Renin-Angiotensin-Aldosterone System in Women Using Combined Oral Contraceptive: A Systematic Review

Objective  To describe the effects of combined oral contraceptives (COC) on the renin-angiotensin-aldosterone system (RAAS). Data sources  This is a systematic review according to the criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), registered in PROSPERO under the ID: CRD42020200019. Searches were performed between August 2020 and December 2021, in the following databases: Medline via Pubmed, Cochrane Central Library, Scientific Electronic Library Online, and Latin American and Caribbean Literature in Health Sciences via Virtual Health Library. The effects of the combined oral contraceptive on plasma renin activity values, plasma renin values, angiotensinogen values— also known as plasma renin substrate— angiotensin, and/or aldosterone values. Study selection  A total of 877 studies were selected and, of these, 10 articles met the eligibility criteria and were included in this review. Data collection  Data were combined through qualitative synthesis and included in a spreadsheet previously prepared by the authors. Data synthesis  The collected samples ranged from 18 to 137 participants, totaling 501 women aged between 18 and 49 years throughout all studies. The studies showed increased activity of plasma renin, plasma renin substrate, angiotensin II, and aldosterone in this population. Conclusion  The findings of this study suggest that the COC promotes greater activation of the RAAS. Supporting the idea that its use is related to an increased risk of cardiovascular events, including systemic arterial hypertension.


Introduction
The adverse effects of the use of the combined oral contraceptive (COC) have been the subject of much research, including the relationship of the COC in the development of systemic arterial hypertension (SAH). [1][2][3][4] One of the main mechanisms that explain this relationship is the action of COC on the renin-angiotensin-aldosterone system (RAAS). 5 A review carried out by Oelkers 5 in 1996 proposed to report the effects of estrogens and progestogens that compose the COC on the RAAS and on the blood pressure (BP). This study pointed out that the estrogenic and progestogenic components are responsible for the activation of the RAAS and may explain the increase in BP in this population. Corroborating this study, a randomized clinical trial showed that women using COC showed a significant increase in the values of plasma renin activity (PRA) when compared to the control group. 6 More recently our research group has verified through an observational study that women using COC had a median 2fold higher plasma renin than women not using COC. 7 In this sense, based on the fact that the RAAS is an important physiological regulator of BP and that the use of COC may be indicated as a generator and sustainer of high blood pressure levels, it is necessary to understand how the RAAS may promote the elevation of BP in users of COC and what the studies show about this relationship. Therefore, this study aims to describe the effects of COC on the RAAS.

Methods
This is a systematic review according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). 8 The searches were conducted between August 2020 and December 2021 in the following databases: Medline via PubMed, Cochrane Central Library, Scientific Electronic Library Online (Scielo), and Latin American and Caribbean Literature on Health Sciences (Lilacs) via Virtual Health Library (VHL). References of the selected papers were also checked to find other studies related to the topic. This review was registered in PROSPERO under id: CRD42020200019.
We considered eligible original studies with control or comparison groups, which evaluated young, healthy women of reproductive age (> 18 years), who were users of COC. The outcomes observed in the studies had to involve the effects of COC on the values of plasma renin activity (PRA), plasma renin values, angiotensinogen values also called plasma renin substrate (PRS), angiotensin and/or aldosterone values, as well as the mechanisms related to their alterations.
Studies with menopausal women, women with cardiovascular diseases or metabolic disorders were not eligible. Studies with obese women, smokers, drinkers, or those undergoing drug treatment were also excluded.
For Search and screening of the articles was performed independently by two reviewers, initially by the titles and abstracts. Subsequently, all articles that met the selection criteria were chosen, and the full text was read. Duplicates were identified and removed using the Rayyan QCRI (Rayyan Systems Inc. Cambridge, MA, EUA) web/mobile application. 9 In case of disagreement about the selection of studies, the decision was discussed among the researchers.
The data from the selected studies were combined by means of qualitative synthesis. Therefore, after confirming the selected articles, the data were assigned to a spreadsheet previously prepared by the authors. Disagreements about the extracted data were discussed among the researchers.
The risk of bias assessment of clinical trials was performed by the Cochrane Collaboration Tool (Cochrane Collaboration, London, UK). 10 This tool critically assesses the risk of bias in studies through 7 domains, namely: random sequence generation, allocation concealment, blinding of participants and professionals, blinding of outcome evaluators, incomplete outcomes, selective outcome reporting, and other sources of bias.
The quality of evidence from observational studies was assessed using the Downs and Black 11 scale whose assessment includes communication (reporting), external validity, internal validity (bias, confounding variables), and statistical power. In each evaluation (except for question 5, in which the maximum value is 2) a score of 0 was assigned for conditions not presented in the study and 1 for identified criteria. Two researchers participated in this step and any differing results would be evaluated by a third researcher, but there was no need.

Results
The selection in the databases resulted in 875 articles. Two articles were identified through the references, resulting in 877 articles; of these, ten studies met the eligibility criteria and were included in this review. ►Figure 1 shows the flowchart of study selection.
The samples of the selected studies comprised 18 to 137 women, with a total of 500 patients throughout all studies, aged 18 to 49 years. Of the ten studies included, four were clinical trials and six were observational studies. The characterization of the studies is presented in Chart 1.
The risk of bias of clinical trials was assessed using the Cochrane Collaboration Tool, 10 as shown in Chart 2. The   Control Group: 22 women with the same characteristics without using COC for at least six months to one year. The collection of the control group was performed between the fifth and tenth day of the menstrual cycle, considering the smallest hormonal variations, and/or on the 28th day without medication (inactive phase).
Plasma renin: kinetic radioimmunoassay with EDTA plasma. Women taking COC had higher serum renin levels (ng/ ml/h) than women not taking this drug (p < 0.01).

Discussion
This literature review concluded that the use of COC is associated with increased PRA, PRS, angiotensin II, and aldosterone in healthy women. This promotes increased activity of the RAAS, which may explain the prevalence of SAH in this population. 3,4 The RAAS is an important hormonal system, regulator of BP and electrolyte homeostasis of the organism. 20 The physiology of this system begins with the secretion of renin, an enzyme released by the renal juxtaglomerular apparatus that cleaves PRS, favoring the production of angiotensin I, later converted into angiotensin II by the action of the angiotensin converting enzyme (ACE). The results observed in studies point to an increase in PRS and PRA in women using COC. 6,7,12,13,15,16,18 One of the mechanisms that justify these findings is that ethinyl estradiol (EE), the synthetic estrogen that composes the COCs, is responsible for inducing the expression of angiotensinogen mRNA. 21 It also has the potential to increase the hepatic production of angiotensinogen, 21 which is accompanied by increased PRA. 4 Moreover, the elevated plasma renin and, consequently, angiotensin II values stimulate the central nervous system and increase sympathetic discharge. This increased sympathetic activity stimulates renal beta-adrenergic cells and favors a higher production of renin. 22 Thus, the mechanism of stimulation of the central nervous system feedbacks the production of renin and maintains the process of activation of the RAAS. ►Figure 2 presents the mechanisms by which the use of COC promotes greater activation of the RAAS.
In the same line of reasoning, Briggs and Briggs 12 developed studies aiming to test different dosages of COC in 137 women aged < 30 years. The PRA values and PRS concentration approximately doubled for the volunteers who were using the two contraceptives with higher EE dosage (50 mcg). In contrast, the renin concentration is reduced by about 30 to 40% of the pre-treatment values. Still in the same study, it was observed that lower doses of EE (30 mcg) resulted in smaller changes compared to higher dosages (50mcg), but the changes were still higher than the population not taking COC, with an increase of 20 to 30% in PRA, 12 to 20% of PRS, and a decrease of 15 to 20% in renin concentration. The decrease in renin concentration is justified by an increase in the levels of angiotensin II that decreases the production of renin through negative feedback, determining the balance of this system. 23 Despite this, the study developed by our research group found a median 2-fold higher renin concentration in women who use COC compared with women who do not. 7 The reasons that justify this opposition between the aforementioned studies are unknown. One hypothesis is the difference in the dosage and time of use of the COCs used in the studies, since the mean age of the selected samples were similar (23 years 7 vs 24 years 12 ). Possibly, the elevation of PRA is accompanied by a decrease in its concentration. However, the fact that our study had a lower EE dosage (15 to 30mcg 7 Vs 50mcg 12 ( with longer use (3 years 7 Vs 1 year 12 ), may have influenced the values of increased plasma renin oncentrations while their activity was normal. It is difficult to know because this has not been verified. This is a fertile field for future investigations.
Complementing the findings of the study by Briggs and Briggs, 12 evidence points out that PRS and PRA levels in women taking COC show elevations comparable to angiotensin II levels. 13,15,17,18 Cain et al. 13 evaluated 17 women taking COCs over a period of 2 to 3 months. Mean blood levels of PRS, PRA, and angiotensin II increased to 330%, 363%, and 314%, respectively, while renin concentration fell to 52% of the control value. 13 In this study, positive correlations were observed between PRA and angiotensin II (r¼0.91), and between PRS and angiotensin II (r¼0.73). 13 These correlations reinforce the idea that changes in the components of the RAAS during COC treatment are interdependent on the elevation of the PRS.
Angiotensin II is the molecule responsible for the majority of the physiological effects of the RAAS. It exerts its actions on target organs and can act by means of conversion into other molecules (angiotensin I-VII, angiotensin I-IX, or angiotensin III) or by binding to its AT1 and AT2 receptors. 23,24 In isolation, angiotensin II has the potential to stimulate the production of antidiuretic hormone, increase the reabsorption of sodium in the kidneys, stimulate sympathetic activity, and trigger direct vasoconstriction of the arterial vessels by binding to AT1 receptors, favoring the elevation of BP. 23 Additionally, when angiotensin II is converted to angiotensin III, it induces the production of aldosterone by the adrenals which will also act mainly on the kidneys. 23 Aldosterone is a mineralocorticoid, which by binding to the mineralocorticoid receptor on the epithelial cells, recruits sodium channels to the surface of renal epithelial cells, increasing sodium reabsorption, potassium excretion, and plasma volume expansion, culminating in BP elevation. 23 In a literature review carried out in 1996, COCs with high doses of EE (>30mcg) were identified as precursors of SAH, noting a high sodium retention effect in this population. 5 In this regard, so-called low-dose COCs ( 30 mcg of EE) have been formulated in an attempt to decrease the effects of EE on sodium retention. Additionally, the progestogenic components of COC have been recognized to antagonize the action of aldosterone (antimineralocorticoid effect) in the distal tubule of the kidney and, thus, increase sodium excretion. However, even in low-dose formulations and with the antimineralocorticoid effect, studies note an increase in aldosterone plasma levels, [14][15][16]19 being this is considered more as a compensatory mechanism than a hypertensive one. 16 It is important to elucidate that the outcomes evaluated may or may not impact clinical issues. We hypothesize that in the long term, the alterations caused in the RAAS lead to a greater development of cardiovascular diseases such as hypertension. The integrity of the arterial vascular endothe-lium is a key instrument in the regulation of RAAS. An intact endothelium favors the balanced production of RAAS substrates such as ACE. The balance of this system is essential for cardiac function, vasomotor tone, and vascular permeability, in addition to preserving blood fluidity. 25,26 In this aspect, the age of the volunteers is a relevant factor, since age is associated with the quality of the endothelial function. 25 However, only cohort studies or randomized clinical trials of a longitudinal nature will be able to confirm this hypothesis. So far, cohort studies have not found an association between COC use and risk of stroke, 27 myocardial infarction, 27 and all-cause mortality. 28 Finally, despite the observational studies in this review showing good methodological quality (Chart 3), the clinical trials had uncertain methodological quality (Chart 2). Future works that investigate this topic should seek to minimize the risk of bias so that the evidence is more robust, and the bases and biological mechanisms are better elucidated.

Conclusion
Although new combinations with lower dosage and antimineralocorticoid action have been formulated to attenuate the adverse effects of COC, the results of this study suggest that COC promotes greater activation of the RAAS. Such conclusion supports the idea that its use provides, in the long and medium term, an increased risk of cardiovascular diseases and development of SAH.

Conflicts to Interest
None to declare.