COMT and Iron deficiency anemia: Theories include iron deficiency secondary to pregnancy, persistently high levels of estrogen during pregnancy, and the decline of estrogen and melatonin during menopause.86 Regarding the role of estrogen in the etiopathogenesis of RLS, Saltzman et al. hypothesized that estrogen may affect the catechol-O-methyltransferase (COMT) enzyme, inhibiting the dopaminergic system, resulting in increased dopamine catabolism.88,89