Estradiol exerts direct excitatory effects at the neuronal membrane, where it augments N-methyl-D-aspartate (NMDA)-mediated glutamate receptor activity.^68,76 This enhances the resting discharge rates of neurons in a number of brain areas, including the hippocampus,^39,68,76 where estradiol increases excitability of the hippocampal CA1 pyramidal neurons and induces repetitive firing in response to Schaffer collateral stimulation.⁷⁶

Estradiol potentiates neuronal excitability by regulating neuronal plasticity. It increases the density of spines and excitatory, NMDA receptor-containing synapses on the apical dendrites of hippocampal CA1 pyramidal neurons via a posttranscriptional mechanism.^78,79 The dendritic spine density on these neurons correlates positively with the levels of circulating estradiol during the estrous cycle of the rat and is decreased by oophorectomy.⁷⁸ Estradiol may thus further increase excitatory input to the CA1 neurons.

Estradiol may affect neuronal excitability by cytosolic neuronal estrogen receptor-mediated, genomically dependent mechanisms. Receptors are particularly abundant in the temporolimbic system, especially in the medial and cortical amygdaloid nuclei, and occur in much fewer numbers in the hippocampal pyramidal cell layer and the subiculum.^61,66 Estrogen receptor-containing neurons colocalize with other neurotransmitters, including γ-aminobutyric acid (GABA).^12,56 By regulating the expression of genes affecting the activity, release, and postsynaptic action of different neurotransmitters and neuromodulators, estrogens may act to increase the excitability of neurons, which concentrate estradiol. For instance, estradiol lessens inhibitory neurotransmission by decreasing GABA synthesis in the corticomedial amygdala by reducing the activity of glutamic acid decarboxylase,⁷⁵ and enhances brain epileptogenic muscarinic neurotransmission by increasing choline acetyl transferase and acetylcholine.⁵⁰

In adult experimental animals, the thresholds of limbic seizures in female rats fluctuate during the estrus cycle inversely to estradiol levels.⁷² Physiologic doses of estradiol activate spike discharges^49,53 and lower the thresholds of seizures induced by electroshock, kindling, pentylenetetrazol, kainic acid, ethyl chloride, and other agents and procedures.^{36,49,59,70,77} In fact, topical brain application, as well as intravenous systemic administration, of estradiol in rabbits produces a significant increase in spontaneous electrically recorded paroxysmal spike discharges.^49,53 The increase is seen within a few seconds of application to suggest a direct membrane rather than a genomic effect and is more dramatic in animals with pre-existent cortical lesions.⁵³ The role of estrogen, however, may be more complex since there is also evidence in some models that estradiol can raise seizure thresholds in the hippocampal region and provide neuroprotection against seizure-induced injury.⁷³

Clinically, Logothetis et al.⁴⁸ showed that intravenously administered conjugated estrogen clearly activated epileptiform in 11 of 16 women and was associated with clinical seizures in four.

Progesterone and particularly some of its neuroactive metabolites, most notably allopregnanolone, exert direct membrane-mediated inhibitory effects by potentiating GABA_A-mediated chloride conductance.^16,57,60 It also potentiates the action of the powerful endogenous inhibitory substance adenosine.⁶² Progesterone itself also substantially diminishes nicotinic acetylcholine receptor-mediated conductance, which may be relevant to autosomal dominant nocturnal frontal lobe epilepsy.⁶

Progesterone may act via genomic mechanisms to influence the enzymatic activity controlling the synthesis and release of various neurotransmitters and neuromodulators produced by progesterone receptor-containing neurons.⁵⁶ Progesterone binds specific cytosolic receptors not only to produce its own characteristic effects, but also to lower estrogen receptor numbers and thereby antagonize estrogen actions.³⁷

Chronic progesterone decreases the number of hippocampal CA1 dendritic spines and excitatory synapses faster than the simple withdrawal of estrogen, counteracting the stimulatory effects of estradiol.⁷⁸ Progesterone and allopregnanolone have also been shown to have neuroprotective effects on hippocampal neurons in kainic acid-induced seizure models.¹⁴

In most adult female animal models, progesterone depresses neuronal firing⁶⁷ and lessens spontaneous and induced epileptiform discharges.^46,59,70 It retards kindling and decreases seizure occurrence.

Backstrom et al.³ found that intravenous infusion of progesterone, sufficient to produce luteal phase serum levels, was
associated with a significant decrease in interictal spike frequency in four of seven women with partial epilepsy.

Most of the membrane effect of progesterone is due to the action of its 3α-hydroxylated (i.e., A-ring-reduced) metabolite, 3α-hydroxy-5α-pregnane-20-one or allopregnanolone (AP).^16,60 AP and the 3,5-hydroxylated natural metabolite of the mineralocorticoid deoxycorticosterone, allotetrahydro-deoxycorticosterone (allo-THDOC), are among the most potent of a number of endogenous neuroactive steroids with a direct membrane effect on neuronal excitability.^16,52,60 AP, but not allo-THDOC, is devoid of hormonal effects and may, together with other related neuroactive steroids, be thought of as an endogenous regulator of brain excitability with anxiolytic, sedative-hypnotic, and anticonvulsant properties.^16,52,60 AP and allo-THDOC hyperpolarize hippocampal and other neurons by potentiating GABA_A-mediated inhibition.^16,60 At physiologic (nanogram) concentrations, they act as positive allosteric modulators of the GABA_A receptor, interacting with an extrasynaptic steroid-specific site near the synaptic receptor to facilitate chloride channel opening and prolong the inhibitory action of GABA on neurons.^{16,51,52,60,80} At higher pharmacologic (micromolar) concentrations, AP also has a direct effect at the synaptic GABA_A receptor to induce chloride currents.^16,60 AP is one of the most potent ligands of GABA_A receptors in the central nervous system, with affinities similar to those of the potent benzodiazepine flunitrazepam, and approximately a thousand times higher than pentobarbital.^16,60 The parent steroid, progesterone, enhances GABA-induced chloride currents only weakly and only in high concentrations.^60,80 Plasma and brain levels of AP parallel those of progesterone in rats. In women, plasma levels of AP correlate with progesterone levels during the menstrual cycle and pregnancy.⁶⁰ However, brain activity of progesterone and AP is not dependent solely on ovarian and adrenal production, as they are both synthesized de novo in the brain.⁹ Their synthesis is region specific and includes the cortex and the hippocampus.⁹ By contrast, allo-THDOC is only synthesized by the adrenal gland and not in the brain.⁶⁰

AP, allo-THDOC, and a number of other endogenous and synthetic pregnane steroids have a potent anticonvulsant effect in bicuculline-, metrazol-, picrotoxin-, pentylenetetrazol-, pilocarpine-, and kainic acid–induced seizures and against status epilepticus, but are ineffective against electroshock and strychnine-induced seizures.^5,16,41,42 The anticonvulsant properties of allopregnanolone resemble those of the benzodiazepine clonazepam.^12,16,42 AP is less potent than clonazepam but may have lower relative toxicity.^41,42 The anticonvulsant effect of AP is greater in female rats in the diestrus-1 part of the ovulatory cycle (equivalent to human midluteal phase when progesterone levels are high) than in estrus (equivalent to ovulation when estrogen levels are high) or in the male.^12,13 Enhanced midluteal efficacy at the GABA_Areceptor may be related to a progesterone-induced enhanced formation of the δ GABA_A receptor subtype. Rapid withdrawal of progesterone in late diestrus makes the GABA_A receptor insensitive to benzodiazepine, but not AP, perhaps as the result of a decrease in the benzodiazepine-sensitive synaptic GABA_A receptors. This effect can be blocked by inhibiting the formation of the α4 subunit of the GABA_A receptor.^51,69

By contrast, some of the sulfated neuroactive steroids have excitatory neuronal effects. They include pregnenolone sulfate and dehydroepiandrosterone sulfate (DHEAS), the naturally occurring sulfated esters of the progesterone precursor pregnenolone, and progesterone metabolite DHEA.⁶⁰ They increase neuronal firing when directly applied to neurons by negatively modulating the GABA_A receptor⁶⁰ and by facilitating glutamate-induced excitation at the NMDA receptor.³⁸ In animal seizure models, pregnenolone sulfate and DHEAS have a proconvulsant effect.³⁵ Of note, serum DHEAS levels are substantially reduced by enzyme-inducing antiepileptic drugs such as phenytoin and carbamazepine.^33,45

The effect of testosterone on experimental seizures appears to be mixed.⁴⁰ Testosterone acts on specific neural receptors to promote aggression, competition, potency, and libido. Aromatization to estradiol, a major testosterone metabolite, potentiates glutamate transmission and seizures.^68,76 Reduction to dihydrotestosterone blocks glutamate, specifically NMDA, transmission.⁶³ Another reduced androgen metabolite, androstanediol, has potent GABAergic, neuroprotective, and antiseizure properties.¹⁵ The net effect of testosterone on neuronal excitability, therefore, may depend on the balance of its conversion to excitatory and inhibitory metabolites, which, in turn, is tissue dependent and varies with the relative local activities of reductase and aromatase enzymes.^68,76 Tissue specificity may be even more complicated. For example, sex- and age-dependent differences in proconvulsant and anticonvulsant actions of sex steroids have been demonstrated between the anterior and posterior regions of the substantia nigra in the rat.⁷⁴