Catamenial epilepsy

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Estradiol levels during the menstrual cycle Estradiol during menstrual cycle.png
Estradiol levels during the menstrual cycle

Catamenial epilepsy is a form of epilepsy in women where seizures are exacerbated during certain phases of the menstrual cycle. In rare cases, seizures occur only during certain parts of the cycle; in most cases, seizures occur more frequently (but not exclusively) during certain parts of the cycle. Catamenial epilepsy is underlain by hormonal fluctuations of the menstrual cycle where estrogens promote seizures and progesterone counteracts seizure activity. [2]

Contents

Since at least ancient Greek times, there has been documented studies of women with epilepsy and its correlation to the menstrual cycle. [3] So catamenial epilepsy is a unique group of seizure disorders and these seizures are affected mainly by fluctuations in the menstrual cycle of estrogen and progesterone and to clarify the diagnosis of catamenial epilepsy charts of seizure activity are drawn during the menstrul cycle and thus three patterns of catamenial epilepsy are identified. [4]

Etymology

"Catamenia" was a scientific word for the menstrual period, formed as a neologism in the 18th century, from the Greek katamēnios = monthly (from kata = "by" + mēn = "month"). [5]

Pathophysiology

Conversion of testosterone to estradiol Reaction-Testosterone-Estradiol.png
Conversion of testosterone to estradiol
Aromatase converts androstenedione to estrone Reaction-Androstendione-Estrone.png
Aromatase converts androstenedione to estrone
Progesterone Progesterone.svg
Progesterone

Levels of the major gonadal hormones estrogen, progesterone, and testosterone vary during the menstrual cycle, and this can trigger catamenial epilepsy. These hormones are synthesized in various locations in the body, including the ovaries, adrenal gland, liver, subcutaneous fat, and brain. [6] There is considerable research showing that these steroidal hormones are important in the pathophysiology of epilepsy. Broadly defined, estrogen and its many forms are thought to be "proconvulsant", whereas progesterone is thought to be "anticonvulsant" by virtue of its conversion to the neurosteroid allopregnanolone. [7]

Estrogen (estradiol, estrone, estriol)

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.

Progesterone

Progesterone levels during the menstrual cycle Progesterone during menstrual cycle.png
Progesterone levels during the menstrual cycle

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]

Classification

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. [14] In recent years, Herzog's 1997 proposal of a twofold increase has generally been accepted: Perimenstrual (C1), Periovulatory (C2), and Luteal (C3). [15] These three classifications are based upon serum estradiol:progesterone ratio, and a 24- to 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, C1

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, C2

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, C3

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]

Menopause

During menopause, there are drastic changes in the production of gonadal hormones. Most of the reproductive hormones, including the estrogens, progesterone and testosterone, diminish initially (perimenopause), becoming irregular, often showing wide and unpredictable fluctuations. 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 found a marked decreased risk of seizures during menopause if there was a catamenial relationship. [17] 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 effect of estrone specifically on epilepsy. Women with epilepsy who do not follow a catamenial pattern may have an unpredictable increase or decrease in seizure activity in perimenopause and menopause, but women with catamenial epilepsy typically follow a more predictable pattern. [18]

Hormone replacement therapy

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]

Treatment

Several treatment methods have been determined exclusively for women with catamenial epilepsy. A great majority of these therapies include progestogens (naturally occurring) or progestins (synthetic progestogen). 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 side effects frequently seen in progesterone therapy usage, including vaginal dryness, dyspareunia, osteoporosis, and cardiovascular disease. [10]

A 2019 Cochrane review found low certainty evidence of no treatment difference between norethisterone and placebo and moderate to low certainty of the no difference with progesterone versus placebo. The review did note however that important clinical effects could not be ruled out due to the small and under powered nature of the studies reviewed. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Estrogen</span> Primary female sex hormone

Estrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.

<span class="mw-page-title-main">Menstrual cycle</span> Natural changes in the human female reproductive system

The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eggs and the cyclic release of estrogen and progesterone. The uterine cycle governs the preparation and maintenance of the lining of the uterus (womb) to receive an embryo. These cycles are concurrent and coordinated, normally last between 21 and 35 days, with a median length of 28 days, and continue for about 30–45 years.

<span class="mw-page-title-main">Estradiol</span> Chemical compound

Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible for the development of female secondary sexual characteristics such as the breasts, widening of the hips and a female pattern of fat distribution. It is also important in the development and maintenance of female reproductive tissues such as the mammary glands, uterus and vagina during puberty, adulthood and pregnancy. It also has important effects in many other tissues including bone, fat, skin, liver, and the brain.

<span class="mw-page-title-main">Follicle-stimulating hormone</span> Gonadotropin that regulates the development of reproductive processes

Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.

<span class="mw-page-title-main">Estrone</span> Chemical compound

Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized from cholesterol and secreted mainly from the gonads, though they can also be formed from adrenal androgens in adipose tissue. Relative to estradiol, both estrone and estriol have far weaker activity as estrogens. Estrone can be converted into estradiol, and serves mainly as a precursor or metabolic intermediate of estradiol. It is both a precursor and metabolite of estradiol.

<span class="mw-page-title-main">Estriol</span> Chemical compound

Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost undetectable. However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far, although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion. Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.

Bioidentical hormone replacement therapy (BHRT), also known as bioidentical hormone therapy (BHT) or natural hormone therapy, is the use of hormones that are identical on a molecular level with endogenous hormones in hormone replacement therapy. It may also be combined with blood and saliva testing of hormone levels, and the use of pharmacy compounding to obtain hormones in an effort to reach a targeted level of hormones in the body. A number of claims by some proponents of BHT have not been confirmed through scientific testing. Specific hormones used in BHT include estrone, estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), and estriol.

<span class="mw-page-title-main">Dydrogesterone</span> Chemical compound

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<span class="mw-page-title-main">Estriol succinate</span> Chemical compound

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<span class="mw-page-title-main">Nomegestrol acetate</span> Chemical compound

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<span class="mw-page-title-main">Conjugated estrogens</span> Estrogen medication

Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations. They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate. CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.

<span class="mw-page-title-main">Estradiol sulfate</span> Chemical compound

Estradiol sulfate (E2S), or 17β-estradiol 3-sulfate, is a natural, endogenous steroid and an estrogen ester. E2S itself is biologically inactive, but it can be converted by steroid sulfatase into estradiol, which is a potent estrogen. Simultaneously, estrogen sulfotransferases convert estradiol to E2S, resulting in an equilibrium between the two steroids in various tissues. Estrone and E2S are the two immediate metabolic sources of estradiol. E2S can also be metabolized into estrone sulfate (E1S), which in turn can be converted into estrone and estradiol. Circulating concentrations of E2S are much lower than those of E1S. High concentrations of E2S are present in breast tissue, and E2S has been implicated in the biology of breast cancer via serving as an active reservoir of estradiol.

<span class="mw-page-title-main">Estradiol (medication)</span> Steroidal hormone medication

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<span class="mw-page-title-main">Estriol (medication)</span> Chemical compound

Estriol (E3), sold under the brand name Ovestin among others, is an estrogen medication and naturally occurring steroid hormone which is used in menopausal hormone therapy. It is also used in veterinary medicine as Incurin to treat urinary incontinence due to estrogen deficiency in dogs. The medication is taken by mouth in the form of tablets, as a cream that is applied to the skin, as a cream or pessary that is applied in the vagina, and by injection into muscle.

<span class="mw-page-title-main">Estrone (medication)</span> Estrogen medication

Estrone (E1), sold under the brand names Estragyn, Kestrin, and Theelin among many others, is an estrogen medication and naturally occurring steroid hormone which has been used in menopausal hormone therapy and for other indications. It has been provided as an aqueous suspension or oil solution given by injection into muscle and as a vaginal cream applied inside of the vagina. It can also be taken by mouth as estradiol/estrone/estriol and in the form of prodrugs like estropipate and conjugated estrogens.

<span class="mw-page-title-main">Estetrol (medication)</span> Estrogen medication

Estetrol (E4) is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. These investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer. It is taken by mouth.

The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

References

  1. 1 2 Häggström, Mikael (2014). "Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle". WikiJournal of Medicine. 1 (1). doi: 10.15347/wjm/2014.001 . ISSN   2002-4436.
  2. ↑ "Catamenial Epilepsy". Epilepsy Foundation. Retrieved 2019-08-30.
  3. ↑ Temkin, Owsei (March 1, 1994) [First published 1945, Revised 1971]. The Falling Sickness (2nd Revised ed.). Baltimore: Johns Hopkins University Press. ISBN   978-0-8018-4849-0.
  4. ↑ Frank S, Tyson NA. A Clinical Approach to Catamenial Epilepsy: A Review. Perm J. 2020 Dec;24:1-3. doi: 10.7812/TPP/19.145. PMID 33482944; PMCID: PMC7849269.
  5. ↑ Mirriam-Webster Dictionary online, "Catamenia".
  6. 1 2 Scharfman HE, MacLusky NJ (September 2006). "The Influence of Gonadal Hormones on Neuronal Excitability, Seizures, and Epilepsy in the Female". Epilepsia. 47 (9): 1423–40. doi:10.1111/j.1528-1167.2006.00672.x. PMC   1924802 . PMID   16981857.
  7. ↑ Reddy DS, Rogawski MA. Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy (2012). In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US). Available from https://www.ncbi.nlm.nih.gov/books/NBK98218/
  8. ↑ Wong M, Moss RL (1992). "Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons". J Neurosci. 12 (8): 3217–25. doi:10.1523/JNEUROSCI.12-08-03217.1992. PMC   6575649 . PMID   1353794.
  9. ↑ Woolley CS, McEwen BS (1994). "Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism". J Neurosci. 14 (12): 7680–7. doi:10.1523/JNEUROSCI.14-12-07680.1994. PMC   6576901 . PMID   7996203.
  10. 1 2 Herzog AG (2008). "Catamenial epilepsy: Definition, prevalence, pathophysiology and treatment". Seizure. 17 (2): 151–9. doi: 10.1016/j.seizure.2007.11.014 . PMID   18164632.
  11. ↑ Ahmad A, Vohora D (2014). "Proconvulsant effects of estriol, the third estrogen, in the mouse PTZ-kindling model". Neurol. Sci. 35 (10): 1561–6. doi:10.1007/s10072-014-1795-4. PMID   24748480. S2CID   11260353.
  12. ↑ Hsueh AJ, Peck EJ, Clark JH (1976). "Control of uterine estrogen receptor levels by progesterone". Endocrinology. 98 (2): 438–44. doi: 10.1210/endo-98-2-438 . PMID   174899.
  13. ↑ Frye CA (1995). "The neurosteroid 3 alpha, 5 apha-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy". Seizure. 696 (1–2): 113–20. doi: 10.1016/0006-8993(95)00793-p . PMID   8574658. S2CID   54356210.
  14. ↑ Duncan S, Read CL, Brodie MJ (1993). "How common is catamenial epilepsy?". Epilepsia. 34 (5): 827–31. doi:10.1111/j.1528-1157.1993.tb02097.x. PMID   8404732. S2CID   1526704.
  15. ↑ Herzog AG, Klein P (1997). "Three patterns of catamenial epilepsy". Epilepsia. 38 (10): 1082–8. doi: 10.1111/j.1528-1157.1997.tb01197.x . PMID   9579954.
  16. 1 2 El-Khayat HA, Soliman NA, Tomoum HY, Omran MA, El-Wakad AS, Shatla RH (2008). "Reproductive hormonal changes and catamenial pattern in adolescent females with epilepsy". Epilepsia. 49 (9): 1619–26. doi: 10.1111/j.1528-1167.2008.01622.x . PMID   18435756.
  17. ↑ Rościszewska D (1978). "Menopause in women and its effects on epilepsy". Neurol Neurochir Pol. 12 (3): 315–19. PMID   355909.
  18. ↑ Røste LS, Taubøll E, Svalheim S, Gjerstad L (2008). "Does menopause affect the epilepsy?". Epilepsia. 17 (2): 172–5. doi: 10.1016/j.seizure.2007.11.019 . PMID   18164217.
  19. ↑ Harden CL (2008). "Hormone Replacement Therapy: Will it affect seizure control and AED levels?". Seizure. 17 (2): 176–80. doi:10.1016/j.seizure.2007.11.026. PMC   2288738 . PMID   18187348.
  20. ↑ Maguire, Melissa J.; Nevitt, Sarah J. (2019-10-14). "Treatments for seizures in catamenial (menstrual-related) epilepsy". The Cochrane Database of Systematic Reviews. 10 (10): CD013225. doi:10.1002/14651858.CD013225.pub2. ISSN   1469-493X. PMC   6953347 . PMID   31608992.
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