Paul F. Kaplan

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.

Short-term oral progesterone administration antagonizes the effect of transdermal estradiol on endothelium-dependent vasodilation in young healthy women

Very few studies have explored the cardiovascular effects of progesterone in premenopausal women. This study aimed to examine the short-term effects of oral progesterone alone, transdermal estrogen alone, and progesterone and estrogen combined on flow-mediated dilation (FMD) in healthy reproductive-aged women. We suppressed endogenous estrogens and progesterone in 17 premenopausal women for 10-12 days using a gonadotropin-releasing hormone antagonist. On day 4 (hormone suppression condition), subjects were tested (n = 17) and were then supplemented with either 200 mg micronized progesterone (n = 8) orally or 0.1 mg estradiol (n = 9) transdermally per day. On day 7 (progesterone-first or estradiol-first condition), subjects were tested and began supplementation with both hormones (n = 17) and were tested again on day 10 (combined hormone condition). FMD of the brachial artery was assessed using B-mode arterial ultrasound, combined with synchronized Doppler analysis. As a result, significant differences in FMD were observed between hormone suppression (7.85 ± 1.06%) and estrogen-first conditions (10.14 ± 1.40%; P < 0.05). The estradiol-induced increase was abolished when oral progesterone was also supplemented (6.27 ± 0.96%). In contrast, we observed a trend toward a decrease in FMD with unopposed progesterone administration, but no statistically significant differences were found between the progesterone-first (6.66 ± 1.23%), hormone suppression (7.80 ± 1.23%), and combined hormone conditions (7.40 ± 1.29%). In conclusion, these data suggest that short-term oral micronized progesterone administration antagonizes the beneficial effect of transdermal estradiol on FMD.

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.

Characteristics of scheduled bleeding manipulation with combined hormonal contraception in university students

BACKGROUND There is a lack of information concerning the decision factors and sources of information influencing women who purposefully deviate from the prescribed use of their combined hormone contraceptives to exert elective control of their scheduled bleeding. STUDY DESIGN A self-administered email survey of scheduled bleeding practices and beliefs was distributed to 11,900 female students at the University of Oregon. Assessment of survey participant characteristics, scheduled bleeding manipulation features and attitudes and knowledge toward hormonal contraception was analyzed. RESULTS Of 1719 respondents to the survey, 1374 (79.9%) reported using combined hormonal contraception currently or recently. Approximately 17% of these women altered their scheduled bleeding pattern by deviating from package instructions. Of these, 50% indicated they delayed or skipped their scheduled bleeding for convenience or personal choice. Within this group, 47% of women indicated they learned to modify their scheduled bleeding from health care professionals, while 30% indicated such knowledge was obtained from family or friends. Characteristics that decreased the likelihood of this practice included being of Asian race, use of hormonal contraceptive for bleeding cycle regulation, following a regular exercise program, and personal preference for a monthly cycle. CONCLUSIONS The majority of university females who choose to modify their scheduled bleeding cycle with combined hormonal contraceptives do so for convenience rather than to avoid menstrual symptoms, and many learn from nonmedical sources. There is some disparity between the preferences of menstruation frequency and actual scheduled bleeding pattern behaviors, suggesting potential for improvement in patient education.

Short-term administration of progesterone and estradiol independently alter carotid-vasomotor, but not carotid-cardiac, baroreflex function in young women

The individual effects of estrogen and progesterone on baroreflex function remain poorly understood. We sought to determine how estradiol (E2) and progesterone (P4) independently alter the carotid-cardiac and carotid-vasomotor baroreflexes in young women by using a hormone suppression and exogenous add-back design. Thirty-two young women were divided into two groups and studied under three conditions: 1) after 4 days of endogenous hormone suppression with a gonadotropin releasing hormone antagonist (control condition), 2) after continued suppression and 3 to 4 days of supplementation with either 200 mg/day oral progesterone (N = 16) or 0.1 to 0.2 mg/day transdermal 17β-estradiol (N = 16), and 3) after continued suppression and 3 to 4 days of supplementation with both hormones. Changes in heart rate (HR), mean arterial pressure (MAP), and femoral vascular conductance (FVC) were measured in response to 5 s of +50 mmHg external neck pressure to unload the carotid baroreceptors. Significant hormone effects on the change in HR, MAP, and FVC from baseline at the onset of neck pressure were determined using mixed model covariate analyses accounting for P4 and E2 plasma concentrations. Neither P4 (P = 0.95) nor E2 (P = 0.95) affected the HR response to neck pressure. Higher P4 concentrations were associated with an attenuated fall in FVC (P = 0.01), whereas higher E2 concentrations were associated with an augmented fall in FVC (P = 0.02). Higher E2 was also associated with an augmented rise in MAP (P = 0.01). We conclude that progesterone blunts whereas estradiol enhances carotid-vasomotor baroreflex sensitivity, perhaps explaining why no differences in sympathetic baroreflex sensitivity are commonly reported between low and high combined hormone phases of the menstrual cycle.