The etiology of premenstrual dysphoric disorder: 5 interwoven pieces
A better understanding of the causes of PMDD can lead to improved diagnosis and treatment
AUDIO: Listen to Dr. Raffi discuss treatment of menstrual–related mood and anxiety disorders.
Putting together the 5 pieces of the puzzle
Because PMDD is heritable, it must have an underlying neurobiologic pathophysiology. Brain imaging studies show differences in structure and function in women with PMDD across the menstrual cycle. Conversion of progesterone to ALLO and the GABAergic influence of this metabolite is a topic of interest in current research. Similarly, the role of estrogen and its connection to serotonin and other neurotransmitters such as BDNF have been implicated.
The link between a history of stress, trauma, and PMDD raises the question of biologic resiliency and illness in these patients, as it connects to the HPA and HPG axis and production of inflammatory stress hormones and steroid hormones and their metabolites. PMDD can be conceptualized as variable sensitivity to hormonal response to stress,58 thus contextualizing biochemical and psychological resiliency.
Further research is needed to clarify the possibility of a shared pathophysiology between endocrine-related mood disorders such as postpartum depression (PPD) and PMDD because current research is controversial.59,60 In PPD, women who are exposed to high levels of progesterone and estrogen during pregnancy (just like in the mid-luteal phase) have a sudden drop in these hormones postpartum.
The ‘withdrawal theory.’ The affective symptoms of PMDD resolve almost instantaneously after the start of menstruation. Perhaps this type of immediate relief is akin to substance use disorders and symptoms of withdrawal. It could be that reinstatement of a certain amount of gonadal steroids in the follicular phase of the cycle diminishes a withdrawal-like response to these steroids.
Currently, the main leading theory is that PMDD is a result of “an abnormal response to normal hormonal changes.”61 A new study also has shown that the change in estradiol/progesterone levels (vs the steady state) was associated with PMDD symptoms.62 Thinking of PMDD as a disorder of withdrawal offers an alternative (yet complementary) perspective to the current theory: PMDD may be caused by the absence or diminishing of the above-named hormones and their metabolites in the late luteal phase (in the context of developed “tolerance” during the early- to mid-luteal phase).
Considering the interplay between neurotransmitters and neurosteroids, both a “serotonin withdrawal theory” (caused by a drop in steroid hormones) and a “GABAergic withdrawal theory” (due to the decline in progesterone) could be proposed. This theory would be supported by the fact that SSRIs seem to mitigate symptoms of PMDD as well as the genetic association between PMDD and ESR1. It is more than likely that the “withdrawal” is caused by the interactions between estrogen-serotonin, progesterone-ALLO, and GABA receptors, and the complementary fashion in which progesterone and estrogen influence each other.
