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BRIEF REPORT |
Division of Endocrinology, Diabetes and Hypertension (E.D.S., G.K.A., V.R., E.W.S.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; and Department of Medicine (P.N.H.), University of Utah School of Medicine, Salt Lake City, Utah 84132
Address all correspondence and requests for reprints to: Ellen W. Seely, M.D., Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: eseely{at}partners.org.
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Abstract |
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Objective: We examined in postmenopausal women the relationships between endogenous sex hormone concentrations and both blood pressure (BP) and renal vascular resistance (RVR), at baseline and in response to infused angiotensin II (AngII).
Subjects, Interventions, and Main Outcome Measures: A total of 34 hypertensive, postmenopausal women were studied in low-sodium and/or high-sodium balance. Serum estradiol, serum progesterone, BP, and RVR were measured at baseline. BP and RVR were remeasured after AngII infusion.
Results: In low-sodium balance, the increases in systolic and diastolic BP in response to infused AngII were blunted with increased serum progesterone concentrations (P < 0.05). The increase in RVR in response to infused AngII was also blunted with increased serum progesterone concentrations (P < 0.005). The relationships between progesterone concentration and vascular response to AngII were independent of age, body mass index, and estradiol concentration. There were no significant correlations between estradiol concentration and BP or RVR response to AngII. There were no significant correlations between sex hormone concentrations and baseline BP or RVR. In high-sodium balance, there were no significant associations between sex hormone concentrations and vascular measures.
Conclusions: In postmenopausal women in low-sodium balance, the pressor and renovascular responses to AngII are blunted with increased endogenous progesterone concentrations. Our findings suggest a role for endogenous progesterone in modulating vascular function, even within the low postmenopausal range.
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Introduction |
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The greater incidence of hypertension in postmenopausal vs. premenopausal women suggests that ovarian sex hormone deficiency contributes to postmenopausal hypertension, but consistent relationships between endogenous sex hormone levels and blood pressure (BP) have not been demonstrated (4). One small study found higher endogenous estradiol and progesterone concentrations in normotensive vs. hypertensive postmenopausal women, suggesting possible vasoactive effects of endogenous estradiol and progesterone, even within the postmenopausal range (5).
We therefore examined the relationships between BP and endogenous estradiol and progesterone concentrations in postmenopausal women in sodium balance, at baseline and in response to the vasoconstrictor angiotensin II (AngII). Because our prior experience demonstrated that the renal circulation is exquisitely sensitive to AngII and estrogen-induced changes in activation of the renin-angiotensin system (6, 7), we also examined the relationships between endogenous sex hormone levels and renal vascular resistance (RVR).
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Subjects and Methods |
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A total of 34 hypertensive postmenopausal women studied by the international Hypertensive Pathotype consortium (6) was included in this post hoc analysis. Postmenopausal was defined as 1 yr or more of amenorrhea and serum FSH more than 30 IU/liter. Hypertension was defined as diastolic BP (DBP) higher than or equal to 100 mm Hg off antihypertensive medications, or higher than or equal to 90 mm Hg on antihypertensive medication(s), or treatment with two or more antihypertensive medications. Subjects taking exogenous estrogens or progestins or with active medical problems were excluded.
Protocols
All antihypertensive medications were discontinued at least 2 wk before study start. Subjects were given isocaloric meals containing 200 mEq sodium daily for 7 d before admission. Twenty-four hour urinary sodium was then measured. Subjects were admitted to the General Clinical Research Centers of Brigham and Women’s Hospital or University of Utah Medical Center. The institutional review boards at each site approved the protocols, and each subject provided written informed consent.
After fasting and remaining supine overnight, blood was drawn for estradiol, progesterone, plasma renin activity (PRA), AngII, aldosterone, and cortisol using an iv catheter. Baseline systolic BP (SBP) and DBP were measured in triplicate with an automatic sphygmomanometer (Dinamap; Critikon, Tampa, FL), and median values were used in the analyses. Mean arterial pressure (MAP) was calculated as [(SBP – DBP)/3 + DBP]. After a loading dose (8 mg/kg) and 1-h infusion (12 mg/min) of para-aminohippurate (PAH), serum PAH concentration was measured. Renal plasma flow was calculated from the serum PAH concentration, and RVR was calculated as MAP/renal plasma flow, as previously described (6). Next, AngII-amide (Ciba-Geigy, Summit, NJ) was infused (3 ng/kg·min) for 50 min, and PAH was remeasured. BP was measured every 2 min throughout the AngII infusion.
Subjects were then given low-sodium isocaloric meals containing 10 mEq sodium daily for 7 d. The procedures described previously were repeated. Subjects were included in the low-sodium and high-sodium analyses if 24-h urinary sodium excretion was less than 40 and more than 140 mmol, respectively.
Laboratory procedures
Serum progesterone was measured using the solid phase RIA Coat-A-Count procedure, and serum estradiol was measured using double-antibody 125I RIA (Diagnostic Products Corp., Los Angeles, CA). The interassay coefficients of variation were less than 7.0% for estradiol and less than 5.5% for progesterone, and analytical sensitivities were 1.4 pg/ml (5.1 pmol/liter) and 3.0 ng/dl (0.1 nmol/liter), respectively. Serum cortisol and FSH were measured with the Access Immunoassay System (Beckman, Chaska, MN). PRA, serum aldosterone, plasma AngII, serum PAH, and urinary sodium were measured as previously described (6).
Statistical analysis
Data are presented as means ± SD. The Shapiro-Wilks test was used to assess normality. For variables with skewed distributions, log transformation was performed to normalize the data. The Wilcoxon signed-ranks test was used to compare parameters in low-sodium vs. high-sodium balance among subjects studied in both low-sodium and high-sodium balance. Pearson correlation coefficients were used to examine relationships between variables, and best-fit lines were obtained by linear regression using the least-squares method. Multivariate linear regression models were used to examine the effects of sex hormone concentrations and covariates on outcome variables. P < 0.05 was considered significant. Analyses were performed using SPSS version 15.0.1 for Windows (SPSS, Inc., Chicago, IL).
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Results |
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shows baseline characteristics of the subjects. As expected, weight, BP, urinary sodium, and RVR were significantly lower, and PRA, plasma AngII, and serum aldosterone were significantly higher in low-sodium vs. high-sodium balance among subjects studied in both low-sodium and high-sodium balance (n = 29). Mean estradiol concentrations were 4.9 ± 4.5 and 4.1 ± 3.5 pg/ml (18.0 ± 16.5 and 15.1 ± 12.9 pmol/liter), and mean progesterone concentrations were 33.8 ± 16.3 and 31.0 ± 14.1 ng/dl (1.1 ± 0.5 and 1.0 ± 0.5 nmol/liter) in low-sodium and high-sodium balance, respectively.
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). However, there were significant inverse correlations between log progesterone, and the increase in SBP, DBP, and MAP in response to infused AngII (Table 2 and Fig. 1, A and B). That is, the pressor effects of infused AngII were blunted with increased serum progesterone concentrations. There were no significant associations between log estradiol and pressor response to AngII. With respect to RVR, there were no significant correlations between log estradiol or log progesterone and baseline RVR (Table 2), although log progesterone tended to correlate inversely with baseline RVR. Similar to our findings for BP, there was an inverse correlation between log progesterone and the increase in RVR in response to infused AngII (Table 2 and Fig. 1C). The AngII-induced increase in RVR was blunted with increased serum progesterone concentrations. There were no significant associations between log estradiol and RVR response to AngII. The log progesterone/log estradiol ratio did not significantly correlate with BP or RVR, at baseline or in response to AngII.
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In high-sodium balance, sex hormone concentrations did not significantly correlate with baseline BP or RVR, or with the AngII-induced increase in BP or RVR.
There were no significant correlations between serum estradiol and progesterone concentrations, or between sex hormone concentrations and PRA, plasma AngII, serum aldosterone, or serum cortisol in either low-sodium or high-sodium balance.
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Discussion |
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Refractoriness to the pressor effects of AngII is well documented during normal pregnancy (8). The effective pressor dose of infused AngII was shown to increase with higher endogenous progesterone concentrations during human pregnancy, consistent with our findings in postmenopausal women. Exogenous progestin administration, at doses chosen to approximate levels achieved during the reproductive cycle or pregnancy, has blunted the pressor response to AngII (9, 10, 11) and norepinephrine (12), although two studies failed to demonstrate this effect (13, 14). Our study demonstrates for the first time the inverse relationship between endogenous progesterone concentration and pressor response to AngII within the low postmenopausal progesterone range.
Consistent with our findings, many studies showed no effect of estrogen administration on pressor response to infused AngII (9, 10, 11, 13). In a study that showed that estrogen treatment blunted the pressor response to high-dose AngII (14), estrogen treatment had no effect at low AngII doses, including the dose used in this study, which more closely approximate in vivo AngII levels.
We next examined the relationships between endogenous sex hormone concentrations and renal vascular function, which is more sensitive than BP to both AngII and estrogen-mediated effects (6, 7). Consistent with our results for BP, we found that the increase in RVR in response to infused AngII was blunted with increased serum progesterone concentrations. In support of our findings, exogenous progesterone has blunted AngII-induced renal vasoconstriction in premenopausal women (13). Although we found no relationship between endogenous estradiol concentration and RVR, a previous study found that premenopausal women with higher endogenous estradiol concentrations had higher RVR (15), which may reflect the differing effects of premenopausal vs. postmenopausal estradiol concentrations.
There are several possible mechanisms by which progesterone may blunt AngII-induced vasoconstriction. Progesterone is a vasodilator, and progesterone receptors are expressed in both endothelial and vascular smooth muscle cells (16). Barbagallo et al. (12) demonstrated that progesterone has direct calcium-dependent vasorelaxant effects, independent of estrogen, and suggested that future studies explore the relationships between postmenopausal endogenous progesterone levels and risk of hypertension. Furthermore, progesterone inhibited AngII-stimulated production of the vasoconstrictor endothelin-1 in endothelial cells (16) and decreased AngII receptor concentration in uterine smooth muscle in animal studies (17).
It is interesting that we observed relationships between progesterone concentration and vascular responsiveness in low-sodium but not high-sodium balance. The vasodilatory effects of progesterone may be attenuated by a high-sodium diet because high-sodium intake augments responsiveness to several vasoconstrictors, including AngII (18). Our data suggest that a low-sodium diet may enable the vasodilatory effects of progesterone to be manifest.
Our findings suggest that even postmenopausal progesterone levels have physiological importance. After menopause, progesterone and estradiol are thought to have primarily adrenal, rather than ovarian, origins (19). Future studies are needed to explore the factors that regulate postmenopausal adrenal sex hormone production.
Our study has several limitations. Our small sample size may have precluded detection of relationships between estradiol concentration and vascular measures. The reliability of sex hormone measurement is decreased at the lower ranges of detection, but the coefficients of variation for progesterone and estradiol were small, even in the postmenopausal range. Because increased variability in measurements would tend to dilute associations, our findings may underestimate the strength of these relationships. Future studies may be enhanced by the use of increasingly sensitive progesterone assays. Because our study included hypertensive, predominantly Caucasian women, our findings may not apply to normotensive women or women of other ethnicities.
In summary, we have shown that the pressor and renovascular responses to infused AngII are blunted with increased endogenous progesterone concentrations in postmenopausal women in low-sodium balance. A growing literature has established the physiological importance of variation in postmenopausal estradiol levels (1, 2, 3). Of interest, one study of postmenopausal women with progesterone concentrations similar to those observed in our study found that women with slow vs. rapid rates of bone loss had higher progesterone concentrations, whereas estradiol concentrations were similar in the two groups (20). Our findings build on these previous studies by defining for the first time relationships between postmenopausal progesterone concentration and vascular function. Our study also highlights the importance of studying the physiological effects of endogenous progesterone as well as estradiol concentrations in postmenopausal women.
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Footnotes |
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Disclosure Statement: The authors have nothing to disclose.
First Published Online September 25, 2007
Abbreviations: AngII, Angiotensin II; BP, blood pressure; DBP, diastolic BP; MAP, mean arterial pressure; PAH, para-aminohippurate; PRA, plasma renin activity; RVR, renal vascular resistance; SBP, systolic BP.
Received July 2, 2007.
Accepted September 17, 2007.
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