(Hypertension. 1997;29:980-985.)
© 1997 American Heart Association, Inc.
Articles |
Age, Gender, and Non-modulation
A Sexual Dimorphism in Essential Hypertension
From the Departments of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Mass, and Università La Sapienza, Rome, Italy.
Correspondence to Naomi D.L. Fisher, Endocrine-Hypertension Division, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115. E-mail ndfisher{at}bics.bwh.harvard.edu
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Abstract |
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Abstract The angiotensinogen gene is one of the very few related by linkage analysis to human hypertension, but the linkage has been consistently shown only among males. Moreover, polymorphisms in this gene predict an abnormal renal responsiveness to angiotensin II, a feature of non-modulation, but again, only among males. To pursue these related bridges between genetics and physiology, we evaluated the effects of sex on a second feature of non-modulation, the aldosterone response to infused angiotensin II during low sodium balance. We tested the resultant hypothesis—that non-modulation would be less frequent in women—by conducting identical protocols on 225 hypertensive inpatients (70 women, 155 men). Non-modulation was strikingly less frequent among women (26%; 95% confidence interval, 16% to 37%) than men (49%; 95% confidence interval, 40% to 57%) (P=.001). We tested the hypothesis that sex steroids play a role by comparing young, premenopausal women (<35 years) with women who were perimenopausal (45 to 55 years) and postmenopausal (>55 years). Among the youngest women, the frequency of non-modulation was only 7%, significantly less than in young men (41%, P=.02). A steady increase in non-modulation frequency accompanied advancing age in women, reaching 47% in those older than 55 years, equal to the fraction of men affected. Age influenced non-modulation frequency in men far less. We conclude that a striking sex difference underlies the non-modulation phenotype and that female sex hormones may confer protection against a genotypic predisposition in women. This "override" of genotype, manifest by a very low frequency of non-modulation in young women, may participate in their known protection against cardiovascular disease.
Key Words: angiotensinogen • angiotensin II • sodium • genotype
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Introduction |
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Sexual dimorphisms in essential and secondary hypertension are unequivocal.1 Until the age of 50 years, women have lower BP than men, but this protection disappears rapidly with increasing age. Recent studies in genetics and physiology provide some intriguing insights. AGT is one of the few genes related by linkage analysis to human hypertension, but in the largest study to date, linkage was found only among males.2 More recently, a common polymorphism in this gene associated with hypertension was found to predict abnormal renal vascular responsiveness to Ang II,3 one feature of the NM phenotype. Again, the effect of AGT genotype on renal vascular response was evident only among males. In contrast, phenotype did not depend on genotype among females, and females showed greater renal responsiveness to Ang II. Prompted by these observations, we undertook a systematic analysis of adrenal responsiveness to Ang II in 225 hypertensive men and women on the premise that sex would influence the expression of this genetic disorder. Our rationale reflected the possibility that the pattern of renal responsiveness in women represented a physiological process unrelated to NM. The results confirm a striking sex effect on the frequency of NM. The finding that younger women especially are protected against its expression promises a clue to the responsible mechanism.
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Methods |
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We studied 225 individuals with essential hypertension (70 women and 155 men), with similar protocols in Boston, Mass, and Rome, Italy. Protocols were approved by the Human Subjects Committees at each site, and informed written consent was obtained from each subject. The women ranged in age from 18 to 66 years (43±1.4, mean±SE), and the men from 19 to 71 (45.6±1). Twenty-six of the participants were black, 196 white, 2 Indian, and 1 Japanese. Race was determined by self-identification and supported by physical appearance. The term black is used instead of African American because not all of the subjects were American.
Hypertension was defined as a seated systolic BP greater than 140 mm Hg and diastolic BP greater than 90 mm Hg measured manually with a standard mercury sphygmomanometer on at least three visits. All subjects were screened with a physical examination; laboratory tests, including serum electrolytes, liver function tests, and complete blood count; and electrocardiogram. Subjects with known or suspected secondary hypertension or with renal insufficiency (creatinine clearance <70 mL/min) were excluded from the study. Antihypertensive medications, if used, were discontinued at least 2 weeks before the study. Angiotensin-converting enzyme inhibitors were discontinued 3 months before the study. All women were questioned about their use of hormone preparations. Six were taking estrogen, two for contraception and four for postmenopausal hormonal replacement therapy.
On admission to the metabolic ward, each subject was placed on a constant isocaloric diet of 10 mmol sodium and 100 mmol potassium, with 2000 mL water per day. Some subjects began their low sodium diet as outpatients. From admission, daily 24-hour urine collections were obtained for measurement of sodium, potassium, and creatinine. After 4 to 7 days, when external sodium balance had been achieved (urinary sodium equaling dietary sodium), upright posture studies and Ang II infusions were performed on separate days. Each study began at 8 AM, after the subjects had been fasting and recumbent overnight.
On the first study day during low salt balance, hormonal and hemodynamic responses to a postural stimulus were assessed in a subset of subjects. Blood was drawn from an intravenous catheter after subjects had been recumbent overnight and again after 2 hours in the standing position for measurement of PRA and plasma aldosterone concentration. BP and heart rate were monitored at the same time. Subjects with low-renin hypertension, defined by conventional criteria, were excluded from further study.
While remaining in low salt balance, on the next study day each subject received an infusion of Ang II amide (CIBA-Geigy) at 3 ng/kg per minute for 40 minutes, delivered by an electronic infusion pump (Baxter Corp). The dose of 3 ng/kg per minute was used because it has been found to stimulate aldosterone release with minimal pressor effects. Blood was drawn for measurement of PRA and plasma aldosterone, cortisol, and Ang II concentrations before and at the end of the Ang II infusion. During the infusion, BP was monitored every 2 minutes with an indirect recording sphygmomanometer.
Laboratory Procedures
Blood samples were collected on ice and spun immediately, and
the plasma was frozen until assay. Serum and urinary sodium and
potassium levels were measured by flame photometry, with lithium as an
internal standard. Serum and urinary creatinine levels were measured by
an autoanalyzer technique. PRA, aldosterone, Ang II, and cortisol were
assayed by radioimmunoassay techniques previously
described.4 5
Statistical Analyses
Subjects were classified as modulators or NM on the basis of
formal analyses that have demonstrated NM to be a distinct subgroup of
essential hypertension.6 We and others have previously
defined NM as individuals in whom sodium intake fails to modify the
responsiveness of the renal vasculature and adrenal gland to Ang II.
Specific abnormalities defined in this subset include failure of sodium
loading to enhance the renal vascular response to Ang II, failure of
sodium loading to increase basal renal blood flow, and failure of
sodium restriction to enhance adrenal responsiveness to Ang II. The
present study assessed the increment in plasma aldosterone after
infusion of Ang II (3 ng/kg per minute), shown to fit a bimodal
distribution in the general hypertensive population, with modulators
having a rise in aldosterone similar to that of normotensive subjects
and NM having a much smaller increase (<416 pmol/L [<15 ng/dL]).
This criterion is the most frequently applied. A subset of these
individuals has been classified in previous
publications.6 7 The data were not collected with an
attempt to categorize women by menopausal status: follicle-stimulating
hormone values were not obtained for all women, and many had undergone
hysterectomy so that cessation of menses was prematurely induced.
Because we postulated that sex hormones might underlie a large part of
the observed sex differences in NM frequency, we analyzed women as four
cohorts, with age as a surrogate for hormonal status. Those younger
than 35 years were considered premenopausal; those between 35 and 45
years, predominantly premenopausal; those between 45 and 55 years,
perimenopausal; and those older than 55 years, postmenopausal. To
control for the effect of age, we grouped men in the same age brackets.
The six women taking exogenous estrogen were analyzed separately, but
their eventual inclusion did not affect the results. Sixteen percent of
the women and 16% of the men had non–insulin-dependent diabetes
mellitus; their inclusion did not influence the results, and they were
not removed.
Sex difference in the frequency of modulation status was analyzed by
two-tailed Fisher's exact test. Two-tailed t tests were
used for comparison of baseline variables and hormonal responses
between sexes. Logistic regression was used for determination of which
variables influenced the modulator-NM phenotype, which is a dichotomous
variable. Group means are presented with the SE as the index of
dispersion. The 
level for significance was .05 or less.
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Results |
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Women and men had similar mean ages, body mass index, admission BP, and serum potassium and urinary sodium excretions during a low sodium intake (Table 1
). As expected, men had
significantly higher serum and urinary creatinine. Blacks added
proportionately more women than men, but the number was very small.
Urinary potassium excretion was higher among men.
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The overall frequency of NM among women was about half that of men
(26% [95% CI, 16% to 37%] versus 49% [95% CI, 40% to 57%])
(P=.001, Fig 1). This difference was
significant in both of the admitting centers analyzed separately. Basal
plasma aldosterone concentration was similar between the sexes, but the
response to Ang II infusion was dramatically different, with a rise of
1094±155 pmol/L (39.4±6 ng/dL) in the women, double that of the men
(494±31 pmol/L [17.8±1.1 ng/dL], P=.0003) (Fig 2, Table 2). Sex also exerted a strong
influence on adrenal responsiveness to a second stimulus, upright
posture. As with Ang II infusion, the response of women (2003±250
pmol/L [72.2±9 ng/dL]) greatly exceeded that of men (1309±133
pmol/L [47.2±4.8 ng/dL]) (P=.01, Fig 2). There was no sex
difference in either basal or responsive PRA or Ang II concentrations
(upright PRA was 2.4±0.2 ng Ang I/L per second in women and 2.3±0.1
in men). Men had a higher plasma cortisol concentration both at
baseline and after Ang II infusion (Table 2).
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A plot of individual aldosterone responses to Ang II infusion reveals
the shift to greater values among the women (Fig 3).
Notably, a subset of subjects with responses greater than 2080 pmol/L
(75 ng/dL) were all women.
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Classified by age, the premenopausal women (<35 years old) had a very
low frequency of NM (7%), which rose steadily with advancing age,
reaching 38% among those at perimenopause (45 to 55 years old) and
47% in those older than 55 (Fig 4). The contribution of
age to NM frequency was highly significant among the women, whether
examined by logistic regression (P=.007) or by correlation
analysis (r=.98, F=74.5, P=.001). Age also
contributed to NM frequency in men, but, as is evident from Fig 3
, its
effect was modest, reaching borderline significance in logistic
regression (P=.04) but not in correlation analysis
(r=.76, F=2.74, P=NS). Differences in aldosterone
responsiveness between men and women were most marked in those women
younger than 45 years and then diminished with age, disappearing
altogether in subjects older than 55 (Fig 5). Sex
rendered a more substantial effect than did age upon adrenal
responsiveness, when the frequency of NM was examined by logistic
regression or aldosterone responsiveness by correlation analysis.
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Of the six women taking estrogen-containing compounds, three were among the highest responders, with aldosterone responses of 2691, 4078, and 4494 pmol/L (97, 147, and 162 ng/dL). The one NM was 60 years old.
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Discussion |
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This study of 225 subjects demonstrated a striking sex difference in the frequency of a common intermediate phenotype of hypertension, NM. Forty-nine percent of men but only 26% of women were affected. The analysis emerged as an examination of the interaction between sex and the genetics and physiology of hypertension, with hypotheses from recent reports that showed the effect of AGT genotype to be evident phenotypically only among males.
The sex difference in NM frequency could not be attributed to dissimilarities in age, BP, body mass index, or sodium balance. In addition to Ang II, potassium is an important stimulus for aldosterone secretion. Serum potassium concentration did not differ between men and women. There was a difference in urinary potassium excretion, but it was opposite that necessary to explain the results. Urinary potassium was lower among the women, despite equal prescribed intake for 5 to 7 days before the study. Nor does the answer lie in higher female levels of corticotropin; plasma cortisol concentration was consistently higher among the men. Studies in normotensive individuals have shown higher rates of urinary cortisol excretion in men than women and higher male cortisol responses to psychological stress8 9 ; corticotropin secretion was greater in males than females in a small group of healthy subjects.10 These results raise intriguing possibilities about a sexually dimorphic influence of stress on cortisol production and perhaps on cardiovascular reactivity more generally.
Sexual dimorphisms of hypertension are abundant in animal models.1 11 In humans, a strong sex difference underlies at least one cause of secondary hypertension, renal artery stenosis, in which fibromuscular dysplasia affects predominantly women.12 Cushing's disease also affects women disproportionately.13 The epidemiological literature is vast, containing multiple studies that unequivocally demonstrate a striking influence of sex on BP.14 Among young and middle-aged cohorts, women have lower systolic and diastolic BPs than men. A lower prevalence of hypertension is accompanied by a significantly lower risk of cardiovascular morbidity and mortality.14 However, the protection conferred on women is not lifelong, dissipating rapidly after the age of 50. Some researchers have attributed the increase in high BP to age, and others have related it directly to menopause.15 16
Age was a contributing factor in the expression of the NM phenotype, which was more frequent as both sexes grew older. In addition to the well-accepted decrease in renin with age, aldosterone secretion is also diminished, with basal levels lowered by as much as 45%.17 Blunted responses in aldosterone release to sodium depletion, upright posture, and Ang II have been reported in small groups of elderly individuals, although these effects were documented in subjects much older (generally >65 years) than those observed in the present study.18 19
The steady increase in NM frequency with advancing age was much more apparent and more significant among women, suggesting that sex derives its influence from female sex hormones, which decline with age. Candidates include progesterone, estrogens, or their relative concentrations. In menstruating women, for example, estradiol concentrations are as low as 180 pmol/L (50 pg/mL) during the follicular stage but reach 735 to 1450 pmol/L (200 to 400 pg/mL) at ovulation; however, they are never as low as in the postmenopausal period, when they hover at a nadir of 37 pmol/L (10 pg/mL). The demonstrated fall in aldosterone responsiveness coincides with the known physiology of peri-menopause. A significant increase in gonadotropins is seen from about 5 years before the actual cessation of menses,20 21 which occurs at an average age of 50 to 51 years in the United States, followed soon thereafter by a fall in circulating estrogen. Plasma progesterone concentration falls to about one third of premenopausal values. Although androgens also fall, particularly dehydroepiandrosterone and dehydroepiandrosterone sulfate and testosterone to a lesser extent, the data on NM in aging men argue against a strong role for male sex steroids in protection against the NM phenotype.
Before the era of low-dose oral contraceptives, exogenous estrogen was associated with hypertension in 5% to 15% of users, imparting a relative risk of 2 to 2.5 for oral contraceptive users versus nonusers.22 Similar large doses of estrogens in oral contraceptives reduced renal blood flow by 25% in healthy women.23 These pharmacological doses, which cause huge increases in AGT, PRA, and Ang II, act very differently from physiological doses. The association with hypertension is no longer clear with the newer preparations of oral contraceptives, for example, and a definite beneficial effect of estrogen on cardiovascular risk has emerged.24
The sodium-lithium countertransport genotype is a much stronger predictor of hypertension in men than women.25 Furthermore, mean countertransport activity is significantly higher in NM compared with either normally modulating hypertensive or normotensive subjects.26 Sex, therefore, seems to play a similar role in governing the expression of each feature: Women show much less NM than do men, and women show less of an effect of countertransport genotype on BP. This similarity suggests that in fact these two phenotypes may reflect the same underlying phenomenon.
Data from our study and others provide clues to the mechanisms underlying the relation between sex and NM. The fact that older women express the same frequency as older men makes an X-linked genetic contribution extremely unlikely. The earlier documentation of sexually dimorphic effects of AGT gene polymorphisms on the expression of one index of NM—the renal vascular response to Ang II3 —probably provides a more compelling approach to the mechanism. The results of the present study can be interpreted as an extension of the observation from renal hemodynamics to adrenal aldosterone release, although we do not yet have information on genotype in this cohort.
Estrogen is one of the main stimulants of hepatic AGT production. However, the interactions among estrogen, AGT, and NM may be entirely unrelated to circulating levels of AGT. No differences in circulating PRA or Ang II, either basal or stimulated, emerged in this study. We have proposed defects in the tissue renin-angiotensin system, defects that are undetectable in serum concentrations of any measurable hormones, to explain the NM phenotype.27 Regulation of the AGT gene by estrogens occurs at the transcriptional level, where the role of estrogen in modifying gene expression may be complex. Although estrogen is known to stimulate gene transcription, NM may be accompanied by a defect in the regulatory region, which could modify the way estrogen controls AGT expression. Conversely, the actions of estrogen on its response elements in the 5' flanking region may be differentially regulated by molecular variants of AGT.
In addition, estrogen may render effects at the receptor level. Although this mechanistic explanation is speculative, chronic estrogen treatment is known to modify Ang II receptor density in the adrenal cortex and pituitary.28 29 Furthermore, sex differences in the renin-angiotensin system are not isolated to AGT; higher prorenin concentrations have been noted in men, for example.30 In a recent study of elements of the renin-angiotensin system in postmenopausal women, higher plasma renin and prorenin as well as lower AGT concentrations characterized those women without estrogen replacement.31 Animal studies suggest that estradiol may be involved in lowering Ang II–induced hypertension in females through its effects on the central nervous system.32
Finally, the beneficial effects of estrogen may be at least partly unrelated to the renin-angiotensin system. Direct vasodilation has been shown in animal and human models.33 34 A lower total peripheral resistance has been reported in hypertensive women than men and is manifest only during the premenopausal years.35 Related mechanisms may include release of nitric oxide (a vasodilator), shown to be significantly higher during peak estrogen phases of the menstrual cycle, and endothelin (a vasoconstrictor), shown to be higher in men than women.36 37
NM can now be designated as an example of sexual dimorphism affecting a very common intermediate phenotype of human hypertension. Furthermore, on the basis of hypertension frequencies reported in recent epidemiological data,38 two thirds of the protection against hypertension conferred on young white women can be statistically accounted for by the NM phenotype. Amidst the highly complex interplay of factors that determine tissue responses to Ang II, it appears that female sex hormones play a leading role. We speculate that they enable an "override of genotype," amounting to phenotypic protection in women. We suggest that although genotype reveals itself in men, female sex hormones, either directly or indirectly, lessen the effect of a genetic predisposition in women.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported in part by a National Institutes of Health grant (MO1RR02635) to the Brigham and Women's Hospital General Clinical Research Center. Personal research of Dr Fisher was supported by the related Clinical Associate Physician award (MO1RR02635-10S1).
Received August 9, 1996; first decision September 24, 1996; accepted October 18, 1996.
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A. Benetos, K. Okuda, M. Lajemi, M. Kimura, F. Thomas, J. Skurnick, C. Labat, K. Bean, and A. Aviv Telomere Length as an Indicator of Biological Aging : The Gender Effect and Relation With Pulse Pressure and Pulse Wave Velocity Hypertension, February 1, 2001; 37(2): 381 - 385. [Abstract] [Full Text] [PDF]
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M. Giacche, A. Vuagnat, S. C. Hunt, P. N. Hopkins, N. D. L. Fisher, M. Azizi, P. Corvol, G. H. Williams, and X. Jeunemaitre Aldosterone Stimulation by Angiotensin II : Influence of Gender, Plasma Renin, and Familial Resemblance Hypertension, March 1, 2000; 35(3): 710 - 716. [Abstract] [Full Text] [PDF]
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 A. Ylitalo, K. E. J. Airaksinen, A. Hautanen, M. Kupari, M. Carson, J. Virolainen, M. Savolainen, H. Kauma, Y. A. Kesaniemi, P. C. White, et al. Baroreflex sensitivity and variants of the renin angiotensin system genes J. Am. Coll. Cardiol., January 1, 2000; 35(1): 194 - 200. [Abstract] [Full Text] [PDF]
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 L. P. Audoly, S. L. Tilley, J. Goulet, M. Key, M. Nguyen, J. L. Stock, J. D. McNeish, B. H. Koller, and T. M. Coffman Identification of specific EP receptors responsible for the hemodynamic effects of PGE2 Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H924 - H930. [Abstract] [Full Text] [PDF]
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N. D. L. Fisher, S. Hurwitz, C. Ferri, X. Jeunemaitre, N. K. Hollenberg, and G. H. Williams Altered Adrenal Sensitivity to Angiotensin II in Low-Renin Essential Hypertension Hypertension, September 1, 1999; 34(3): 388 - 394. [Abstract] [Full Text] [PDF]
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M. Horiguchi, M. Kimura, J. Skurnick, and A. Aviv Parameters of Lymphocyte Na+-Ca2+ Regulation and Blood Pressure : The Gender Effect Hypertension, November 1, 1998; 32(5): 869 - 874. [Abstract] [Full Text] [PDF]
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 T. Rankinen, T. Rice, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard G protein {beta}3 polymorphism and hemodynamic and body composition phenotypes in the HERITAGE Family Study Physiol Genomics, February 28, 2002; 8(2): 151 - 157. [Abstract] [Full Text] [PDF]
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 P. N. Hopkins, S. C. Hunt, X. Jeunemaitre, B. Smith, D. Solorio, N. D.L. Fisher, N. K. Hollenberg, and G. H. Williams Angiotensinogen Genotype Affects Renal and Adrenal Responses to Angiotensin II in Essential Hypertension Circulation, April 23, 2002; 105(16): 1921 - 1927. [Abstract] [Full Text] [PDF]
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