(Hypertension. 1995;25:848-853.)
© 1995 American Heart Association, Inc.
Articles |
Circulating Nitric Oxide (Nitrite/Nitrate) Levels in Postmenopausal Women Substituted With 17ß-Estradiol and Norethisterone Acetate
A Two-Year Follow-up Study
From the Department of Obstetrics and Gynecology, Clinic of Endocrinology, University Hospital, Zurich, Switzerland (M.R., B.I., P.J.K.); and the Department of Medicine, Center for Clinical Pharmacology, University of Pittsburgh (Pa) Medical Center (E.K.J., R.K.D.).
Correspondence to Dr Raghvendra K. Dubey, Center for Clinical Pharmacology, Department of Medicine, 623 Scaife Hall, University of Pittsburgh Medical Center, Pittsburgh, Pa 15213-2582.
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Abstract |
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Abstract Postmenopausal women (PMW) have an increased risk of cardiovascular disease that is attenuated by hormone replacement therapy (HRT). Inasmuch as hypertension and atherosclerosis are associated with diminished endothelium-derived nitric oxide (NO), we investigated whether HRT augments NO release in PMW. We determined serum levels of nitrite/nitrate (NO2+NO3) at baseline and during the 6th, 12th, and 24th months of the study in two groups of PMW. One group (HRT-PMW, n=13) received continuous transdermal administration of 17ß-estradiol (Estraderm-TTS-50) supplemented with oral norethisterone acetate (NETA) on days 1 through 12 of each month, and the other group (control PMW, n=13) did not receive HRT. Blood samples in the HRT-PMW group were collected without regard to whether subjects were taking NETA at the time of blood sampling. Serum NO2+NO3 levels increased in HRT-PMW for the duration of the study, whereas serum NO2+NO3 levels remained unchanged in control PMW. When all samples regardless of timing of collection with respect to NETA treatment were included in the statistical analysis, the change in NO2+NO3 levels in HRT-PMW was significantly greater compared with the change in control PMW (P=.037). Likewise, when only those samples collected when estradiol-treated subjects were not taking oral NETA were included in the statistical analysis, the change in NO2+NO3 levels in the HRT-PMW group remained significant (P=.047) compared with control PMW. In contrast, when only those samples collected when estradiol-treated subjects were taking NETA were included in the analysis, the change in NO2+NO3 levels in the HRT-PMW group was not significant (P=.23) compared with control PMW. These results indicate that HRT increases NO levels in PMW, an effect that may contribute to the cardiovascular protection afforded by HRT in PMW. In addition, our data suggest, but do not prove, that concomitant administration of a progestin may attenuate the beneficial effects of estrogen replacement therapy with regard to NO release.
Key Words: nitric oxide • estradiol • norethindrone • progestational hormones • menopause • cardiovascular diseases
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Introduction |
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Several lines of evidence suggest that estrogens are cardioprotective. First, compared with men, women within the reproductive age group are protected against cardiovascular disease.1 Second, the reduced risk of cardiovascular disease in premenopausal women diminishes with the onset of menopause.2 Third, estrogen replacement therapy appears to reduce markedly the risk of cardiovascular disease in postmenopausal women (PMW).3 4
Although the cardioprotective benefits of estrogens appear well established, the mechanism of this cardioprotective effect remains unclear and is the subject of intense investigation. To date, alterations in plasma concentrations of lipoproteins,4 hemostatic factors,4 5 glucose,5 and insulin5 and reductions in arterial blood pressure5 have been put forward as possible explanations for estrogen-induced cardioprotection. However, these factors alone cannot explain the positive effects of estrogens on the cardiovascular system.
A hypothesis that has not been tested sufficiently is that estrogen-induced cardioprotection is mediated by estrogen-induced increases in the release of nitric oxide (NO) from the vascular endothelium. The rationale for this hypothesis is that NO release is reduced in cardiovascular diseases such as hypertension and atherosclerosis,6 and NO has several actions that are cardioprotective, such as vasodilation,7 8 inhibition of platelet adhesion and aggregation,6 9 and inhibition of smooth muscle cell proliferation and migration.10 11
Several studies support the NO hypothesis for estrogen-induced cardioprotection. Using acetylcholine (an endothelium-dependent dilator), Hayashi et al12 demonstrated that compared with aortic rings of male rabbits, basal release of NO from rings of female rabbits was increased and correlated with circulating estradiol levels. In another study, acetylcholine infusions caused constriction of coronary arteries in ovariectomized, atherosclerotic monkeys, and this vasoconstrictive effect of acetylcholine was reversed to vasodilation by continuous treatment with transdermal estrogen.13 This finding was recently confirmed in PMW, in whom estradiol acutely attenuated abnormal coronary vasomotor responses to acetylcholine.14 Further support for the NO hypothesis is found in the facts that estradiol induced constitutive NO synthase activity in cultured endothelial cells15 and administration of NG-nitro-L-arginine methyl ester (L-NAME, a competitive inhibitor of NO synthase) to oophorectomized ewes attenuated the uterine artery blood flow augmentation induced by estradiol.16
Although several animal studies support the NO hypothesis, very few studies have addressed this hypothesis in humans. Since NO is an extremely labile molecule,17 this dearth of clinical studies is in part due to the difficulty of measuring NO release from the vascular endothelium in intact humans. Also, although much in vivo work on NO synthesis has been performed with the use of NO synthase inhibitors and stimulators,7 8 16 17 long-term studies in humans with these approaches are problematic.
More recently, however, it has been established that NO decomposes rapidly in biological solutions into nitrite (NO2) and nitrate (NO3).18 These stable compounds can be analyzed in serum, plasma, or both,19 20 21 22 23 and NO2+NO3 levels have been used as markers for NO synthase activity in vivo.19 20 21 22 23 Indeed, metabolic tracer studies in humans with the use of L-[guanidino-15N2]arginine have clearly demonstrated that increased nitrate production in serum in vivo was derived from NO generated from the terminal guanidino nitrogen atom of labeled L-arginine.22
Using the newly established marker (NO2+NO3) for in vivo NO synthesis, we recently tested the NO hypothesis regarding the cardioprotective mechanism of estrogen in humans.21 In that study, we demonstrated that circulating NO2+NO3 levels increased with follicular development and directly correlated with levels of estradiol but not with levels of progesterone, follicle-stimulating hormone (FSH), or luteinizing hormone.21 Although our results provided evidence for estrogen-induced NO synthesis, the contribution of other circulating factors that might also increase with the development of the follicle could not be ruled out, and no cause-and-effect relationship could be established. Accordingly, the major purpose of the present study was to further test the hypothesis that increased NO release could contribute to the cardioprotective effects of estrogen.
Another important yet open question regarding estrogen-induced cardioprotection is whether progestins diminish the cardioprotective effect of estrogens. Since administration of an estrogen to PMW without concomitant treatment with a progestin increases the risk of endometrial cancer, the combined administration of a progestin with an estrogen is currently the preferred method of hormone replacement therapy (HRT) in PMW. However, if progestins do indeed diminish estrogen-induced cardioprotection, the optimal combination of estrogens and progestins in HRT will have to be reevaluated. Unfortunately, this issue remains unresolved, and data have been presented that both support24 and refute5 the hypothesis that progestins block estrogen-induced cardioprotection. Therefore, a secondary objective of the present study was to assess whether any effect of estrogen replacement therapy on serum NO2+NO3 levels was attenuated by concomitant administration of a progestin.
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Methods |
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Subjects
Twenty-six healthy, postmenopausal European white women were enrolled in the study. Inclusion criteria were as follows: (1) last menses not less than 6 months nor more than 48 months from the time of enrollment, (2) never treated with HRT, (3) serum FSH less than 140 IU/L, (4) 17ß-estradiol levels less than 40 pmol/L, and (5) at least 45 years of age. All women enrolled in the study had similar lifestyles and dietary habits, and all gave written informed consent to the study, which was approved by the Institutional Medical Research Committee on Clinical Investigation.
Protocol
Subjects were randomly assigned to receive either HRT (HRT-PMW
group, n=13) or no HRT (control PMW group, n=13). The HRT-PMW group
received 17ß-estradiol through a transdermal patch (Estraderm-TTS-50,
Ciba) that was applied to the hips and replaced every 3 to 4 days. The
HRT-PMW group also received a daily dose of 1 mg norethisterone acetate
(NETA) orally from days 1 through 12 of each month. Blood samples for
serum NO2+NO3 levels were drawn at baseline
(ie, before HRT was initiated) and then again at 6, 12, and 24 months
into HRT. The samples were withdrawn anytime during the month without
regard to whether subjects were taking NETA at the time of blood
sampling. All blood samples were drawn early in the morning after
subjects had fasted overnight. None of subjects had any infection, nor
were they taking any other medications 2 weeks before as well as at the
time of blood sampling. Samples were collected in ice-cold tubes, and
serum was separated by centrifuging the sample at 800g for
10 minutes. The samples were stored at -20°C until analysis.
Nitrite/Nitrate Analysis
Serum NO2+NO3 levels were measured with
the use of the Greiss reagent as previously
described.21 25 Briefly, aliquots (250 µL) of serum were
diluted with ultrapure water (500 µL, Seromed Biochrom) and incubated
at room temperature with 250 µL substrate buffer (0.1 mol/L
imidazole, 210 µmol/L NADPH, 3.8 µmol/L flavine adenine
dinucleotide; pH 7.6) in the presence of nitrate-reductase
(Aspergillus niger, 70 IU/L; Boehringer Mannheim) for 45
minutes to convert NO3 to NO2. Total
NO2 (NO2+NO3) was then analyzed by
reacting the samples with Greiss reagent (58 mmol/L sulfanilamide and
3.8 mmol/L naphthalene-ethylene diamine dihydrochloride in 0.5 mol/L
H3PO4; Spectroquant, Merck). Reacted samples
were treated with 200 µL trichloroacetic acid (1.2 mol/L) and
centrifuged for 5 minutes at 8000g, and the absorbance of
the supernatant was measured at 525 nm. Amounts of NO2 in
serum were estimated from a standard curve of NaNO2
obtained by enzymatic conversion of NaNO3 (0 to 32
µmol/L, Merck). Since very little or no NO2 is found in
serum,21 25 we did not attempt to differentiate between
NO2 and NO3 but rather enzymatically converted
all NO3 to NO2. Therefore, we report results as
NO2+NO3.
Hormone Analysis
Serum 17ß-estradiol levels were analyzed with a previously
described radioimmunoassay method21 using a commercially
available radioimmunoassay kit (Diagnostic Products Corp). Serum FSH
levels were estimated by means of a radioimmunoassay kit produced by
Immuno Diagnostic Systems as previously described.21
Statistics
The person performing the NO2+NO3 assay
was unaware of whether the sample was from a subject in the HRT-PMW
group or the control PMW group. Baseline measurements of serum
NO2+NO3 levels were obtained from all 26
subjects. Seventeen of the 26 subjects had plasma levels of
NO2+NO3 reevaluated at 6, 12, and 24 months
after the baseline samples had been obtained. The remaining 9 subjects
had NO2+NO3 levels redetermined at two of the
three time points, but data for one time point was unobtainable because
the subject did not keep the scheduled clinic appointment. To ascertain
whether plasma levels of NO2+NO3 varied with
time into treatment, the 17 subjects for whom complete data sets were
available were analyzed by a two-factor ANOVA with repeated measures
(factor A: treatment group; factor B: time period). This analysis
revealed that the effect of treatment on plasma
NO2+NO3 levels was not significantly affected
by time into the study (P=.699). Since time into treatment
appeared not to affect the outcome and since a repeated-measures design
could not be used on the 9 subjects with incomplete data sets,
NO2+NO3 levels for the postbaseline samples
were averaged for all 26 subjects. The change from baseline plasma
levels of NO2+NO3 was calculated and compared
between the two groups with an unpaired, two-tailed Student's
t test (with unequal variances). For assessment of the
effects of estradiol in the presence and absence of NETA, in the
estradiol-treated group, all postbaseline serum
NO2+NO3 determinations obtained while subjects
were not taking NETA were averaged, and all samples obtained while
subjects were taking NETA were averaged separately. For all but 4
subjects, the change (
, determined as postbaseline averages minus
baseline) could be computed when the subjects both were and were not
taking NETA. These values were also compared with the control PMW
group values using an unpaired, two-tailed Student's t
test (with unequal variances). The criterion of significance was a
value of P<.05. Data are presented as mean±SEM.
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Results |
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Serum 17ß-estradiol levels were significantly (P<.01) higher in the HRT-PMW group compared with the control PMW group (133±30 versus <40 pmol/L). Furthermore, in HRT-PMW, serum 17ß-estradiol levels were similar regardless of whether subjects were or were not taking NETA at the time of blood sampling (133±30 versus 130±26 pmol/L).
The average baseline serum NO2+NO3 level
in all 26 subjects was 20.2±2.4 µmol/L. In the control PMW group,
the time-averaged (6 to 24 months) NO2+NO3
level remained remarkably stable (change from baseline
NO2+NO3 level, 0.11±1.1 µmol/L). In
contrast, in the HRT-PMW group, the time-averaged (6 to 24 months)
NO2+NO3 level increased from baseline by
6.3±2.6 µmol/L (P=.037 compared with the average
NO2+NO3 obtained in the control PMW group).
When the time-averaged NO2+NO3 level in the
HRT-PMW group was calculated by including only samples collected while
the subjects were not taking NETA, the change from baseline
NO2+NO3 level was still significantly increased
compared with the NO2+NO3 level obtained in
the control group (P=.047) (Figure, top). In
contrast, when the time-averaged NO2+NO3 level
in the HRT-PMW group was calculated by including only samples collected
while the subjects were taking NETA, the
NO2+NO3 level in the HRT-PMW group was not
significantly different from the NO2+NO3
level obtained in the control group (P=.230) (Figure,
bottom).
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In our previous study,21 we observed that 17ß-estradiol levels and NO2+NO3 levels in normal cycling women (during the follicular phase) ranged from 300 to 930 pmol/L and 38±3.0 µmol/L, respectively. These values are statistically greater than the 17ß-estradiol levels (<40 pmol/L) and NO2+NO3 levels (20.2±2.4 µmol/L) observed in the 26 PMW subjects at baseline in the present study. Furthermore, after initiation of HRT, the levels of both 17ß-estradiol (133±30 pmol/L) and NO2+NO3 (30±4.8 µmol/L) normalized compared with levels in cycling women.
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Discussion |
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This study tested the hypothesis that estrogens increase NO production in vivo. In a previous study, we observed that in normal cycling women, physiological increases in circulating NO2+NO3 levels during follicular development directly correlate with 17ß-estradiol but not with progesterone, FSH, or luteinizing hormone.21 Although these observations were consistent with the hypothesis that estrogens increase NO production in vivo, a direct cause-and-effect relationship could not be established. Therefore, the results of the present study provide the first direct evidence for a cause-and-effect relationship between estradiol and NO production.
NO is a labile substance with a short half-life, and its direct measurement has proved to be difficult. Since the time Marletta et al18 demonstrated that in biological solutions NO decomposes rapidly into nitrite (NO2) and nitrate (NO3), several in vivo and in vitro studies have used changes of NO2+NO3 in biological fluids (serum/plasma and urine) and culture media as an index of NO production.19 20 21 22 23 Schultz and Raij26 reported that increases in NO2+NO3 levels in the serum of rats treated with endotoxin were inhibited by coadministration of the NO synthase inhibitor L-NAME, suggesting that NO2+NO3 levels do reflect endogenous NO production. Because of ethical reasons, similar studies in humans have not been conducted. However, using metabolic tracer studies with L-[guanidino-15N2]arginine as a substrate for NO synthesis, Hibbs et al22 demonstrated in humans that increased nitrate production in serum is derived from NO generated from the terminal guanidino nitrogen atom of the labeled L-arginine. Although NO is the primary source for circulating NO2+NO3, their levels could be influenced by high, but not low, nitrate diets.23 Using NO2+NO3 as a marker, Evans et al23 and Hibbs et al22 have shown that in the presence of a low nitrate diet, endogenous production of NO in humans can be measured. Since the current study was conducted in white European women consuming a diet that could be characterized as a low nitrate diet according to the classification of Evans et al, the endogenous changes in NO production could be measured by assaying changes in NO2+NO3 levels.
There are additional reasons for concluding that the measurement of NO2+NO3 in the serum, as in the present study, would reflect the basal (endogenous) production of NO and is not due to dietary nitrate intake: (1) Nitrate excretion in humans exceeds its intake.22 (2) Urinary nitrate reaches its maximal level 4 to 6 hours after an oral load and returns to baseline after approximately 18 hours27 ; thus, it is likely that after 14 hours (overnight) of fasting, dietary nitrates would have been eliminated from the blood by urinary excretion. (3) Nitrate levels are significantly higher in urine compared with serum.22 Having said that, it is also possible that other factors may have influenced the nitrate levels. This remains a limiting factor of the present study, and future well-controlled studies need to be conducted.
In the present study, the controlled administration of estrogen within the same group of subjects strongly supports the notion that increases in NO2+NO3 were caused by 17ß-estradiol administration. The contribution of other ovarian hormones could be ruled out as there is no follicular development in PMW. Additionally, dietary nitrates cannot account for the changes in serum NO2+NO3 levels, as no changes in serum NO2+NO3 levels were observed in control PMW on a similar diet. Two weeks before as well as at the time of sample withdrawal, the subjects were free of infection and trauma and were not taking other medications. Therefore, these well-known inducers of NO production can also be ruled out as contributing to the NO2+NO3 response observed in the current study.
Importantly, the increases in serum NO2+NO3 levels in samples collected after 6, 12, and 24 months of estradiol administration did not vary significantly. It is possible that the effects of estrogen are rapid and receptor operated and that the upregulation of estrogen receptors in the vasculature of PMW contributes to the increased NO synthesis. Indeed, in PMW with little or no circulating estradiol, the estrogen receptors in blood vessels are reported to be lost or decreased.28 Furthermore, changes in steroid nuclear receptors in most circumstances occur in hours.29 However, whether short-term treatment (days or months) with estradiol would also induce a similar increase in NO2+NO3 levels remains unknown and needs to be investigated further.
The present study also suggests that progestins may attenuate estrogen-induced NO production. In this regard, we observed that estradiol-induced NO synthesis was diminished when subjects were taking oral NETA. If this result is reproducible, it may have implications for the therapeutic design of HRT in PMW. Furthermore, the full magnitude of the estradiol effect on NO production in the present study may have been underestimated, as carryover effects of NETA on NO2+NO3 levels may have persisted into the NETA-free time intervals.
Our observation that no significant increases in serum NO2+NO3 levels were observed when estradiol was coadministered with NETA suggests that in the presence of NETA, NO production decreases. Progestins have been reported to impair the cardioprotective effects of estrogens24 as well as enhance the vascular damage associated with hypertension.30 However, combined therapy of conjugated estrogens with medroxyprogesterone acetate has recently been shown to have better cardioprotective effects compared with estrogens alone.5 In the present study, we have demonstrated a detrimental effect of NETA on circulating NO2+NO3 levels during estradiol substitution. Additionally, we have previously shown that luteal increases in progesterone levels in hormonally stimulated menstrual cycles decrease serum NO2+NO3 levels, even in the presence of high concentrations of 17ß-estradiol.21 However follicular phase concentrations of progesterone do not impair NO synthesis.21 Several factors may contribute to the failure of estrogen to induce serum NO2+NO3 levels in the presence of NETA: (1) The level of NETA, which is commonly used in a dosage of 1 mg/d for HRT in Europe, could be high enough to abrogate estradiol-induced NO synthesis via a receptor-operated mechanism. In this regard, progesterone inhibits estrogen-induced endothelium-dependent responses associated with the production of NO31 but is unable to inhibit cytokine-induced NO synthesis in cultured endothelial cells.32 Thus, it is plausible that NETA exerts its effects by directly inhibiting/downregulating estrogen-stimulated constitutive NO synthase activity. (2) NETA may directly inhibit and/or downregulate NO synthase activity independently of the effects of estradiol. (3) NETA may alter the clearance of NO2+NO3. Finally, since NETA is an artificial derivative of testosterone and possesses not only gestagenic but also androgenic properties, it is quite different from natural progesterone. Thus, it is uncertain whether other progestins would also inhibit estrogen-induced NO production.
The precise mechanism by which estradiol may induce/stimulate NO release still remains unclear. It is conceivable that estrogens, via a receptor-operated mechanism,29 33 stimulate NO synthase activity, increase NO synthase protein, and/or increase the levels of essential cofactors for NO synthase. Indeed, it has been demonstrated that estradiol-induced increases in uterine blood flow are inhibited by L-NAME,16 suggesting that estradiol stimulates/increases NO synthesis. Furthermore, 17ß-estradiol has been shown to induce the expression of constitutive NO synthase enzyme and NO2+NO3 production in cultured human aortic endothelial cells.15 However, one can only speculate on whether increases in NO synthesis in the present study are due to the stimulation of NO synthase, constitutive or inducible. Additionally, estradiol might decrease the level of NO scavengers, such as superoxide anions, factors that are known to accelerate the inactivation/breakdown of intracellular NO. Alternatively, estradiol is known to improve lipid metabolism,34 prevent abnormal vascular growth and narrowing of the blood vessel,14 30 35 and enhance blood flow,16 factors that are known to increase endothelium-derived NO release.36 37
Finally, we can only speculate on which cells are the main source for the increase in circulating NO2+NO3, because in addition to endothelial cells, several other cell types synthesize NO.6 17 Considering the fact that 17ß-estradiol induces NO synthesis in cultured human aortic endothelial cells via stimulation of constitutive NO synthase activity15 and augments acetylcholine- induced basal release of NO from endothelium,12 13 14 15 16 it is possible that the increases in circulating levels of NO2+NO3 we observed are solely endothelium derived. However, other possibilities cannot be ruled out and need to be investigated further.
In conclusion, we provide the first clinical evidence that estradiol treatment in PMW is accompanied by a significant increase of circulating NO2+NO3 levels, and these levels are returned approximately to those observed in premenopausal women. Although increases of serum NO2+NO3 levels are much lower when estradiol is coadministered with NETA, the overall HRT (estradiol and estradiol+NETA) significantly increases serum NO2+NO3 levels. These results strongly suggest that the cardioprotective effects of estradiol, as well as of HRT, could at least be partly mediated through estradiol-induced NO synthesis. Furthermore, in PMW a balanced treatment with estradiol and an appropriate progestin in an adequate dose may play a pivotal role in regulating normal cardiovascular function by modulating NO synthesis.
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health (HL-40319 and HL-35909), Bethesda, Md. The authors acknowledge the technical assistance of the staff of the Endocrinology Laboratory of the University Hospital Zurich.
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