Circulating Levels of Allopregnanolone, an Anticonvulsant Metabolite of Progesterone, in Women with Partial Epilepsy in the Postcritical Phase

Abstract

Summary:Purpose: Several lines of evidence indicate that there exists a relation between ovarian hormones and epilepsy. Estrogens decrease seizure threshold and increase brain excitability, whereas progesterone has an inhibitory effect and reduces epileptiform activity. Recently considerable interest has turned to neuroactive steroids, a group of progesterone metabolites, as endogenous modulators of excitability of the central nervous system (CNS). Their ability to alter neuronal firing rapidly occurs through interaction with ␥-aminobutyric acid (GABA) A receptor complex. In a previous experience, serum allopregnanolone (3␣-OH-5␣-pregnan-20-one) levels were measured in 15 women with partial epilepsy in the intercritical phase, and no significant differences were found between patients and control subjects. Methods:To find out if there are changes in serum allopregnanolone levels after epileptic seizure, blood samples were drawn immediately, 15 min, and 6 h after a seizure in seven fertile females with partial epilepsy.Results: The most interesting finding is that allopregnanolone increases in serum during the first 15 min after partial seizures (p < 0.05) and decreases after 6 h.Conclusions: These data are consistent with a role for allopregnanolone in the control of neuronal excitability and seizures. Key Words: Neurosteroids-AllopregnanoloneEpilepsy-Women-Postictal.The ability of ovarian sex steroid hormones, estrogens and progesterone, to influence seizure threshold is well documented. Estrogens increase brain excitability and appear to activate interictal epileptiform activity (1,2), whereas progesterone has an inhibitory effect and reduces epileptiform activity (3,4). Even though these properties are well defined in experimental models and to some extent in humans also, the clinical relation between sex hormones and epilepsy has not been fully explained. Moreover, the commonly observed rhythmic variation in seizure frequency related to the menstrual cycle has yet to be completely understood. Although some studies have not observed the existence of a catamenial epilepsy (5), most of them support it, reporting nevertheless different percentages of catamenial exacerbation of seizures in women with epilepsy. Tauboll et al. (6) reported catamenial exacerbation in 78%, and Rosciszewska (7) in 67% of women with epilepsy. In contrast, Duncan et al. (8) and Dickerson (9) identified catamenial exacerbation in only 12.5 and 10%, respectively. Differences in the definition of catamenial epilepsy, variations in cycle intervals, and interindividual variability are responsible for these different data. Concentrations of plasma estradiol (E 2 ) and progesterone measured throughout the ovarian cycle in women with catamenial epilepsy has made it possible to relate the exacerbation in seizure frequency to an increase in the E 2 /progesterone ratio, with absolute or relative hyperestrogenism (3,10).Recently Herzog et al. (11) proposed three hormonally based patterns of catamenial epilepsy in which fluctuations in the absolute...

Decreased allopregnanolone levels in cerebrospinal fluid obtained during status epilepticus

“…The few available studies on peripheral AP in epileptic patients suggest the presence of reduced interictal levels 15 and biphasic changes following a seizure. 6 However, almost all of our patients had no epilepsy before developing SE.…”

“…Indeed, the role of AP has been investigated both in animal models, and humans and inhibition of 5a-reductase by finasteride consistently resulted in increased epileptic activity. 2,4,6,15 No information is instead available for 5breductase, which synthesizes PREG. Thus, it is possible that a reduced activity of 5a-reductase in SE could be responsible for lower AP availability in CSF.…”

“…5 Despite this evidence, few data are currently available on the possible role of AP and PS in human epileptic disorders. 6 One of the reasons for this still incomplete knowledge is the difficulty in quantifying with high specificity the neuroactive steroids by currently available methods. 7 To address this question, Rustichelli et al 8 recently set a method based on the removal of interfering phospholipids from samples; PS was clearly detected and measured using this method.…”

Sex and hormonal influences on seizures and epilepsy

“…Finally, seizures also affect levels of allogregnanolone, the seizure-limiting metabolite of progesterone. Allopregnanolone levels were significantly elevated immediately following a seizure and returned back to normal within six hours postictally (Galli et al, 2001). …”

The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABAA Receptors

“…Androstanediol is also present in abundant amounts in females. Serum levels of androstanediol in men and women are 3 to 5 nM, which is in the same range as the concentrations of allopregnanolone in women in the luteal phase of the menstrual cycle (Galli et al, 2001). Therefore, it is conceivable that sex differences in the molecular targets or action of androstanediol could be involved in its gender-specific actions.…”