Reduced serum level of THDOC, an anticonvulsant steroid, in women with perimenstrual catamenial epilepsy

Abstract

SUMMARYPurpose: Seizure exacerbation in catamenial epilepsy (CE) is associated with the decrease in progesterone secretion and increase in estradiol secretion during the premenstrual period. Moreover, experimental evidence suggests that tetrahydrodeoxycorticosterone (THDOC), a positive modulator of the type A receptor for γ -aminobutyric acid (GABA), and dehydroepiandrosterone sulfate (DHEAS), a negative modulator of this receptor, might play a crucial role in modulating seizure frequency during the menstrual cycle. Following these studies it seems of interest to investigate possible variations, among other hormonal parameters, of THDOC and DHEAS in CE patients. Methods: The serum concentrations of progesterone (P4), pregnenolone, allopregnanolone (AP), THDOC, DHEAS, cortisol, and DHEAS/cortisol ratio were measured throughout the menstrual cycle at the 7th, 11th, 15th, 19th, 23rd, and 27th day from the onset of spontaneous menstrual blood loss in young premenopausal women with CE (n = 17) and age-matched controls (n = 13). Results: At each time of the study, the serum concentration of THDOC and the DHEAS/cortisol ratio were lower (p < 0.05) in women with CE than in control women. The concentrations of P4, pregnenolone, and AP did not differ between the two groups of subjects. Conclusions: The reduced serum concentration of THDOC and the reduced DHEAS/cortisol ratio detected throughout the menstrual cycle in women with CE might play a role in CE. Moreover, the peculiar pattern of CE seizure exacerbation might suggest that these neuroendocrine variations are worth investigating in other epileptic syndromes, particularly in those characterized by relevant and uncontrolled variations in seizure frequency.

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

“…During the menstrual cycle, circulating progesterone levels are low in the follicular phase, but rise in the midluteal phase for approximately 10 to 11 days before declining in the late luteal phase. Circulating AP levels parallel those of its parent progesterone (Tuveri et al, 2008). Although the dynamics of brain AP during the menstrual cycle have not been studied, it is likely that local synthesis of GABA A receptor-modulating neurosteroids occur in regions relevant to epilepsy such as the hippocampus and amygdala (Reddy, 2011).…”

“…Alterations in ovarian hormones and modification of GABAergic inhibition are an intensely investigated hypothesis guiding research into pathophysiological mechanisms underlying catamenial epilepsy (Scharfman and MacLusky, 2006;Tuveri et al, 2008;Reddy, 2009). The main concern is the lack of a suitable mouse model to investigate the pathophysiological mechanisms of catamenial seizure exacerbations.…”

“…Neurosteroids poten-tiate both synaptic and extrasynaptic GABA A receptors and thereby play a significant role in the pathophysiology of epilepsy (Reddy, 2011). Ovarian cycle-linked fluctuations in progesterone and neurosteroids have been proposed to affect seizure susceptibility Maguire et al, 2005;Tuveri et al, 2008). Seizures decrease in the midluteal phase when serum progesterone levels are high and increase premenstrually when progesterone levels fall, causing the perimenstrual-type catamenial epilepsy.…”

Estrous Cycle Regulation of Extrasynaptic δ-Containing GABAA Receptor-Mediated Tonic Inhibition and Limbic Epileptogenesis

“…We employed 300 nM AP to uncover the d-subunit-specific effects of neurosteroids on tonic conductance because d-containing GABA A Rs display greater sensitivity to neurosteroids at physiological or supraphysiological levels. Although the exact physiological levels of AP in the extracellular space within the hippocampus are unknown, the levels may range from 10 to 120 nM, depending on the physiological or other conditions such as estrous cycle or pregnancy (Murri and Galli, 1997;Bernardi et al, 1998a,b;Concas et al, 1998;Genazzani et al, 1998;Tuveri et al, 2008;Reddy, 2009). Even at low or physiological levels (30 nM), AP can elicit similar greater response in diestrus than in estrus per the standard linear concentration-response relationship (fractional response of maximal peak current).…”

“…These neurosteroids are increased in parallel to their precursor progesterone during the menstrual cycle (Tuveri et al, 2008). Progesterone and neurosteroids have anxiolytic, anticonvulsant, and neuroprotective properties (Reddy, 2004;Reddy et al, 2005) and have been shown to play a significant role in epilepsy, anxiety, and depression (Smith et al, 1998b;Reddy, 2003;van Broekhoven and Verkes, 2003;Reddy and Jian, 2010).…”