WTF PMDD?
Premenstrual Dysphoric Disorder (PMDD) is characterized by severe symptoms related to sensitivity to hormonal fluctuations during the luteal phase of the menstrual cycle. It is far beyond the symptoms of PMS with many women who experience it saying “I don’t even know who I am in those weeks” followed by “As soon as I get my period, I am back to my normal self!” It affects approximately 1.2 to 6.4% of women.
The “why” behind PMDD has only been recently studied and there are several etiologies that have been prorposed:
Hypothalamic-Pituitary-Gonadal (HPG) Axis: An abnormal response to normal hormonal fluctuations of the HPG axis is considered a key mechanism.
Allopregnanolone (ALLO) and GABA-A Receptor Dysfunction: Allopregnanolone is a neuro-active steroid produced from progesterone, originating in the ovaries, adrenals, and the brain itself. It acts as a modulator of GABA-A receptors, similar to alcohol and benzodiazepines. Women with PMS/PMDD have been found to have lower levels of progesterone and ALLO compared to controls. A decreased or paradoxical sensitivity of the GABA-A receptor to allopregnanolone, as well as rapid withdrawal of ALLO, may trigger PMDD symptoms. Epigenetic changes to the receptor may also play a role.
Progesterone: While progesterone deficiency was historically hypothesized as a cause, this has not been reliably confirmed. Some studies show high, and others show low progesterone levels in the luteal phase. Notably, adding progesterone back during ovarian suppression in women with PMDD actually worsens symptoms, suggesting the relationship is complex.
Serotonin System Alterations: Disruptions in serotonergic function are considered a contributing factor.
Hypothalamic-Pituitary-Adrenal (HPA) Axis: Alterations in the HPA axis response are implicated, particularly in relation to stress and trauma.
Immune Function: Altered immune function has been identified as a potential contributing mechanism.
Calcium Homeostasis: Disruptions in calcium regulation may play a role.
Circadian Rhythms: Altered circadian rhythms have been associated with PMDD.
Genetic Factors: Polymorphisms in the gene for ESR1 (estrogen receptor 1) have been identified as a potential genetic contributor.
Brain Region Responses: Abnormal responses in brain regions involved in emotion processing and regulation during the luteal phase have been observed.
Inflammation: Inflammatory pathways are also considered part of the pathophysiology.
Trauma and Early Life Stress as a Pathophysiological Contributor:
Early life trauma is strongly associated with PMDD. It is theorized that early life trauma leads to persistent alterations in HPA axis activity, neurophysiology, neuroanatomy, and inflammatory markers. Studies have found that emotional abuse and/or chronic trauma during childhood may be most strongly associated with the development of PMDD.
