Contraceptive use, both oral and parenteral, is associated with increased arterial stiffness in young healthy women

doi:10.21203/rs.3.rs-5018497/v1

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Contraceptive use, both oral and parenteral, is associated with increased arterial stiffness in young healthy women

https://doi.org/10.21203/rs.3.rs-5018497/v1

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Purpose:Previous studies on the impact on arterial health of contraceptive use, or across the menstrual phases, have yielded differing results. Furthermore, there is little research on the differences based on the delivery method of the contraceptive, oral vs parenteral contraceptives. In this study, we examine arterial health using three different clinical physiological measures of arterial function and structure in contraceptive users and non-users.

Methods: Young, healthy, non-smoking, women, between 18.0-25.9 years of age were enrolled in the study (n = 577). Menstrual phase and contraceptive use and type were assessed by questionnaire. Arterial stiffness was measured using pulse-wave velocity (PWV) and augmentation index (AIx). Arterial thickness was measured using carotid-intima media thickness (cIMT). Venous blood samples were analysed for various biomarkers, which were used in multivariate regressions to adjust for the effects of contraceptive use on the vascular measures.

Results: Contraceptive users had a significantly higher PWV than non-users. The menstrual phase did not significantly impact PWV. The type of contraceptive, oral or parenteral, did not impact PWV. AIx and cIMT did not differ between any studied groups. Systolic blood pressure, Body Mass Index, serum lipids, C-reactive protein, and sex hormone binding globulin concentrations were higher in the contraceptive using group, but in multivariable models, adjusting for age, these biomarkers had only limited impact on the positive association between contraceptive use and PWV.

Conclusion: Contraceptive users have higher PWV than non-users already in young healthy women.

Young female adults

Pulse-wave velocity

Endocrine hypertension

PWV

Menstrual phase

Contraceptive

Arterial stiffness

cIMT

Cardiovascular risk factors

An increased arterial stiffness is associated with an increased cardiovascular risk and predicts cardiovascular events independently of established cardiometabolic risk factors blood pressure and hyperlipidemia [1]. Men display higher pulse-wave velocity, PWV, considered as the gold standard of arterial stiffness measurements, than women, and have a higher risk of cardiovascular disease (CVD), but this changes after menopause, after which women experience an increasing risk, with the odds ratio of women to men approaching equality for the risk of cardiovascular disease [2]. Hormonal factors are thought to be involved but studies on the effect of hormonal replacement therapy (HRT) on post-menopausal women have been contradictive, with some studies reporting beneficial effects and others detrimental effects on measures of arterial stiffness [3–6]. In premenopausal women, studies on the relationship between the menstrual phases and arterial stiffness have also yielded conflicting results, with some studies reporting an increased stiffness and others a decreased arterial stiffness [7–10]. Contraceptives are delivered as oral contraceptive pills (OCP) or as parenteral contraceptives (PCP), the latter available in preparations such as subdermal, spiral, or vaginal. We identified only five studies that have investigated the effect of the use of oral contraceptives on blood pressure and arterial stiffness, whose results were discordant much like those of HRT in postmenopausal women. Hickson et al., in 2011 [11], and Yu et al., in 2014 [12] observed higher PWV in the OCP group, while Priest et al., in 2018 [13] and Enea et al., in 2021 [14] observed no differences between the groups. However, Enea et al. observed higher central BP’s and AIx (augmentation index) in the OCP group. In Sweden, the use of OCP is prevalent, as shown in a 1997 study where 93% of the women reported having used OCP [15], but a study published in 2016 reported trends towards increasing prevalences of PCP contraceptive use [16]. In this study, we examined measures of vascular structure and function by analysing PWV, AIx, and cIMT in users of OCP and PCP as well as across the menstrual phases of the non-users of contraceptives, in a large cohort of young, healthy non-smoking women.

Study population

The cross-sectional Lifestyle, Biomarkers and Atherosclerosis study (LBA) population are young, healthy adults (ages 18 to 25.9). The LBA study recruitment was done through community advertising and has been previously described in detail [17]. During two subsequent visits to the Örebro University physiology laboratory, the subjects underwent arterial stiffness examinations and filled out a questionnaire on their general health status, use of contraceptives or other medication and the date of the first day of their last menstruation. Women between 18 and 26 years of age, with a self-assessed good health, either using contraceptives or having had a menstruation within the last 35 days were included in the study. Smokers and subjects suffering from chronic disease were excluded. For subgroup comparison, the contraceptive users were grouped into users of OCP, vaginal contraceptives, intrauterine contraceptives, transdermal and subcutaneous contraceptives, and alternatively into users of estrogen containing contraceptives vs. all non-estrogen users (which includes users of gestagen CP). The date of onset of menstruation was used to assess the menstrual phase, with early follicular phase (EF) corresponding to day 1–8, late follicular phase (LF) day 9–15, early luteal phase (EL) day 16–23 and late luteal phase (LL) day 24 and − 1. The study was approved by the Regional Ethics Review Board, Uppsala, ref 2014/224.

Arterial stiffness and cIMT measurements

For PWV, carotid and femoral pulse waves were recorded with applanation tonometry with simultaneously electrocardiography (ECG) recording to get the pulse transit time. For AIx, radial artery tonometry was performed at the subject’s right wrist and the aortic pressure waveform was derived from the radial waveform by a validated transfer function. An average of AIx_HR75, standardized to a heart rate of 75, was derived. cIMT was measured using a high-resolution ultrasound B-mode system, (GE Healthcare, Vivid E9, Chicago, Illinois, US) with a 12 MHz linear array transducer. An average of three measurements was reported for each subject. Details on the methodology has been previously described [17].

Laboratory investigations

Samples were collected after an overnight fast into sodium citrate fluoride vacutainer tubes for glucose analysis and serum and plasma vacutainer tubes for the rest of the analyses (BD Vacutainer; BD AB, Stockholm, Sweden). HsCRP was analyzed on a Siemens ADVIA 1800 Chemistry instrument with a CV of 5% at 0.74 mg/L with the Siemens High Sensitivity CRP Assay (ADVIA 1800 Chemistry System; Upplands Väsby, Sweden). Total cholesterol (CHOL), Triglycerides (TG), high-density lipoprotein (HDL) and glucose were assayed colorimetrically with Vitros MicroSlide technology (5.1TM FS; Clinical Chemistry Instruments, Raritan, NJ, USA). Direct low-density lipoprotein (direct LDL) was assayed by a two-step colorimetric assay with Vitros MicroWell technology. CHOL (3% CV at 3.9 mmol/L), TG (CV of 4% at 1.3 g/L), HDL (6% CV at 1.0 mmol/L), LDL (5% CV at 2.4 mmol/L) and glucose (4% CV at 4.6 mmol/L) were analyzed on a Vitros 5.1 system (Vitros 5.1TM FS, Clinical Chemistry Instruments, Raritan, NJ, USA). Sex hormone binding globulin (SHBG) was measured on a Roche Cobas system (Roche Diagnostics, Basel, Switzerland).

Statistical analysis

Statistical analyses were performed with statistical software SPSS version 22 (IBM, Armonk, NY, USA). Continuous data in the study population is shown as mean and standard deviation (SD) for normally distributed variables. Normal distribution was appraised by assessment of the size of the SD in comparison with the mean, as well as graphically displayed in a histogram and visually evaluated. Univariate and multivariate linear regression were used to statistically analyze the association between PWV, AIx and contraceptive use. Comparison of group means was done with ANOVA.

Table 1 shows the distribution of OCP and PCP in the population. The number of OCP users are higher than PCP. Only one individual used a transdermal contraceptive. Employing variance analysis with ANOVA for subgroup comparison, we found no difference between the PWV, cIMT, or AIx measurements based on their hormonal delivery system. There were no age or BMI differences between the OCP and PCP groups. SHBG was markedly higher in the vaginal contraceptive group compared to other contraceptive types. Significantly higher SHBG was also observed in the oral contraceptive group compared to the non-using group and the other types, except the vaginal group (Table 1). SHBG was also higher in the estrogen using group compared to non-estrogen users (Table 2) and in the whole contraceptive using group vs non-using (Table 3).

Population characteristics are shown in Tables 2 and 3. The contraceptive users of the study population measured higher vs. non-users on some of the CVD risk variables in this study: SBP, LDL-CH, TG, non-HDL-CH and CRP. The contraceptive group also had higher SHBG and PWV measurements.

Table 3 shows the values in contraceptive users, grouped into users of estrogen-containing contraceptives vs. all non-users of estrogen contraceptives (i.e., including users of gestagen containing contraceptives). The EU group had significantly higher SBP, LDL-CH and non-HDL-CH, triglycerides, CRP, and PWV but no difference in BMI, HDL-CH, fasting serum insulin, AIx or cIMT.

There was variation in mean PWV measurements in the different menstrual phases, with a tendency towards the lowest mean in late luteal phase, but the differences were not statistically significant (Figure 1).

In multivariable linear regression, contraceptive use vs. non-use was positively associated with PWV, in three models (Table 4), and remained significant with adjustment for BMI, age, SBP and SHBG. The inclusion of BMI and systolic blood pressure has the greatest effect on the R² and the β coefficient of the association between PWV and use of contraceptives, with adjustment for SHBG having a slightly lesser impact. Similar results were obtained by testing the same linear models but comparing EU vs NEU (Table 5).

In this study we found a significant association between use of hormonal contraceptives and PWV as a marker of arterial stiffness, but not with AIx or cIMT. This association remained significant after adjustment for established cardiometabolic risk factors BMI, age, blood pressure and SHBG. SHBG, included here as a marker of androgenicity, was strongly dependent on contrapeptive use and contrapeptive modes of administration (Table 1), but had only a limited impact on the association between PWV and contraceptive use (Tables 4 and 5). Furthermore, we found no statistically significant difference in PWV and AIx between OCP and PCP groups (Table 1), or when comparing the menstrual phases of non-users of contraceptives (Fig. 1).

With respect to OCP and arterial stiffness, our findings concord with those of Hickson et al [11] and Yu et el [12], who found an increased arterial stiffness in their OCP groups. Furthermore, like them, we found no significant association between menstrual phase and arterial stiffness, although our cross-sectional study design is not optimal for assessing this particular factor. Our results with respect to PWV differ from those of Priest 2018 [18] and Enea 2021 [14]. Moreover, further contrasting with our findings, Enea et al. found an increased AIx in the OCP group that they stated was difficult to explain in light of the non-significance of PWV in their study. The lack of concordance between PWV and AIx in both our material and that of Enea, is a sign that, while both measurements aim at addressing “arterial stiffness”, they in fact probably correspond to slightly different properties, at different scales, in different parts of the arterial tree [19, 20].

Our study is the first, to our knowledge, to measure arterial stiffness in a PCP group. There was a tendency towards higher PWV in the subcutaneous and vaginal groups (Table 1). While PCP bypass first pass metabolism in the liver, permitting lower dosages than what is typically found in OCPs, pharmacokinetic studies have observed increased plasma concentrations of estrogen in PCP compared to OCP [21]. OCP intake may also be less consistent, with OCP users displaying a lower compliance than parenteral methods [22]. Furthermore, PCPs have been found to confer a greater risk of thromboembolism than OCP [23]. The nature of the differences in CVD risk between OCP and PCP is unknown. Ethinyl-estradiol likely plays a role, being found in OCPs, but typically not as often in PCP, while both contain progestins. At the same time, both estrogens and progestins have been implicated in hypertension, by means of the activation of the renin-angiotensin-aldosterone system (RAAS), altered endothelial function, and oxidative stress [24, 25]. The contraceptive using group in our material indeed had a significantly higher blood pressure than non-users (Table 2).

In this population of young, healthy women, the contraceptive using group, both OCP and PCP, showed increased CVD risk markers, such as a higher lipids and CRP concentration, which concord with the findings of a previous study [26]. The CRP induction caused by orally delivered estrogen has been attributed to the hepatic first-pass effect, not reflecting an increase in systemic inflammation typically associated with an increasing CRP. Nonetheless, our results raise concerns regarding the safety of OCP with respect to arterial health. CRP correlates with endothelial dysfunction [27] and shows a proinflammatory effect on in vitro endothelium [28], which may be parts of the explanation, but its inclusion in multivariable models (Table 4) showed a limited effect on the relationship between contraceptive use and PWV, implying that CRP is only a minor part of the mechanism.

Although the results of ours and previous studies on arterial properties in young women are conflicting, studies on hormone replacement therapy, HRT, in postmenopausal women describing beneficial effects on arterial stiffness are more plentiful [2, 29]. Various mechanisms have been proposed, such as endothelin mediated effects on endothelial cells, and a downstream effect towards a more beneficial lipid profile. In a study with a longer follow up time, post-hoc analyses showed an initially detrimental effect of HRT, with the intervention group having more CVD events. After year 3, the inverse was seen, with fewer episodes in the HRT group. It was speculated that an initial estrogen induced prothrombotic effect was over time outweighed by the benefits of lipid profile changes on the evolution of underlying atherosclerosis [30]. However, in our population of young women, the contraceptive group showed higher values for several of the established CVD risk variables, including lipids.

Our study is limited in its cross-sectional design, from which it is not possible to ascertain the order of the alterations in the variables examined. It may also not be fully representative of the young female population at large due to the recruitment mode. Future studies are warranted with a longitudinal design, examining the impact of OCP and PCP on stiffness and CVD risk markers on follow-up. The strengths of this study are that all subjects were young healthy non-smokers free of any chronic disorders, and its large population size, in a field of research where previous studies have typically studied small samples (n < 100). This provided us with a higher power to detect even minor differences in the studied variables.

There were statistically significant differences in SHBG between OCP, PCP, and the non-contraceptive using groups (Table 1), which are indicative of differences in androgenicity that may also play an important role in CVD risk, nonetheless the small impact it had as an adjustment variable on our multivariable examinations on the effect of contraceptives on stiffness (Tables 4 and 5) suggests that the relationship cannot be attributed to altered androgenicity profiles only.

In conclusion, contraceptive using women exhibited an increased arterial stiffness compared to non-users measured as PWV. Despite significant differences in serum CVD risk biomarkers between NEU or NCU and EU or CU, the inclusion of these biomarkers in adjusted models only moderately affected the association between PWV and contraceptive use, suggesting that contraceptives exert direct actions on the arterial wall by as of yet unidentified additional factors.

PWV

Pulse-wave velocity

IMT

Intima media thickness

OCP,Oral contraceptive pills

Total cholesterol

Triglycerides

HDL-CH

high-density lipoprotein cholesterol

LDL-CH

low-density lipoprotein cholesterol

CVD

Cardiovascular disease

BMI

Body mass index.

Acknowledgements
This work was supported by AFA Insurance [grant 130275]; Region Örebro County’s Research Committee, Örebro, Sweden [OLL-780061]; and Umeå University, Umeå, Sweden [RV-865861]. None of the funding sources had an influence on the design or production of the article. We thank Professor emeritus Torbjörn Bäckström, Umeå, for valuable viewpoints on an early version of this paper.

Author Contributions

All authors contributed to the study conception and design, data collection and analysis. The first draft of the manuscript was written by Paul Pettersson-Pablo and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Conflict of interest

None of the authors has a conflict of interest to declare.

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Table 1 to 5 are available in the Supplementary Files section.

No competing interests reported.

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You are reading this latest preprint version

Contraceptive use, both oral and parenteral, is associated with increased arterial stiffness in young healthy women

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Abstract

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Introduction

Subjects and methods

Study population

Arterial stiffness and cIMT measurements

Laboratory investigations

Statistical analysis

Results

Discussion

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

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