Neurosteroid replacement therapy for catamenial epilepsy, postpartum depression and neuroendocrine disorders in women

Neurosteroids are involved in the pathophysiology of many neuroendocrine disorders in women. This review describes recent advancements in pharmacology of neurosteroids and emphasizes the benefits of neurosteroid replacement therapy for the management of neuroendocrine disorders such as catamenial epilepsy (CE), postpartum depression (PPD) and premenstrual brain conditions. Neurosteroids are endogenous modulators of neuronal excitability. A variety of neurosteroids are present in the brain including allopregnanolone (AP), allotetrahydro-deoxycorticosterone and androstanediol. Neurosteroids interact with synaptic and extrasynaptic GABA_A receptors in the brain. AP and related neurosteroids, which are positive allosteric modulators of GABA_A receptors, are powerful anticonvulsants, anxiolytic, antistress and neuroprotectant agents. In CE, seizures are most often clustered around a specific menstrual period in women. Neurosteroid withdrawal-linked plasticity in extrasynaptic receptors has been shown to play a key role in catamenial seizures, anxiety and other mood disorders. Based on our extensive research spanning two decades, we have proposed and championed neurosteroid replacement therapy as a rational strategy for treating disorders marked by neurosteroid-deficiency, such as CE and other related ovarian or menstrual disorders. In 2019, AP (renamed as brexanolone) was approved for treating PPD. A variety of synthetic neurosteroids are in clinical trials for epilepsy, depression and other brain disorders. Recent advancements in our understanding of neurosteroids have entered a new era of drug discovery and one that offers a high therapeutic potential for treating complex brain disorders.