What has been overlooked is: (1) differences in CYP1B1 activity in humans versus rodents; (2) the promiscuity of CYP1B1 for various non-estrogenic substrates (and thereby the effects of CYP1B1 inhibitors unrelated to estrogen metabolism); (3) the lack of direct/causative evidence about CYP1B1 effects on 16αHE1 production; and (4) limitations of interpreting urinary estrogen data (2HE1/16α-HE1 ratio) to draw associations between CYP1B1 activity, 16αHE1 production, and their pathogenic roles in PAH. The gene discussed is CYP1B1; the disease is pulmonary arterial hypertension.