Jessica R. Meendering

Nitric oxide and noradrenaline contribute to the temperature threshold of the axon reflex response to gradual local heating in human skin

The initial skin blood flow response to rapid local heating is an axon reflex, which may be mediated by calcitonin gene‐related peptide and substance P released from C‐fibres. We investigated the role of nitric oxide (NO) and noradrenaline on the temperature threshold for the axon reflex during gradual local heating. 36 subjects participated in two studies. Using microdialysis, we examined the following interventions: NO synthase inhibition (10 mmNG‐nitro‐l‐arginine methyl ester, l‐NAME); low‐dose NO infusion (1.0 μm sodium nitroprusside, SNP); adrenergic blockade (10 mm bretylium tosylate); and low‐dose (0.1 μm) noradrenaline infusion. Laser‐Doppler flowmetry was used to measure red blood cell flux. Skin was heated at a rate of 0.1°C min−1 from 33°C to 40°C. Compared to control skin sites, the axon reflex response was shifted to a higher temperature in 4 subjects in the l‐NAME sites (control, 37.0 ± 0.3°C, n= 16; l‐NAME, 39.8 ± 0.1°C, n= 4; P < 0.001) and absent in 12 subjects. The response was also absent in l‐NAME plus low‐dose SNP sites and not altered by low‐dose SNP infusion alone. Adrenergic blockade, with and without low‐dose noradrenaline infusion, also abolished the axon reflex response in all subjects. Low‐dose noradrenaline infusion alone shifted the axon reflex to a significantly lower temperature threshold compared to control sites (control, 38.2 ± 0.5°C; noradrenaline, 37.7 ± 0.4°C, P < 0.05, n= 5). These results suggest that endogenous NO and noradrenaline contribute to the temperature threshold of the axon reflex response during gradual local heating of the skin.

Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

Medroxyprogesterone acetate (MPA) is widely known for its use in combination hormone therapy for postmenopausal women. However, MPA is also commonly used in young women for contraception and treatment of a number of gynecological conditions. Despite its widespread use, the cardiovascular effects of MPA in young women are unclear. Therefore, the purpose of this study was to determine the acute effects of MPA when used in combination with estradiol on markers of cardiovascular risk in young women. We suppressed endogenous estrogens and progesterone in 10 premenopausal women using a gonadotropin-releasing hormone antagonist (GnRHa) for 10 days. On day 4 of GnRHa subjects received 0.1 mg of estradiol (GnRHa+E(2)), and on day 7 5 mg of MPA was added (GnRHa+E(2)+MPA). Endothelium-dependent vasodilation and endothelium-independent vasodilation of the brachial artery, lipids, homocysteine, high-sensitivity C-reactive protein, and endothelin-1 were assessed during treatment with GnRHa, GnRHa+E(2), and GnRHa+E(2)+MPA. Four additional subjects were tested to validate the efficacy of the GnRHa model and confirm the findings. Endothelium-dependent vasodilation was greater during GnRHa+E(2) than during GnRHa or GnRHa+E(2)+MPA (P = 0.006). Endothelin-1 was lower during GnRHa+E(2) than GnRHa alone (P = 0.039). Endothelin-1 increased with the addition of MPA and was not significantly different from GnRHa alone. There were no differences in the other markers of cardiovascular risk between hormone treatment days. These data suggest that acute MPA administration negates the beneficial effects of estradiol on endothelium-dependent vasodilation in young women. In addition, these data suggest that estradiol decreases endothelin-1 concentrations and the addition of MPA may counteract the effect of estradiol on endothelin-1.

17β-estradiol and progesterone independently augment cutaneous thermal hyperemia but not reactive hyperemia.

Please cite this paper as: Brunt, Miner, Meendering, Kaplan, and Minson (2011). 17β‐Estradiol and Progesterone Independently Augment Cutaneous Thermal Hyperemia But Not Reactive Hyperemia. Microcirculation 18(5), 347–355.

A combined oral contraceptive containing 30 mcg ethinyl estradiol and 3.0 mg drospirenone does not impair endothelium-dependent vasodilation.

BACKGROUND Ethinyl estradiol (EE) increases endothelium-dependent vasodilation in young women, but certain progestins paired with EE in combination oral contraceptive pills (OCPs) have been shown to antagonize the vasodilatory effects of EE. Therefore, the purpose of this study was to investigate how endothelial function, serum biomarkers and resting blood pressures change across an OCP cycle in women using a monophasic OCP formulation containing the progestin drospirenone. STUDY DESIGN Twelve women were studied during two hormone phases of their OCP cycle: once at the end of 3 weeks of active pills (30 mcg EE and 3.0 mg drospirenone) and once at the end of a week of placebo pills (no exogenous hormones) RESULTS Endothelium-dependent vasodilation was greater during the active phase compared to the placebo phase (p<.001). In contrast, there was no difference in endothelium-independent dilation between hormone phases. CONCLUSION These data suggest that the combination of 30 mcg EE and 3.0 mg drospirenone used in the active phase of this OCP increases endothelium-dependent vasodilation compared to a placebo phase.

Ethinyl estradiol-to-desogestrel ratio impacts endothelial function in young women

BACKGROUND Ethinyl estradiol (EE) and progestins have the ability to alter endothelial function. The type of progestin and the ratio of EE to progestin used in oral contraceptive pills (OCPs) may determine how they affect the arterial vasculature. STUDY DESIGN In this study, we investigated endothelial function across a cycle in very low dose (VLD) and low dose (LD) combination EE and desogestrel (DSG) OCP users during two phases: active (VLD=20 mcg EE/150 mcg DSG; LD=30 mcg EE/150 mcg DSG) and pill-free. Endothelial function was also measured during an EE-only hormone phase (10 mcg EE) in group VLD. RESULTS Endothelium-dependent vasodilation was greater during the active phase compared to the pill-free phase in group LD (9.02+/-0.72% vs. 7.33+/-0.84%; p=.029). This phase difference was not observed in group VLD (5.86+/-0.63% vs. 6.56+/-0.70%; p=.108). However, endothelium-dependent vasodilation was higher during the EE-only phase, compared to the active and pill-free phases (8.92+/-0.47% vs. 5.86+/-0.63%, and 6.56+/-0.70%; p<.001) in group VLD. CONCLUSIONS These data suggest DSG may antagonize the vasodilatory activity of EE and that this effect is further modulated by the EE-to-DSG ratio.

Depot-Medroxyprogesterone Acetate and Endothelial Function Before and After Acute Oral, Vaginal, and Transdermal Estradiol Treatment

Young women using depot-medroxyprogesterone acetate (DMPA) contraception have low circulating estrogen and elevated synthetic progestin. Low estrogen and certain progestins have been shown to impact endothelial function even in young healthy women. The purpose of this study was to investigate how DMPA affects endothelial function and serum biomarkers of cardiovascular risk before and after acute oral, vaginal, and transdermal estradiol treatments. Seven young women participated on 3 study days during a normal 12-week DMPA cycle, during weeks 3, 6, and 9. An additional 8 young women participated on 6 separate days during a 12-week DMPA cycle, 3 times on DMPA only and 3 times when using DMPA plus acute estradiol treatments. Wall tracking of high-resolution ultrasound images of the brachial artery were used during endothelium-dependent flow-mediated dilation and nitroglycerin administration to test endothelial function. Serum samples were analyzed for cardiovascular indexes at each study visit. All of the estradiol treatments increased endothelium-dependent flow-mediated dilation compared with DMPA only (P<0.001). Endothelium-dependent flow-mediated dilation was not different among DMPA-only treatment days. Endothelium-independent vasodilation and cholesterol levels were unchanged across DMPA-only and DMPA plus estradiol cycles. These data suggest that acute estradiol treatments improve endothelium-dependent flow-mediated dilation in young hypoestrogenic women using DMPA.