disruption of hypothalamic and pituitary function by the seizures.

because the latter reects a ''permanency'' of the ovarian failure.

Contraceptive methods can be divided into two subgroups as hormonal and non-hormonal. Hormonal contraceptives include combined-oral contraceptives, progestin only pills, hormonal implants, progestin releasing intrauterine systems, depomedroxyprogesterone acetate injections, and vaginal rings. Non-hormonal contraceptive methods include male and female condoms, copper intrauterine device, tubal ligation and vasectomy of the companion.

Combined oral contraceptives are a widely used and well accepted form of contraception. Combined-oral contraceptives are highly effective when used consistently and correctly, and are well tolerated by most women. Combined-oral contraceptives contain a combination of an estrogen and a progestin. Since their introduction, several progestins have been developed for use in combined-oral contraceptives. Conversely, the estrogen component has remained largely unchanged, with the vast majority of combined-oral contraceptives containing ethinylestradiol (EE) or, more commonly in the past, mestranol, the 3-methyl ether of EE. The estrogen component of combined-oral contraceptives is responsible for suppressing FSH, providing endometrial stability, and potentiating the activity of the progestin component, e.g., by increasing progestin receptor concentrations. However synthetic progestins may directly inuence ovarian function by a direct inhibition of the ovarian steroid biosynthesis. Modern combined-oral contraceptives have two components: EE and a progestin. Both are on their own able to inhibit ovulation. In modern combined-oral contraceptives ovulation inhibition is mainly achieved by the progestin and not by ethinylestradiol. The typical daily progestin dose in today's combined-oral contraceptives is about 1.5—2 times the ovulation-inhibiting dose (Schwenkhagen&Stodieck, 2008).

The choice of a contraceptive drug can be challenging for women with epilepsy due to possible interactions between AEDs and hormonal contraception. Enzyme-inducing AEDs can cause hormonal contraception to fail and can increase the risk of teratogenicity. Higher doses of oral contraceptives can overcome pharmacologic failure but may create additional risks (Burakgazi et al, 2009).

In women with epilepsy failure rates of oral contraceptives may increase to 6% depending on the antiepileptic drug they are taking (Morell, 1996). Drugs such as phenobarbital (PB), primidone (PRM), phenytoin (PHT), carbamazepine (CBZ), oxcarbazepine (OXC) at doses above 600 mg daily and topiramate (TPM) at doses above 200 mg (Doose et al, 2003) may cause induction of hepatic cytochrome P450, reducing the effects of contraceptives to block ovulation. VPA and felbamate (FBM) inhibit the hepatic microsomal system and do not reduce, and can even increase, the levels of the steroid hormones of oral contraceptives. Other drugs such as gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), pregabalin (PGB), vigabatrin (VGB), and levetiracetam (LEV) do not affect the serum concentrations of contraceptives (Tatum et al, 2004) (Table 1). To avoid lack of efficacy of contraception used in a patient that is on therapy with enzyme-inducing AEDs when the "morning-after pill" is used at the same time, the first dose of levonogestrel should be 1.5 mg (twice the usual dose of 750 μg), and after 12 hours the recommended 750 μg are reinstated (Mayor, 2004; Perruca, 2004). Moreover, oral contraceptives can reduce levels of LTG by 25% to 70%. If the woman

The Impact of Epilepsy on Reproductive Functions 61

et al, 2001, 2003; Stodieck &Schwenkhagen, 2004; Christensen, 2007). These uctuations are most likely due to an induction of UGT1A4, the enzyme responsible for the glucoronidation of lamotrigine, by EE. VPA levels also seem to be reduced by the concomitant use of hormonal contraceptives (Herzog et al, 2005; Galimberti, 2006). Just as with lamotrigine the magnitude of observed uctuations of the VPA levels appear to vary interindividually. Hormonal contraceptives which are adversely affected by hepatic cytochrome P450 enzyme-

Table 3. Hormonal contraceptives which are adversely affected by hepatic cytochrome P450

In addition to induction of cytochrome P450 enzyme system, several AEDs induce the production of sex hormone binding globulin (SHBG) to which the progestins are tightly bound, resulting in lower concentrations of free progestin that may also lead to combined-

While higher dose combined-oral contraceptives are one contraceptive option for women on enzyme-inducing AEDs, a variety of other options are available. Injectable contraception (depot medroxyprogesterone acetate) appears effective with AED use, but the potential for

Non-hormonal contraceptive methods are not contraindicated in women with epilepsy. If contraception is addressed as a permanent measure, the safest method is tubal ligation or vasectomy of the companion. Intrauterine devices are an alternative to pharmacologic approaches because they lack drug-drug interactions and side effects (Burakgazi et al, 2009). There is no evidence that combined-oral contraceptives increase seizures in women with

Ovarian reserve shrinks throughout life and reaches a critical threshold level at the inception of the menopause. At this point, a woman notes her rst skipped menstrual period. The menopausal transition begins with the onset of rst menstrual irregularity, or skipped menses, and ends with the nal menstrual period. Progressive loss of ovarian follicles results in decreased production of inhibin and a loss of restraint on FSH secretion. The monotropic increase in FSH leads to variable hormonal patterns, depending on the available ovarian follicles and their degree of responsiveness. Once follicles reach a critically low level, ovulation becomes progressively less likely and prolonged amenorrhea ensues. In addition to ovarian factors that contribute to reproductive senescence in women, there is accumulating evidence that as in rodents, hypothalamic-pituitary dysfunction accompanies reproductive aging and contributes to the process. As knowledge about the menopausal

inducing AEDs are given in Table 3.

Progestin only pill Morning after pill

enzyme-inducing AEDs

Implants (etonorgestrel)

Various combined estrogen/progesterone preparations

Transdermal patch (norelgestromin and ethinyl estradiol)

Vaginal ring (etonorgestrel/ethinyl estradiol ring)

oral contraceptive failure (Dutton C, Foldvary-Schaefer, 2008).

epilepsy (Dutton C, Foldvary-Schaefer, 2008).

**5. Epilepsy and menopause** 

bone mineral density loss is a concern. (Dutton C, Foldvary-Schaefer, 2008)

**Oral** 

is taking AEDs, which reduce steroid hormone levels, oral contraceptives must contain a minimum of 50 μg of EE. If there is a hemorrhage, the dose should be raised to 75 or 100 μg. During the first months of oral contraceptive use, and once ovulation has been eliminated, complementary contraceptive methods are recommended. To improve contraceptive efcacy, the use of a combined-oral contraceptives that contains a progestin well above the dose needed to inhibit ovulation may be recommended. Ovulation-inhibiting doses of progestins are given in table 1.


Table 1. Ovulation-inhibiting doses of progestins (without additional estrogen) (Kuhl, 2005)

Commonly used AEDs which do and do not interact with oral contraceptives are given in Table 2.


Table 2. Commonly used AEDs which do and do not interact with oral contraceptives

Most drug—drug interaction studies have focused on the effect of AEDs on oral contraceptive safety. Much less is known about the result of a co-prescription of hormonal contraceptives on AEDs, which is surprising, since it is known for a long time that oral contraceptives have a strong inuence on drug metabolizing enzymes. (Schwenkhagen&Stodieck, 2008).

In combined oral contraceptives, during the period ''on the pill'' lamotrigine levels decrease by approximately 50%, followed by an increase of lamotrigine levels in the contraceptivefree week up to 80— 100% of the baseline lamotrigine level. This is often clinically relevant and may result in an increased risk of seizure recurrence especially in week 2 and 3 on the pill or in concentration-dependent adverse effects at the end of the pill-free interval (Sabers

is taking AEDs, which reduce steroid hormone levels, oral contraceptives must contain a minimum of 50 μg of EE. If there is a hemorrhage, the dose should be raised to 75 or 100 μg. During the first months of oral contraceptive use, and once ovulation has been eliminated, complementary contraceptive methods are recommended. To improve contraceptive efcacy, the use of a combined-oral contraceptives that contains a progestin well above the dose needed to inhibit ovulation may be recommended. Ovulation-inhibiting doses of

Table 1. Ovulation-inhibiting doses of progestins (without additional estrogen) (Kuhl, 2005) Commonly used AEDs which do and do not interact with oral contraceptives are given in

**Drugs which reduce the effects of** 

**oral contraceptives** 

**Progestin mg/day**  Chlormadinone acetate 1.7 Cyproterone acetate 1.0 Desogestrel/3-keto-desogestrel 0.06 Dienogest 1.0 Drospirenone 2.0 Gestodene 0.04 Levonorgestrel 0.06 Norethisterone 0.4 Norethisterone acetate 0.5 Nomegestrol acetate 5.0

progestins are given in table 1.

**Drugs which do not reduce the effects** 

Clonazepam Barbiturates Ethosuximide Carbamazepine Felbamate Oxcarbazepine Gabapentin Phenytoin Levetiracetam Primidone

Lamotrigine Topiramate (>200 mg/day)

Table 2. Commonly used AEDs which do and do not interact with oral contraceptives

Most drug—drug interaction studies have focused on the effect of AEDs on oral contraceptive safety. Much less is known about the result of a co-prescription of hormonal contraceptives on AEDs, which is surprising, since it is known for a long time that oral contraceptives have a strong inuence on drug metabolizing enzymes.

In combined oral contraceptives, during the period ''on the pill'' lamotrigine levels decrease by approximately 50%, followed by an increase of lamotrigine levels in the contraceptivefree week up to 80— 100% of the baseline lamotrigine level. This is often clinically relevant and may result in an increased risk of seizure recurrence especially in week 2 and 3 on the pill or in concentration-dependent adverse effects at the end of the pill-free interval (Sabers

**of oral contraceptives** 

(Schwenkhagen&Stodieck, 2008).

Tiagabine Valproate

Table 2.

et al, 2001, 2003; Stodieck &Schwenkhagen, 2004; Christensen, 2007). These uctuations are most likely due to an induction of UGT1A4, the enzyme responsible for the glucoronidation of lamotrigine, by EE. VPA levels also seem to be reduced by the concomitant use of hormonal contraceptives (Herzog et al, 2005; Galimberti, 2006). Just as with lamotrigine the magnitude of observed uctuations of the VPA levels appear to vary interindividually. Hormonal contraceptives which are adversely affected by hepatic cytochrome P450 enzymeinducing AEDs are given in Table 3.


Table 3. Hormonal contraceptives which are adversely affected by hepatic cytochrome P450 enzyme-inducing AEDs

In addition to induction of cytochrome P450 enzyme system, several AEDs induce the production of sex hormone binding globulin (SHBG) to which the progestins are tightly bound, resulting in lower concentrations of free progestin that may also lead to combinedoral contraceptive failure (Dutton C, Foldvary-Schaefer, 2008).

While higher dose combined-oral contraceptives are one contraceptive option for women on enzyme-inducing AEDs, a variety of other options are available. Injectable contraception (depot medroxyprogesterone acetate) appears effective with AED use, but the potential for bone mineral density loss is a concern. (Dutton C, Foldvary-Schaefer, 2008)

Non-hormonal contraceptive methods are not contraindicated in women with epilepsy. If contraception is addressed as a permanent measure, the safest method is tubal ligation or vasectomy of the companion. Intrauterine devices are an alternative to pharmacologic approaches because they lack drug-drug interactions and side effects (Burakgazi et al, 2009). There is no evidence that combined-oral contraceptives increase seizures in women with epilepsy (Dutton C, Foldvary-Schaefer, 2008).
