Effects of the hormone replacement therapy on arterial stiffness and hemodynamics in the perimenopausal women

doi:10.21203/rs.3.rs-4967480/v1

Objective

This study aimed to examine the effect of hormone replacement therapy on arterial stiffness and hemodynamics in the perimenopausal women.

Methods

Sixty perimenopausal women were recruited for the present cohort study among the patients visiting our menopause clinic. 30 women, who were prescribed to do the hormone replacement therapy (HRT) from several months to 1 year, were investigated, together with another age-matched group (Control group) of 30 perimenopausal women without HRT. All participants underwent 2 serial carotid pulse wave velocity (PWV) and wall shear stress (WSS) assessments of the carotid artery at 1-year interval.

Results

Compared with the baseline value, there was no significant difference in PWV over 12 months between HRT and Control group, however, the WSS value increased significantly for both groups in 1 year (p < 0.05). After 1 year of the follow-up, the PWV at BS value was significantly lower in the HRT group than in the Control one (p < 0.05), but there was no significant statistical difference in the WSS value between two groups. Multiple linear regression analyses revealed that Triglycerides and HDL cholesterol were independently correlated with the changes in PWV (p < 0.05).

Conclusions

The hormone replacement therapy appears to impact on the arterial stiffness without affecting hemodynamics in the perimenopausal women. The time-mediated influence on WSS seems to overrule the potential HRT-mediated influence, thus the change of WSS cannot be excluded. Further research is needed to understand clearly the mechanism underlying the obtained results.

menopause

menopausal hormone therapy

pulse wave velocity

wall shear stress

The decline in arterial stiffness among perimenopausal women correlated with hormone replacement therapy.

PWV can be used to assess the effects of hormone replacement therapy onarterial stiffness in perimenopausal women.

Cardiovascular disease continues to be the leading cause of death and disability for the elderly and middle-aged women, who have spent nearly the half of their lives in the postmenopausal state. The perimenopause, which spans 2–8 years, begins with irregular menstrual cycles and ends with the final menstrual period. This period without the potentially protective effects of estrogen is related to an increased risk of the clinical and subclinical cardiovascular disease ^[1]. Hormone replacement therapy (HRT) can improve the perimenopause related symptoms ^[2], but many high-quality evidences for the effect of HRT on the cardiovascular health have been obtained for the women in postmenopausal. On the other hand, few data are available for the perimenopause women ^[3].

It has been shown that an increase in the aortic stiffness is an independent marker of the cardiovascular risk ^[4]. Pulse wave velocity (PWV) is considered the gold standard in evaluating the arterial stiffness as noted in the ESC/ESH guidelines ^[5]. Ultrafast ultrasound imaging has been demonstrated to be an effective method to evaluate the carotid stiffness through carotid PWV with a high reproducibility^[6]. Meanwhile, the progression of subclinical atherosclerosis has been strongly linked to a hemodynamic parameter, wall shear stress (WSS), which is a direct mechanical frictional force generated by flowing blood on the vessel wall^[7]. In addition, a lower WSS enhances the development and progression of atherosclerosis in the cerebral arteries, while a higher WSS inside the vasculature provokes plaque rupture ^{[8, 9]}. According to the relevant researches so far, the PWV value is directly related to the overall elasticity of arterial wall, however, the development of atherosclerosis is influenced strongly by the hemodynamic disorders^{[9, 10]}. There has been few or no research that observed simultaneously the elasticity of arterial wall and the hemodynamics inside arterial lumen. Thus, this study aims at elucidating the effects of HRT on arterial stiffness and hemodynamics perspectives for the perimenopausal women.

Participants in the study

Women aged 40–60 years old were included in this study if they were perimenopause (> 3 months and < 5 years since irregular menstrual cycles and other menopause-related symptoms, or within 12 months of the menopause). Only women with intact uterus were included. Women with hormonal treatment in the past, or a history of severe systemic disease including coronary heart disease, hypertension, diabetes mellitus, renal or liver dysfunction as well as malignant tumors, were also excluded. Ethics approval was granted by the Institutional Review Board of the hospital (TJ-IRB20220513), and all participants provided the written informed consent.

Study design

The investigation is a longitudinal cohort one that enrolled 60 perimenopausal women between 2022 and 2023. The patients underwent the evaluation of PWV and WSS at the baseline and 1-year follow-up. At every study visit, the participant information on demographics, menopause status, use of menopausal hormone therapy, and medical and cardiovascular disease(CVD) family history was recorded. In addition, the measurement of weight, height, blood pressure, laboratory tests laboratory tests (lipid and blood concentrations of follicle stimulating hormone,estradiol,progesterone) were performed. The menopausal symptoms were assessed by the Chinese version of the modified kupperman menopausal index (KMI) at the baseline and 1-year follow-up. According to the use of HRT, all patients were divided into two groups: the HRT group (n = 30) and Control one (n = 30). The Women in the HRT group were treated with estrogen therapy (ET), or estrogen + progestogen therapy (EPT) for several months to 1 year.

Carotid PWV Measurement

The carotid ultrasound imaging was performed for the participant in the supine position by using the Aixplorer ultrasound system (SuperSonic Imagine, Aix-en-Provence, France), equipped with an SL 10 − 2 probe, in the vascular PWV mode. Then, the probe was adjusted to make it parallel to the artery wall and avoid the venous structure as much as possible. By enabling the vascular PWV mode, the region-of-interest box (4 \(\:\times\:\)3 cm²) was moved to cover the common carotid artery, and two red lines tracked automatically the anterior and posterior walls of carotid artery. Meanwhile, the participant was instructed to hold his/her breath for 5 sec, and the images were automatically acquired. The mean PWVs in the region of interest box were calculated as follows; PWV (m/s) = D length (m)/D time (s), where D length represents the width of region-of-interest box, and D time is the time of pulse wave propagation in the region of interest box. The software identifies automatically the beginning of systole (BS) and end of systole (ES) (Fig. 1). The variance in PWV measurements at BS and ES was calculated as \(\:\varDelta\:\pm\:\). In the present study, the \(\:\varDelta\:\pm\:\)values were controlled to be\(\:\:<\:\)20% of the PWV values at BS and ES. All measurements were made three times for each side of the common carotid artery, and the mean values were calculated.

Carotid WSS Measurement

The ALOKA LISENDO 880 Ultrasound system (Hitachi, Tokyo, Japan), equipped with 13–15 MHz probe, was used for the WSS data acquisition. During the examination, the patients were connected to the electrocardiogram. After the routine measurement on the middle segment of the common carotid artery, the VFM vascular key was enabled on the color Doppler. VFM is vascular vector flow mapping. Three additional cross-beam data were acquired to measure the actual velocity of blood flow. At least, three heartbeats were required for the WSS analysis, which were saved as raw data. The Raw data sets were analyzed offline by using the DAS-RS1 software (Hitachi, Ltd., Japan). In this study, the viscosity coefficient of 4.0×10^− 3 Pa. s was used to estimate the shear stress in blood. The software automatically calculated the WSS at each measured point and in each frame. Among these values, the WSS mean values at the beginning of diastole (BD) and BS were calculated by selecting manually the time phase (Fig. 2).

Statistical Analysis

Statistical analyses were performed by employing SPSS version 17.0 (SPSS, Chicago, IL). The continuous variables are presented as mean\(\:\pm\:\)SD, and the categorical ones as frequency (percentage). Normality plots were obtained by using the Kolmogorov-Smirnov test.

Differences between the two groups were analyzed by the independent Student’s t test or Mann–Whitney U-test for the continuous variables and the Chi-squared test or Fisher’s exact test for the categorical ones. A paired-sample t-test was also used to compare the differences among all participants’ PWV and WSS values between baseline and 1-year follow-up points. Δ(PWV) was calculated as the follow-up PWV minus the baseline one. Δ(WSS) was also obtained to be the follow-up WSS minus the baseline one. The correlations of Δ(PWV) and Δ(WSS) with various clinical parameters were analyzed with the Spearman’s correlation coefficient (r). The least-square linear regression was used to evaluate the multivariate correlations of Δ(PWV) and Δ(WSS) with various clinical parameters. A two-tailed P value < 0 .05 was considered to indicate the statistical significance.

We enrolled 60 perimenopausal women who visited the ultrasound department in our hospital between March and July 2022. The present investigation includes the participants with the complete data on carotid PWV and WSS at the baseline and 1-year follow-up. Overall, two women in the HRT group and five women in the Control one dropped out owing to losing the follow-up, and 53 participants were finally analyzed.

Baseline characteristics

In total, 53 patients were included in the analysis with 28 patients in the HRT group and 25 patients in the Control one. As shown in Table 1, at the baseline, there was no statistical difference in the clinical characteristics and carotid ultrasound parameters including PWV and WSS between two groups.

Table 1

Baseline characteristics of the participants.
	HRT (n = 28)	Control (n = 25)	\(\:\text{t}\:/{\chi\:}\)²	P value
Age (years)	48.6\(\:\pm\:\)4.333	49.18\(\:\pm\:\)3.85	0.53	0.60
Height(cm)	157.05\(\:\pm\:\)4.55	158.99\(\:\pm\:\)4.80	1.47	0.15
Weight(kg)	53.18\(\:\pm\:\)9.59	56.44\(\:\pm\:\)9.22	1.25	0.22
BMI (kg/m²)	21.55\(\:\pm\:\)3.83	22.34\(\:\pm\:\)3.63	0.75	0.46
BSA (kg/m²)	2.00\(\:\pm\:\)0.27	1.79\(\:\pm\:\)0.30	-0.89	0.37
Heart rate (bpm)	73.50\(\:\pm\:\)11.09	75.34\(\:\pm\:\)11.79	0.57	0.57
SBP (mmHg)	121.29\(\:\pm\:\)16.23	118.65\(\:\pm\:\)21.74	0.51	0.61
DBP (mmHg)	68.85\(\:\pm\:\)15.91	71.97\(\:\pm\:\)10.85	0.78	0.44
Total cholesterol (mg/dL)	4.81\(\:\pm\:\)0.67	5.19\(\:\pm\:\)1.05	1.41	0.16
LDL (mg/dL)	2.60\(\:\pm\:\)0.75	3.08\(\:\pm\:\)0.97	1.82	0.07
HDL (mg/dL)	1.85\(\:\pm\:\)0.47	1.7497\(\:\pm\:\)0.53	-0.69	0.49
Triglycerides (mg/dL)	1.35\(\:\pm\:\)0.92	1.39\(\:\pm\:\)1.04	-1.27	0.21
E2 (pmol/L)	133.95\(\:\pm\:\)214.66	149.88\(\:\pm\:\)280.41	-1.38	0.17
Progesterone(nmol/L)	0.41\(\:\pm\:\)0.36	0.64\(\:\pm\:\)0.70	1.16	0.25
Testosterone (nmol/L)	0.50\(\:\pm\:\)0.33	9.49\(\:\pm\:45.76\)	0.76	0.45
FSH (mIU/mL)	62.72\(\:\pm\:\)40.17	54.82\(\:\pm\:\)35.13	-0.70	0.49
LH (mIU/mL)	43.15\(\:\pm\:\)18.99	32.24\(\:\pm\:\)19.69	-1.81	0.08
Prolactin (mIU/mL)	211.30\(\:\pm\:158.97\)	297.31\(\:\pm\:183.79\)	1.56	0.13
KMI (score)	16.00\(\:\pm\:\)6.58	16.41\(\:\pm\:\)7.58	0.16	0.88
Hypertension
Yes	3(7.5%)	5(12.5%)	0.14	0.71
No	37(92.5%)	35(87.5%)
Hyperlipidemia			0.88	0.35
Yes	12(30%)	16(40%)
No	28(70%)	24(60%)
Carotid plaque
Yes	5(12.5%)	7(17.5%)	0.83	0.36
No	35(87.5%)	31(77.5%)
BMI, body mass index; BSA, body surface area; SBP, systolic blood pressure; DBP, diastolic blood pressure.; LDL, low-density lipoprotein; HDL, high-density lipoprotein; LH, Luteinizing hormone.
Data are expressed as mean \(\:\pm\:\) SD which is standard deviation, or as number (percentage).

Changes of PWV and WSS at the 1-year follow-up

The ultrasound characteristics of the two groups according to time from the baseline to one-year follow-up are presented in Fig. 3.

Significant improvements were observed in both WSS at BD and WSS at BS, compared with the baseline value in the two groups (p < 0.05 in Table 2). However, there was no significant statistical difference in PWV at BS and PWV at ES, compared with the baseline value (p > 0.05 in Table 2).

Table 2

Carotid ultrasound parameters at the baseline and 1-year follow-up.
	At baseline	At 1-year follow-up	Change from the baseline	\(\:t\:\)	P *
PWV at BS (m/s)
HRT(n = 28)	5.48\(\:\pm\:\)1.10	5.32\(\:\pm\:\)0.97	-0.13\(\:\pm\:\)1.56	-0.35	0.73
Control(n = 25)	6.04\(\:\pm\:\)1.11	6.15\(\:\pm\:\)1.35	0.11\(\:\pm\:\)1.47	0.30	0.77
\(\:\:\:\:\:\:\:\:t\)	1.58	2.10	0.46
P	0.12	0.04	0.65
PWV at ES (m/s)
HRT(n = 28)	7.09\(\:\pm\:\)1.41	7.67\(\:\pm\:\)1.55	0.37\(\:\pm\:\)1.83	0.86	0.40
Control (n = 25)	8.27\(\:\pm\:\)2.08	8.07\(\:\pm\:\)1.76	-0.20\(\:\pm\:\)2.15	-0.38	0.71
\(\:\:\:t\)	1.95	0.71	-0.84
P	0.06	0.49	0.41
WSS at BD (Pa)
HRT(n = 28)	0.44\(\:\pm\:\)0.07	0.47\(\:\pm\:\)0.08	0.04\(\:\pm\:\)0.07	2.25	0.04
Control (n = 25)	0.43\(\:\pm\:\)0.08	0.50\(\:\pm\:\)0.09	0.06\(\:\pm\:\)0.07	3.52	0.00
\(\:\:\:t\)	-0.30	0.63	1.02
P	0.77	0.53	0.32
WSS at BS (Pa)
HRT(n = 28)	0.87\(\:\pm\:\)0.16	0.97\(\:\pm\:\)0.18	0.11\(\:\pm\:\)0.14	3.21	0.00
Control (n = 25)	0.80\(\:\pm\:\)0.11	0.93\(\:\pm\:0.\)13	0.13\(\:\pm\:\)0.09	5.62	0.00
\(\:\:\:t\)	-1.31	-0.75	0.56
P	0.20	0.46	0.58
Data are expressed as mean\(\:\pm\:\)SD. P < 0.05 are indicated in bold. The change from the baseline in each group are expressed as the PWV or WSS value at the 1-year follow-up minus that at the baseline. \(\:p\), the independent Student’s t-test was used to compare the difference between HRT and Control groups. \(\:p\ast\:\:\), a paired-sample t-test was used to compare the difference between the baseline and 1-year follow-up in each group; PWV at BS, PWV at the beginning of systole (BS); PWV at ES, PWV at the end of systole (ES); WSS at BD, WSS at the beginning of diastole (BD).

The PWV at BS was significantly lower in the HRT group than the Control one after the 1-year follow-up (p < 0.05 in Table 2), but there was no significant statistical difference in PWV at ES, WSS at BD and WSS at BS (p > 0.05 in Table 2).

We further compared the changes in ultrasound parameters with respect to the baseline. There was no significant difference between the HRT group and the control one in PWV and WSS at the 1-year follow-up (p > 0.05 in Table 2)

Independent Determinants of the carotid Δ(PWV) and Δ(WSS)

To evaluate the relationship between the ultrasound parameters changed from the baseline and the cardiovascular risk factors, we applied a correlation analysis by using Spearman’s coefficient (r). The data analysis revealed that SBP and DBP were independently correlated with Δ(PWV) at BS (p < 0.05). However, none of the cardiovascular risk factors were significantly associated with Δ(PWV) at ES (p > 0.05). There was a statistically significant correlation between LDL cholesterol and Δ(WSS) at BD (p < 0.05). Additionally, DBP and KMI score were found to be associated greatly with Δ(WSS) at BS (p < 0.05).

Multiple linear regression analyses revealed that triglycerides and HDL were independently correlated with Δ(PWV) at BS (p < 0.05 in Table 3). Δ(WSS) at both BD and BS decrease to remain significantly associated with the KMI score and LDL cholesterol (p < 0.05 in Table 3).

The principal finding in this study was that perimenopausal women with HRT had a significantly lower PWV, compared with the Control group according to time from the baseline to 1 year, however, WSS did not change significantly between the two groups. The WSS values of both groups increased over the course of time.. Moreover, KMI score and LDL were associated with lower WSS, while triglycerides and HDL were related with an increase in PWV.

Reproductive aging includes 7 stages ranging from the onset of menstrual cycles at menarche and the reproductive age to the perimenopausal and postmenopausal phases. The STRAW study defined the menopause transition (MT) as the time when a menstrual cycle becomes variable or other menopause-related symptoms begin until the time of the final menstrual period. The perimenopause begins with the onset of intermenstrual cycle irregularities or other menopause-related symptoms, and extends for 12 months after menopause, thus persisting for 1 year even after the MT^[11]. In the Women’s Health Initiative trial, the largest randomized controlled trial to date to assess the efficacy of HRT, the follow-up data have demonstrated that starting the HRT earlier in the menopausal transition period yields beneficial effects on the cardiovascular health, and reduces all-cause mortality, compared with starting the HRT later^[12].

Most recently, the SWAN heart study also reported that PWV increased significantly within 1 year of the final menstrual period, which was not explained by the adjustment for traditional cardiovascular disease risk factors^[13]. A multicentric randomized trial demonstrated that the age at menopause, the time since menopause, and the use of HRT are independently associated with the thickening and stiffening of large arteries, moreover, it blunted the impact of menopause aging on the large arteries^[14]. The benefits of HRT appear to outweigh its risks for most symptomatic women who are younger.

The results of HRT that improves arterial stiffness showed that HRT significantly lowered the PWV value within 4 weeks. It seems to be largely independent of estrogen’s effects on blood pressure, and dependent on the direct action on arterial wall ^[15]. On the other hand, a randomized pilot trial concluded that HRT demonstrated a positive effect on the cardiac output and diastolic blood pressure, but PWV did not significantly change from the baseline to 12 months ^[16]. Due to hormone therapy significantly improving the composition of sera relevant for the vascular protection, E2 as hormone therapy decreases PWV and augmentation index in the early postmenopausal women ^[17].

PWV largely reflects the structural arterial stiffness, whereas WSS is a hemodynamic factor, which is an important parameter in the biomechanics of atherosclerosis. In the ideal state, the WSS can be estimated to be directly proportional to the blood flow and viscosity, and inversely proportional to the vessel diameter^[8]. To decipher the relationship between hemodynamics and hormonal therapy in the perimenopausal women, we tested the hemodynamic index, WSS. Generally, our results show that the WSS values increased over time, but it seems to be independent of the hormonal therapy. A previous study reported that, among perimenopausal women, different intensity levels of exercise can improve greatly the endothelial function and have a remarkable impact on WSS by regulating the endothelial-derived vasoconstrictors and vasodilators ^[18]. The vascular endothelium is well-known to be sensitive to estrogens, which have direct and indirect effects on the cardiovascular system. The rapid effects of estrogen occur through upregulating the endothelial nitric oxide synthase expression and activity, which can lead to the arterial vasodilation. Longer-term effects involve changes in the gene and protein expression^[19]. In the cross-sectional analyses of reproductive hormones and subclinical cardiovascular disease, higher E2 levels were related to a smaller carotid interadventitial diameter, suggesting less carotid remodeling, whereas higher estrone levels were connected to the brachial flow mediated dilation, indicating better endothelial function^[20]. According to the follow-up data in the SWAN study, the decrease in E2 levels and higher follicle stimulating hormone levels were associated with an increase in the carotid adventitial diameter progression, independent of systolic pressure, body mass index, and lipid^[21]. These overall studies suggest that lower estrogen levels are directly related to larger carotid arterial diameter in the menopausal women, leading to less ability to compensate for hemodynamic changes and a decrease in WSS.

In our study, total cholesterol (TC)and high-density lipoprotein (HDL) were associated with an increase in PWV. The SWAN study has already shown that, as women transition through menopause, the protective effect of HDL was reduced, which was possibly related to changes in the HDL subclasses and HDL cholesterol efflux capacity ^[22]. Another evidence shows that higher HDL-C, levels in the perimenopausal women are independently associated with greater carotid intima-media thickness progression, suggesting that the quality of HDL might be altered and not be cardioprotective^[23]. The change of E2 levels is related to lipids or lipoproteins profile, and a great decline in E2 was independent and significantly negatively associated with Triglycerides (TG) and LDL-C in the perimenopausal women^[24]. These findings suggest that the atheroprotective effect of HDL might be diminished, whereas the effect of LDL-C was stronger when women come to be over the menopause transition.

A valid modified KMI scale for Chinese was used to quantify the severity and intensity of menopausal symptoms, including somatic, mental, genitourinary tract symptoms^[25]. Hot flashes or night sweats, which are the vasomotor symptoms, are the common ones in the perimenopausal and postmenopausal women. According to the previous reports, the HRT was highly effective in relieving the overall menopausal symptoms, and significant improvements were also observed in both KMI and menopause rating scale scores(MRS) for the women whom HRT was carried out^[26]. The previous study revealed that the PWV was significantly associated with the severity of hot flashes, and might provide an objective standard to evaluate the severity of vasomotor symptoms^[27].

Our study had some limitations. Firstly, the sample size was insufficient. Although both arterial stiffness and hemodynamics were observed simultaneously, changes for the perimenopausal women are rare at present, the extension of sample size can make the results more representative. Secondly, the follow-up period was not enough. Therefore, the impact of HRT on subclinical atherosclerosis indicators might not be idenitfied. In future work, it would be beneficial to monitor the changes in arterial stiffness and haemodynamics in the women from premenopause to perimenopause and even postmenopause over a longer period of time. The main strength of this study is that it is the first longitudinal analysis to examine the effect of HRT in the perimenopausal women on arterial stiffness and hemodynamics which are two important early measures of the atherosclerosis progression .

In this study, the HRT gave an impact on the arterial stiffness of PWV in the perimenopausal women without affecting hemodynamics, WSS, which increased over time for all participants.These results indicated that the use of HRT blunted the effect of menopause aging on the large arteries. However, the time-mediated influence on WSS seemed to overrule the potential HRT-mediated one, and the change of WSS cannot be excluded. Further investigation is required to elucidate whether there is a causal relationship.

Contributors

Yi Zhou contributed to the conception and design of the study, was primarily responsible for the acquisition, analysis, and interpretation of the data, and was involved in drafting the manuscript.

Xiao.Guo.Chen contributed to the acquisition, analysis, and interpretation of data and critically revised the manuscript.

Yu.Huang ,Shan.Wang and Li Xue Yin contributed to the analysis, and interpretation of data and critically revised the manuscript.

All authors provided final approval of the version to be submitted.

Funding

This work was supported by National Key research and Development Program [2020YFC2008001].

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

This study was approved by the Institutional Review Board of the hospital (TJ-IRB20220513), and all participants provided the written informed consent.

Consent to participate

Informed consent was obtained from all individual participants included in the study

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Effects of the hormone replacement therapy on arterial stiffness and hemodynamics in the perimenopausal women

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusions

Figures

What does this study adds to the clinical work

Introduction

Methods

Participants in the study

Study design

Carotid PWV Measurement

Carotid WSS Measurement

Statistical Analysis

Results

Baseline characteristics

Changes of PWV and WSS at the 1-year follow-up

Discussion

Conclusions

Declarations

References

Status:

Version 1