What are the sex‑related differences in plasma renin activity and aldosterone concentrations—including effects of menstrual cycle phase, age, dietary sodium, and estrogen therapy—and how should these differences influence interpretation of the aldosterone‑to‑renin ratio?

Sex-Related Differences in Renin and Aldosterone Concentrations

Premenopausal women have lower renin activity and lower aldosterone production compared to men, while men exhibit higher renin levels and upregulated renin-angiotensin-aldosterone system (RAAS) activity due to androgenic effects. 1

Baseline Sex Differences in RAAS Activity

Hormonal Modulation of the RAAS

• Estrogens and progesterone in premenopausal women reduce renin activity, decrease angiotensin-converting enzyme (ACE) activity, lower aldosterone production, and upregulate the protective arm of the RAAS (ACE2, angiotensin 1-7, AT2 receptors). 1
• Androgens in men increase renin levels, enhance ACE activity, and upregulate the classical RAAS pathway (angiotensin II, AT1 receptors), leading to higher baseline RAAS activity. 1
• The "classical" RAAS axis (angiotensin II, ACE, AT1 receptors) has higher activity in males, promoting sympathetic activation, vasoconstriction, aldosterone release, and sodium retention. 1
• The protective RAS arm (ACE2, angiotensin 1-7, AT2 receptor, MAS receptor) is more strongly expressed in premenopausal women, mediating vasodilation and diuresis/natriuresis. 1

Direct Comparisons Between Sexes

• Younger men (ages 20-39) have significantly higher median renin concentrations (27.6 vs 17.0 mIU/L, P = 0.034) compared to age-matched women. 2
• Younger women (ages 20-39) paradoxically have higher median aldosterone (369 vs 244 pmol/L, P = 0.028) and higher aldosterone-to-renin ratio (ARR) (20.7 vs 10.3, P = 0.001) despite lower blood pressure than men. 2
• Premenopausal women exhibit lower renin-angiotensin-aldosterone system activity before menopause, which influences prescribing patterns favoring diuretics and calcium-channel blockers over ACE inhibitors and angiotensin receptor blockers. 1

Age-Related Changes and Menopause Effects

Postmenopausal Alterations

• After menopause, the loss of estrogen's protective effects results in upregulation of renin-angiotensin receptors and increased sodium sensitivity. 3
• Postmenopausal women experience markedly increased sodium sensitivity due to upregulation of renin-angiotensin receptors and loss of estrogen's natriuretic actions. 3
• The classical RAAS axis becomes dominant after menopause, enhancing sympathetic activation, vasoconstriction, aldosterone secretion, and sodium retention. 3
• The protective RAS arm (ACE2, angiotensin 1-7, AT2 receptor, MAS receptor) loses its counter-regulatory influence after menopause. 3

Age-Dependent Trends

• Renin decreases with advancing age in both sexes during low-salt diet (P < 0.001) and ad libitum salt intake (P = 0.05). 4
• Aldosterone does not correlate with age in essential hypertensive patients. 4
• The ARR increases significantly with age due to declining renin, independent of sex or BMI in multivariable analysis. 4
• In women aged ≥60 years, plasma aldosterone falls significantly (369 pmol/L at ages 20-39 vs 264 pmol/L at ≥60 years, P = 0.005), while no change occurs in males. 2

Menstrual Cycle Phase Effects

Luteal vs. Follicular Phase Differences

• Aldosterone levels are significantly higher during the luteal phase compared to the follicular phase (P = 0.006) in women with regular menstrual cycles. 5
• Progesterone levels are markedly elevated during the luteal phase (P < 0.0001), correlating with increased aldosterone. 5
• All women studied during the luteal phase had positive fludrocortisone suppression tests, while all three with negative tests were studied during the follicular phase. 5
• Aldosterone was significantly higher (P = 0.01) in women studied during the luteal phase compared to men, but not during the follicular phase. 5

Clinical Implications for Testing

• The menstrual cycle phase may affect the outcome of aldosterone suppression testing used to diagnose primary aldosteronism. 5
• Timing of ARR testing within the menstrual cycle should be considered, as luteal-phase testing may produce false-positive results. 5

Effects of Exogenous Hormones

Hormone Replacement Therapy (HRT)

• Combined HRT (conjugated estrogens 0.625 mg + medroxyprogesterone 2.5 mg daily) significantly increases aldosterone [baseline 150 pmol/L → 434 pmol/L at 6 weeks, P < 0.001] and plasma renin activity (PRA) [2.3 → 5.1 ng/mL/h, P < 0.001]. 6
• Direct renin concentration (DRC) decreases with combined HRT [21 → 14 mU/L, P < 0.01], leading to marked increases in ARR calculated by DRC [7.8 → 30.4, P < 0.001]. 6
• Three patients exceeded the ARR cutoff value (70) after 6 weeks of HRT when using DRC, representing potential false-positive screening results for primary aldosteronism. 6
• ARR calculated by PRA does not change significantly with combined HRT (P = 0.282), indicating the method of renin measurement critically affects interpretation. 6

Oral Contraceptives

• Oral ethynylestradiol/drospirenone contraceptives can produce false-positive ARR results during screening for primary aldosteronism, but only when calculated using DRC and not PRA. 7
• False-positive ratios can occur during the luteal menstrual phase and while taking oral contraceptives containing ethynylestradiol/drospirenone. 7
• Implanted subdermal etonogestrel does not produce false-positive ARR results. 7

Clinical Implications for ARR Interpretation

Sex-Specific Reference Ranges

• Current Endocrine Society guidelines use a single ARR threshold for all patients, but demographic variations suggest age- and sex-specific reference ranges are needed. 2
• Women aged 20-39 years have significantly higher ARR (20.7 vs 10.3, P = 0.001) than age-matched men despite lower blood pressure, highlighting potential for false-positive results. 2
• The ARR shows significant sex differences in both the 20-39 year and ≥60 year age groups. 2

Dietary Sodium Considerations

• Dietary salt restriction stimulates renin and can produce false-negative ARR results. 7
• A liberal salt diet should be encouraged before ARR measurement to improve test accuracy. 7
• Postmenopausal women should limit sodium intake to <1,500 mg/day due to increased sodium sensitivity from upregulated renin-angiotensin receptors. 3

Medication Effects and Testing Protocols

• Diuretics should be ceased at least 6 weeks and other interfering medications at least 2 weeks before ARR measurement. 7
• Mineralocorticoid receptor antagonists (spironolactone, eplerenone) should be withdrawn at least 4 weeks before testing. 8
• Beta-blockers, alpha-methyldopa, clonidine, and NSAIDs suppress renin, raising the ARR with potential for false positives. 7
• Dihydropyridine calcium blockers, ACE inhibitors, and angiotensin receptor antagonists stimulate renin and can produce false negatives. 7

Optimal Testing Conditions

• Blood should be collected midmorning from seated patients following 2-4 hours of upright posture to improve sensitivity. 7
• Testing should be performed with unrestricted salt intake and normal serum potassium levels. 8
• Hypokalemia should be corrected before testing, as potassium regulates aldosterone and uncorrected hypokalemia can lead to false negatives. 7
• For a positive ARR test, plasma aldosterone concentration should be at least 10 ng/dL in addition to the elevated ratio. 8
• The specificity of the ARR improves if a minimum plasma renin activity of 0.5 ng/mL/h is used in calculations. 8

Common Pitfalls in Clinical Practice

False-Positive Scenarios

• Premenopausal women aged 20-39 years are at high risk for false-positive ARR due to physiologically higher ratios despite normal blood pressure. 2
• Luteal-phase testing in menstruating women may yield false-positive results due to progesterone-mediated aldosterone elevation. 5
• Combined HRT use produces false-positive ARR when calculated using DRC but not PRA. 6
• Advancing age increases ARR due to declining renin, potentially causing false positives in elderly patients without true primary aldosteronism. 4

False-Negative Scenarios

• Follicular-phase testing may produce false-negative results due to lower aldosterone levels. 5
• Medications that stimulate renin (diuretics, ACE inhibitors, ARBs, dihydropyridine calcium blockers) lower the ARR and cause false negatives. 7
• Dietary salt restriction stimulates renin and produces false-negative results. 7
• Uncorrected hypokalemia suppresses aldosterone secretion and leads to false negatives. 7

Algorithmic Approach to ARR Interpretation

1. Verify patient preparation: Confirm 6-week cessation of diuretics, 4-week cessation of spironolactone/eplerenone, 2-week cessation of other interfering medications, correction of hypokalemia, and liberal salt intake. 7, 8

2. Document demographic factors: Record patient age, sex, menopausal status, menstrual cycle phase (if premenopausal), and use of hormonal contraceptives or HRT. 2, 5, 6

3. Interpret ARR in context:

   • For women aged 20-39 years, expect physiologically higher ARR (median 20.7) compared to age-matched men (median 10.3). 2
   • For women on combined HRT, use PRA-based ARR rather than DRC-based ARR to avoid false positives. 6
   • For premenopausal women, consider repeating testing during follicular phase if luteal-phase result is borderline positive. 5
   • For elderly patients (≥60 years), recognize that age-related renin decline elevates ARR independent of primary aldosteronism. 4

4. Confirm positive screening: The ARR is a screening test only and should be repeated once or more before proceeding to confirmatory suppression testing (saline infusion or oral salt loading). 7, 8

5. Proceed to confirmatory testing: If ARR remains elevated on repeat testing with proper preparation, perform intravenous saline suppression test or oral salt-loading test. 8