Sistema renina-angiotensina-aldosterona em mulheres usuárias de contraceptivo oral combinado: Revisão sistemática

Santos, Priscilla Araújo dos; Oliveira, Alice Miranda de; Alves, Caroline Queiroz; Souza Filho, Clóvis Figueiredo; Ladeia, Ana Marice Teixeira; Petto, Jefferson

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Revista Brasileira de Ginecologia e Obstetrícia

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Sumário

Review Article • Rev Bras Ginecol Obstet. 44 (07) • Jul 2022 • https://doi.org/10.1055/s-0042-1745790 copiar

Sistema renina-angiotensina-aldosterona em mulheres usuárias de contraceptivo oral combinado: Revisão sistemática

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

Objetivo

Descrever os efeitos do contraceptivo oral combinado (COC) no sistema renina-angiotensina-aldosterona (SRAA).

Fontes dos dadosTrata-se de uma revisão sistemática de acordo com os critérios do Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), registrada no PROSPERO sob ID: CRD42020200019. As buscas foram realizadas entre agosto de 2020 e dezembro de 2021 nas bases de dados: Medline via Pubmed, Biblioteca Cochrane Central, Scientific Electronic Library Online, e Literatura Latino-americana e do Caribe em Ciências da Saúde via Biblioteca Virtual em Saúde. Consultado os artigos sobre os efeitos do contraceptivo oral combinado nos valores da atividade da renina plasmática, valores plasmáticos da renina, valores do angiotensinogênio – também conhecido como substrato da renina plasmática –, valores da angiotensina e/ou aldosterona.

Seleção dos estudosForam selecionados 877 estudos e, destes, 10 artigos preencheram os critérios de elegibilidade e foram incluídos nesta revisão.

Coleta de dadosOs dados foram combinados por meio de síntese qualitativa e inclusos em uma planilha elaborada previamente pelos autores.

Síntese dos dadosAs amostras coletadas variavam entre 18 e 137 participantes, totalizando 501 mulheres com idade entre 18 e 49 anos em todos os estudos. Os estudos apresentaram aumento da atividade da renina plasmática, do substrato da renina plasmática, da angiotensina II e da aldosterona nessa população.

Conclusão

Os achados deste estudo sugerem que o COC promove maior ativação do SRAA. Apoiando a ideia de que o seu uso esteja relacionado ao aumento do risco de eventos cardiovasculares, incluindo a hipertensão arterial sistêmica.

Palavras-chave
anticoncepcionais; pressão arterial; sistema renina-angiotensina; hipertensão; saúde da mulher

Author, year	Objective	Study design	Sample	Intervention or exposure protocol	Method (RAAS)	Results
Straznicky et al. (1998)⁶6 Straznicky NE, Barrington VE, Branley P, Louis WJ. A study of the interactive effects of oral contraceptive use and dietary fat intake on blood pressure, cardiovascular reactivity and glucose tolerance in normotensive women. J Hypertens 1998; 16 (03) 357-368 DOI: 10.1097/00004872-199816030-00013. https://doi.org/10.1097/00004872-1998160...	To prospectively investigate the interaction effects of COC use and short-term dietary fat intake on 24 hour ambulatory BP, cardiovascular reactivity, and glucose tolerance.	Randomized and Crossover Clinical Trial	Total: 31 women Age: 18–45 years old	Experimental diets were designed to produce maximal changes in plasma low-density lipoprotein cholesterol concentration. Investigations were carried out on the last 2 days of each diet, which were scheduled to coincide with days 15–21 of the pill intake cycle (for the 16 COC users) or days 21–27 of the menstrual cycle (16 volunteers in the control group).	PRA: measured by incubating plasma for 3h in the presence of converting enzyme inhibitors and angiotensinases (EDTA and phenylmethylsulfonyl fluoride).	PRA was significantly higher in COC users than in non-users with both low-fat (2.0 ± 0.8 vs. 1.3 ± 0.7ng/ml per hour, p= 0.02) and rich diet in fat (1.9 ± 0.6 versus 1.3 ± 0.8ng/ml per hour, p= 0.03), and was not influenced by dietary change.
Briggs and Briggs (1982)¹²12 Briggs MH, Briggs M. Randomized prospective studies on metabolic effects of oral contraceptives. Acta Obstet Gynecol Scand Suppl 1982; 105: 25-32 DOI: 10.3109/00016348209155314. https://doi.org/10.3109/0001634820915531...	To compare the metabolic impact of different oral contraceptive formulations on new oral contraceptive acceptors in healthy young women.	Prospective Randomized Clinical Trials	Total: 137 women Age: < 30-years-old	Study 1: The volunteers were randomized to 6 cycles of treatments in one of 4 groups: Group 1: 0.15mg LNG + 30mcg EE. Group 2: 0.50mg NET + 35mcg EE. Group 3: 1.00mg NET + 35mcg EE. Group 4: 2.00 mg EDA + 30 mcg EE. Two blood samples were taken on consecutive days during the late pretreatment cycle (days 25–28) and during each treatment cycle on any of the last two days of tablet ingestion. Study 2: Participants volunteers were randomized to receive the following formulations for 12 treatment cycles: Single-phase – (x 21) 0.150mg LNG and 30mcg EE. Single-phase – (x 21) 0.250mg LNG and 50mcg EE. Biphasic – (x 10) 0.050mg LNG and 50mcg EE; (x 11) 0.125mg LNG and 50mcg EE. Three-phase – (x 6) 0.050mg LNG and 30mcg EE; (x 5) 0.075mg LNG and 40mcg EE; (x 11) 0.125mg LNG and 30mcg EE. Measurements of PRA, PRS, and renin concentration were performed pre-treatment and every 6 cycles.		With the administration of the two products with the highest dose of estrogen ( 0.250mg LNG + 50 mcg EE, and the biphasic), PRA and PRS concentration approximately doubled (p< 0.001). In contrast, renin concentration was reduced by about 30–40% from pretreatment values (p< 0.001) for the same formulations. Changes with the two lower dose products were minor but still statistically significant (p< 0.01). The increase in PRA was 20–30%, the PRS concentration 12–20%, while the drop in renin concentration was about 15–20%.
Cain et al. (1971)¹³13 Cain MD, Walters WA, Catt KJ. Effects of oral contraceptive therapy on the renin-angiotensin system. J Clin Endocrinol Metab 1971; 33 (04) 671-676 DOI: 10.1210/jcem-33-4-671. https://doi.org/10.1210/jcem-33-4-671...	Evaluate the levels of angiotensin II, PRA, PRS, and renin concentration during treatment with estrogen and progestin oral contraceptives.	Clinical Trial	Total: 27 women Age: 19–47-years-old	Study 1: blood levels of angiotensin II were measured at intervals during the menstrual cycle in 3 women not treated with COC and during a single treatment cycle in 7 women who received 1mg of ethynediol diacetate and 0.1mg of mestranol (Ovulen) daily. Blood samples were collected after at least three hours of normal activity. Study 2: angiotensin II levels of 17 normal young women were measured before, during and after treatment with 1mg of EDA and 0.1mg of mestranol (Ovulen) or 2.5mg of Lynestrenol and 0.075mg of mestranol (Lyndiol). There were 10 women being studied for two months and 7 women for three months. In addition, the levels of PRS, PRA, and plasma renin concentration were measured in thirteen subjects before, during, and after COC therapy.	Angiotensin II: determined by extraction and radioimmunoassay. PRS, PRA, and renin concentration: kinetic enzyme bioassay procedures.	Study 1: In the 7 women treated with COC, blood levels of angiotensin II increased markedly and significantly (p< 0.005) to about three times control levels. Ten days after stopping treatment, blood levels of angiotensin II had returned to the normal range. Study 2: In the 10 women treated with COC for two months, the levels of angiotensin II in the blood increased approximately three times above the baseline values (2.7 ± 1.0ng/100ml to 8.5 ± 2.9ng/100ml). After two months of treatment, mean values returned to normal in the third month and below baseline in the fourth month. In the 7 women treated with COC for three months, an identical pattern of response to angiotensin II was observed (mean increase to 8.6ng/100ml), with a fall to normal (2.6 ± 1.4ng/100ml) one month after discontinuation of treatment and values below baseline in the following month. Mean plasma levels of PRS, PRA, and angiotensin II in blood increased to 330%, 363%, and 314%, respectively, while the concentration of renin dropped to 52% of the control value. One month after the end of COC treatment, all values returned to normal.
De Leo et al. (2001)¹⁴14 De Leo V, la Marca A, Morgante G. et al. Evaluation of plasma levels of renin-aldosterone and blood pressure in women over 35 years treated with new oral contraceptives. Contraception 2001; 64 (03) 145-148 DOI: 10.1016/s0010-7824(01)00237-2. https://doi.org/10.1016/s0010-7824(01)00...	To evaluate the clinical and hormonal effects of a new extra-low dose oral contraceptive, 15mcg EE and 60mcg gestodene, on RAAS in a group of 10 healthy women treated for 3 months, compared to a formulation containing the same hormones at a higher dose.	Clinical Trial	Total: 18 women Age: 35–39 years old	Group 1: 10 women used 15mcg EE / 60mcg gestodene (Arianna®, Schering). Group 2: 8 women used 20mcg EE / 75mcg gestodene (Fedra®, Schering). Blood samples were obtained before the study and after 3 months of contraceptive use for renin and aldosterone assay. In the first group, the sample was collected between days 18 and 21 of the menstrual cycle, between 8:30 and 9:30 am, after an hour of rest in the sitting position. In the second group, the sample was obtained during the third month of contraceptive use.	PRA and aldosterone: radioimmunoassay with Diasorin kits (DiaSorin SpA. Saluggia, Italy).	The contraceptive formulations studied showed insignificant changes in the value of PRA and aldosterone. Slight increase in PRA from baseline (16 ± 4% for group 2 and 18 ± 5% for group 1) and a slight reduction in plasma aldosterone levels (3.6 ± 0.5% and 4.6 ± 0.5%, respectively).
Kang et al. (2001)¹⁵15 Kang AK, Duncan JA, Cattran DC. et al. Effect of oral contraceptives on the renin angiotensin system and renal function. Am J Physiol Regul Integr Comp Physiol 2001; 280 (03) R807-R813 DOI: 10.1152/ajpregu.2001.280.3.R807. https://doi.org/10.1152/ajpregu.2001.280...	Verify the effects of synthetic estrogens on RAAS activity and test the hypothesis that the use of COC decreases renin secretion.	Comparative observational cross-section	Total: 54 women Age: 25 ± 1 years	Study 1: 34 volunteers participated in the study, 15 COC users and 19 non-users. All were advised to adhere to a diet that maintained their normal caloric intake (sodium intake > 150mmol/day, protein intake 1–1.5g/kg/day) for 7 days prior to the study. Volunteers who were not COC users were studied in the follicular phase of menstruation. All COC users were studied between days 7 and 21 of their cycle, a period when they were ingesting 30mcg EE. Study 2: 20 volunteers participated in the study, 10 COC users and 10 non-COC users. Lower body negative pressure was used to activate RAAS by discharging arterial baroreceptors. Blood was collected at baseline for plasma norepinephrine, angiotensinogen, angiotensin II, plasma renin concentration, PRA, and aldosterone. Lower body negative pressure was incremental starting at 215 mmHg for 15 min, evolving to 225 mmHg for 15 min, and 240 mmHg for 15 min.	Angiotensin II: radioimmunoassay, in precooled tubes containing EDTA and angiotensinase inhibitor (0.1ml Bestatin solution, Buhlmann Laboratories). Aldosterone: radioimmunoassay, using the Coat-A-Count system. Angiotensinogen: measured indirectly by converting endogenous angiotensinogen to angiotensin I, then quantifying the amount of angiotensin I by radioimmunoassay. PRA: two-site immunoradiometry, where two monoclonal antibodies to human active renin are used.	Angiotensin II, PRA, angiotensinogen, and aldosterone increased significantly (p< 0.05) at baseline in the oral contraceptive group. Incremental lower body negative pressure resulted in increases in most RAAS components, which were not significantly different between groups.
Giribela et al. (2015)¹⁶16 Giribela CR, Consolim-Colombo FM, Nisenbaum MG. et al. Effects of a combined oral contraceptive containing 20 mcg of ethinylestradiol and 3 mg of drospirenone on the blood pressure, renin-angiotensin-aldosterone system, insulin resistance, and androgenic profile of healthy young women. Gynecol Endocrinol 2015; 31 (11) 912-915 DOI: 10.3109/09513590.2015.1062860. https://doi.org/10.3109/09513590.2015.10...	Evaluate the impact of a COC containing 20 mcg EE and 3 mg Drospirenone on BP, RAAS, insulin resistance, and androgenic profile of healthy young women using this COC.	Comparative observational	Total: 81 women Age: 18–40 years (average 30 ± 1)	49 healthy volunteers used COC containing 20mcg of EE and 3mg of drospirenone in a 24 day regimen of active pills followed by a 4 day break. 32 women with the same clinical characteristics who depend on male preservatives or non-hormonal intrauterine device were part of the control group.	PRA and aldosterone: enzymatic kinetic radioimmunological assay.	Significant increase in aldosterone (from 9.7 ± 1.0 to 20.8 ± 2.0; p= 0.0001) and in PRA (from 1.9 ± 0.2 to 4.2 ± 0.4; p= 0.0001).
Zakheim et al. (1976)¹⁷17 Zakheim RM, Molteni A, Mattioli L, Mullis KB. Angiotensin I-converting enzyme and angiotensin II levels in women receiving an oral contraceptive. J Clin Endocrinol Metab 1976; 42 (03) 588-589 DOI: 10.1210/jcem-42-3-588. https://doi.org/10.1210/jcem-42-3-588...	Studying the serum conversion of angiotensin I to enzymatic activity in women taking COC.	Comparative observational	Total: 22 women Age: 23.7 ± 1.1 for COC users; 26.5 ± 2.8 for non-COC users.	Enzyme conversion of angiotensin I, plasma angiotensin II, and BP were measured in 11 healthy women receiving oral estrogens ( norethindrone/mestranol, l7a-ethinyl-17-hydroxy-5(10)-estren-3-one and ethinylestradiol 3-methyl ether), 5 mg per day, for at least one year. The same measurements were performed in 11 healthy women who were not COC users and 11 healthy men of similar ages.	Enzymatic conversion of angiotensin I: modified Cushman and Cheung method. Plasma angiotensin II: radioimmunoassay kit provided by Schwartz-Mann Co (Orangeburg, N.J.) with the Boyd, Landon, and Peart procedure.	Plasma levels of angiotensin II increased significantly (p< 0.05) in women on Enovid. Insignificant changes in the enzyme conversion activity of angiotensin I were observed.
Hollenberg et al. (1976)¹⁸18 Hollenberg NK, Williams GH, Burger B, Chenitz W, Hoosmand I, Adams DF. Renal blood flow and its response to angiotensin II. An interaction between oral contraceptive agents, sodium intake, and the renin-angiotensin system in healthy young women. Circ Res 1976; 38 (01) 35-40 DOI: 10.1161/01.res.38.1.35. https://doi.org/10.1161/01.res.38.1.35...	To test the hypothesis that the use of COC is related to activation of the renin-angiotensin system, and that the responsiveness of the renal vasculature to angiotensin II provides an index of endogenous angiotensin II concentration in the vicinity of the renal vascular receptor.	Observational	Total: 86 women Age: < 49 years old	Data were available on renal blood flow and urinary sodium excretion for all volunteers. PRA measurements and angiotensin II levels were obtained for 19 subjects taking COC and 54 normal subjects not taking COC in identical clinical conditions.	Angiotensin II: measured by a dual antibody radioimmunoassay method. PRA: angiotensin radioimmunoassay.	PRS increased approximately 3-fold in association with a notable increase in circulating PRA (p= 0.01) and angiotensin II levels (p= 0.01) relative to sodium intake and excretion.
Cherney et al. (2007)¹⁹19 Cherney DZ, Scholey JW, Cattran DC. et al. The effect of oral contraceptives on the nitric oxide system and renal function. Am J Physiol Renal Physiol 2007; 293 (05) F1539-F1544 DOI: 10.1152/ajprenal.00351.2007. https://doi.org/10.1152/ajprenal.00351.2...	To examine the mechanisms by which women who are COC users maintain normal renal and systemic hemodynamic function, given the activation of RAAS.	Observational	Age: 18–49 years old	COC users were studied during the first 21 days of the menstrual cycle, and non-COC users were studied during the first 7 days of the menstrual cycle. Each study was performed after 7 days of a controlled diet consisting of 150mmol/day of sodium and 1.5 g/kg/day of protein. Compliance was determined by measuring 24 hour urinary sodium, potassium, and urea excretion on the 7th day. Blood samples were collected for inulin blank and for basal values of renin, PRA, angiotensin II, and aldosterone.	PRA: Two-site immunoradiometric assay, where two monoclonal antibodies to active human renin are used. Angiotensin II: radioimmunoassay. Aldosterone: radioimmunoassay, using the Coat-A-Count system. Angiotensinogen: measured indirectly by the endogenous conversion of angiotensinogen to angiotensin I.	Baseline aldosterone values (p= 0.03) and angiotensin II levels (p= 0.012) were high in women using COC. PRA levels were not significantly different between the two groups at baseline.
Oliveira et al. (2020)⁷7 Oliveira SS, Petto J, Diogo DP, Santos AC, Sacramento MS, Ladeia AM. Plasma renin in women using and not using combined oral contraceptive. Int J Cardiovasc Sci 2020; 33 (03) 208-214 DOI: 10.36660/ijcs.20180021. https://doi.org/10.36660/ijcs.20180021...	To test the hypothesis that there is a difference between plasma renin levels in women who use and do not use COC, as well as determine its relationship to C-reactive protein.	Comparative observational cross-section	Total: 44 women Age: 20–30 years old	Group COC: 22 women using low-dose COC for at least one year. Low COC dose with 15-30mcg of EE associated with progestin was considered. Of the COCs used, 100% contained EE. 41% were associated with drospirenone, 27% with gestodene, 14% with levonorgestrel, 9% with chlormadinone acetate and 9% with desogestrel. 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).

Author, year	Random Sequence Generation	Allocation concealment	Blinding of participants and professionals	Blinding of outcome assessors	Incomplete outcomes	Selective outcome report	Other sources of bias
Straznicky et al. (1998)⁶6 Straznicky NE, Barrington VE, Branley P, Louis WJ. A study of the interactive effects of oral contraceptive use and dietary fat intake on blood pressure, cardiovascular reactivity and glucose tolerance in normotensive women. J Hypertens 1998; 16 (03) 357-368 DOI: 10.1097/00004872-199816030-00013. https://doi.org/10.1097/00004872-1998160...	High risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias
Briggs and Briggs (1982)¹²12 Briggs MH, Briggs M. Randomized prospective studies on metabolic effects of oral contraceptives. Acta Obstet Gynecol Scand Suppl 1982; 105: 25-32 DOI: 10.3109/00016348209155314. https://doi.org/10.3109/0001634820915531...	High risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias risk	Uncertain risk of bias
Cain et al. (1971)¹³13 Cain MD, Walters WA, Catt KJ. Effects of oral contraceptive therapy on the renin-angiotensin system. J Clin Endocrinol Metab 1971; 33 (04) 671-676 DOI: 10.1210/jcem-33-4-671. https://doi.org/10.1210/jcem-33-4-671...	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias risk	Uncertain risk of bias
De Leo et al. (2001)¹⁴14 De Leo V, la Marca A, Morgante G. et al. Evaluation of plasma levels of renin-aldosterone and blood pressure in women over 35 years treated with new oral contraceptives. Contraception 2001; 64 (03) 145-148 DOI: 10.1016/s0010-7824(01)00237-2. https://doi.org/10.1016/s0010-7824(01)00...	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias	Uncertain risk of bias

Author (year)	Communication External validity Internal validity: bias Confusion variable Power					Total
	(11 points)	(3 points)	(7 points)	(6 points)	(1 point)	(28 points)
Kang et al. (2001)¹⁵15 Kang AK, Duncan JA, Cattran DC. et al. Effect of oral contraceptives on the renin angiotensin system and renal function. Am J Physiol Regul Integr Comp Physiol 2001; 280 (03) R807-R813 DOI: 10.1152/ajpregu.2001.280.3.R807. https://doi.org/10.1152/ajpregu.2001.280...	9	1	3	3	1	17
Giribela et al. (2015)¹⁶16 Giribela CR, Consolim-Colombo FM, Nisenbaum MG. et al. Effects of a combined oral contraceptive containing 20 mcg of ethinylestradiol and 3 mg of drospirenone on the blood pressure, renin-angiotensin-aldosterone system, insulin resistance, and androgenic profile of healthy young women. Gynecol Endocrinol 2015; 31 (11) 912-915 DOI: 10.3109/09513590.2015.1062860. https://doi.org/10.3109/09513590.2015.10...	8	1	4	2	1	16
Zakheim et al. (1976)¹⁷17 Zakheim RM, Molteni A, Mattioli L, Mullis KB. Angiotensin I-converting enzyme and angiotensin II levels in women receiving an oral contraceptive. J Clin Endocrinol Metab 1976; 42 (03) 588-589 DOI: 10.1210/jcem-42-3-588. https://doi.org/10.1210/jcem-42-3-588...	7	1	4	2	1	15
Hollenberg et al. (1976)¹⁸18 Hollenberg NK, Williams GH, Burger B, Chenitz W, Hoosmand I, Adams DF. Renal blood flow and its response to angiotensin II. An interaction between oral contraceptive agents, sodium intake, and the renin-angiotensin system in healthy young women. Circ Res 1976; 38 (01) 35-40 DOI: 10.1161/01.res.38.1.35. https://doi.org/10.1161/01.res.38.1.35...	8	2	4	3	1	18
Cherney et al. (2007)¹⁹19 Cherney DZ, Scholey JW, Cattran DC. et al. The effect of oral contraceptives on the nitric oxide system and renal function. Am J Physiol Renal Physiol 2007; 293 (05) F1539-F1544 DOI: 10.1152/ajprenal.00351.2007. https://doi.org/10.1152/ajprenal.00351.2...	9	1	5	2	1	18
Oliveira et al. (2020)⁷7 Oliveira SS, Petto J, Diogo DP, Santos AC, Sacramento MS, Ladeia AM. Plasma renin in women using and not using combined oral contraceptive. Int J Cardiovasc Sci 2020; 33 (03) 208-214 DOI: 10.36660/ijcs.20180021. https://doi.org/10.36660/ijcs.20180021...	10	3	4	3	1	21

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[1] Address for correspondence Alice Miranda de Oliveira, Av. Santos Dumont, 6061, 42712-740, Estrada do Coco, Portão, Lauro de Freitas, BA, Brazil (e-mail: alicemofisio@gmail.com).