Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy

Bäckström, Torbjörn; Zetterlund, Bo; Blom, S; Romano, Marcello

doi:10.1111/j.1600-0404.1984.tb07807.x

Cited by 217 publications

(87 citation statements)

References 10 publications

(6 reference statements)

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“…The results of the present work confirm the importance of sex steroids in the modulation of central nervous system excitability and seizure threshold, a fact which may have clinical relevance, since increased incidence of seizures has been reported in susceptible women during declining progesterone levels across the menstrual cycle (Backstrom et al 1984;Schachter 1988;Herzog 1995). Progesterone has also been suggested as a helpful therapy in treating seizures (Zimmerman 1986), and testosterone combined with an aromatase inhibitor has been used to improve sexual function and reduce seizures in men with epilepsy (Herzog 1999b).…”

Section: Discussionsupporting

confidence: 86%

Progesterone and Testosterone Modulate the Convulsant Actions of Pentylenetetrazol and Strychnine in Mice

Pesce¹,

Acevedo

Bustamante

et al. 2000

Pharmacology & Toxicology

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The influence of progesterone and testosterone on the incidence of seizures after administration of intraperitoneal pentylenetetrazol and subcutaneous strychnine was evaluated in mice. Pentylenetetrazol and strychnine were administered in doses that induced seizures in 40-50% of control mice in dioestrus (48 and 0.9 mg/kg, respectively). The percentage of seizures induced by pentylenetetrazol and strychnine was significantly lower in female mice in prooestrus/oestrus, when progesterone levels are high, than in dioestrus, when progesterone levels are low. Pretreatment of pentylenetetrazol-challenged mice with progesterone (250 mg/kg) increased the incidence of seizures in prooestrus/oestrus, without affecting seizures in dioestrus. The same pretreatment in strychnine-challenged mice also increased the incidence of seizures in prooestrus-dioestrus, but significantly reduced the incidence of seizures in dioestrus. In addition, progesterone pretreatment significantly increased the percentage of deaths induced by strychnine in prooestrus-oestrus, reducing deaths in dioestrus. Orchidectomized male mice had a significantly higher incidence of seizures after administration of pentylenetetrazol and strychnine than control mice. Administration of 11 daily doses of 250 mg/kg of testosterone to castrated mice significantly reduced the incidence of seizures induced by pentylenetetrazol. These results confirm the modulatory influence of reproductive steroids on the excitability of the central nervous system and the possible clinical importance of progesterone and testosterone in the management of partial epilepsy.Several investigations have shown a relationship between reproductive steroids and central nervous system excitability. The active metabolite of progesterone, allopregnanolone, is a neurosteroid which exhibits hypnotic, anxiolytic and anticonvulsant actions (Bitran et al. 1991(Bitran et al. & 1995Galli et al. 1996;Korneyev & Costa 1996;Wilson & Biscardi 1997). Allopregnanolone exhibits potent inhibitory actions in the central nervous system, acting on the GABA-benzodiazepine-chloride channel macromolecular complex by an allosteric interaction with the GABA A receptor, with potentiation of the chloride channel current (Schumacher & Baulieu 1995;Rupprecht et al. 1996;Brot et al. 1997; Kellog et al. 1998). Neurosteroids are also synthetized within the central and peripheral nervous systems, mainly by glial cells (Schumacher & Baulieu 1995). Testosterone has more inconsistent actions, since it is metabolized to oestradiol, which can exacerbate seizures, and dihydrotestosterone, which inhibits NMDA-type glutamate transmission and may have antiseizure effects (Herzog 1999a). On the other hand, ovarian steroids modify the behavioural response to activation of the benzodiazepine receptor, reducing withdrawal anxiety and hyperactivity in mice (Bitran & Dowd 1996;Reddy & Kulkarni 1997). The number of seizures occurring during the benzodiazepine withdrawal syndrome is significantly less in prooestrus-oestrus, where p...

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Section: Discussionsupporting

confidence: 86%

Progesterone and Testosterone Modulate the Convulsant Actions of Pentylenetetrazol and Strychnine in Mice

Pesce¹,

Acevedo

Bustamante

et al. 2000

Pharmacology & Toxicology

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“…Protection against epileptic seizures was one of the first identified central actions of exogenously administered progesterone (Selye, 1942;Craig, 1966), and it is believed that fluctuations in endogenous progesterone levels can affect seizure susceptibility in women with epilepsy (Bä cktröm et al, 1984;Herzog, 1999;Rogawski and Reddy, 2004). In recent years, numerous studies have confirmed the powerful anticonvulsant activity of progesterone in diverse animal seizure models (Landgren et al, 1978;Holmes and Weber, 1984;Reddy and Kulkarni, 1997;Mohammad et al, 1998;Kokate et al, 1999;Frye and Scalise, 2000).…”

mentioning

confidence: 99%

Anticonvulsant Activity of Progesterone and Neurosteroids in Progesterone Receptor Knockout Mice

Reddy

Castaneda

O’Malley

et al. 2004

J Pharmacol Exp Ther

161

177

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Many of the biological actions of progesterone are mediated through the progesterone receptor (PR), a nuclear transcription factor. Progesterone is well recognized to protect against seizures in animal models. Although this activity has been attributed to the progesterone metabolite allopregnanolone, a GABA A receptor-modulating neurosteroid with anticonvulsant properties, PRs could also play a role. Here, we used PR knockout (PRKO Ϫ/Ϫ ) mice bearing a targeted deletion of the PR gene that eliminates both isoforms of the PR to investigate the contribution of the PR to the anticonvulsant activity of progesterone. The protective activity of progesterone was examined in female and male homozygous PRKO mice and isogenic wild-type controls in the pentylenetetrazol (PTZ), maximal electroshock, and amygdala-kindling seizure models. In all three models, the anticonvulsant potency of progesterone was undiminished in PRKO mice compared with control mice. On the contrary, there was a substantial increase in the anticonvulsant potency of progesterone in the PTZ and kindling models. The antiseizure activity of progesterone in PRKO mice was reversed by pretreatment with finasteride, a 5␣-reductase inhibitor that blocks the metabolism of progesterone to allopregnanolone. Unlike progesterone, the neurosteroids allopregnanolone and allotetrahydrodeoxycorticosterone exhibited comparable anticonvulsant potency in PRKO and wild-type mice. The basis for the heightened progesterone responsiveness of PRKO mice is not attributable to pharmacokinetic factors, because the plasma allopregnanolone levels achieved after progesterone administration were not greater in the PRKO mice. These studies provide strong evidence that the PR is not required for the antiseizure effects of progesterone, which mainly occurs through its conversion to the neurosteroid allopregnanolone.

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“…Progesterone metabolites such as allopregnanolone, in contrast, are potent barbiturate-like ligands at the GABA-chloride ionophore (1 1). Progesterone reduces neuronal metabolism (12) and discharge rates (13), and suppresses kindling (14), epileptiform discharges (15), and experimental (16) as well as clinical seizures (17).…”

mentioning

confidence: 99%

Three Patterns of Catamenial Epilepsy

1997

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Summary:Purpose: On the basis of the neuroactive properties of estradiol and progesterone and the menstrually related cyclic variations of their serum concentrations, we propose the existence of three hormonally based patterns of seizure exacerbation. Because previous reports both support and refute the concept of catamenial epilepsy, we test the hypothesis by charting seizures and menses and measuring midluteal serum progesterone levels to estimate the frequency of epileptic women with catamenial seizure exacerbation.Methods: One hundred eighty-four women with intractable complex partial seizures (CPS) charted their seizure occurrence and onset of menstruation on a calendar for one cycle during which they had a midluteal blood sample taken for serum progesterone determination on day 22. Levels >5 ng/ml were considered ovulatory. The cycle was divided into four phases with onset of menstruation being day 1: menstrual (M) = -3 to +3, follicular (F) = 4 to 9, ovulatory (0) = 10 to -13, and luteal (L) = -12 to -4. Average daily seizure frequency for each phase was calculated and compared among phases by repeatedmeasures analysis of variance (ANOVA) and the StudentNewman-Keul's test, separately for ovulatory and anovulatory cycles.Results We propose the existence of three hormonally based patterns of seizure exacerbation in epilepsy (1). Seizures do not occur randomly in most men and women with epilepsy (2). They tend to cluster in >50% of cases (2). Seizure clusters in turn may occur with temporal rhythmicity in a significant proportion of men (29%) and women (35%) with epilepsy (3). In women, seizures may cluster in relation to the menstrual cycle; such seizures are commonly termed catamenial epilepsy (4) and may be attributable to (a) the neuroactive properties of steroid hormones and (b) the cyclic variation in serum levels.Estradiol inhibits y-aminobutyric acid (GABA) and potentiates glutamatergic transmission (5). It increases neuronal metabolism and discharge rates (5,6). It pro-

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Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy

Cited by 217 publications

References 10 publications

Progesterone and Testosterone Modulate the Convulsant Actions of Pentylenetetrazol and Strychnine in Mice

Progesterone and Testosterone Modulate the Convulsant Actions of Pentylenetetrazol and Strychnine in Mice

Anticonvulsant Activity of Progesterone and Neurosteroids in Progesterone Receptor Knockout Mice

Three Patterns of Catamenial Epilepsy

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