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(Circulation. 1997;95:39-45.)
© 1997 American Heart Association, Inc.

Articles

Effects of Estrogen Replacement Therapy on the Renin-Angiotensin System in Postmenopausal Women

Heribert Schunkert, MD; A.H. Jan Danser, PhD; Hans-Werner Hense, MD; Frans H.M. Derkx, MD, PhD; Susanne Kurzinger, BS; Gunter A.J. Riegger, MD

the Klinik und Poliklinik fur Innere Medizin II, University of Regensburg (Germany) (H.S., S.K., G.A.J.R.); the Departments of Pharmacology and Internal Medicine, Erasmus University, Rotterdam, the Netherlands (A.H.J.D., F.H.M.D); and Institut fur Epidemiologie und Sozialmedizin, University of Munster (Germany), and GSF Forschungszentrum, Institut fur Epidemiologie, Munich-Neuherberg, Germany (H.-W.H.).

Correspondence to PD Dr H. Schunkert, Klinik und Poliklinik fur Innere Medizin II, University of Regensburg, D-93042 Regensburg, FRG.

	Abstract

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Background Oral estrogen replacement therapy (ERT) is known to stimulate the synthesis of angiotensinogen. The effects of such therapy on renin, ACE, and aldosterone are less clear. This seems noteworthy, however, since further activation of the system could be disadvantageous to postmenopausal women who replace estrogen in the context of heart failure, coronary artery disease, or hypertension.

Methods and Results Estrogen status and components of the renin-angiotensin system were examined in a population-based sample of postmenopausal women and age-matched men. Renin was quantified immunoradiometrically, ie, independent of substrate abundance; aldosterone, angiotensinogen, and ACE activity were determined by standard methods. Renin levels were lower in women with ERT (n=107; 12.0±0.7 mU/L) compared with women without ERT (n=223; 16.6±0.9 mU/L; P=.001) or men (n=342, 20.5±1.5 mU/L, P<.0001). In contrast, angiotensinogen was higher in women with ERT (1.36±0.08 mg/L) compared with women without ERT (1.03±0.02 mg/L; P<.0001) or compared with men (0.97±0.01 mg/L; P<.0001). Renin suppression was seen with either oral or transdermal estrogen replacement (-30% and -31%, respectively; both P<.001). In contrast, the increase of angiotensinogen was limited to women taking oral estrogens (+58%, P<.001). Multivariate analysis revealed that these estrogen effects were independent of age, body mass index, blood pressure, and/or antihypertensive medication. Finally, only marginal differences between groups were observed for serum ACE activity and aldosterone.

Conclusions Aside from a well-documented induction of angiotensinogen, ERT is related to a substantial suppression of renin, a phenomenon that might have received little attention because of widely used indirect measurements of the hormone.

Key Words: renin • hormones • angiotensin • estrogen • menopause

	Introduction

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The role of estrogen in the regulation of angiotensinogen gene expression or serum levels is well documented.^{1 2} In contrast, the information available on the relation between estrogen status and renin levels is less clear. Most studies performed in women with high estrogen levels, eg, during intake of oral contraceptives, revealed no change or a significant increase of plasma renin activity.^{3 4 5 6 7} Likewise, reports on the effects of estrogen replacement in postmenopausal women were inconsistent, suggesting either unchanged or elevated plasma renin activity.^{8 9 10 11 12}

These findings raised concern because a (patho)physiological situation with increased angiotensinogen (renin substrate) and unchanged or even increased renin levels may favor the development of arterial hypertension and therefore increase the overall cardiovascular morbidity.^{2 13 14} Fortunately, scrutinous investigations failed to demonstrate an increase of blood pressure in women replacing estrogens; rather, unchanged or slightly lower blood pressure levels were observed in women receiving such therapy.^{2 15 16}

Most previous investigations that addressed the renin-angiotensin system in women with high versus low estrogen status relied on measurements of plasma renin activity.^{4 10 11} This enzyme kinetic assay is based on measurement of angiotensin I that is released by renin through cleavage of renin substrate. The kinetics of this reaction are in part dependent on the concentration of renin substrate.¹⁷ Angiotensinogen, however, as mentioned above, is largely altered by the estrogen status. To avoid this potential interaction, Derkx and coworkers¹⁸ saturated plasma with exogenous angiotensinogen before measurement of renin enzymatic activity. Using this modification, these investigators demonstrated that women taking oral contraceptives, ie, those with high estrogen status, displayed a 40% decrease of renin compared with age-matched control subjects. Furthermore, plasma of the same women taking oral contraceptives (without addition of exogenous renin substrate) was characterized by elevations of angiotensinogen by 300% and, surprisingly, plasma renin activity by 15%.¹⁸ Thus, measurements of plasma renin activity may substantially overestimate in vivo circulating renin levels when high levels of angiotensinogen interfere in the assay. In the light of these findings, a recently developed immunoradiometric assay that makes use of a specific monoclonal renin antibody establishes a further improvement for measurement of renin levels since this assay allows quantification of renin without any alteration by interfering substrate levels.¹⁹

These findings and methodological modifications prompted us to reevaluate the effects of estrogen replacement therapy (ERT) on renin levels. Through the use of an immunoradiometric assay for renin as well as a precise assay for angiotensinogen that involves cleavage of the protein by recombinant human renin, the present findings suggest reciprocal effects of estrogen on the circulating levels of these components of the renin-angiotensin system. These findings may be of specific relevance for postmenopausal women with hypertension or heart failure who intend to replace estrogen but are concerned about a potential induction of the renin-angiotensin system by such therapy.

	Methods

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Study Population
The subjects of this study had initially participated in the MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease), Augsburg, baseline survey of 1984/1985 and its follow-up examination in 1987/1988.²⁰ Subjects originate from a sex-age–stratified random sample of all German residents of the Augsburg study area. In 1994, a second follow-up examination including biochemical and anthropometric measurements was offered to a total of 1010 men and women, 52 to 65 years of age, of whom 672 (66%) attended.

All subjects responded to a questionnaire on medical history, physical activities, medication, and personal habits. The information on drug or ERT was verified by inspection of prescription forms or medications brought to the MONICA center. All women were specifically asked about the use of transdermal or oral estrogen supplements. Participants who were unable to provide the respective information at the center were contacted again by telephone to provide precise names and dosages of their current medications. Body height and weight were recorded with the patient in light clothing, and body mass index was computed as weight in kilograms divided by height in meters squared (kg/m²). Resting blood pressure was measured after subjects had been in a sitting position for a minimum of 30 minutes. Blood pressure was read three times at the patient's right arm by two investigators using a mercury sphygmomanometer. The mean of three measurements was used for this study. Hypertension was defined as blood pressure 160/95 mm Hg or when subjects were receiving long-term antihypertensive medication.

Biochemical Measurements
Blood was drawn from nonfasting subjects who were in a supine resting position for at least 30 minutes. All determinations of circulating components of the renin-angiotensin system were carried out in duplicate. Immunoreactive renin was quantified in 200 µL of plasma, with the use of an immunoradiometric assay kit (Nichols Institute) and the methods proposed by Derkx et al.¹⁹ Cross-reactivity of the monoclonal renin antibody with prorenin is 1%. Results are expressed as milliunits per liter, with the international reference preparation 68/356 as the standard.¹⁹ Aldosterone was quantified in 100 µL of serum by standard radioimmunoassay (Peninsula). For determination of angiotensinogen, 10 µL of serum and 50 ng of recombinant human renin (a generous gift of Dr Fischli, Hoffmann-LaRoche, Basel, Switzerland) were used to generate angiotensin I, as previously described.²¹ Angiotensin I was measured by standard radioimmunoassay (Peninsula). ACE activity was determined by a fluorometric assay, as previously described in detail.²² 17ß-Estradiol concentrations were quantified by enzyme-linked immunosorbent assay (Pharmacia).

Statistics
In the present cohort, values measured for serum angiotensinogen, renin, and aldosterone were nonnormally distributed and slightly skewed to the right. Therefore, comparisons were performed with the use of both raw data and logarithmically transformed values to account for the deviation from normal distribution. However, the use of logarithmically transformed values did not result in perceivable differences in results and confirmed the principal observations with respect to the interaction between estrogen status and components of the renin-angiotensin system. In fact, for most comparisons, the use of logarithmically transformed values resulted in higher significance levels. ACE activity was almost normally distributed in our study sample. Therefore, all analyses that include ACE activity are presented as an untransformed variable.

To assess the statistical significance of differences in mean values between subjects with high or low estrogen status, t tests for the comparison of independent samples were performed. In the case of three or more comparisons, eg, comparisons between postmenopausal women using various estrogen replacements, ANOVA for multiple comparisons was performed. In postmenopausal women, 17ß–circulating estradiol was used as a binary variable to differentiate between serum estradiol concentrations characteristic for untreated women after menopause, ie, levels <20 ng/L, and low levels found in premenopausal women, for example, in the luteal phase (>20 ng/L). Women receiving conjugated estrogens were not included in this analysis, since estrone is the principal metabolite in these women. Of the remainder, 22 women presented with circulating estradiol levels <20 ng/L despite these women acknowledging the use of ERT (9 oral and 20 transdermal). On the other hand, 29 of the untreated postmenopausal women presented with premenopausal levels of estradiol. Most of these women (n=21) revealed postmenopausal follicle-stimulating hormone levels, which may suggest that these women were truly postmenopausal but might have had intermittent bursts of estradiol release (data not shown). Exclusion of these women had no effect on the general findings.

For multivariate comparisons, each component of the renin-angiotensin system was entered as the dependent variable into regression models that included age, systolic blood pressure, body mass index, use of a ß-blocker, use of an ACE inhibitor, and estrogen replacement status as control variables. Diastolic blood pressure was excluded from regression models because of high correlation with systolic blood pressure (r=.74) to avoid multicollinearity in our analyses. Finally, the interaction of concomitant medication and renin levels was examined in more detail by separation of women into groups either taking ß-blockers (which are known to suppress renin), ACE inhibitors (which are known to stimulate renin), and those without medication. For this purpose, all women taking ß-blockers and ACE inhibitors who participated in the present survey as well as all postmenopausal women of the 1995 survey who used this medication (ACE inhibitors, n=19; ß-blockers, n=21) were included. Within these expanded groups, t tests were carried out to compare renin levels in women with or without ERT. Data are presented as mean±SEM, and values of P<.05 were considered significant.

	Results

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Anthropometric Data
Anthropometric data of subjects evaluated in the present cross-sectional study are shown in Table 1. Postmenopausal women receiving ERT (n=107), those not replacing estrogen (n=223), and men (n=342) were similar with regard to arterial blood pressure and prevalence of diabetes mellitus (Table 1). It was noticed, however, that mean age, body mass index, and heart rate were slightly lower in women replacing estrogen compared with women not receiving hormone therapy (Table 1). Furthermore, a slightly smaller percentage of women with ERT received antihypertensive medication (P=NS). Twenty-seven women were taking conjugated estrogens, 51 estradiol, and 29 a fixed combination of estradiol and estriol. Of the 107 women with ERT, 54 were taking an estrogen-progestin combination. Forty-two women were using transdermal formulations of estrogen and 65 were replacing estrogen orally. ERT was related to a significant increase of serum estradiol levels (Table 1).

View this table: [in this window] [in a new window]   Table 1. Anthropometric and Biochemical Data of Participants

Estrogen Status and Renin
Postmenopausal women replacing estrogen presented with lower renin levels than those found in postmenopausal women without replacement or those in men (Table 1 and Figs 1 and 2). Suppression of renin levels was observed on either form of estrogen replacement regardless of the mode of application (oral or transdermal) or the specific estrogen used (estradiol, conjugated estrogens, or estradiol plus estriol) (Figs 1 and 2). Renin levels were similarly suppressed in women taking estrogen only (11.5±0.9 mU/L) or an estrogen/progestin combination (12.4±0.8 mU/L, P=NS), both being significantly lower compared with women without hormone replacement (both P<.05). After exclusion of women receiving conjugated estrogens (since conjugated estrogens mainly affect estrone levels), postmenopausal women with high circulating 17ß-estradiol, ie, levels >20 ng/L or normal luteal-phase estrogen concentrations (n=97), displayed significantly lower renin levels than found in women with low estradiol levels (n=208; 12.5±0.8 versus 15.7±0.8 mU/L; ln [renin], 2.37±0.05 versus 2.55±0.06; both P<.05).

View larger version (34K): [in this window] [in a new window]   Figure 1. A through C, Heart rate, serum angiotensinogen, and renin levels in women without estrogen replacement therapy (no ERT), with use of transdermal estrogen formulations (transdermal ERT), and use of oral estrogen formulations (oral ERT). Heart rate was significantly lower in women with either oral or transdermal estrogen substitution. Likewise, active renin was significantly suppressed in women with either estrogen treatment. In contrast, serum angiotensinogen was significantly elevated only in women with oral estrogen substitution.

View larger version (24K): [in this window] [in a new window]   Figure 2. A and B, Serum angiotensinogen and renin levels in women without estrogen replacement therapy (no ERT), with use of estradiol formulations (E2), use of conjugated estrogen formulations (conj. E), and use of combined estradiol and estriol formulations (E2 + E3). Active renin was suppressed regardless of the estrogen formulation used. In contrast, serum angiotensinogen was significantly elevated in women taking conjugated estrogens and combined estradiol and estriol formulations.

Exclusion of women taking antihypertensive medication or exclusion of all hypertensive women did not affect the significant inverse association between ERT and renin levels (Table 2). Furthermore, a multivariate analysis carried out on all women that included age, systolic blood pressure, body mass index, and medication with a ß-blocker or an ACE inhibitor as covariates revealed that estrogen replacement was independently associated with lower renin levels (Table 3). Finally, renin levels in men were higher than those found in women regardless of ERT (Table 1).

View this table: [in this window] [in a new window]   Table 2. Angiotensinogen and Renin Levels After Exclusion of Women With Hypertension

View this table: [in this window] [in a new window]   Table 3. Multivariate Analysis of Factors With Potential Effect on Renin or Angiotensinogen Levels

The sample size allowed us to study the interaction of antihypertensive medication, estrogen status, and renin levels. ACE inhibition was related to feedback induction of renin levels in women with low or high estrogen status (Fig 3). However, in women with estrogen replacement, ACE inhibition was related to significantly lower renin levels than found in women without replacement (Fig 3). Interestingly, in women who received ß-blocker treatment, estrogen replacement was related to a smaller absolute difference in renin levels (Fig 3).

View larger version (11K): [in this window] [in a new window]   Figure 3. Renin levels in postmenopausal women with antihypertensive therapy, ie, use of either a ß-blocker or an ACE inhibitor (ACE-I). The pair of columns on the left represents women using ß-blockers without (-ERT) or with estrogen replacement therapy (+ERT); the pair on the right represents women using ACE inhibitors. Renin levels were significantly lower in those women replacing estrogen regardless of whether ß-blockers (-50%) or ACE inhibitors (-78%) were being used.

Estrogen Status and Angiotensinogen
Estrogen replacement in postmenopausal women was related to a significant increase of serum angiotensinogen levels (Table 1). However, this increase was limited to those women using oral ERT (Fig 1). Because conjugated estrogens were most frequently used for oral substitution, the highest angiotensinogen levels were observed in this subgroup (Fig 2). Angiotensinogen levels were found to be increased to a similar extent in women taking formulations that contained an estrogen only (1.39±0.11 mg/L) or an estrogen/progestin combination (1.34±0.09 mg/L; P=NS), both being significantly higher compared with women without hormone replacement (P<.001 for both). Postmenopausal women with premenopausal circulating estradiol presented with angiotensinogen levels that were significantly higher than found in women with natural postmenopausal estradiol levels (1.37±0.08 versus 1.04±0.02 mg/L; ln [angiotensinogen], 0.182±0.04 versus -0.004±0.02; both P<.0001).

Exclusion of women taking antihypertensive medication or exclusion of all hypertensive women did not affect the significant association between ERT and serum angiotensinogen levels (Table 2). Furthermore, a multivariate analysis revealed that estrogen replacement was independently associated with higher serum angiotensinogen levels (Table 3). Finally, angiotensinogen levels in men were similar to those found in postmenopausal women without ERT (Table 1). Interestingly, regression analysis failed to demonstrate a significant inverse correlation between renin and angiotensinogen (r=-.086, P=.12).

Estrogen Status and ACE
ACE activity was slightly lower in postmenopausal women with ERT compared with those without (Table 1). Lowest levels were measured in women using the combination of estradiol and estriol (22.7±1 versus 26.0±0.5 U/L in women without ERT; P<.05). Likewise, there was a trend toward lower ACE activity in women with premenopausal levels compared with those with postmenopausal levels of estradiol (24.6±0.6 versus 26.1±0.5 U/L; P=.06). However, exclusion of women receiving antihypertensive medication and/or those with hypertension resulted in a loss of the association between estrogen status and ACE activity. Furthermore, multivariate analysis revealed no significant association between these parameters.

Estrogen Status and Aldosterone
In women using ERT, aldosterone levels were slightly lower than in women with low estrogen status. However, statistical analysis failed to demonstrate any significant difference between groups. Furthermore, aldosterone levels were similar in women and men (Table 1).

	Discussion

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Substantial evidence suggests that the estrogen status has significant impact on cardiovascular morbidity and mortality.^{23 24} In particular, ERT lowers cardiovascular mortality and improves vascular reactivity in postmenopausal women.^{23 24 25 26} The underlying mechanisms are incompletely understood.²⁷ Activation of the renin-angiotensin system, or high renin levels, on the other hand, has been implicated to be an adverse factor in vascular and cardiac pathophysiology.¹⁴ In the present study, several lines of evidence suggest that the estrogen status affects the level of renin in the circulation. First, women replacing estrogen during menopause presented with significantly lower renin levels than those not using such therapy; second, women with premenopausal circulating estradiol levels displayed renin levels that were lower than found in women with postmenopausal estradiol levels; third, these differences were evident also in women using ACE inhibitors (despite feedback activation of renin by this medication) as well as in women using ß-blockers (despite suppression of renin by this medication); and fourth, women displayed lower renin levels than men.

These observations may have several implications for postmenopausal women. Most importantly, the elevation of angiotensinogen, a potentially disadvantageous effect in women using oral estrogen replacement,^{1 2} seems to be opposed by a substantial decrease of renin levels during such treatment. Thus, given that the Michalis-Menten constant of the reaction of renin on its only known substrate is in the range of angiotensinogen serum concentrations,¹⁷ the in vivo effect of these reciprocal actions may be well balanced. We cannot exclude that the induction of angiotensinogen still may be detrimental in some women with hypertension or heart failure who replace estrogen orally. However, women using transdermal estrogen replacement were found to display low renin levels without concomitant induction of angiotensinogen. Given that some investigators propose renin to be the rate-limiting enzyme of the circulating renin-angiotensin system,³ this study suggests that the overall activity of the system may be blunted in some postmenopausal women on ERT, in particular when transdermal estrogen formulations are being used.

The reciprocal effects of ERT on renin and angiotensinogen suggest that differential mechanisms may be involved in the regulation of these proteins or the expression of respective genes. In fact, the angiotensinogen promoter has been shown to be directly controlled by estrogen through estrogen response elements.^{28 29} Albeit the renin promoter contains putative estrogen response elements as well, cAMP (or ß-adrenergic activity) has been found to largely regulate its expression.^{30 31} In this regard, it may be noteworthy that estrogen has been shown to interfere with catecholamine synthesis^{32 33} and to decrease circulating levels of norepinephrine and epinephrine as well as heart rate.^{34 35 36} Likewise, in the present study, postmenopausal women treated with estrogens presented with significantly lower heart rates. Taken together, these data may allow us to hypothesize that renin levels were blunted in part by estrogen-mediated suppression of ß-adrenergic activity. Feedback downregulation, ie, through induction of angiotensinogen, offers yet another potential mechanism of renin suppression,¹⁵ although we were unable to demonstrate such association in univariate or multivariate analysis. Likewise, we obtained no evidence that addition of progestin to the replacement therapy affected renin levels. Finally, differences in renin levels between men and women may result from lower circulating androgens in women, since a low androgen status has been related to low renin levels in experimental rats.³⁷

Regardless of the mechanism(s) responsible for renin suppression in postmenopausal women, subjects with a low renin profile may display a blunted therapeutic response to inhibitors of the renin-angiotensin system.^{38 39 40} On the other hand, we observed in a small subgroup that ACE inhibitor–mediated feedback induction of renin (a well-known response that results in high angiotensin I levels and that may subsequently affect angiotensin II levels) was suppressed in women concomitantly taking ERT. These data reemphasize the multiple interactions between the renin-angiotensin system and estrogen status. Therefore, attention should be called to the question of whether or not ACE inhibitors are as efficacious in female patients as is being documented in male patients.⁴¹ In fact, given the present findings, the role of ACE inhibitors in the treatment of hypertension or heart failure should be reassessed precisely with respect to the estrogen status.

Albeit we found a tendency toward lower concentrations of aldosterone and ACE in women using ERT, no consistent estrogen-dependent alterations were observed. The slightly lower ACE activity found in women replacing estradiol is in agreement with a recent report of Proudler et al.⁴² These authors found that women treated with an estrogen/progestogen combination for 6 months displayed a 20% decrease of serum ACE that was most pronounced in women with high baseline ACE values. Nevertheless, the present multivariate analysis did not confirm independent associations between estrogen status and serum concentrations of aldosterone or ACE, since in the general population these components may be largely under the control of other factors.

A limitation of the present study is that population-based surveys may be biased by confounding factors that were left unrecognized in multivariate analysis. In fact, Egeland and coworkers⁴³ observed in a community study that several parameters differed in women with or without subsequent use of ERT even before this therapy was started. Furthermore, our study, like other cross-sectional studies before,⁴⁴ did not allow correction for a pill-taking cycle. However, the principal finding that renin was lower in women with a high estrogen status was (1) highly consistent in those with or without hypertension, (2) found independent of concomitant medications, and (3) confirmed by measurements of serum estradiol. Nevertheless, prospective studies should reassess this observation through the use of an assay that allows quantification of renin independent of its substrate.

Conclusions
In healthy middle-aged subjects, circulating renin and angiotensinogen levels are regulated discordantly by the estrogen status. Our finding that renin is substantially suppressed in women with high estrogen levels suggests a mechanism that may account in part for the protective effects of the hormone on the cardiovascular system.

	Acknowledgments

 
This study was supported by the Deutsche Forschungsgemeinschaft (DFG Schu 617/3-1, 9-1, and 10-1), an Astra Award for Cardiovascular Research (H.S.), and the Bundesministerium fur Forschung und Technologie (H.S., H.W.H.). The authors wish to thank the participants of this survey for their great enthusiasm. Furthermore, we wish to acknowledge the excellent technical support by R.J.A. de Bruin and H. Baier.

Received May 2, 1996; revision received August 14, 1996; accepted August 24, 1996.

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