**1. Introduction**

52 Novel Aspects on Epilepsy

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#### **1.1 Regulation of female reproductive system**

Regulation of female reproductive system consists of very complex interactions between the hypothalamus, neurohypophysis and ovaries. Beginning from the embryologic stage, female reproductive system is regulated by the brain. Ovarian hormone production is supressed by the hypothalamo-hypophyseal control mechanism till the end of the childhood period when the puberty begins. During puberty, menstrual cyclicity and timely ovulation, which are the result of the precise integration within different components of the reproductive system, are achieved. After puberty, comes the reproductive period which generally lasts about 30-35 years. During reproductive period, from daily social behavior to sexual life and reproduction, many important issues depend on normal ovarian folliculogenesis and hormonogenesis. Menopause refers to the final menstrual period accompanying the permanent cessation of ovarian function and menstruation.

Gonadotropin releasing hormone receptor (GnRHR) is secreted from hypothalamus and delivered to the anterior pituitary via the hypophyseal portal circulation where it binds to the GnRHR on the surface of gonadotropes triggering the synthesis and secretion of the gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). In the female, LH stimulates the production of androgens by the thecal cells that surround the growing ovarian follicle. During the terminal stages of follicular growth, LH also drives the production of progesterone from the granulosa cells of the preovulatory follicle. FSH binds to receptors on the surface of ovarian granulosa cells stimulating the expression of aromatase enzymes that convert thecal androgens to estradiol. The Hypothalamushypophysis-gonadal (HPG) axis is subject to both positive feed-forward and negative feedback regulation at several levels. At the level of the hypothalamus, early recognition of the pulsatile nature of gonadotropin releasing hormone secretion led to the notion of a central ''pulse generator", the inherent oscillatory activity of which controls the secretory rhythm of GnRH neurons (Knobil, 1980). Hypothalamic pulse generator is extensively modulated by a multitude of higher level inputs including photoperiod, environmental stress, metabolic state and nutritional status, as well as various endocrine mediators. (Bliss, 2010)

The Impact of Epilepsy on Reproductive Functions 55

Fig. 1. Three patterns of catamenial epilepsy. During normal ovulatory cycles, both perimenstrual (C1) and periovulatory (C2) patterns can occur in isolation or together. During inadequate luteal phase cycles, the (C3) pattern can occur with increased seizures during the entire second half of the cycle. (Herzog AG. Catamenial epilepsy: definition,

prevalence pathophysiology and treatment. Seizure 2008;17:151)

#### **1.2 Impact of epilepsy on female reproductive system**

Epilepsy is a neurological disorder clinically characterized by recurrent seizures ranging from a very mild form of disruption in attention for a few seconds, to a severe form of muscle spasms and loss of consciousness. Epilepsy is a major public health problem worldwide. The prevalence of epilepsy increases with age (Brodie et al, 2009; Wallace et al, 1998) from 90 per 100,000 people of age 65–70 years, to 150 per 100,000 in those older than 80 years. The treatment goals are suppression and prevention of the seizures. For these purposes, antiepileptic drugs (AED) are used.

Epilepsy has a gender-related pathophysiology and consequences. Therefore, being a woman with epilepsy is not the same as being a man with epilepsy (Taubøll et al, 2008); in fact, the frequency and severity of seizures can increase on certain days of the menstrual cycle (Herzog et al, 1997). Seizures generally exacerbate during the 3 different periods of the menstrual cycle: in perimenstrual and periovulatory periods in normal cycles, and in inadequate luteal phase in abnormal cycles (Figure 1). This type of epilepsy is defined as catamenial epilepsy and is under the influence of estrogen and progesterone. Estrogen has been shown to increase seizure activity, while progesterone decreases it by raising the seizure threshold level (Frye, 2008). Progesterone is converted to allopregnanolone in the brain. Allopregnanolone has been suggested as a primary compound responsible for decreased seizure susceptibility (Scharfman and MacLusky, 2006).

Estrogen acts as a proconvulsant in several animal models of epilepsy, including amygdalal kindling and pentylenetetrazol administration in ovariectomized rats (Hom and Buterbaugh, 1986). Estrogen induces the formation of new excitatory synapses in the CA1 region of the hippocampus; and further, this estrogenic induction involves activation of Nmethyl-Daspartate (NMDA) receptors (McEwen, 2002). Increasing the complexity of hippocampal synaptic density is likely a mechanism for the proconvulsant activity of estrogen. Standard hormone replacement in postmenopausal women with epilepsy, which includes estrogen and a progestin, can be postulated to have an effect on seizures that is more evident than that of oral contraceptives in cycling women with epilepsy. This is because reproductive hormone levels during menopause are low and unchanging. Therefore, the brain hormonal milieu in which exogenous hormones are introduced is markedly different in menopause from that in menstruating women.

In the ovariectomized animals, however, the hormonal changes in the animals are abrupt in contrast to the gradual hormonal changes found in the menopausal transition. It might be the concerted lack of estradiol and progesterone that facilitate the seizure susceptibility. Both estradiol and progesterone affect γ-amino butyric acid (GABA) ergic function (Scharfman et al, 2005; Nakumura et al, 2005; Kokate et al, 1994). The simultaneous decrease of estrogen and progesterone may thereby lead to a decrease in GABAergic inhibition, facilitating seizures. Recently published results by Lavaque et al (2006) suggest age-related focal production of sex hormones especially prominent in the hippocampus and cerebral cortex. The expression of the steroidogenic acute regulatory protein was found to increase particularly in these areas. The hippocampus and cerebral cortex are areas associated with seizure initiation and propagation. It is therefore discussed how pathological disturbances in the local estrogen production after menopause may contribute to an increase in seizures in some women (Veliskova, 2007).

Estrone is the primary estrogen after menopause, and its main source is subcutaneous fat. This might be of importance for overweight women with epilepsy. Little is known on the influence of estrone on epilepsy. An altered ratio of estradiol/estriol/estrone might be of importance; however, this has not been investigated. Most likely, however, the hormonal changes in menopause may not affect the different types of epilepsy in the same way.

Epilepsy is a neurological disorder clinically characterized by recurrent seizures ranging from a very mild form of disruption in attention for a few seconds, to a severe form of muscle spasms and loss of consciousness. Epilepsy is a major public health problem worldwide. The prevalence of epilepsy increases with age (Brodie et al, 2009; Wallace et al, 1998) from 90 per 100,000 people of age 65–70 years, to 150 per 100,000 in those older than 80 years. The treatment goals are suppression and prevention of the seizures. For these

Epilepsy has a gender-related pathophysiology and consequences. Therefore, being a woman with epilepsy is not the same as being a man with epilepsy (Taubøll et al, 2008); in fact, the frequency and severity of seizures can increase on certain days of the menstrual cycle (Herzog et al, 1997). Seizures generally exacerbate during the 3 different periods of the menstrual cycle: in perimenstrual and periovulatory periods in normal cycles, and in inadequate luteal phase in abnormal cycles (Figure 1). This type of epilepsy is defined as catamenial epilepsy and is under the influence of estrogen and progesterone. Estrogen has been shown to increase seizure activity, while progesterone decreases it by raising the seizure threshold level (Frye, 2008). Progesterone is converted to allopregnanolone in the brain. Allopregnanolone has been suggested as a primary compound responsible for

Estrogen acts as a proconvulsant in several animal models of epilepsy, including amygdalal kindling and pentylenetetrazol administration in ovariectomized rats (Hom and Buterbaugh, 1986). Estrogen induces the formation of new excitatory synapses in the CA1 region of the hippocampus; and further, this estrogenic induction involves activation of Nmethyl-Daspartate (NMDA) receptors (McEwen, 2002). Increasing the complexity of hippocampal synaptic density is likely a mechanism for the proconvulsant activity of estrogen. Standard hormone replacement in postmenopausal women with epilepsy, which includes estrogen and a progestin, can be postulated to have an effect on seizures that is more evident than that of oral contraceptives in cycling women with epilepsy. This is because reproductive hormone levels during menopause are low and unchanging. Therefore, the brain hormonal milieu in which exogenous hormones are introduced is

In the ovariectomized animals, however, the hormonal changes in the animals are abrupt in contrast to the gradual hormonal changes found in the menopausal transition. It might be the concerted lack of estradiol and progesterone that facilitate the seizure susceptibility. Both estradiol and progesterone affect γ-amino butyric acid (GABA) ergic function (Scharfman et al, 2005; Nakumura et al, 2005; Kokate et al, 1994). The simultaneous decrease of estrogen and progesterone may thereby lead to a decrease in GABAergic inhibition, facilitating seizures. Recently published results by Lavaque et al (2006) suggest age-related focal production of sex hormones especially prominent in the hippocampus and cerebral cortex. The expression of the steroidogenic acute regulatory protein was found to increase particularly in these areas. The hippocampus and cerebral cortex are areas associated with seizure initiation and propagation. It is therefore discussed how pathological disturbances in the local estrogen production after menopause may contribute to an increase in seizures

Estrone is the primary estrogen after menopause, and its main source is subcutaneous fat. This might be of importance for overweight women with epilepsy. Little is known on the influence of estrone on epilepsy. An altered ratio of estradiol/estriol/estrone might be of importance; however, this has not been investigated. Most likely, however, the hormonal changes in menopause may not affect the different types of epilepsy in the same way.

**1.2 Impact of epilepsy on female reproductive system** 

decreased seizure susceptibility (Scharfman and MacLusky, 2006).

markedly different in menopause from that in menstruating women.

in some women (Veliskova, 2007).

purposes, antiepileptic drugs (AED) are used.

Fig. 1. Three patterns of catamenial epilepsy. During normal ovulatory cycles, both perimenstrual (C1) and periovulatory (C2) patterns can occur in isolation or together. During inadequate luteal phase cycles, the (C3) pattern can occur with increased seizures during the entire second half of the cycle. (Herzog AG. Catamenial epilepsy: definition, prevalence pathophysiology and treatment. Seizure 2008;17:151)

The Impact of Epilepsy on Reproductive Functions 57

inadequate levels of pituitary follicle-stimulating hormone (FSH); whereas levels of

The brain controls reproductive function primarily through hypothalamic regulation of pituitary secretion. The left and right vagus nerves exert different modulatory influences on ovarian structure and function (Gerendai & Halasz, 1997). The reproductive neuroendocrine system, like many other brain systems, shows a lateralized asymmetry that might, by virtue of ipsilaterally predominating effects, contribute to the development of distinct reproductive endocrine disorders in association with unilateral left- and right-sided epileptic foci (Herzog, 2007). Unilateral temporolimbic discharges are associated with laterally differing, consistent, predictable, stochastic directional changes in hormonal secretion at all levels of the reproductive neuroendocrine axis, that is, hypothalamus, pituitary, and ovary (Herzog et al, 2003). These directional changes are consistent with the finding that different reproductive disorders may develop in relation to left- and right-sided temporolimbic epilepsy. Specifically, left temporal lobe epilepsy (LTLE) is associated with significantly higher pulse frequencies of GnRH secretion (Herzog et al, 2003; Herzog, 2008). Higher GnRH pulse frequency, in turn, is associated with higher LH/FSH ratios and higher serum testosterone levels. This combination of neuroendocrine changes characterizes PCOS and is consistent with the previously suggested association between left unilateral TLE and PCOS. Antiepileptic drugs, on the other hand, also have substantial and differential effects on reproductive hormone levels. The first report suggesting a high incidence of menstrual disorders linked to obesity, hyperandrogenism, and polycystic ovaries in women taking VPA for epilepsy was published in 1993 (Isojarvi). Changes in serum androgen levels have been detected before and during pubertal development in young girls taking VPA for

Studies by Murialdo et al (1997) have also reported a high prevalence of menstrual disorders and hyperandrogenic anovulation in VPA treated women with epilepsy. However, the study by Bauer et al (2008) did not show any differences between carbamazepine- and VPAtreated women with epilepsy with respect to reproductive endocrine parameters. Although the interpretation of the results of this study is difficult, because the age of the patients, the duration of medication, and seizure frequency in the different treatment groups were not given (Isojärvi, 2005). Other studies have also addressed the issue of reproductive endocrine function in women with epilepsy. Luef et al (2002) reported similar frequencies of menstrual disorders and PCOS in women taking carbamazepine and VPA for epilepsy. It has been suggested that obesity and associated hyperinsulinemia could be implicated in the development of PCOS and hyperandrogenism in women taking VPA. It seems that obesity and related hyperinsulinemia may exacerbate the VPA-related reproductive endocrine disorders in women with epilepsy. It seems likely that VPA has a direct effect on ovarian androgen production, or as an enzyme inhibitor, it may inhibit the metabolism of sex

steroids and thereby lead to increased serum androgen levels (Isojärvi et al, 2005).

Several studies have suggested that the reproductive endocrine effects of AEDs may be reversible if the medication is discontinued. In a prospective study, the replacement of VPA with lamotrigine resulted in normalization of endocrine function during a 1-year follow-up in 12 women with a previously identified endocrine disorder (PCOS or hyperandrogenism, or both) likely to be related to VPA. Serum insulin and testosterone levels returned to normal 2 months after VPA was discontinued, and the levels remained normal thereafter

luteinizing hormone (LH) are normal or elevated (Isojärvi, 2008; Herzog, 2008).

epilepsy (Vainionpää, 1999).

(Isojärvi et al, 2005).

Reproductive dysfunction is common among women with epilepsy primarily due to the dysfunction in the temporolimbic system. This system has integral roles in reproductive endocrine regulation and feedback as well as in sexual and reproductive function (Herzog, 1989). Consequently, the development of epileptiform discharges in medial temporal lobe structures may disrupt hypothalamic regulation of pituitary secretion and, hence, alter gonadal function.

In addition, most of the AEDs (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and topiramate) may also alter endocrine function by inducing the cytochrome P450 isoenzyme 3A4 in women with epilepsy (Luef, 2009). Therefore, certain AEDs may accelerate hepatic elimination of hormonal preparations and decrease the serum concentrations of bioactive sex steroids.

Epileptic women have increased risk of polycystic ovary syndrome (PCOS), premature ovarian failure (POF), and hormonal contraceptive failure; as well as osteoporosis (Figure 2).

Fig. 2. Possible changes in epileptic women according to different stages of female life AED, anti-epileptic drug; PCOS, polycystic ovary syndrome.

### **2. Epilepsy and polycystic ovary syndrome**

PCOS is characterized by enlarged ovaries with multiple small cysts and a hypervascularized, androgen-secreting stroma leading to the associated signs of androgen excess (hirsutism, alopecia, acne), obesity, and menstrual-cycle disturbance (oligo or amenorrhea) (Balen, 1999). The most common reproductive endocrine disorder in women with epilepsy, as well as in women in the general population, is PCOS. PCOS occurs in 10- 20% of women with epilepsy compared to 5-6% of women in the general population (Bauer et al, 2008; Knochenhauer et al, 1998; Herzog, 2002; Herzog et al, 2003). The prevalence of PCOS in women with epilepsy is greater, even if they are not taking AEDs; and it is more frequent in women who take valproic acid (VPA), primarily if initiated before the age of 20. PCOS is probably not a single nosological entity, but rather the common endpoint for a number of pathophysiological mechanisms, some of which may be attributable to epilepsy itself (Herzog et al, 1986, 2003) or to the use of AEDs, most notably valproate. PCOS represents the failure of the ovarian follicle to complete normal maturation during the menstrual cycle or a series of cycles -- a failure that is perhaps related to the presence of

Reproductive dysfunction is common among women with epilepsy primarily due to the dysfunction in the temporolimbic system. This system has integral roles in reproductive endocrine regulation and feedback as well as in sexual and reproductive function (Herzog, 1989). Consequently, the development of epileptiform discharges in medial temporal lobe structures may disrupt hypothalamic regulation of pituitary secretion and, hence, alter

In addition, most of the AEDs (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and topiramate) may also alter endocrine function by inducing the cytochrome P450 isoenzyme 3A4 in women with epilepsy (Luef, 2009). Therefore, certain AEDs may accelerate hepatic elimination of hormonal preparations and decrease the serum

Epileptic women have increased risk of polycystic ovary syndrome (PCOS), premature ovarian failure (POF), and hormonal contraceptive failure; as well as osteoporosis (Figure 2).

Fig. 2. Possible changes in epileptic women according to different stages of female life

PCOS is characterized by enlarged ovaries with multiple small cysts and a hypervascularized, androgen-secreting stroma leading to the associated signs of androgen excess (hirsutism, alopecia, acne), obesity, and menstrual-cycle disturbance (oligo or amenorrhea) (Balen, 1999). The most common reproductive endocrine disorder in women with epilepsy, as well as in women in the general population, is PCOS. PCOS occurs in 10- 20% of women with epilepsy compared to 5-6% of women in the general population (Bauer et al, 2008; Knochenhauer et al, 1998; Herzog, 2002; Herzog et al, 2003). The prevalence of PCOS in women with epilepsy is greater, even if they are not taking AEDs; and it is more frequent in women who take valproic acid (VPA), primarily if initiated before the age of 20. PCOS is probably not a single nosological entity, but rather the common endpoint for a number of pathophysiological mechanisms, some of which may be attributable to epilepsy itself (Herzog et al, 1986, 2003) or to the use of AEDs, most notably valproate. PCOS represents the failure of the ovarian follicle to complete normal maturation during the menstrual cycle or a series of cycles -- a failure that is perhaps related to the presence of

AED, anti-epileptic drug; PCOS, polycystic ovary syndrome.

**2. Epilepsy and polycystic ovary syndrome** 

gonadal function.

concentrations of bioactive sex steroids.

inadequate levels of pituitary follicle-stimulating hormone (FSH); whereas levels of luteinizing hormone (LH) are normal or elevated (Isojärvi, 2008; Herzog, 2008).

The brain controls reproductive function primarily through hypothalamic regulation of pituitary secretion. The left and right vagus nerves exert different modulatory influences on ovarian structure and function (Gerendai & Halasz, 1997). The reproductive neuroendocrine system, like many other brain systems, shows a lateralized asymmetry that might, by virtue of ipsilaterally predominating effects, contribute to the development of distinct reproductive endocrine disorders in association with unilateral left- and right-sided epileptic foci (Herzog, 2007). Unilateral temporolimbic discharges are associated with laterally differing, consistent, predictable, stochastic directional changes in hormonal secretion at all levels of the reproductive neuroendocrine axis, that is, hypothalamus, pituitary, and ovary (Herzog et al, 2003). These directional changes are consistent with the finding that different reproductive disorders may develop in relation to left- and right-sided temporolimbic epilepsy. Specifically, left temporal lobe epilepsy (LTLE) is associated with significantly higher pulse frequencies of GnRH secretion (Herzog et al, 2003; Herzog, 2008). Higher GnRH pulse frequency, in turn, is associated with higher LH/FSH ratios and higher serum testosterone levels. This combination of neuroendocrine changes characterizes PCOS and is consistent with the previously suggested association between left unilateral TLE and PCOS.

Antiepileptic drugs, on the other hand, also have substantial and differential effects on reproductive hormone levels. The first report suggesting a high incidence of menstrual disorders linked to obesity, hyperandrogenism, and polycystic ovaries in women taking VPA for epilepsy was published in 1993 (Isojarvi). Changes in serum androgen levels have been detected before and during pubertal development in young girls taking VPA for epilepsy (Vainionpää, 1999).

Studies by Murialdo et al (1997) have also reported a high prevalence of menstrual disorders and hyperandrogenic anovulation in VPA treated women with epilepsy. However, the study by Bauer et al (2008) did not show any differences between carbamazepine- and VPAtreated women with epilepsy with respect to reproductive endocrine parameters. Although the interpretation of the results of this study is difficult, because the age of the patients, the duration of medication, and seizure frequency in the different treatment groups were not given (Isojärvi, 2005). Other studies have also addressed the issue of reproductive endocrine function in women with epilepsy. Luef et al (2002) reported similar frequencies of menstrual disorders and PCOS in women taking carbamazepine and VPA for epilepsy. It has been suggested that obesity and associated hyperinsulinemia could be implicated in the development of PCOS and hyperandrogenism in women taking VPA. It seems that obesity and related hyperinsulinemia may exacerbate the VPA-related reproductive endocrine disorders in women with epilepsy. It seems likely that VPA has a direct effect on ovarian androgen production, or as an enzyme inhibitor, it may inhibit the metabolism of sex steroids and thereby lead to increased serum androgen levels (Isojärvi et al, 2005).

Several studies have suggested that the reproductive endocrine effects of AEDs may be reversible if the medication is discontinued. In a prospective study, the replacement of VPA with lamotrigine resulted in normalization of endocrine function during a 1-year follow-up in 12 women with a previously identified endocrine disorder (PCOS or hyperandrogenism, or both) likely to be related to VPA. Serum insulin and testosterone levels returned to normal 2 months after VPA was discontinued, and the levels remained normal thereafter (Isojärvi et al, 2005).

The Impact of Epilepsy on Reproductive Functions 59

a result of direct disruption of hypothalamic and pituitary function by the seizures. It has been suggested that women with POF were more likely to have catamenial exacerbation of

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

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

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

their seizures than women without POF.

**4. Contraception and epilepsy** 

(Schwenkhagen&Stodieck, 2008).

risks (Burakgazi et al, 2009).

#### **3. Epilepsy and premature ovarian failure**

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

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 cases of POF remains elusive (Kodaman, 2010).

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 disruption of hypothalamic and pituitary function by the seizures.

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 a result of direct disruption of hypothalamic and pituitary function by the seizures. It has been suggested that women with POF were more likely to have catamenial exacerbation of their seizures than women without POF.
