Differential effects of oral and transdermal menopausal hormone therapy on prostacyclin and thromboxane in platelets

Menopausal hormone therapies (MHT) may increase thrombotic risk but modulate endothelial function and reduce development of vascular lesions. This study compared effects of MHT on prostanoid-modulated adenosine triphosphate (ATP) secretion from platelets in relationship with endothelial reactive hyperemia (RH) index and carotid intima medial thickness (CIMT). Participants were healthy, recently menopausal women of the Kronos Early Estrogen Prevention Study (KEEPS) randomized to one of three treatments: oral conjugated equine estrogen (oCEE, 0.45 mg/day), transdermal 17β-estradiol (tE2, 50 µg/day) each with intermittent oral progesterone or placebo pills and patch (PL). Prostacyclin and thromboxane A₂ were assessed by quantification of their stable metabolites (6-keto-prostaglandin F1_α, 6-k-PGF1_α; thromboxane B₂, TXB₂), using ELISA. Dense granule ATP secretion from activated platelets was determined by bioluminescence; RH and CIMT were determined by fingertip tonometry and ultrasound, respectively. After 48 months of treatment, platelet content of 6-k-PGF1_α and TXB₂ was significantly lower in oCEE compared to the PL. Inhibition of ATP secretion by exogenous activation of cAMP associated with platelet 6-k-PGF1_α (r = -0.41, P = 0.04) and TXB₂ (r = 0.71, P = 0.0005) only in the oCEE group. Serum and platelet content of 6-k-PGF1_α and TXB₂ associated positively in the PL and tE2 groups. Serum 6- k-PGF1_α positively associated with RH in the oCEE group (r = 0.73, P = 0.02), while serum TXB₂ positively associated with CIMT in the tE2 group (r = 0.64, P = 0.01). Thus, oCEE and tE2 differentially affect prostanoid- mediated platelet secretory pathways but alone would not account for an increased thrombotic risk for oral MHT. Furthermore, platelet-derived prostanoids may contribute to RH and vascular remodeling in healthy menopausal women.