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

Abstract

Women are more susceptible to orthostatic intolerance. Peripheral α-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 (E2, 0.2 mg day−1, patch; days 4–16), and progesterone (P4, 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, E2, and E2+P4, in eight HT (s.e.m. = 22 ± 1 years, CSI −871 ± 86 mmHg min) and eight LT (21 ± 1 years, CSI −397 ± 65 mmHg min) women. In separate probes, NA was infused alone, and co-infused with the nitric oxide synthase inhibitor NG-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 (logEC50 GnRH −4.02 ± 0.39, E2+P4 −5.18 ± 0.31, P < 0.05); this response was reversed with Keto (E2+P4 logEC50 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.

Figures

Figure 1. Dose–response curves to cutaneous microdialysis infusions of noradrenaline (NA) during GnRH antagonist (GnRH), oestradiol (E2) and combined oestradiol and progesterone (E2+P4) in high tolerance (A) and low tolerance (B) women

E2+P4 administration enhanced vasoconstriction compared to GnRH antagonist administration in high tolerance women (*P < 0.05) but not low tolerance women.

Figure 2. Effect of COX inhibition (Keto) on cutaneous vascular responses to NA in high tolerance women during GnRH antagonist (A), E2 (B) and E2+P4 (C)

COX inhibition enhanced vasoconstriction during GnRH antagonist administration (*P < 0.05) but attenuated the response during E2+P4 administration (*P < 0.05).

Figure 3. Effect of COX inhibition (Keto) on cutaneous vascular responses to NA in low tolerance women during GnRH antagonist (A), E2 (B) and E2+P4 administration (C)

COX inhibition enhanced vasoconstriction during GnRH antagonist administration (*P < 0.05) but responses were similar during E2 and E2+P4 administration.