Progesterone enhances adrenergic control of skin blood flow in women with high but not low orthostatic tolerance

Women are more susceptible to orthostatic intolerance. Peripheral alpha-adrenergic responsiveness is important in orthostasis and is lower in women compared to men, and is modulated by female sex hormones. We tested the hypothesis that oestradiol attenuates peripheral cutaneous adrenergic responses in women with low orthostatic tolerance (LT), whereas progesterone enhances adrenergic responses in women with high orthostatic tolerance (HT). After completing a maximal lower body negative pressure test to determine level of orthostatic tolerance (cumulative stress index, CSI), women self administered a gonadotropin releasing hormone (GnRH) antagonist for 16 days to suppress endogenous sex hormone production. Oestradiol (E(2), 0.2 mg day(-1), patch; days 4-16), and progesterone (P(4), 200 mg day(-1), oral; days 12-16) were administered. Skin blood flow responses to graded intradermal microdialysis infusions of noradrenaline (NA) were measured during GnRH antagonist, E(2), and E(2) + P(4), in eight HT (S.E.M. = 22 +/- 1 years, CSI -871 +/- 86 mm Hg min) and eight LT (21 +/- 1 years, CSI -397 +/- 65 mm Hg min) women. In separate probes, NA was infused alone, and co-infused with the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 10 mM), the non-selective cyclooxygenase inhibitor ketorolac tromethamine (Keto, 10 mM), and combined L-NMMA + Keto (10 mM each). Progesterone administration enhanced adrenergic responses in HT women (logEC(50) GnRH -4.02 +/- 0.39, E(2) + P(4) -5.18 +/- 0.31, P < 0.05); this response was reversed with Keto (E(2) + P(4) logEC(50) NA + Keto -3.82 +/- 0.35, P < 0.05). In contrast, no change in adrenergic responsiveness occurred in LT women during any hormone condition. These data indicate differential regulation of cutaneous adrenergic responses by progesterone via the cyclooxygenase pathway in women with high and low orthostatic tolerance.