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.

Identifying factors associated with falls in postmenopausal breast cancer survivors: a multi-disciplinary approach.

OBJECTIVE: To identify neuromuscular, balance, and vision factors that contribute to falls in recently treated breast cancer survivors (BCS) and explore links between fall risk factors and cancer treatment. DESIGN: Case-control plus prospective observation. SETTING: Comprehensive cancer center. PARTICIPANTS: BCS (N=59; mean age, 58y) within 2 years of chemotherapy completion and/or on adjuvant endocrine therapy. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Objective measures of postural control, vision, and neuromuscular function included: (1) a sensory organization test (SOT), (2) a visual assessment battery, (3) muscle mass by dual energy x-ray absorptiometry, and (4) neuromuscular function with strength by repetition maximum, power by timed stair climb, and gait speed by 4m walk. Falls were self-reported for the past year (retrospective) and monthly for 6 months (prospective). RESULTS: Fifty eight percent of BCS reported falls in the past year. BCS with a history of falls had lower SOT scores with a vestibular deficit pattern in postural control (P<.01) and took longer to read letters on the contrast sensitivity chart (P<.05). Vestibular score on the SOT mediated the relationship between treatment and falls among BCS who received chemotherapy only, but not adjuvant endocrine therapy. CONCLUSIONS: Results of this project suggest that balance disturbances of vestibular origin and delays in detecting low contrast visual stimuli are associated with falls in BCS. Future studies that track falls and fall risk factors in BCS from diagnosis through treatment are warranted, as are studies that can identify treatment-related vestibular dysfunction and altered visual processing.

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.

Endothelial function, endothelin-1, and fibrinogen in young women using the vaginal contraceptive ring.

OBJECTIVE: To assess the effects of the vaginal contraceptive ring cycle on indices of cardiovascular health and risk by studying healthy women during the active hormone phase compared with the ring-free phase of a standard 21/7-day cycle. DESIGN: Observational prospective cohort; 4 weeks' duration. SETTING: Department of Human Physiology, University of Oregon. PATIENT(S): Twenty healthy women. INTERVENTION(S): Endothelial function testing using standard flow-mediated vasodilation of the brachial artery and sublingual nitroglycerin administration. All participants underwent venous blood collection. MAIN OUTCOME MEASURE(S): Endothelium-dependent and endothelium-independent vasodilation of the brachial artery using Doppler ultrasound imaging. Baseline levels of high-density lipoprotein, low-density lipoprotein, triglycerides, total cholesterol, endothelin-1, and fibrinogen. RESULT(S): The active hormone phase of the vaginal ring cycle showed significantly higher vasodilation compared with the ring-free phase. The active hormone phase also showed increased fibrinogen levels compared with the ring-free phase. Low-density lipoprotein lipid levels also fluctuated and were significantly higher during the ring-free phase. CONCLUSION(S): Preliminary study observations of improved endothelial function and lowered low-density lipoprotein levels during the active hormone phase versus the ring-free phase suggest that the vaginal contraceptive ring has beneficial effects on vascular health in women.

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.

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.

Endothelial function across an oral contraceptive cycle in women using levonorgestrel and ethinyl estradiol.

Oral contraceptive pills (OCPs) are a popular contraception method. Currently, lower-dose ethinyl estradiol formulations are most commonly prescribed, although they have been linked to increased arterial vascular risk. The aim of this study was to investigate endothelial function in healthy young women using lower-dose ethinyl estradiol OCPs. We examined flow-mediated, endothelium-dependent and nitroglycerin-mediated, endothelium-independent vasodilation of the brachial artery, comparing two doses of ethinyl estradiol/levonorgestrel OCPs in 15 healthy young women on two study days: once during the active phase and once during the placebo phase of an OCP cycle. Group low dose (LD) (n=7) active pills contained 150 microg levonorgestrel/30 microg ethinyl estradiol versus Group very low dose (VLD) (n=8) with 100 microg levonorgestrel/20 microg ethinyl estradiol. Endothelium-dependent vasodilation was lower during the active phase in Group VLD (5.33 +/- 1.77% vs. 7.23 +/- 2.60%; P=0.024). This phase difference was not observed in Group LD (8.00 +/- 0.970% vs. 7.61 +/- 1.07%; P=0.647). Endothelium-independent vasodilation did not differ between phases in either group. Finally, we measured endothelium-dependent vasodilation in two additional women who received 10 microg of unopposed ethinyl estradiol. Endothelium-dependent vasodilation was increased by unopposed ethinyl estradiol compared with the placebo phase (10.88 +/- 2.34% vs. 6.97 +/- 1.83%). These results suggest that levonorgestrel may antagonize the activity of ethinyl estradiol. Thus both the progestin type and estradiol dose need to be considered when assessing arterial vascular risk of OCP use in women.

Menstrual cycle and sex affect hemodynamic responses to combined orthostatic and heat stress.

Women have decreased orthostatic tolerance compared with men, and anecdotal evidence suggests women are more susceptible to orthostatic intolerance in warm environments. Because estrogen and progesterone affect numerous physiological variables that may alter orthostatic tolerance, the purpose of our study was to compare orthostatic tolerance across the menstrual cycle phases in women during combined orthostatic and heat stress and to compare these data with those of men. Eight normally menstruating women and eight males (22 +/- 4.0 and 23 +/- 3.5 yr, respectively) completed the protocol. Women were studied during their early follicular (EF), ovulatory (OV), and midluteal (ML) phases. Men were studied twice within 2-4 wk. Heart rate, cardiac output, blood pressure, core temperature (T(c)), and cutaneous vascular conductance (CVC) were measured during three head-up tilt tests, consisting of two tilts in the thermoneutral condition and one tilt after a 0.5 degrees C rise in T(c). There was no difference in orthostatic tolerance across the menstrual cycle phases, despite higher CVC in the ML phase after heating (EF, 42.3 +/- 4.8; OV, 40.1 +/- 3.7; ML, 57.5 +/- 4.5; P < 0.05). Orthostatic tolerance in the heat was greater in men than women (P < 0.05). These data suggest that although many physiological variables associated with blood pressure regulation fluctuate during the menstrual cycle, orthostatic tolerance in the heat remains unchanged. Additionally, our data support a clear sex difference in orthostatic tolerance and extend upon previous data to show that the sex difference in the heat is not attributable to fluctuating hormone profiles during the menstrual cycle.

Effects of menstrual cycle and oral contraceptive use on calf venous compliance.

Numerous studies have shown that the female sex hormones estrogen and progesterone have multiple effects on the vasculature. Thus our goal was to investigate the effects of estrogen and progesterone on calf venous compliance by looking for cyclic changes during the early follicular, ovulatory, and midluteal phases of the menstrual cycle and during high and low hormone phases of oral contraceptive use. Additionally, we wanted to compare the venous compliance of normally menstruating women, oral contraceptive users, and men. We studied eight normally menstruating women (23 +/- 1 yr of age) during the early follicular, ovulatory, and midluteal phases of the menstrual cycle. Nine triphasic oral contraceptive users (21 +/- 1 yr of age) were studied during weeks of high and low hormone concentrations. Eight men (23 +/- 1 yr of age) were studied twice within 2-4 wk. With the use of venous occlusion plethysmography with mercury in-Silastic strain gauges, lower limb venous compliance was measured by inflating a venous collection cuff that was placed on the thigh to 60 mmHg for 8 min and then reducing the pressure to 0 mmHg at a rate of 1 mmHg/s. Venous compliance was calculated as the derivative of the pressure-volume curves. There were no differences between early follicular, ovulatory, and midluteal phases of the menstrual cycle or between high and low hormone phases of oral contraceptive use (P > 0.05). Male venous compliance was significantly greater than in normally menstruating women (P < 0.001) and oral contraceptive users (P < 0.002). These data support a sex difference but also suggest that venous compliance does not change with menstrual cycle phase or during the course of oral contraceptive use.