Progesterone and progesterone metabolites are important modulators of central nervous system function through their interactions with the γ-aminobutyric acid (GABA)A receptor. GABA, neurosteroids, and other modulators of GABAA, such as benzodiazepines, barbiturates, and alcohol, typically inhibit neuronal excitability. The resulting anxiolytic, anticonvulsant, sedative, and anesthetic effects are involved in mood, response to stress, and cognition.
The impact of neurosteroids has been demonstrated in women with premenstrual dysphoric disorder: onset of negative mood symptoms has been correlated with peak progesterone levels, and symptoms intensified with progesterone withdrawal in the late luteal phase of the menstrual cycle. These symptoms were not present during anovulatory cycles without the corpus luteum, the primary source of progesterone and metabolites.
The focus of this article is the paradox of why high levels of progesterone and neurosteroids, which typically are associated with anxiolytic activity, instead induce irritability, anxiety, and mood fluctuations in women with premenstrual dysphoric disorder.