The impact of progestogens on RAAS – a systematic review

BACKGROUND: Progestogens, synthetic analogues of progesterone, are widely used in clinical practice for contraception, hormone replacement therapy, and the management of gynecological disorders. Understanding the specific impacts of different progestogens on the renin-angiotensin-aldosterone system (RAAS) is crucial due to their potential effects on cardiovascular and renal outcomes. OBJECTIVE: This systematic review aims to synthesize existing research on the effects of various progestogens on the RAAS and associated clinical outcomes. METHODS: We conducted a comprehensive search of databases up to the search date, including randomized controlled trials (RCTs), cohort studies, case-control studies, cross-sectional studies, and qualitative studies. The NIH Study Quality Assessment Tool for Controlled Intervention Studies was used to evaluate the quality of the included studies. Data extraction and quality assessment were performed independently by two reviewers, with discrepancies resolved through discussion. RESULTS: Forty-two studies on drospirenone (DRSP) were the most extensively investigated, showing either decreased or unchanged blood pressure (BP), mostly unchanged serum sodium, and an increased risk of hyperkalemia only in patients with mild renal impairment. Sixteen studies on norethindrone (NET/NETA) presented conflicting results on BP and a higher risk of hyperkalemia. Other progestogens, such as levonorgestrel (LNG) and medroxyprogesterone acetate (MPA), showed varied effects on RAAS parameters. Notably, changes in plasma renin activity (PRA), serum aldosterone, and angiotensin II levels were inconsistent across different progestogens and study designs. CONCLUSION: The effects of progestogens on the RAAS are complex and varied, influenced by the type of progestogen, dosage, and combination with estrogen. While some progestogens like DRSP may offer benefits in BP management with minimal electrolyte disturbances, others like NET/NETA might require more careful monitoring due to their associated risks. These findings highlight the importance of personalized medicine approaches in the use of progestogens, tailored to individual patient characteristics and specific hormonal profiles. Further research with standardized methodologies is needed to clarify these effects and guide clinical practice. TRIAL REGISTRATION: This review was prospectively registered with PROSPERO.