Effects of Ethinylestradiol on the Renin- Angiotensin-Aldosterone-System and on Plasma Transcortin in Women and Men*†

Oelkers, W.; Blümel, A.; Schöneshöfer, M.; Schwartz, U.; Hammerstein, J.

doi:10.1210/jcem-43-5-1036

Cited by 40 publications

(14 citation statements)

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“…A promoter region in the angiotensinogen gene is responsive to estrogen (31). Ingestion of ethinyl estradiol as part of an OC results in increases in plasma angiotensinogen to levels only marginally less than those seen in pregnancy (32). In the present study, we observed that a clear difference exists between OC users and control subjects in the systemic and renal hemodynamic response to Ang II infusion, with OC users exhibiting increased responsiveness to Ang II infusion.…”

Section: Discussionsupporting

confidence: 45%

Effects of Oral Contraceptive Use on the Renal and Systemic Vascular Response to Angiotensin II Infusion

Ahmed¹,

Kang²,

Burns³

et al. 2004

Journal of the American Society of Nephrology

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Abstract.We have previously shown that users of oral contraceptive (OC) medications exhibit increased plasma levels of angiotensin II (Ang II) with only modest hemodynamic consequences, suggesting estrogen-mediated Ang II type 1 (AT 1 ) receptor downregulation. Accordingly, in 10 women who were OC users and 10 women who, as OC nonusers, served as controls, all mean age 26 Ϯ 1 yr, we examined the renal and peripheral hemodynamic response to graded Ang II infusion, plasma and urine cyclic guanosine monophosphate (cGMP) levels as a surrogate marker for AT 1 and/or AT 2 receptormediated activation of the nitric oxide pathway, and AT 1 receptor expression in skin biopsies. The OC nonusers were studied during the follicular and luteal phases of the menstrual cycle, whereas OC users were studied once during the 21-d medication phase. Subjects ingested a controlled sodium diet for 7 d before each study. Renal hemodynamic function was assessed using standard inulin and p-aminohippurate clearance techniques. AT 1 receptor mRNA levels in skin biopsy samples were assessed using a real-time PCR protocol. In response to graded Ang II infusion, OC users exhibited renal and peripheral hemodynamic responses that were augmented compared with those of OC nonusers, in conjunction with evidence of increased tissue AT 1 receptor expression. Plasma cGMP levels and 24-h urinary cGMP excretion did not differ. These data suggest that, contrary to our original hypothesis, OC use does not appear to be associated with AT 1 receptor downregulation. The factor protecting OC users from the hemodynamic impact of increased Ang II levels remains elusive.Gender and estrogen status are important determinants of renin angiotensin system (RAS) function and the renal and systemic response to angiotensin II (Ang II) (1-3). This laboratory has previously shown that ethinyl estradiol use in the form of the oral contraceptive (OC) pill results in dramatic increases of circulating RAS components, including Ang II; yet, in normal women, the hemodynamic consequences are modest, consisting of a small increase in BP and filtration fraction (1). Ang II, the primary effector of the RAS, is a multifunctional peptide hormone, the actions of which are primarily mediated by two receptors, Ang II type 1 (AT 1 ) and type 2 (AT 2 ). The majority of the physiological and pathophysiological effects of Ang II occur via the AT 1 receptor. The function of the AT 2 receptor is controversial, but it may act in opposition to AT 1 receptors (4). It has been reported in some (5-8) but not all (1-3) studies that high estrogen decreases circulating renin and Ang II levels, downregulates AT 1 receptor expression in vascular smooth muscle cells, adrenal cortex, and hypothalamus (9 -11), and upregulates renal AT 2 receptor expression (4). It has also been demonstrated that the hemodynamic response to Ang II infusion is blunted in high-estrogen states, such as the luteal phase of the normal menstrual cycle (3), and in normal pregnancy (12)(13)(14). Therefore, we hypothesized that wome...

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Section: Discussionsupporting

confidence: 45%

Effects of Oral Contraceptive Use on the Renal and Systemic Vascular Response to Angiotensin II Infusion

Ahmed¹,

Kang²,

Burns³

et al. 2004

Journal of the American Society of Nephrology

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“…19,20 Indeed, this activation of the RAAS has been proposed as a potential mechanism of estrogen-associated hypertension. Transdermal estrogen avoids this effect on the liver, and no effect on PRA or aldosterone has been shown in this and prior studies.…”

Section: The Renin-angiotensin-aldosterone Systemmentioning

confidence: 99%

Estradiol With or Without Progesterone and Ambulatory Blood Pressure in Postmenopausal Women

et al. 1999

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Abstract-The purpose of this study was to determine whether transdermal estradiol and intravaginal progesterone given in doses to mimic the premenopausal state would lower blood pressure (BP) in postmenopausal women. Fifteen healthy postmenopausal women were studied in each of 3 conditions: on placebo, after 8 weeks of transdermal estradiol 0.2 mg twice per week, and again 2 weeks after addition of intravaginal progesterone 300 mg/d. Women were studied at each point after 2 days of 100 mmol/d sodium intake. Twenty-four-hour ambulatory BP monitoring was performed, and blood was assayed for estradiol, progesterone, and hormones of the renin-angiotensin-aldosterone system (RAAS). ANOVA with pairwise comparisons was used for analysis. Urinary sodium excretion was similar at each time point. Levels of estrogen and progesterone similar to those in premenopausal women were achieved. On estradiol, nocturnal systolic BP (110Ϯ3 mm Hg), diastolic BP (63Ϯ2 mm Hg), and mean BP (77Ϯ2 mm Hg) fell significantly (PϽ0.02) compared with placebo systolic BP (116Ϯ2 mm Hg), diastolic BP (68Ϯ2 mm Hg), and mean BP (82Ϯ2 mm Hg). Daytime BP followed the same trend but was significantly lower only for mean BP. There was no activation of the RAAS. The addition of progesterone resulted in no further fall in BP but a significant activation of the RAAS. Thus, contrary to what is often assumed, administration of estradiol with or without progesterone not only did not raise BP but rather substantially lowered BP. This BP-lowering effect may be responsible for the lower incidence of hypertension in premenopausal than in postmenopausal women. (Hypertension. 1999;33:1190-1194.)Key Words: hypertension Ⅲ women Ⅲ blood pressure monitoring, ambulatory Ⅲ renin-angiotensin system P remenopausal women have a lower incidence of cardiovascular disease than age-matched men 1 ; however, after menopause the incidence of cardiovascular disease in women is similar to that in men. Much of the focus of investigation to explain this change in risk has been on estrogen-induced effects producing a more beneficial lipid profile in the premenopausal woman. However, beneficial changes in lipid profiles appear to account for only 25% to 50% of the cardiovascular benefit 2,3 seen in premenopausal women, thereby raising the question of other estrogeninduced cardiovascular benefits that may be lost at menopause.Hypertension is considered a major risk factor for cardiovascular disease. Of note, several studies have shown that the incidence of hypertension is lower in women than men until approximately the age of 51 years 1 . After this time, the incidence of hypertension in women exceeds that in men. Since 51 years is the average age of menopause in the United States, this observation raises the question of whether the loss of the gonadal sex steroids, estradiol and progesterone, contributes to the rise in blood pressure (BP). This possibility is contrary to the common belief in clinical practice that estrogens raise BP. In part, this belief stems from the observed hyperten...

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“…In two studies (10,15), a differential BP response to oral and transdermal estrogen has been described, demonstrating that transdermal HRT reduces ABP, but oral HRT does not affect office BP. A possible mechanism responsible for this finding is that oral estrogens increase hepatic expression of angiotensinogen (34,35). The hepatic effect of transdermally delivered estrogen, in which first liver passage effects are avoided, is less pronounced than that of oral estrogen, and no significant increase in the renin-substrate concentration has been observed (36,37).…”

Section: Discussionmentioning

confidence: 99%

“…Estrogen increases prostacyclin production (38), endothelium-dependent vasodilation (39), calcium channel blockade (40), and bradykinin production (20)(21)(22). Previous studies using oral estrogen have demonstrated increases in plasma renin activity and aldosterone concentration, likely through a hepatic-induced increase in angiotensinogen production (34,35). Our previous study also showed increases in the plasma angiotensin II and bradykinin concentrations in hypertensive postmenopausal women, suggesting that an estrogen-induced increase in angiotensin II may be balanced by an increase in bradykinin to maintain BP (22).…”

Section: Discussionmentioning

confidence: 99%

Effects of Hormone Replacement Therapy on Office and Ambulatory Blood Pressure in Japanese Hypertensive Postmenopausal Women

Sumino

Ichikawa²,

Kumakura³

et al. 2003

Hypertens Res

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in postmenopausal women are poorly understood. HRT has been reported to decrease (6-16) or not to change (17-25) BP in normotensive and hypertensive postmenopausal women. The lack of an effect might be dependent on the type, dose, and route of estrogen and progesterone used as well as the methods used for the measurement of BP.HRT has been considered relatively contraindicated for patients with hypertension. This stems from the observed hypertensive effects of oral contraceptives, documented in the 1970s (26,27). Because hypertension is considered a major risk factor for the development of cardiovascular disease

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Effects of Ethinylestradiol on the Renin- Angiotensin-Aldosterone-System and on Plasma Transcortin in Women and Men*†

Cited by 40 publications

References 0 publications

Effects of Oral Contraceptive Use on the Renal and Systemic Vascular Response to Angiotensin II Infusion

Effects of Oral Contraceptive Use on the Renal and Systemic Vascular Response to Angiotensin II Infusion

Estradiol With or Without Progesterone and Ambulatory Blood Pressure in Postmenopausal Women

Effects of Hormone Replacement Therapy on Office and Ambulatory Blood Pressure in Japanese Hypertensive Postmenopausal Women

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