Catamenial epilepsy

Our understanding of the major gonadal hormones, estrogen, progesterone, and testosterone, has significantly increased in the last century. These hormones are synthesized in various locations in the body, including the ovaries, adrenal gland, liver, subcutaneous fat, and brain ^[4]. There is considerable research showing that these steroidal hormones take part in an important role in the pathophysiology of epilepsy. Broadly terms, estrogen and its many forms is thought to be “proconvulsant,” whereas progesterone thought to be “anticonvulsant.”

Estrogen can be found in the female body in various forms, all of which affect women with catamenial epilepsy. Estrone (E1), estradiol (E2), and estriol (E3) are the three principal circulating estrogens. These three forms influence neuronal excitability, but very little is known about their interactions and the relative concentrations of E1/E2/E3 and how they may influence the seizure frequency behavior in women with epilepsy. In normally menstruating women, serum estradiol levels are typically present by day 10 of the menstrual cycle, and persists until ovulation.

• Estrone’s main source is adipose tissue (subcutaneous fat), where it is formed by aromatization of androstenedione. Estrone is the major estrogen after menopause, and this hormone could be very influential in seizure control of the catamenial woman if she is severely overweight or obese.

• Estradiol represents the most prolific estrogen ligand receptor in the female body, particularly in non-pregnant females, and is a more effective activator of estrogen receptor function than estrone or estriol. Estradiol directly increases NMDA mediated receptors of glutamate activity at the neuronal membrane. Through this mechanism hippocampal pyramidal neurons CA1 are excited, and a repetitive firing response is induced. ^[5] Dendritic spine density on CA1 hippocampal pyramidal cells is dependent upon estradiol levels, showing a direct correlation during normal fluctuations during the menstrual cycle. Estradiol has been shown to apply its affects on dendritic spine density of hippocampal cells by using a mechanism that required activation of NMDA receptors. ^[6] Furthermore, Herzog postulates that, “estradiol may thus further increase excitatory input to the CA1 neurons.” ^[7] Through many animal models, as well as human-use of estrogen-based hormone replacement therapy, estrogens have been seen to increase the excitability of neurons, leading to a decreased seizure threshold. In female adult rat experimental trials, the limbic seizure threshold fluctuates inversely to estradiol levels during the estrous cycle.

• Estriol is known to inhibit GABA and to promote kindling and epileptiform discharges. ^[8] Estriol is only produced in significant quantities during pregnancy via placental aromatization of fetal androgen, however it can also be synthesized in smaller quantities (non-pregnancy) by the liver by hydroxylation of estrone.

Similar to estrogen, progesterone receptors bind several molecules other than only progesterone. Progestagens are group of natural non-synthetic hormones, including progesterone, which binds to progesterone receptors. Other than progesterone, progestagens have several neuroactive metabolites, most notably allopregnanolone. Progesterone has been shown to lower the number of estrogen receptors, and thus act as an antagonist to estrogen actions. ^[9] In trials, both progesterone and allopregnanolone administration have shown a neuroprotective effect on hippocampal neurons in seizure models induced by kainic acid. ^[10]

The proper classification for catamenial epilepsy has been debatable for several decades. Researchers have defined catamenial epilepsy from the broadest definition of a “greater than” approach indicating an increase in seizure frequency or severity during any specific phase of the menstrual cycle, to a “sixfold increase” in average daily seizure frequency during specific times in the cycle. ^[11] In recent years, Herzog’s 1997 proposal of an admittedly arbitrary “twofold” increase has generally been accepted: Perimenstrual (C1), Periovulatory (C2), and Luteal (C3). ^[12] These three classifications are based upon serum estradiol:progesterone ratio, and a 24-34 day menstrual cycle in which menses begins on day 1, and ovulation occurs 14 days prior to menstruation. By this measure, approximately one third of women with epilepsy would be classified under the designation of catamenial epilepsy.

Perimenstrual classification (in normal cycles, days -3 to 3 of menstruation) is associated with a twofold or greater increase in average daily seizure occurrence during the menstrual phase (M) compared to the follicular (F) and luteal (L) phases. The menstrual phase is characterized by drastic decreases in progesterone and estrogen levels. The estradiol:progesterone ratio is highest during the days before menstruation (C1) and ovulation (C2). Perimenstrual seizure exacerbation has been recognized as the withdrawal of the protective effects of progesterone.
In a 2009 study, it was found that patients with C1 pattern of catamenial epilepsy had overall lower progesterone levels than healthy controls during the M phase. ^[13]

Periovulatory classification (in normal cycles, days 10 to -13) is associated with a twofold or greater increase in average daily seizure occurrence during the O phase compared to the (F) and (L) phases. The ovulatory phase is characterized by a surge of estrogen before ovulation, while an associated progesterone surge does not occur until ovulation actually occurs. This estrogen effect, without a corresponding progesterone surge of protection, intensifies seizure events.

Luteal classification (abnormal or inadequate luteal phase cycles, days 10 to 3) is associated with a twofold or greater increase in average daily seizure occurrence during the O, L and M phases. anovulatory females do not typically have a midcycle surge of progesterone, but still experience a surge in estrogen. These women have abnormally low progesterone levels during the O, L and M, regardless of whether ovulation occurs.
In El-Khayat’s study, it was found that patients with C3 pattern of catamenial epilepsy had overall lower progesterone levels than healthy controls during the L phase of the menstrual cycle. ^[13]

During menopause, there are drastic changes in the production of gonadal hormones. Most of the reproductive hormones, including the estrogens, progesterone and testosterone, diminish at first (perimenopause), becoming irregular, often with wide and unpredictable fluctuations in levels. As menopause progresses, there is cessation of estrogen production by the ovaries. Rosciszewska was one of the first researchers to report an increased risk of seizures during perimenopause, but a marked decreased risk of seizures during menopause if there was a catamenial relationship.^[14] This difference may be associated with the radical fluctuations of estradiol and progesterone during the perimenopausal period than what is experienced during the menopausal period and menstrual cycles of reproductive years. Recall that estrone is the predominant estrogen present during menopause (from subcutaneous fat), and little is known about the affect of estrone specifically on epilepsy. Women with epilepsy who do not follow a catamenial pattern may have an increase or decrease in seizure activity in perimenopause and menopause. ^[15]

The use of hormone replacement therapy (HRT), such as Premarin, has shown severe effects on the seizure patterns of women with catamenial epilepsy. During perimenopause, HRT use was not associated with an increase in seizures; however HRT use after perimenopause was significantly associated with an increase in seizures. Women progressing through peri- and post-menopause using HRT may be in greater need of anticonvulsant medication monitoring to maintain or reduce seizure occurrence. ^[16]

Several treatment methods have been determined exclusively for women with catamenial epilepsy. A great majority of these therapies include progestagens (naturally occurring) or progestin (synthetic progestagen). Drug interactions are an important factor when using progesterone therapy, as many antiseizure medications augment hepatic metabolism of gonadal steroids, and increase serum protein binding to hormones. There are many unfortunate side effects of progesterone therapy, including vaginal dryness, dyspareunia, osteoporosis, and cardiovascular disease.^[7]

• Cyclic progesterone therapy supplements with progesterone during the luteal phase when progesterone is normally low, and gradually reduces the supplementation premenstrually.

• Suppressive progestin therapy intends to suppress the menstrual cycle entirely by using injectable progestins or gonadotropin-releasing hormones (GnRH).