Obstetrics & Gynecology:
Effect of Hot Flushes on Vascular Function: A Randomized Controlled Trial
Tuomikoski, Pauliina MD1; Ebert, Pia MD1; Groop, Per-Henrik MD, PhD2,3; Haapalahti, Petri MD, PhD4; Hautamäki, Hanna MD1; Rönnback, Mats MD, PhD2,3; Ylikorkala, Olavi MD, PhD1; Mikkola, Tomi S. MD, PhD1
From the 1Department of Obstetrics and Gynecology, Helsinki University Central Hospital, 2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, 3Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, and 4Division of Clinical Physiology and Nuclear Medicine, Helsinki University Central Hospital, Helsinki, Finland.
Supported by unrestricted grants from the Finnish Society for Menopause Research, the Päivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Nylands Nation, the Orion Research Foundation, the Finnish-Norwegian Medical Foundation, the Finnish Medical Foundation, and the Helsinki University Central Hospital Research Fund
The authors thank Professor Seppo Sarna from the Department of Public Health at Helsinki University for his assistance with the statistical analyses.
Corresponding author: Tomi S. Mikkola, MD, PhD, Associate Professor, Helsinki University Central Hospital, Department of Obstetrics and Gynecology, Haartmaninkatu 2, PO Box 140, FIN-00029 HUS, Helsinki, Finland; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To compare the vascular responses to hormone therapy in women with and without hot flushes.
METHODS: We randomly assigned 143 healthy, recently postmenopausal women (mean age 52.4±0.2 years, time since menopause 19.5±0.9 months) with intolerable hot flushes (more than seven moderate/severe episodes per day) or tolerable hot flushes (fewer than three mild episodes per day) to receive 1 mg of transdermal estradiol gel, oral estradiol (2 mg) with and without daily medroxyprogesterone acetate, or placebo for 6 months. Vascular function was assessed by pulse–wave analysis and endothelial function testing with nitroglycerin and salbutamol challenges.
RESULTS: Hot flushes did not affect the changes in arterial or aortic stiffness or endothelial function in response to various forms of hormone therapy. However, in women with tolerable hot flushes, oral estrdiol caused a decrease of 13.2% (P=.028) in the time to the first systolic peak (dependent on the rapid phase of ventricular ejection) after nitroglycerin. In addition, the time to the reflected wave (dependent on pulse–wave velocity) after nitroglycerin was decreased by 8.4% (P=.018). These effects were not seen in women with intolerable hot flushes or with the other treatment regimens.
CONCLUSION: Women without troublesome hot flushes are susceptible to unfavorable vascular effects after oral estrogen treatment, resulting in less compliant vasculature.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00668603.
LEVEL OF EVIDENCE: I
Postmenopausal hormone therapy (HT) was once recommended for the prevention of cardiovascular disease. This recommendation was based on the marked reduction (approximately 40–60%) of cardiovascular disease risk in the numerous observational studies1–3 when recently postmenopausal women, typically with severe vasomotor hot flushes, had decided to initiate HT. However, when older women with no or minimal vasomotor hot flushes were treated in randomized, double-blind, placebo-controlled trials, HT had no beneficial effect in secondary4 or primary5,6 prevention of cardiovascular disease. There are various explanations for these divergent data, such as healthy user bias in the observational studies, difference in time since menopause when initiating HT, and a difference in hot flush status between the populations in observational and randomized HT studies.7,8
The cause of hot flushes is not understood in detail, but menopause-associated hypoestrogenism is accompanied by vasodilatation in cutaneous arterioles; this is eliminated by restoration of estrogen levels.9,10 This may also affect larger arteries, and indeed women with hot flushes may have reduced flow-mediated dilation,11 an overall adverse cardiovascular risk profile,12 as well as reduced bone mineral density13 compared with asymptomatic women. We have previously shown that there is a relationship between hot flushes and arterial vasodilatation after a nitroglycerin challenge in recently postmenopausal women.14 We hypothesized that hot flushes, besides affecting baseline vascular function, may also affect vascular responses to HT. Therefore, the present trial was designed to compare the vascular responses to HT in women with and without hot flushes. Additionally, since oral and transdermal administration of estrogens results in different estrogenic milieus, we compared oral and transdermal estrogen, the former alone and in combination with medroxyprogesterone acetate.
One hundred forty-three healthy, nonsmoking women (mean age 52.4±0.2 years, time since menopause 19.5±0.9 months) were included in this study. Details of recruitment and subject selection have been presented before,14 and only the main points are repeated here. The study was carried out at the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland. The enrollment period was from May 2005 to May 2007, and follow-up lasted until December 2007. Inclusion criteria were time since the last menstruation (within 6–36 months), the level of follicle-stimulating hormone (FSH) more than 30 units/L, and no previous use of HT. Exclusion criteria were smoking, hysterectomy, blood pressure higher than140/90 mm Hg, body mass index higher than30 kg/m2, any clinically significant disease, or drug treatment. Hot flushes were rated by using a hot flush weekly weighted score that scores mild symptoms as 1, moderate symptoms as 2, and severe symptoms as 3.15–17 For the present study, women experiencing seven or more moderate/severe hot flushes per day were classified as having “intolerable” hot flushes (n=68, likely to initiate HT in clinical practice), whereas women with a maximum of three mild hot flushes/day were classified as having “tolerable” hot flushes (n=75, likely not to initiate HT in clinical practice). The study was approved by the Ethics Committee of Helsinki University Central Hospital, and it was conducted according to the principles of The Declaration of Helsinki. The study (SYMPTOM) has been registered in the National Agency for Medicine (EudraCT 2004–005091–16) and the U.S. National Institutes of Health Clinical Research Registry (No. NCT00668603). Written informed consent was obtained from all participants.
The participants were randomly assigned (sealed envelope) in blocks of four with regard to the hot flush status at baseline (intolerable or tolerable hot flushes respectively) and treated in a placebo-controlled, double-blind trial for 6 months with either estradiol (E2) or placebo. Estradiol was given either orally (2mg/d) or transdermally as a gel (1 mg/d). One group of women was randomly assigned to receive oral E2 2 mg/d combined with daily medroxyprogesterone acetate 5 mg/d (Fig. 1). The anticipated mean change in pulse–wave analysis to HT was estimated as 6.6 units with a standard deviation of 1. The comparisons were calculated to achieve 80% power to detect a 15% difference in the responses to HT between women with intolerable and tolerable hot flushes at a conventional alpha-level of 0.05 based on a previous study by our investigators.18 The appearance of all regimens was identical (always both tablets and gel) to guarantee the double-blind character of the trial. Compliance was evaluated by counting the unused study regimens. Each woman showing endometrial thickness 9 mm or more at 6 months received medroxyprogesterone acetate (5 mg/d) for 2 weeks to initiate endometrial shedding; this was started after completion of vascular examination.
Serum samples collected at baseline and at 6 months were used for the assessment of estrone (E1) and E2. The level of E1 was assayed as a dansyl derivative by liquid chromatography–tandem mass spectrometry based on the method described by Nelson et al19 with some modifications. Briefly, deuterated E1 (D4-estrone; CDN Isotopes Inc., Pointe-Claire, Canada) was used as an internal standard. Calibrators containing E1 at 25–1,000 pmol/L (Riedel-deHaën, Buchs, Switzerland) were prepared in 4% bovine albumin. The column was directly connected to the electrospray ionization probe, and dansylated E1 was detected in positive mode. Data were acquired and processed by using Analyst software 1.4.2 (Sciex, Applied Biosystems Inc., Foster City, CA). The intraassay and interassay coefficients of variation were between 7.8% and 12%. Levels of E2 were determined by radioimmunoassay, using an established, commercially available kit (E2-2; Diasorin Inc, Stillwater, MN) as indicated by the manufacturer. The intraassay and interassay coefficients of variations were less than 6.1%. The serum samples were also used for the assessment sex-hormone binding globulin, thyroid-stimulating hormone, and FSH using routine laboratory methods.
Vascular function was assessed by pulse–wave analysis (SphygmoCor 7.0; AtCor Medical, Sydney, Australia), as described previously.14,20 Briefly, three series of baseline artery wave forms, recorded from the right radial artery using a micromanometer (SPC-301; Millar Instruments, Houston, TX), were used for the calculation of a central aortic wave form.20–22 Pulse waves were analyzed for 1) the augmentation index, a measure of systemic arterial stiffness,23 2) the time to the return of the reflected wave (TR), a measure of aortic stiffness,24 3) the timing (Te) of the first systolic peak, a measure of left ventricular function,25 and 4) the endothelial function index, which expresses the endothelium-dependent vasodilatation (change in the augmentation index after salbutamol, releasing nitric oxide) as a percentage of the endothelium-independent vasodilatation (change in the augmentation index after nitroglycerin).14,26,27 Pulse–wave analyses at baseline and at 6 months of a given treatment were performed by four investigators (P.T., P.E., H.H., and T.S.M) for their respective patients.
Normality was assessed with the Shapiro-Wilk test. At baseline, women with intolerable and tolerable hot flushes were compared with the Student t test, and data that were non-normally distributed after logarithmic transformations were compared with the Mann–Whitney U test. The relationships between variables were investigated by using Pearson’s product-moment correlation coefficient for normally distributed variables and Spearman’s nonparametric correlation coefficient for variables with non-normal distribution. Normally distributed data in the different treatment groups were compared by means of one-way analysis of variance (ANOVA). Non-normally distributed data were compared with the Kruskal–Wallis test, and post hoc analyses were made with the Mann–Whitney U test with Bonferroni corrections. Two-way between-groups ANOVA was used to explore the impact of hot flushes and HT on different variables derived from the pulse–wave analysis. Owing to the multicollinearity between these variables, a univariable instead of multivariable approach was used. The effect of treatment on the dependent variables was assessed as the value at 6 months expressed as a percentage of that at baseline. Analysis of covariance was used to explore the impact of possible covariates including time since last menstruation (owing to its skewed distribution this variable was converted to ranks) and the levels of E1 and E2 expressed as percentages from baseline on the responses of different vascular variables. In all ANOVAs, Tukey honestly significant differences and Games–Howell post hoc comparisons were used for variables with equal and unequal variances, respectively. Change in the hot flush weekly weighted score was assessed as absolute change from baseline because of the baseline values of 0 in 22 women. Independence among subgroups of symptoms and treatments at baseline and at 6 months were tested with the χ2 test. Statistical analyses were performed with SPSS 14.0 software for Windows (SPSS Inc. Chicago, IL). Data are presented as mean±standard error regardless of the pattern of distribution. A two-tailed P<.05 was considered statistically significant.
At baseline, there were no differences in age, body mass index, or levels of E1 or E2 between women with tolerable and intolerable hot flushes (Table 1). The women with intolerable hot flushes showed a shorter time period (16.9±1.3 months compared with 21.8±1.2, P=.002) since the onset of menopause and slightly lower (67.9±2.8 units/L compared with 78.7±3.4, P=.044) levels of FSH compared with the women with tolerable hot flushes. At baseline, women with intolerable and tolerable hot flushes differed in vascular function only in Te and TR, which were longer (P=.021 and P=.033, respectively) after nitroglycerin challenge in women with intolerable hot flushes (Table 1). No correlations between basic clinical characteristics and the levels of E1 or E2 and pulse–wave analysis variables were found (Table 1). Vascular function at baseline was comparable between the eight subgroups of hot flushes and treatment regimens (Table 2).
Of the 143 women at baseline, 124 (86.7%) were studied with pulse–wave analysis at 6 months. Serum samples were collected from the 143 women at baseline and from 137 women at the end of the study period. Eight women with tolerable symptoms and six women with intolerable symptoms were either lost during follow-up or pulse–wave analysis data were not obtained at 6 months. Three women quit after withdrawal of consent, and two women left because of uterine bleeding. The drop-outs were evenly distributed between the two study groups and between the different treatment groups.
At 6 months, the levels of E1 and E2 were increased in all active treatment groups compared with the placebo group (P<.001 for all). Transdermal E2 caused only a threefold rise in E1 levels, whereas oral E2 and oral E2 plus medroxyprogesterone acetate brought about more robust increases in E1 (20-fold and 14-fold, respectively) that were similar regarding the two oral treatments (P=.428) and significantly greater than with transdermal E2 (P<.001) (Table 3). The levels of E2 increased significantly in connection with all active treatments compared with placebo (P<.001 for all), and the increases were similar among all active treatment groups (Table 3). The increases in E1 and E2 concentrations were also similar in women with intolerable and tolerable hot flushes. A significant decrease in the number and severity of hot flushes, assessed as absolute change in the hot flush weekly weighted score, was observed in women with intolerable hot flushes (−113.0±10.0), whereas no effect (−3.7±1.3) was seen in women with tolerable hot flushes (P<.001 for difference between groups). When women with intolerable hot flushes were analyzed separately, all active treatments were equally effective in reducing the hot flush weekly weighted score compared with placebo (Table 4), whereas the use of placebo led to a nonsignificant (22.6%) decrease in the hot flush weekly weighted score. No effect of treatment on the change in the hot flush weekly weighted score in women with tolerable symptoms was seen.
The four different study regimens did not lead to any significant changes in the augmentation index, and the responses were similar in women with intolerable and tolerable hot flushes. Similarly, the changes in Te and TR before nitroglycerin were unaffected by both hot flush status and treatment regimens. Changes in the levels of E1 or E2 or the time since menopause were not associated with these variables. However, significant interaction between hot flush status and the effect of treatment was found with both changes in Te (P=.009) and TR (P=.006) after the nitroglycerin challenge. Therefore, separate analyses were carried out for women with intolerable and tolerable hot flushes. No significant treatment effect was detected in women with intolerable hot flushes. However, in women with tolerable hot flushes, the use of oral E2 alone was associated with significant reductions in both Te and TR after nitroglycerin (Fig. 2). With oral E2 use, Te was decreased by 13.2% (to 86.8±5.0% from baseline, P=.028), and TR was decreased by 8.4% (to 91.6±3.2% from baseline, P=.018) when compared with placebo (108.3±4.4% and 106.0±3.4%, respectively). The time to the reflected wave (dependent on pulse wave velocity) after nitroglycerin was decreased by 8.4% (to 91.6±3.2% from baseline, P=.018) when compared with placebo (108.3±4.4% and 106.0±3.4%, respectively). The changes caused by oral E2 were also significantly different from those associated with transdermal E2 (Te 111.2±4.1% and TR 106.1±2.1%) or oral E2 plus medroxyprogesterone acetate (Te 111.6±8.4% and TR 107.4±4.8%) (Fig. 2). These changes in Te and TR after nitroglycerin were not associated with time since menopause or the changes in levels of E1 and E2.
Our data show that hot flush status affects vascular responses to HT and that only in women with tolerable hot flushes oral E2 leads to less receptive vasculature. We compared the vascular responses, as assessed by pulse–wave analysis, to various forms of HT in recently menopausal women with intolerable or tolerable hot flushes. Women in our study were considered to represent either those likely to initiate HT (intolerable hot flushes) or those not likely to use HT (tolerable hot flushes) in clinical practice. We have recently shown that women with intolerable hot flushes have prolonged Te and TR after a nitroglycerin challenge,14 and this was confirmed in the present study. It is possible that women with troublesome hot flushes have an elevated sympathetic tone, because the autonomic nervous system regulates both left ventricular ejection and aortic smooth muscle tone. This explanation is further supported by our present data indicating that this baseline difference vanished after HT treatment, when hot flushes were alleviated or disappeared. Obviously we cannot rule out the possibility that 6-month HT treatment could also result in structural and not only functional changes in the vasculature. However, since these changes were seen only in women with tolerable hot flushes, hot flush status appears to be a determinant of the vascular reaction to HT in recently menopausal women.
The use of oral E2 alone in women with tolerable, but not with intolerable, hot flushes was accompanied by a decrease of the rapid phase of ventricular ejection and an earlier return of the reflected wave after nitroglycerin challenge. These findings in women with tolerable hot flushes are potentially unfavorable, since a more rapid return of the reflected wave indicates acceleration of wave velocity and decreased vasodilatation—in other words less compliant vasculature.28 This effect was not seen during the transdermal use of E2 or during the combined use of oral E2 and medroxyprogesterone acetate. It is possible that the higher circulating estrogen levels, especially those of E1, during the use of oral rather than transdermal E2 are involved. This could result in differences in the up-regulation of estrogen receptors in the vascular wall29 or hepatic modulation of the renin-angiotensin system30 or vasoactive agents, such as nitric oxide and endothelin-1.31 Of these explanations, the activation of hepatic and/or gastrointestinal regulation of various biological factors by oral estrogen may be a key factor. Furthermore, these effects could be mediated by cytokines or inflammatory markers32 stimulated by oral HT. Oral33,34 but not transdermal35,36 estrogen therapy has been shown to increase the concentrations of various inflammatory markers (eg, C-reactive protein [CRP]), although the HT-related increase in CRP is most likely to be a result of metabolic hepatic activation rather than being a sign of an acute-phase vascular response.37 Whether this is also the case with other inflammatory markers is not clear, but it has been shown that hot flush status among premenopausal, perimenopausal, and postmenopausal women influences interleukin-8 levels.38
It has been suggested that vascular responses to E2 with and without medroxyprogesterone acetate differ, although this has not been clearly confirmed in all clinical trials.39–41 Our data support the concept of medroxyprogesterone acetate–related vascular differences, since we detected less compliant vasculature in women with tolerable hot flushes when receiving oral E2 but not when it was accompanied by medroxyprogesterone acetate. We cannot deduce the exact mechanisms behind this difference, but one possibility is that medroxyprogesterone acetate counteracts the effect of oral estrogen treatment. This is supported by the results of a study showing that oral estrogen alone or in combination with low-dose medroxyprogesterone acetate (2.5 mg) increased the levels of CRP and serum amyloid A protein, but not if oral estrogen was accompanied by a higher dose (5.0 mg) of medroxyprogesterone acetate.34 Similar results have also been shown when high-dose (20 mg) cyclic medroxyprogesterone acetate was used.42 Synthetic progestins such as medroxyprogesterone acetate also have androgenic40,43 properties, and thus, medroxyprogesterone acetate may reduce the strength of estrogen-mediated vascular effects. Therefore, in addition to dose, medroxyprogesterone acetate–related vascular effects may also be dependent on hot flush status.
Our study has some limitations. First, we studied only lean, white women, and thus, our results may not be generalizable to obese women or women of other ethnic origins. Second, we used hot flush diaries, and therefore, the number and severity of hot flushes are subjective. However, when women consider using HT, it is commonly based on their subjective experience of the severity of hot flushes. In addition, this method of classifying self-reported hot flushes into three categories according to the severity of sweating has been shown to be reliable.16 Third, an exposure time of more than 6 months could have been needed to reveal additional differences, although 3- to 6-month HT treatments have been commonly used in vascular function studies.29 Finally, we had a limited number of women in the subgroups, and thus, it is possible that in a larger study population more robust differences could have been revealed.
Assuming that our two study groups were representative of HT users and non-users in long-term observational studies, our findings support the claim that women with and without hot flushes are not comparable in their vascular responses to HT. Based on our results, it appears that women without troublesome hot flushes are susceptible to unfavorable vascular effects brought about by oral E2 treatment, resulting in less compliant vasculature. This could partly explain the divergent results between observational studies1,2 and randomized clinical trials in which HT-related cardiovascular disease effects have been assessed, since in observational studies, women were likely to have experienced hot flushes when initiating HT, whereas women entering clinical trials did not have troublesome hot flushes. Thus, in future studies assessing HT and cardiovascular disease end-points, hot flush status should be considered as a potential confounding factor.
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