Neurobiology of Disease 72 (2014) 193–197
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Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi
Review
Gender issues in the neurobiology of epilepsy: A clinical perspective Barbara S. Koppel a,⁎, Cynthia L. Harden b,c a b c
Department of Neurology, New York Medical College and Metropolitan Hospital, New York, NY, United States Department of Neurology, Hofstra North Shore-LIJ School of Medicine, Great Neck, NY, United States Division of Epilepsy and Electroencephalography, Cushing Neuroscience Institutes, Brain and Spine Specialists, Great Neck, NY, United States
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Article history: Received 21 March 2014 Revised 25 August 2014 Accepted 29 August 2014 Available online 16 September 2014 Keywords: Epilepsy Sex hormones Catamenial epilepsy Sexual dysfunction Estrogen Progesterone Testosterone
a b s t r a c t A patient's hormonal milieu contributes to the timing of emergence of several epilepsy syndromes that are known to begin at puberty and recede with the end of reproductive potential. One's hormonal balance at any particular moment contributes to seizure occurrence in both men and women. The best studied condition, catamenial epilepsy, refers to seizure clusters occurring in a cyclical pattern related to menses. Treatment of epilepsy using hormones complements standard antiepileptic therapy and its use will be reviewed, along with some other medications unique to catamenial epilepsy, such as diuretics. Seizures and “silent” epileptiform discharges in turn affect the hypothalamic pituitary axis and can cause release of hormones at inappropriate times leading to sexual dysfunction, menstrual irregularity, infertility and premature termination of reproductive states. Combined with psychological consequences of epilepsy, this sexual dysfunction has deleterious effects on the quality of life in patients and their partners. © 2014 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . Relationships between hormonal states and seizure occurrence Epilepsy effects on sex steroid regulation . . . . . . . . . . Hormones as antiepileptic treatment . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of Interest . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Long known for their influence on mood and cognitive function, the sex hormones have also been known to affect seizure threshold since Locock's observations in 52 patients (Locock, 1857) and Gowers' in 46
⁎ Corresponding author at: Metropolitan Hospital Rm 7C5, 1901 First Ave., New York, NY 10029. Fax: +1 212 4237851. E-mail address: [email protected] (B.S. Koppel). Available online on ScienceDirect (www.sciencedirect.com).
http://dx.doi.org/10.1016/j.nbd.2014.08.033 0969-9961/© 2014 Elsevier Inc. All rights reserved.
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women with menstrually-related attacks (Gowers, 1881). Based on patterns of seizure occurrence in catamenial epilepsy, and later confirmed by assays of hormone levels throughout the menstrual cycle, estrogen is considered to be excitatory (lowering seizure threshold), while progesterone is calming (antiepileptic) (Fig. 1). Clinical studies which contribute to understanding the pathophysiology of catamenial epilepsy will be reviewed, and the influence of sex hormones on epilepsy syndromes in general will be described, including experience gained from case reports. Successes and limitations of hormonal treatment of epilepsy will be described.
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B.S. Koppel, C.L. Harden / Neurobiology of Disease 72 (2014) 193–197
Fig. 1. Three patterns of catamenial epilepsy: perimenstrual (C1) and periovulatory (C2) exacerbations during normal ovulatory cycles and entire second half of the cycle (C3) exacerbation during inadequate luteal phase cycles where day 1 is the first day of menstrual flow and Day −14 is the day of ovulation. F = follicular phase; O = periovulatory; L = Luteal phase; M = perimenstrual. E2 = Estradiol; P = Progesterone.
Conversely, the effects of epilepsy and epileptiform activity on gonadotropin release and subsequent state of hormonal balance and related dysfunction will be reviewed. Relationships between hormonal states and seizure occurrence Sex hormones such as estrogen, androgen and progesterone, along with their metabolites, play a role in brain development and network formation. During parturition female hormones may be neuroprotective for birth-related trauma and anoxia. Postnatally, estrogen promotes cognitive function and memory formation, through immediate gene transcription. Modulation of neurotransmitters, specifically NMDA and glutamate in the case of estrogens and GABAA in the case of
progesterone, set a state of excitation or inhibition. Androgen is metabolized to 17β estradiol (by aromatization) or androstenedione (by glucuronidation) and these metabolites have opposite effects on the excitability of cortex (Sivaraaman and Mintzer, 2011). It has even been proposed that some of these hormone metabolites, such as androsterone, which, like progesterone metabolites, modulates GABA receptors, may be protective against seizures (Kaminski et al., 2005; Frye, 2010). However, this simple paradigm of hormonal influence on seizure threshold is difficult to confirm in patients. In fact, cortical excitability as measured using transcranial magnetic stimulation, admittedly of the motor cortex and not the limbic system, was not different in ovulatory or anovulatory cycles and was the same for women with epilepsy of all types, not just catamenial, displaying maximal excitability in the
B.S. Koppel, C.L. Harden / Neurobiology of Disease 72 (2014) 193–197
luteal phase whereas controls had maximal excitability in the follicular stage of the cycle (Badawy et al., 2013). Outside these immediate central effects, hormones act in a slower, sustained manner on receptors remote from their production site to prepare the adult male or female for mating and reproduction, including preparing the uterus for pregnancy each month (Frye, 2010). The indirect evidence for hormonal influences on seizure breakthroughs comes from tracking seizure frequency at various phases of the reproductive lifespan and throughout individual menstrual cycles. Epilepsy syndromes in general can also be influenced by hormonal background (Persad et al., 2004). Certain syndromes such as juvenile myoclonic epilepsy, generalized tonic clonic activity on waking, benign rolandic epilepsy, photosensitive epilepsy, reading epilepsy and some generalized epilepsy syndromes present during adolescence (or menarche in girls), when levels of sex hormones rise due to puberty (Grϋnewald et al., 1992; Velišková et al., 2010; Velišková and Desantis, 2013). Indirect influences on epileptic syndromes through effects on sleep also occur with changes in prolactin (Lin et al., 2002). During pregnancy, seizures abate in some cases, presumably due to higher levels of progesterone and the presence of estriol, a form of estrogen potentially less epileptogenic than estradiol (Alam et al., 2013). During perimenopause, with rapid shifts of both estrogen and progesterone levels, seizure frequency increases. This is exacerbated in women with associated sleep disturbances. In menopause, the predominant estrogen form, estrone, is also presumably less epileptogenic and has been shown to reduce seizures in catamenial epilepsy patients as well as in experimental models (Harden et al., 1999, 2003; Rǿste et al., 2008). Hormonal infusion causes corresponding effects on the spike-wave patterns seen on electroencephalogram, ie estrogen increases (Lin et al., 1952; Logothetis et al., 1959) and progesterone decreases epileptiform discharges (Bäckstrom et al., 1984). Various reports of increased seizures after administration of hormones or their releasing factors appear in the literature (Fig. 2) (Milani et al., 2007; Akaboshi and Takeshita, 2000; Gatti et al., 2013) but conclusions from these, other than avoiding hormones if possible in the presence of brain lesions or epilepsy, cannot be made. The effect of hormones on the total number of seizures throughout a woman's individual menstrual cycle will be discussed below, but it is also interesting to note that more partial seizures become generalized in anovulatory cycles, where the ratio of estrogen to progesterone is altered in favor of estrogen during the second half of the cycle (Herzog et al., 2011). Catamenial (Greek for monthly) epilepsy refers to clusters of seizure attacks at specific, recurrent times of the menstrual cycle. Most women report an increase in seizure frequency in the perimenstrual days, a smaller number notice an increase during the periovulatory days, or in both, and the smallest group notice them in the entire second half of the cycle (12 days of the luteal phase instead of the 2–3 days
Fig. 2. Proportion of women with increase in seizure frequency while taking placebo versus two doses hormone replacement in the form of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA).
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immediately preceding menses, presumably in cycles where ovulation failed to occur) (Herzog et al., 1997). The first pattern was noted by many women who generally relate an increase in seizures during the premenstrual and menstrual period, but needed to be confirmed by keeping careful seizure/menstrual diaries. Measurement of hormone levels throughout the cycle confirms the pattern of natural surges and declines of estrogen and progesterone. Elevated levels of hormones throughout the cycle lead to enlarged ovaries and somewhat to polycystic ovary syndrome, which can also be measured by ultrasound, (Murialdo et al., 1997). Markedly frequent seizures, primarily limbic, are required to cause this polycystic ovary syndrome, as it was not found in a study of 101 women, 36 with generalized and 65 with partial, not necessarily temporal lobe, epilepsy (Zhou et al., 2012). During the follicular phase which starts the cycle (although counting of the days of each cycle begins with the menses of the previous cycle by gynecologic tradition), estradiol levels rise until ovulation occurs, 14 days prior to menses, followed by gradual falling, and simultaneous rising of progesterone and allopregnanolone until the immediate premenstrual period when they fall (unless fertilization has occurred in which both stay up throughout the pregnancy). If no egg was released, this pattern does not occur because there is no stimulation of the corpus luteum to begin progesterone secretion. The ratio of estradiol, which is thought to be proconvulsant through its action on synaptic density of hippocampal dendrites, to progesterone, which is thought to be anticonvulsant through its modulation of the GABAA receptors, may explain changes in seizure frequency throughout the menstrual cycle. (Anovulatory cycles occur in about 10% of normal cycles but are more frequent (28%) in women with epilepsy) (Herzog et al., 2011). Determining if a cycle is anovulatory clinically relies on daily basal temperature measurement to determine the lowest one which corresponds to ovulation, or in the laboratory by daily progesterone level measurement: levels fail to peak if there is no ovulation. Anovulatory cycles are normal at the end of the reproductive period, ie perimenopause, as well as in women with irregular periods (Pack, 2010). In fact women with more irregular menses during the ages of 18–22 have a higher incidence of epilepsy. In defining catamenial epilepsy, although the timing of these clusters of attacks is well-described, the absolute number of attacks necessary to call a pattern catamenial has been defined differently over the many years of observation. The simplest definition is what was noted originally by the women themselves: an increase from the patient's usual daily rate, whatever it was, instead of an arbitrary number. Reddy has chosen doubling of number of the individual's own seizure frequency per day to determine the pattern, which is easy to work with (Reddy and Rogawski, 2009). Interestingly, mood changes throughout the cycle exhibit similar patterns, with dysphoria found premenstrually in most women but in midcycle (at ovulation) in a few, and probably share the same hormonal relationships (Bäckstrom et al., 2011). Epilepsy effects on sex steroid regulation Disruption of normal pulsatile secretions of the hypothalamicpituitary-gonad axis after generalized seizures, with an increase in LH levels in both men and women and an increase in FSH in women, and an increase in prolactin levels after partial seizures especially originating in the nearby temporal lobe (Dana-Haeri et al., 1984; Sperling et al., 1986) are presumed to be responsible for the sexual and reproductive complications of chronic epilepsy. The dysregulation of normal hormone patterns by these seizures, or even by epileptiform discharges that pass through the HPA, results in menstrual irregularity and anovulatory cycles leading to infertility, premature menopause (Harden et al., 2003; Bauer and Cooper-Mahkorn, 2008) and overall effects on libido and sexual function in both men and women (Sivaraaman and Mintzer, 2011; Morris and Vanderkolk, 2005). In addition, sleep and mood can be deleteriously affected by hormonal disruptions (Duncan et al., 2009; Zelená et al., 2011). Even in patients without observable seizures, interictal epileptiform discharges especially from the right
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temporal lobe (Herzog et al., 2003b) that pass through to the hypothalamus cause release of gonadotropin-releasing hormone from the hypothalamus which in turn causes the release of gonadotropins such as lutenizing hormone and follicle-stimulating hormone (LH/FSH) which act on the periphery to produce testosterone in the Leydig cells and spermatozoa in the Sertoli cells in men, and estrogen and progesterone from ovaries in women. An elevation in prolactin levels further contributes to irregular menses or amenorrhea, galactorrhea and infertility. Birth rates go up after temporal lobectomy surgery for epilepsy (Baird et al., 2003; Herzog, 2013). Men with epilepsy have lower testosterone levels than controls, with fewer children and sexual interest (Herzog et al., 1986; Isojärvi et al., 2004). If epilepsy has begun in childhood, physical characteristics of masculinity will be abnormal as well (El-Khayat et al., 2003). Using an International Inventory of Erectile Function in 40 epileptic men with regular partners (ie with no extenuating factors such as stigma of an attack occurring with an unfamiliar partner), specific areas of dissatisfaction were correlated with hormonal changes, ie increased FSH and SHBG (sex hormone binding globulin) and decreased DHEAS (dehydroepiandrosterone sulfate)and FAI (free androgen index) which contribute to loss of libido, erectile dysfunction or dissatisfaction with sexual intercourse in up to 50% of a series of 40 men with epilepsy (Kuba et al., 2006). Although this study did not correlate scores with duration of epilepsy, the patients had a high seizure frequency of 1–15/month, of all types. Despite their young age (18–44) these men had problems with potency seen in older-aged men whose testosterone levels decline naturally. Other studies of men with epilepsy confirm a higher than control rate of sexual dysfunction (20%); 70% had subnormal bioactive testosterone levels compared to 18% with normal S-scores measuring sexual interest and potency (Herzog, 2003a). Fertility is also affected by epilepsy: a 40% lower birth rate was discovered in a population-based study of men with epilepsy (Artama et al., 2004), which improved if remission was achieved prior to adulthood (Löfgren et al., 2009). The conundrum of whether epilepsy changes hormone levels or whether different levels of hormones found in patients with epilepsy affect the frequency of seizures is not limited to sex hormones. It has long been known that stress hormones such as cortisol are different in patients with epilepsy, and that they can be manipulated to treat some epilepsy syndromes such as infantile spasms (Reddy, 2013). Appetite-related hormones are also found in lower or higher levels in patients with epilepsy compared to controls, but whether they are epileptogenic or a product of the seizures is not yet known (Aydin et al., 2009). Hormones as antiepileptic treatment There is a vast difference in the effects of endogenous hormones on seizure threshold and success of therapy substituting pharmacologic formulations of hormones (Herzog et al., 2012; Harden and Pennel, 2013). The form and timing of these substitutes in a patient with catamenial epilepsy is important, and in fact, in some patients with absence epilepsy, progesterone therapy may increase absence attacks (Grϋnewald et al., 1992). Treatment of catamenial epilepsy is easier in women with perimenstrual pattern, as a fall in endogenous levels of progesterone are more predictable than in those with seizures throughout the “luteal” phase whose levels are low due to failure of ovulation in that cycle. Interactions between endogenous hormones and particular antiseizure medications play a role, but that is discussed elsewhere. Observations of a beneficial effect of hormonal use for contraception was made early in the use of long acting (depot) preparations of medroxyprogesterone, with a 39% decrease in seizure frequency in one year (Zimmerman et al., 1973; Mattson et al., 1984), but a direct mechanism was not proven (ie the absence of menses might reduce perimenstrual seizure clusters). In a study of 25 women with
seizures in the perimenstrual period or the second half of the month, treatment with progesterone 200 mg twice daily resulted in improvement in 18 women, more so in those receiving 10 days compared to 2 days of supplementation each month. (Herzog 1995). In a study of 294 women with intractable partial seizures, only those with a C1, ie perimenstrual, average daily seizure frequency N 3, demonstrated a significant response with 38% showing decreased seizure frequency using 200 mg oral lozenges bid in the second half of the cycle, compared to 11% placebo. Those women whose seizure clusters were associated with estrogen surge or midluteal phase patterns, or who had no pattern to their seizures, failed to show improvement with natural progesterone supplementation. Synthetic progesterone, devoid of reproductive effects, would be required for low progesterone states such as the midluteal phase of the cycle. (Herzog et al., 2012) Suppression of estrogen requires alternative approaches, such as depomedroxyprogesterone or GnRH analog. Less is known about the efficacy of progesterone in other types of epilepsy, although a decline by 54.7% in primary and 59% in secondary generalized seizures was noted in a group of 36 women with seizures throughout the second half of their menstrual cycles who were found to have low serum levels of progesterone on days 22, 27 and 28 of the cycle. The one woman with myoclonic seizures had a 46% decline in seizure frequency (Motta et al., 2013). A synthetic preparation, norethisterone, was not found to help 9 patients with catamenial epilepsy (Dana-Haeri et al., 1984) while another synthetic gonadotropic hormone did help one patient with absence and perimenstrual generalized seizures. Because of water and electrolyte imbalances that play a role in lowering the seizure threshold of some patients during the menstrual cycle, the diuretic acetazolamide is also helpful in a few patients (Harden and Pennel, 2013). Using extra doses of the patient's regular antiepileptic medication may be helpful, but can lead to toxicity and suffers from the same unpredictability of menstrual cycles timing and intermittent ovulatory failure, so that combination with hormonal treatment (if contraception is desired) would be helpful. Intermittent use of benzodiazepines has similar concerns with toxicity or development of tolerance, although clobazam was successful in one study (Feely et al., 1982). Hormonal manipulation in men is more difficult, but one logical approach is to move the breakdown of testosterone in the direction away from production of estradiol by blocking aromatase. Aromatase inhibitors, such as finasteride, have been used to treat prostate hypertrophy, and some success was reported in the treatment of men with complex partial epilepsy (Herzog et al., 1998), as well as some with some other aromatase inhibitors (Harden and MacLusky, 2005). However, when finasteride was used for treatment of male-pattern baldness in women, seizure frequency increased (Herzog and Frye, 2003). Conclusion An understanding of the interplay between reproductive hormones, seizures, and epilepsy syndromes will allow better therapies, targeted at individual situations as well as prevention of ongoing deleterious effects on the epilepsy patient's hormonal status throughout their lifespan. Newer ways to assess local hormonal milieus will play a significant role in improvement of quality of life in epilepsy patients. Conflicts of Interest Dr. Koppel has no conflicts of interest. Dr. Harden has no conflicts of interest. References Akaboshi, S., Takeshita, K., 2000. A case of atypical absence seizures induced by leuprolide acetate. Pediatr. Neurol. 23, 266–268. Alam, M.N., Ahmad, A., Al-Abbasi, F.A., Ahmad, A., 2013. Female ovarian steroids in epilepsy: a cause or remedy. Pharmacol. Rep. 65, 802–812.
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Contents lists available at ScienceDirect
Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi
Review
Gender issues in the neurobiology of epilepsy: A clinical perspective Barbara S. Koppel a,⁎, Cynthia L. Harden b,c a b c
Department of Neurology, New York Medical College and Metropolitan Hospital, New York, NY, United States Department of Neurology, Hofstra North Shore-LIJ School of Medicine, Great Neck, NY, United States Division of Epilepsy and Electroencephalography, Cushing Neuroscience Institutes, Brain and Spine Specialists, Great Neck, NY, United States
a r t i c l e
i n f o
Article history: Received 21 March 2014 Revised 25 August 2014 Accepted 29 August 2014 Available online 16 September 2014 Keywords: Epilepsy Sex hormones Catamenial epilepsy Sexual dysfunction Estrogen Progesterone Testosterone
a b s t r a c t A patient's hormonal milieu contributes to the timing of emergence of several epilepsy syndromes that are known to begin at puberty and recede with the end of reproductive potential. One's hormonal balance at any particular moment contributes to seizure occurrence in both men and women. The best studied condition, catamenial epilepsy, refers to seizure clusters occurring in a cyclical pattern related to menses. Treatment of epilepsy using hormones complements standard antiepileptic therapy and its use will be reviewed, along with some other medications unique to catamenial epilepsy, such as diuretics. Seizures and “silent” epileptiform discharges in turn affect the hypothalamic pituitary axis and can cause release of hormones at inappropriate times leading to sexual dysfunction, menstrual irregularity, infertility and premature termination of reproductive states. Combined with psychological consequences of epilepsy, this sexual dysfunction has deleterious effects on the quality of life in patients and their partners. © 2014 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . Relationships between hormonal states and seizure occurrence Epilepsy effects on sex steroid regulation . . . . . . . . . . Hormones as antiepileptic treatment . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of Interest . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Long known for their influence on mood and cognitive function, the sex hormones have also been known to affect seizure threshold since Locock's observations in 52 patients (Locock, 1857) and Gowers' in 46
⁎ Corresponding author at: Metropolitan Hospital Rm 7C5, 1901 First Ave., New York, NY 10029. Fax: +1 212 4237851. E-mail address: [email protected] (B.S. Koppel). Available online on ScienceDirect (www.sciencedirect.com).
http://dx.doi.org/10.1016/j.nbd.2014.08.033 0969-9961/© 2014 Elsevier Inc. All rights reserved.
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women with menstrually-related attacks (Gowers, 1881). Based on patterns of seizure occurrence in catamenial epilepsy, and later confirmed by assays of hormone levels throughout the menstrual cycle, estrogen is considered to be excitatory (lowering seizure threshold), while progesterone is calming (antiepileptic) (Fig. 1). Clinical studies which contribute to understanding the pathophysiology of catamenial epilepsy will be reviewed, and the influence of sex hormones on epilepsy syndromes in general will be described, including experience gained from case reports. Successes and limitations of hormonal treatment of epilepsy will be described.
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Fig. 1. Three patterns of catamenial epilepsy: perimenstrual (C1) and periovulatory (C2) exacerbations during normal ovulatory cycles and entire second half of the cycle (C3) exacerbation during inadequate luteal phase cycles where day 1 is the first day of menstrual flow and Day −14 is the day of ovulation. F = follicular phase; O = periovulatory; L = Luteal phase; M = perimenstrual. E2 = Estradiol; P = Progesterone.
Conversely, the effects of epilepsy and epileptiform activity on gonadotropin release and subsequent state of hormonal balance and related dysfunction will be reviewed. Relationships between hormonal states and seizure occurrence Sex hormones such as estrogen, androgen and progesterone, along with their metabolites, play a role in brain development and network formation. During parturition female hormones may be neuroprotective for birth-related trauma and anoxia. Postnatally, estrogen promotes cognitive function and memory formation, through immediate gene transcription. Modulation of neurotransmitters, specifically NMDA and glutamate in the case of estrogens and GABAA in the case of
progesterone, set a state of excitation or inhibition. Androgen is metabolized to 17β estradiol (by aromatization) or androstenedione (by glucuronidation) and these metabolites have opposite effects on the excitability of cortex (Sivaraaman and Mintzer, 2011). It has even been proposed that some of these hormone metabolites, such as androsterone, which, like progesterone metabolites, modulates GABA receptors, may be protective against seizures (Kaminski et al., 2005; Frye, 2010). However, this simple paradigm of hormonal influence on seizure threshold is difficult to confirm in patients. In fact, cortical excitability as measured using transcranial magnetic stimulation, admittedly of the motor cortex and not the limbic system, was not different in ovulatory or anovulatory cycles and was the same for women with epilepsy of all types, not just catamenial, displaying maximal excitability in the
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luteal phase whereas controls had maximal excitability in the follicular stage of the cycle (Badawy et al., 2013). Outside these immediate central effects, hormones act in a slower, sustained manner on receptors remote from their production site to prepare the adult male or female for mating and reproduction, including preparing the uterus for pregnancy each month (Frye, 2010). The indirect evidence for hormonal influences on seizure breakthroughs comes from tracking seizure frequency at various phases of the reproductive lifespan and throughout individual menstrual cycles. Epilepsy syndromes in general can also be influenced by hormonal background (Persad et al., 2004). Certain syndromes such as juvenile myoclonic epilepsy, generalized tonic clonic activity on waking, benign rolandic epilepsy, photosensitive epilepsy, reading epilepsy and some generalized epilepsy syndromes present during adolescence (or menarche in girls), when levels of sex hormones rise due to puberty (Grϋnewald et al., 1992; Velišková et al., 2010; Velišková and Desantis, 2013). Indirect influences on epileptic syndromes through effects on sleep also occur with changes in prolactin (Lin et al., 2002). During pregnancy, seizures abate in some cases, presumably due to higher levels of progesterone and the presence of estriol, a form of estrogen potentially less epileptogenic than estradiol (Alam et al., 2013). During perimenopause, with rapid shifts of both estrogen and progesterone levels, seizure frequency increases. This is exacerbated in women with associated sleep disturbances. In menopause, the predominant estrogen form, estrone, is also presumably less epileptogenic and has been shown to reduce seizures in catamenial epilepsy patients as well as in experimental models (Harden et al., 1999, 2003; Rǿste et al., 2008). Hormonal infusion causes corresponding effects on the spike-wave patterns seen on electroencephalogram, ie estrogen increases (Lin et al., 1952; Logothetis et al., 1959) and progesterone decreases epileptiform discharges (Bäckstrom et al., 1984). Various reports of increased seizures after administration of hormones or their releasing factors appear in the literature (Fig. 2) (Milani et al., 2007; Akaboshi and Takeshita, 2000; Gatti et al., 2013) but conclusions from these, other than avoiding hormones if possible in the presence of brain lesions or epilepsy, cannot be made. The effect of hormones on the total number of seizures throughout a woman's individual menstrual cycle will be discussed below, but it is also interesting to note that more partial seizures become generalized in anovulatory cycles, where the ratio of estrogen to progesterone is altered in favor of estrogen during the second half of the cycle (Herzog et al., 2011). Catamenial (Greek for monthly) epilepsy refers to clusters of seizure attacks at specific, recurrent times of the menstrual cycle. Most women report an increase in seizure frequency in the perimenstrual days, a smaller number notice an increase during the periovulatory days, or in both, and the smallest group notice them in the entire second half of the cycle (12 days of the luteal phase instead of the 2–3 days
Fig. 2. Proportion of women with increase in seizure frequency while taking placebo versus two doses hormone replacement in the form of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA).
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immediately preceding menses, presumably in cycles where ovulation failed to occur) (Herzog et al., 1997). The first pattern was noted by many women who generally relate an increase in seizures during the premenstrual and menstrual period, but needed to be confirmed by keeping careful seizure/menstrual diaries. Measurement of hormone levels throughout the cycle confirms the pattern of natural surges and declines of estrogen and progesterone. Elevated levels of hormones throughout the cycle lead to enlarged ovaries and somewhat to polycystic ovary syndrome, which can also be measured by ultrasound, (Murialdo et al., 1997). Markedly frequent seizures, primarily limbic, are required to cause this polycystic ovary syndrome, as it was not found in a study of 101 women, 36 with generalized and 65 with partial, not necessarily temporal lobe, epilepsy (Zhou et al., 2012). During the follicular phase which starts the cycle (although counting of the days of each cycle begins with the menses of the previous cycle by gynecologic tradition), estradiol levels rise until ovulation occurs, 14 days prior to menses, followed by gradual falling, and simultaneous rising of progesterone and allopregnanolone until the immediate premenstrual period when they fall (unless fertilization has occurred in which both stay up throughout the pregnancy). If no egg was released, this pattern does not occur because there is no stimulation of the corpus luteum to begin progesterone secretion. The ratio of estradiol, which is thought to be proconvulsant through its action on synaptic density of hippocampal dendrites, to progesterone, which is thought to be anticonvulsant through its modulation of the GABAA receptors, may explain changes in seizure frequency throughout the menstrual cycle. (Anovulatory cycles occur in about 10% of normal cycles but are more frequent (28%) in women with epilepsy) (Herzog et al., 2011). Determining if a cycle is anovulatory clinically relies on daily basal temperature measurement to determine the lowest one which corresponds to ovulation, or in the laboratory by daily progesterone level measurement: levels fail to peak if there is no ovulation. Anovulatory cycles are normal at the end of the reproductive period, ie perimenopause, as well as in women with irregular periods (Pack, 2010). In fact women with more irregular menses during the ages of 18–22 have a higher incidence of epilepsy. In defining catamenial epilepsy, although the timing of these clusters of attacks is well-described, the absolute number of attacks necessary to call a pattern catamenial has been defined differently over the many years of observation. The simplest definition is what was noted originally by the women themselves: an increase from the patient's usual daily rate, whatever it was, instead of an arbitrary number. Reddy has chosen doubling of number of the individual's own seizure frequency per day to determine the pattern, which is easy to work with (Reddy and Rogawski, 2009). Interestingly, mood changes throughout the cycle exhibit similar patterns, with dysphoria found premenstrually in most women but in midcycle (at ovulation) in a few, and probably share the same hormonal relationships (Bäckstrom et al., 2011). Epilepsy effects on sex steroid regulation Disruption of normal pulsatile secretions of the hypothalamicpituitary-gonad axis after generalized seizures, with an increase in LH levels in both men and women and an increase in FSH in women, and an increase in prolactin levels after partial seizures especially originating in the nearby temporal lobe (Dana-Haeri et al., 1984; Sperling et al., 1986) are presumed to be responsible for the sexual and reproductive complications of chronic epilepsy. The dysregulation of normal hormone patterns by these seizures, or even by epileptiform discharges that pass through the HPA, results in menstrual irregularity and anovulatory cycles leading to infertility, premature menopause (Harden et al., 2003; Bauer and Cooper-Mahkorn, 2008) and overall effects on libido and sexual function in both men and women (Sivaraaman and Mintzer, 2011; Morris and Vanderkolk, 2005). In addition, sleep and mood can be deleteriously affected by hormonal disruptions (Duncan et al., 2009; Zelená et al., 2011). Even in patients without observable seizures, interictal epileptiform discharges especially from the right
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temporal lobe (Herzog et al., 2003b) that pass through to the hypothalamus cause release of gonadotropin-releasing hormone from the hypothalamus which in turn causes the release of gonadotropins such as lutenizing hormone and follicle-stimulating hormone (LH/FSH) which act on the periphery to produce testosterone in the Leydig cells and spermatozoa in the Sertoli cells in men, and estrogen and progesterone from ovaries in women. An elevation in prolactin levels further contributes to irregular menses or amenorrhea, galactorrhea and infertility. Birth rates go up after temporal lobectomy surgery for epilepsy (Baird et al., 2003; Herzog, 2013). Men with epilepsy have lower testosterone levels than controls, with fewer children and sexual interest (Herzog et al., 1986; Isojärvi et al., 2004). If epilepsy has begun in childhood, physical characteristics of masculinity will be abnormal as well (El-Khayat et al., 2003). Using an International Inventory of Erectile Function in 40 epileptic men with regular partners (ie with no extenuating factors such as stigma of an attack occurring with an unfamiliar partner), specific areas of dissatisfaction were correlated with hormonal changes, ie increased FSH and SHBG (sex hormone binding globulin) and decreased DHEAS (dehydroepiandrosterone sulfate)and FAI (free androgen index) which contribute to loss of libido, erectile dysfunction or dissatisfaction with sexual intercourse in up to 50% of a series of 40 men with epilepsy (Kuba et al., 2006). Although this study did not correlate scores with duration of epilepsy, the patients had a high seizure frequency of 1–15/month, of all types. Despite their young age (18–44) these men had problems with potency seen in older-aged men whose testosterone levels decline naturally. Other studies of men with epilepsy confirm a higher than control rate of sexual dysfunction (20%); 70% had subnormal bioactive testosterone levels compared to 18% with normal S-scores measuring sexual interest and potency (Herzog, 2003a). Fertility is also affected by epilepsy: a 40% lower birth rate was discovered in a population-based study of men with epilepsy (Artama et al., 2004), which improved if remission was achieved prior to adulthood (Löfgren et al., 2009). The conundrum of whether epilepsy changes hormone levels or whether different levels of hormones found in patients with epilepsy affect the frequency of seizures is not limited to sex hormones. It has long been known that stress hormones such as cortisol are different in patients with epilepsy, and that they can be manipulated to treat some epilepsy syndromes such as infantile spasms (Reddy, 2013). Appetite-related hormones are also found in lower or higher levels in patients with epilepsy compared to controls, but whether they are epileptogenic or a product of the seizures is not yet known (Aydin et al., 2009). Hormones as antiepileptic treatment There is a vast difference in the effects of endogenous hormones on seizure threshold and success of therapy substituting pharmacologic formulations of hormones (Herzog et al., 2012; Harden and Pennel, 2013). The form and timing of these substitutes in a patient with catamenial epilepsy is important, and in fact, in some patients with absence epilepsy, progesterone therapy may increase absence attacks (Grϋnewald et al., 1992). Treatment of catamenial epilepsy is easier in women with perimenstrual pattern, as a fall in endogenous levels of progesterone are more predictable than in those with seizures throughout the “luteal” phase whose levels are low due to failure of ovulation in that cycle. Interactions between endogenous hormones and particular antiseizure medications play a role, but that is discussed elsewhere. Observations of a beneficial effect of hormonal use for contraception was made early in the use of long acting (depot) preparations of medroxyprogesterone, with a 39% decrease in seizure frequency in one year (Zimmerman et al., 1973; Mattson et al., 1984), but a direct mechanism was not proven (ie the absence of menses might reduce perimenstrual seizure clusters). In a study of 25 women with
seizures in the perimenstrual period or the second half of the month, treatment with progesterone 200 mg twice daily resulted in improvement in 18 women, more so in those receiving 10 days compared to 2 days of supplementation each month. (Herzog 1995). In a study of 294 women with intractable partial seizures, only those with a C1, ie perimenstrual, average daily seizure frequency N 3, demonstrated a significant response with 38% showing decreased seizure frequency using 200 mg oral lozenges bid in the second half of the cycle, compared to 11% placebo. Those women whose seizure clusters were associated with estrogen surge or midluteal phase patterns, or who had no pattern to their seizures, failed to show improvement with natural progesterone supplementation. Synthetic progesterone, devoid of reproductive effects, would be required for low progesterone states such as the midluteal phase of the cycle. (Herzog et al., 2012) Suppression of estrogen requires alternative approaches, such as depomedroxyprogesterone or GnRH analog. Less is known about the efficacy of progesterone in other types of epilepsy, although a decline by 54.7% in primary and 59% in secondary generalized seizures was noted in a group of 36 women with seizures throughout the second half of their menstrual cycles who were found to have low serum levels of progesterone on days 22, 27 and 28 of the cycle. The one woman with myoclonic seizures had a 46% decline in seizure frequency (Motta et al., 2013). A synthetic preparation, norethisterone, was not found to help 9 patients with catamenial epilepsy (Dana-Haeri et al., 1984) while another synthetic gonadotropic hormone did help one patient with absence and perimenstrual generalized seizures. Because of water and electrolyte imbalances that play a role in lowering the seizure threshold of some patients during the menstrual cycle, the diuretic acetazolamide is also helpful in a few patients (Harden and Pennel, 2013). Using extra doses of the patient's regular antiepileptic medication may be helpful, but can lead to toxicity and suffers from the same unpredictability of menstrual cycles timing and intermittent ovulatory failure, so that combination with hormonal treatment (if contraception is desired) would be helpful. Intermittent use of benzodiazepines has similar concerns with toxicity or development of tolerance, although clobazam was successful in one study (Feely et al., 1982). Hormonal manipulation in men is more difficult, but one logical approach is to move the breakdown of testosterone in the direction away from production of estradiol by blocking aromatase. Aromatase inhibitors, such as finasteride, have been used to treat prostate hypertrophy, and some success was reported in the treatment of men with complex partial epilepsy (Herzog et al., 1998), as well as some with some other aromatase inhibitors (Harden and MacLusky, 2005). However, when finasteride was used for treatment of male-pattern baldness in women, seizure frequency increased (Herzog and Frye, 2003). Conclusion An understanding of the interplay between reproductive hormones, seizures, and epilepsy syndromes will allow better therapies, targeted at individual situations as well as prevention of ongoing deleterious effects on the epilepsy patient's hormonal status throughout their lifespan. Newer ways to assess local hormonal milieus will play a significant role in improvement of quality of life in epilepsy patients. Conflicts of Interest Dr. Koppel has no conflicts of interest. Dr. Harden has no conflicts of interest. References Akaboshi, S., Takeshita, K., 2000. A case of atypical absence seizures induced by leuprolide acetate. Pediatr. Neurol. 23, 266–268. Alam, M.N., Ahmad, A., Al-Abbasi, F.A., Ahmad, A., 2013. Female ovarian steroids in epilepsy: a cause or remedy. Pharmacol. Rep. 65, 802–812.
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