Changes of in-vivo markers of platelet activation during the menstrual cycle in healthy pre-menopausal female individuals

Background: Sex differences in cardiovascular diseases (CVD) are a matter of immediate concern, with platelets playing a pivotal role as major contributors to CVD. While the protective effects of estrogens on vascular health have been largely investigated, the impact of endogenous reproductive hormones on platelet function is less clear. In the SHOW (Sexual Hormones and Hemostasis: Observations for Women Health) study, we aimed to assess the association between the levels of endogenous reproductive hormones and in-vivo platelet activation among pre-menopausal healthy female subjects. Methods: Serum levels of estradiol, progesterone (PG), testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and in vivo platelet activation markers were quantified at four time-points across the menstrual cycle (day (d) 1, d5 ± 2, d14 ± 2, and d21 ± 2). Results: Among 21 healthy participants (mean age: 30 years), significant variations of thromboxane B2 (TxB2), soluble P-selectin (sP-selectin) and soluble NOX2-derived peptide (sNOX2-dp) are detected across the menstrual cycle. Linear mixed model analysis shows that sP-selection is associated with LH levels (F = 6.400, p = .016) in a time-dependent manner. TxB2 is associated with FSH across all time-points (F = 6.051, p = .019) and is significantly reduced on d1 in individuals with self-reported heavy menstrual bleeding. Soluble CD40L (sCD40L) changes most significantly in individuals with an ovulatory cycle (i.e. PG ≥ 3 ng/ml at d21). Conclusions: In healthy pre-menopausal female subjects, changes of in-vivo platelet activation markers are associated with changes of PG and gonadotropins. These findings suggest the need for caution in the interpretation of platelet biomarkers in clinical studies enrolling pre-menopausal female individuals.