Progesterone, 5a-dihydropogesterone and allopregnanolone’s effects on seizures: A review of animal and clinical studies
Introduction from Dr Markus Reuber, editor-in-chief of Seizure
In women, a link between epilepsy and menstruation has been described since the compilation of the hippocratic writings in the 4th century BC. These early ideas are likely to have been inspired by the human urge to explain unusual experiences (however hard this may be) – rather than by a clear understanding of the relationship. However, the observation that there is a relationship between epileptic seizures and the reproductive cycle has since been confirmed in multiple studies in animals and humans. Menstrual seizure frequency fluctuation is not equally marked in all women with epilepsy, but across women with epilepsy, seizures are more likely during phases of the menstrual cycle when progesterone levels are relatively low and oestrogen levels relatively high (1). When seizures are particularly closely linked to the menstrual cycle epilepsy is characterised as catamenial (2).
Of course, the story of sex hormones is not limited to oestrogen or progesterone. Both are broken down in complex ways in different compartments of the body and have numerous metabolites with a wide range of effects, not only on gene transcription but also on GABA receptor functioning and inflammatory pathways.
In view of its particular interest for the suppression of seizures, my editor’s choice article focuses on the progesterone family. In their fine review of a complex topic, Yinhao Violet Wu and W. McIntyre Burnham summarise the progesterone story that emerges from studies in animals and humans to date, culminating in the clinical potential of a number of progesterone derivatives including Ganaloxone, a synthetic analog of the endogenous neurosteroid allopregnanolone and a positive allosteric modulator of GABA-A receptors (3).
Previous therapeutic interventions focusing on progesterone have been limited by their relatively modest therapeutic effects and considerable potential to cause side effects. Time will tell whether the better understanding of these molecules and their effects on the body summarised in Wu’s and Burnham’s review will provide patients and clinicians with drugs using a novel antiseizure (or even antiepileptic) mode of action suitable for a large group of people with epilepsy.
(1) Verrotti A, D’Egidio C, Agostinelli S, Verrotti C, Pavone P. Diagnosis and management of catamenial seizures: a review. Int J Womens Health 2012;4:535-41.
(2) Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997;38:1082–8.
(3) Wu YV and Burnham WM. Progesterone, 5a-Dihydropogesterone and Allopregnanolone’s Effects on Seizures: A Review of Animal and Clinical Studies. Seizure 2018