Catamenial epilepsy

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 in the body. These three forms influence neuronal excitability, but little is known about their inter-hormone interactions, the relative concentrations and ratios of E1/E2/E3 and how that may influence the seizure frequency behavior in women with epilepsy. In normally menstruating women, serum estradiol levels are typically elevated by day 10 of the menstrual cycle, which 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 may 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 the absence of pregnancy, 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.[8] 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 effects on dendritic spine density of hippocampal cells by using a mechanism that requires activation of NMDA receptors.[9] Furthermore, Herzog postulates that, "estradiol may thus further increase excitatory input to the CA1 neurons."[10] 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.[11] 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) in the liver by hydroxylation of estrone.

Progesterone levels during the menstrual cycle[1]

In general, progesterone administration is anticonvulsant, as supported by experiments in laboratory animals, where injection of progesterone leads to an increase in seizure threshold, or delay to the onset of seizures induced by convulsants.[6]

Similarly to estrogen receptors, progesterone receptors bind several molecules other than progesterone. Progestogens are group of natural non-synthetic hormones, including progesterone, which binds to progesterone receptors. Other than progesterone, progestogens 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.[12] In trials, both progesterone and allopregnanolone administration have shown a neuroprotective effect on hippocampal neurons in seizure models induced by kainic acid.[13]

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.[16]

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 women 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 study by El-Khayat et al., 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.[16]

The use of hormone replacement therapy (HRT), to lessen the effects of menopause, has shown severe negative effects on the seizure patterns of women with catamenial epilepsy. During perimenopause, women with catamenial epilepsy generally experience an increase in seizure frequency, and HRT use does not change this likelihood. However HRT use after perimenopause has been significantly associated with an increase in seizure frequency and severity. Women progressing through peri- and post-menopause using HRT may be in greater need of anticonvulsant medication monitoring to maintain or reduce seizure occurrence. These same results have not been seen in laboratory counterparts. Adult female rats that have been ovariectomized, a parallel state to menopause, show increased seizure frequency overall. There are, however, several factors that could explain this difference, including ovariectomized rats do not have the analogous brain hormones milieu as menopausal women. Several studies following HRT use in women with catamenial epilepsy have demonstrated more influencable data than animal models, in this case.[19]