by Andrea Gruszecki, ND
Introduction
High blood pressure, or hypertension, may be a primary or contributing cause, worldwide, to approximately 7.5 million deaths per year.1,2 Dysregulation of the renin-angiotensin-aldosterone system (RAAS) has a significant effect on blood pressure dynamics and other aspects of health (Figure 1). Hyperaldosteronism may occur for a variety of reasons, and recent evidence indicates that primary aldosteronism, once considered a rare disorder, may be present in a significant number of normotensive and hypertensive individuals.3 These human studies also indicate that there is a wide variety of clinical presentations. Early in the course of the disorder, circulating potassium levels may be within normal limits, and up to 85% of normotensive individuals may only develop hypertension over time as “classical” primary aldosteronism may actually be a later stage of the disease process.4,5 Based on these studies, routine screening of aldosterone levels may be considered an essential aspect of health care.
Primary Aldosteronism
Primary aldosteronism is defined as aldosterone secretion independent of typical regulators such as renin, angiotensin II, or sodium status.3,5 Primary aldosteronism is the most common cause of secondary hypertension. Symptoms of primary aldosteronism may include muscle weakness or cramps, skin sensations (tingling, burning, numbness), low blood potassium (hypokalemia), high blood sodium, high urinary potassium (hyperkaluria), alkalosis, and hypertension independent of elevated cortisol (Cushing’s syndrome). These symptoms occur with significantly elevated urinary aldosterone and urinary sodium excretion. The chronic exposure to high aldosterone levels significantly increases the risk of atrial fibrillation, stroke, and myocardial infarction. Previous human studies agree that higher levels of aldosterone can only induce hypertension and urinary excretion of potassium when renin levels are low.6 This fact allows clinicians to perform a very simple screen, prior to pursuing more complicated confirmatory testing. The presence of a high aldosterone level, high urinary sodium, and suppressed (low) plasma renin should raise suspicion for RAAS dysregulation and possible primary aldosteronism, regardless of the individual’s current blood pressure status, and particularly if there is potassium dysregulation.3,5 Routine screening is most important in populations with increased risk, such as those with hypertension, African-Americans, and aging populations.6,7
When stimulated by adreno-corticotropic hormone (ACTH), both cortisol and aldosterone will rise; and during adrenal insufficiency, both cortisol and aldosterone are low.8 Human studies indicate that during ACTH stimulation, plasma aldosterone concentrations are significantly higher in primary hyperaldosteronism when compared with hypertension due to other causes.9 While aldosterone secretion is also controlled by circulating potassium and RAAS angiotensin II levels, ACTH is independent of the usual aldosterone RAAS/potassium feedback loops. Although studies are needed for confirmation, it is possible that stress-induced endogenous ACTH stimulation plays a role in some types of sporadic primary aldosteronism, as aldosterone may respond to lower levels of stress-induced ACTH stimulation than cortisol does.10,11
The comparison of mineralo-corti-coids (aldosterone) with glucocorticoids (cortisol) may improve diagnosis and treatment, as high levels of aldosterone mimic the effects of high levels of cortisol. Simply checking cortisol levels may not disclose the true cause of symptoms or disease. While not common, it is possible for cortisol/cortisone levels to be low or normal, while aldosterone levels are elevated; it is also possible for the reverse to be true (see Figure 2).12 Each hormone system requires specialized treatments; it is essential, therefore, for both systems to be evaluated if either system is suspect.13-15
Fortunately, the assessment of urinary aldosterone, mineralocorticoid metabolites and urinary potassium may be performed simultaneously with a 24-hour urine hormone assessment (see Figure 2.). Simultaneous assessment of sex hormones and estrogen metabolites, in addition to adrenal hormones, may have additional advantages for clinical interpretation. Two of the estrogen metabolites measured can provide further information about the overall risk of RAAS dysregulation (see Figure 3).16,17
Sex Hormone Effects
The primary sex hormones, such as estrogens and androgens affect vascular angiotensin II sensitivity and regulate different aspects of the RAAS.18 Estrogens have been shown to increase angiotensin and the expression of angiotensin-converting enzyme 2, angiotensin receptor 2, and endothelial nitric oxide synthase. Estrogens decrease renin production, oxidative stress, and the expression of angiotensin-converting enzyme 1 and angiotensin receptor 1 (see Figure 1). The combination of estrogen-related effects favors the vasodilator function of the RAAS, and the effect is mimicked by transdermal bio-identical hormone replacement, which tends to lower blood pressure. Of note, oral conjugated equine estrogen replacements increase angiotensin levels and the risk of hypertension in human studies.19,20 The evaluation of estrogen metabolites may provide additional information regarding the RAAS (see Figure 3). The status of the phase I detoxification estrogen metabolite 4-hydroxyestrone (4OHE1) depends upon the activity of cytochrome P450 1B1 (CYB1B1); this enzyme is associated with hypertension and kidney dysfunction in animal studies.21 The phase II metabolite 2-methoxyestradiol has been shown to decrease RAAS-induced hypertension and kidney dysfunction in animal studies.22 Both metabolite pathways can be managed with nutritional supports.
Testosterone, compared to estrogens, has the opposite effect, and favors the vasoconstriction function of the RAAS, increases blood pressure.18 Progesterone, important for both genders, is a precursor molecule for aldosterone and competes directly with aldosterone for mineralocorticoid receptors.23 Along with estrogens, progesterone also influences signaling pathways to inhibit ACTH-induced aldosterone secretion.24
In addition to sex hormone status, blood glucose regulation is equally important, as high glucose levels can induce the expression of aldosterone synthase, the last enzyme in the aldosterone synthesis pathway.25 In what may become a vicious circle, the high aldosterone levels then inhibit insulin production in pancreatic ß-cells. High aldosterone levels also impair insulin signaling in peripheral tissues and exacerbate glucose intolerance and diabetes.26 Two other biomarkers indicative of metabolic status may be evaluated with urine hormones, glucocorticoids and mineralocorticoids: xanthurenic acid and kynurenic acid (Figure 4). Elevated levels of xanthurenic acid are associated with type II diabetes in human studies and indicate an increased need for vitamin B-6.27 If only kynurenic acid is elevated it is associated with a need for vitamin B-3, the precursor to nicotinamide adenine dinucleotide (NAD+), an essential cellular cofactor.
Interventions
There are several types of inherited (familial) hyperaldosteronism, one of which responds to glucocorticoid therapy.5 There are several other gain-of-function genetic changes also associated with primary aldosteronism; these changes are found either in tumors or in aldosterone-producing cell clusters (APCC) within the adrenal tissues. If a tumor is identified, then surgical removal of the overactive tissues is often curative. Control of APCCs is more difficult and may require pharmaceutical interventions if sodium restriction < 65 mmol (preferably < 50 mmol) daily does not control the primary aldosteronism and increase renin levels. If the cause is unilateral adrenal hyperplasia, then surgery may again be considered; if the adrenal hyperplasia is bilateral, then medication is the preferred treatment.28 Current evidence indicates that mineralocorticoid receptor blockers may be the preferred first-line medication.10
While human studies have not yet been performed, it is possible that early interventions and management of nutritional and lifestyle factors may either prevent or slow the progression of primary hyperaldosteronism. In addition to sodium restriction, interventions that might be considered include the following:
· Normalize body weight if body mass index (BMI) > 25 for women or 27 for men.29
· Vitamin D3
o Vitamin D3 (> 800 IU daily) reduced both systolic and diastolic blood pressure in hypertensive individuals of normal weight. However, vitamin D with calcium, or vitamin D in overweight or obese individuals, may increase blood pressure.30
· Consider anti-hypertensive herbs for high-normal blood pressure or mild hypertension.31 NOTE: Anti-hypertensive herbs may not be appropriate during pregnancy or nursing.
o Aged garlic extract (960 mg QD) may lower systolic pressure by < 10 mmHg.
o Berberine (< 1.5 mg QD) may decrease systolic pressure < 5 mmHg and diastolic pressure 2 mmHg.
o Crataegus (hawthorn species) (500 mg QD) or water-alcohol extracts may decrease systolic pressure < 13 mmHg and diastolic pressure by < 8 mmHg.
o Crocus sativus (saffron) (400 mg QD) may decrease systolic pressure < 11 mHg and diastolic pressure < 5 mmHg.
o Hibiscus sabdariffa (roselle) dried calyx extract (250 mg) or dried calyx (10 gm), has reduced systolic pressure by <15 mmHg and diastolic pressure by <11 mmHg.
o Nigella sativa (black cumin seed) 2.5 mL N. sativa oil BID may decrease systolic pressure <10 mmHg and diastolic pressure < 9 mmHg.
o Zingiber officinale (ginger) constituent (6)-gingerol may antagonize the angiotensin type II receptor and inhibit angiotensin-converting enzyme I activity. A mean dose of 105 mg/kg body weight was required to decrease blood pressure.
· Taurine
o Taurine has antioxidant properties, promotes vascular relaxation and improves vascular inflammation.32 Taurine supplementation decreases hypertension and RAAS activity in animal models.33
o Human studies demonstrate that taurine (six grams/day) reduced systolic, diastolic and mean arterial blood pressure in six weeks in salt-restricted hypertensives; another human study saw results within seven days, compared to placebo.32 Doses as low as three grams have been found effective in other human hypertension studies.
· Stress management, specifically interventions that promote “rest and digest” signaling from the vagus nerve and increased heart rate variability, may decrease mineralocorticoid levels via reduced ACTH “fight or flight” signaling.11,34,35
· Consider bio-identical hormone replacement in post-menopausal women and, possibly, men with testosterone insufficiency to normalize estrogen levels.36,37
o Confirm low hormone levels with laboratory testing and monitor to ensure that supplementation brings levels only into the physiological range.38,39,40
o In post-menopausal women, human studies indicate that hormone replacement therapy significantly reduces blood pressure in both normotensive and hypertensive women.41 Transdermal estradiol was superior to oral conjugated equine estrogens in reducing blood pressure.
o Caution is indicated in men with testosterone insufficiency: use hormone evaluations pre- and post-supplementation both androgens and estrogens to ensure that conversion into vaso-dilating estrogens occurs via the aromatase enzyme. Use supplementation to achieve physiological levels of androgens; high levels of testosterone exacerbate hypertension.42
§ Quercetin, 1,500-3,000 mg daily, in conjunction with other dietary flavonoids such as genistein, may induce aromatase activity in individuals with inherited low-activity forms of the enzyme.43-45
o Modify cytochrome 1B1 activity through diet to decrease hypertension risk.
§ Human studies indicate that 10 grams of ground flaxseed can modify CYP1B1 activity in women; studies on men are required.46
§ Plant compounds such as stilbenes (resveratrol), coumarins (curcumin) flavonoids and flavanols (tea, fruits, vegetables, cocoa), have all been shown to inhibit CYP1B1 in vitro.47,48
o 2-methoxyestradiol production may be improved by providing the nutritional co-factors of catechol-O-methyltransferase with magnesium (350 milligrams) and s-adenosylmethionine (600-1,200 mg daily).49-51
Conclusion
The prevalence of hypertension in adults was estimated to exceed 1.3 billion in 2016. The increased cardiovascular risk that accompanies high blood pressure can be managed most effectively if the cause, rather than the symptom, of hypertension is treated. Routine screening for aldosterone, renin and sodium in adult patients, particularly in those with a family history of hypertension or cardiovascular disease, is the best way to determine if primary aldosteronism is the cause.
References
1. Centers for Disease Control and Prevention (2016) High Blood Pressure Fact Sheet. https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_bloodpressure.htm Accessed 09 August 2019.
2. Bloch M. Worldwide prevalence of hypertension exceeds 1.3 billion. J Am Soc Hypertens. 2016 Oct;10(10):753-754.
3. Baudrand R, et al. Continuum of Renin-Independent Aldosteronism in Normotension. Hypertension. 2017;69(5):950–956.
4. Mantero F, Mattarello MJ, Albiger NM. Detecting and treating primary aldosteronism: primary aldosteronism. Exp Clin Endocrinol Diabetes. 2007 Mar;115(3):171-4.
5. Vaidya A, et al. The Expanding Spectrum of Primary Aldosteronism: Implications for Diagnosis, Pathogenesis, and Treatment. Endocr Rev. 2018 Dec 1;39(6):1057-1088.
6. Brown JM, et al. The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension: A Cohort Study. Ann Intern Med. 2017;167(9):630–641.
7. Lacruz ME, et al. Prevalence and Incidence of Hypertension in the General Adult Population: Results of the CARLA-Cohort Study. Medicine (Baltimore). 2015;94(22):e952.
8. Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol. 2014;4(2):739–769.
9. Inoue K, et al. Clinical Utility of the Adrenocorticotropin Stimulation Test with/without Dexamethasone Suppression for Definitive and Subtype Diagnosis of Primary Aldosteronism. Int J Mol Sci. 2017;18(5):948.
10. Funder JW. The Potential of ACTH in the Genesis of Primary Aldosteronism. Front Endocrinol (Lausanne). 2016;7:40.
11. Kubzansky LD, Adler GK. Aldosterone: a forgotten mediator of the relationship between psychological stress and heart disease. Neurosci Biobehav Rev. 2010;34(1):80–86.
12. Holst JP, et al. Steroid hormones: relevance and measurement in the clinical laboratory. Clin Lab Med. 2004;24(1):105–118.
13. Ruiz AD, et al. Effectiveness of compounded bioidentical hormone replacement therapy: an observational cohort study. BMC Womens Health. 2011 Jun 8;11:27.
14. Atwood CS, et al. Dysregulation of the hypothalamic-pituitary-gonadal axis with menopause and andropause promotes neurodegenerative senescence. J Neuropathol Exp Neurol. 2005 Feb;64(2):93-103.
15. Horstman AM, et al. The role of androgens and estrogens on healthy aging and longevity. J Gerontol A Biol Sci Med Sci. 2012;67(11):1140–1152.
16. Koganti S, et al. 2-methoxyestradiol binding of GPR30 down-regulates angiotensin AT(1) receptor. Eur J Pharmacol. 2014;723:131–140.
17. Jennings BL, et al. Cytochrome P450 1B1 contributes to renal dysfunction and damage caused by angiotensin II in mice. Hypertension. 2012;59(2):348–354.
18. te Riet L, et al. Hypertension Renin–Angiotensin–Aldosterone System Alterations. Circulation Research 2015; 116(6): 960-975.
19. Schunkert H, et al. Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation 1997 Jan 7;95(1):39-45.
20. Ichikawa J, et al. Different effects of transdermal and oral hormone replacement therapy on the renin-angiotensin system, plasma bradykinin level, and blood pressure of normotensive postmenopausal women. Am J Hypertens. 2006 Jul;19(7):744-9.
21. Malik KU, et al. Contribution of cytochrome P450 1B1 to hypertension and associated pathophysiology: a novel target for antihypertensive agents. Prostaglandins Other Lipid Mediat. 2012;98(3-4):69–74.
22. Pingili AK, et al. 2-Methoxyestradiol Reduces Angiotensin II-Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice. Hypertension. 2017 Jun;69(6):1104-1112.
23. Gomez-Sanchez EP. Brain mineralocorticoid receptors in cognition and cardiovascular homeostasis. Steroids. 2014;91:20–31.
24. Szmuilowicz E, et al. Relationship between Aldosterone and Progesterone in the Human Menstrual Cycle. J Clin Endocrinol Metab. 2006;91(10):3981-3987.
25. Shimada H, et al. High glucose stimulates expression of aldosterone synthase (CYP11B2) and secretion of aldosterone in human adrenal cells. FEBS Open Bio. 2017;7(9):1410–1421.
26. Hollenberg NK, et al. Plasma aldosterone concentration in the patient with diabetes mellitus. Kidney Int. 2004;65:1435–1439.
27. Oxenkrug G. Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Molecular Neurobiology 2013:48(2):294-301.
28. Fiquet-Kempf B, et al. Is primary aldosteronism underdiagnosed in clinical practice? Clin Exp Pharmacol Physiol. 2001 Dec;28(12):1083-6.
29. Chen SC, et al. Variations in aging, gender, menopause, and obesity and their effects on hypertension in Taiwan. Int J Hypertens. 2014;2014:515297.
30. Golzarand M, et al. Effect of vitamin D3 supplementation on blood pressure in adults: An updated meta-analysis. Nutr Metab Cardiovasc Dis. 2016 Aug;26(8):663-73.
31. Al Disi SS, Anwar MA, Eid AH. Anti-hypertensive Herbs and their Mechanisms of Action: Part I. Front Pharmacol. 2016;6:323.
32. Abebe W, Mozaffari MS. Role of taurine in the vasculature: an overview of experimental and human studies. Am J Cardiovasc Dis. 2011;1(3):293–311.
33. Chesney RW, Han X, Patters AB. Taurine and the renal system. J Biomed Sci. 2010;17 Suppl 1(Suppl 1):S4.
34. Buric I, et al. What Is the Molecular Signature of Mind-Body Interventions? A Systematic Review of Gene Expression Changes Induced by Meditation and Related Practices. Front Immunol. 2017;8:670.
35. McCraty R, Shaffer F. Heart Rate Variability: New Perspectives on Physiological Mechanisms, Assessment of Self-regulatory Capacity, and Health risk. Glob Adv Health Med. 2015;4(1):46–61.
36. Zarotsky V, et al. Systematic Literature Review of the Epidemiology of Nongenetic Forms of Hypogonadism in Adult Males. J Hormones. 2014;2014: 1-17.
37. Ichikawa A, et al. Effects of long-term transdermal hormone replacement therapy on the renin-angiotensin- aldosterone system, plasma bradykinin levels and blood pressure in normotensive postmenopausal women. Geriatr Gerontol Int. 2008 Dec;8(4):259-64.
38. Lunenfeld B, et al. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. Aging Male. 2015;18(1):5–15.
39. Eliassen AH, et al. Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among premenopausal women. Cancer Res. 2012;72(3):696–706.
40. Coburn SB, et al. Comparability of serum, plasma, and urinary estrogen and estrogen metabolite measurements by sex and menopausal status. Cancer Causes Control. 2019 Jan;30(1):75-86.
41. Ichikawa J, et al. Different effects of transdermal and oral hormone replacement therapy on the renin-angiotensin system, plasma bradykinin level, and blood pressure of normotensive postmenopausal women. Am J Hypertens. 2006 Jul;19(7):744-9.
42. Kumar P, et al. Male hypogonadism: Symptoms and treatment. J Adv Pharm Technol Res. 2010;1(3):297–301.
43. Patel K. Summary of Quercitin. https://examine.com/supplements/quercetin/ Accessed 21 August 2019.
44. Sanderson JT, et al. Induction and inhibition of aromatase (CYP19) activity by natural and synthetic flavonoid compounds in H295R human adrenocortical carcinoma cells. Toxicol Sci. 2004 Nov;82(1):70-9.
45. van Duursen MBM. Modulation of estrogen synthesis and metabolism by phytoestrogens in vitro and the implications for women’s health. Toxicol Res (Camb). 2017;6(6):772–794.
46. McCann SE, et al. Changes in 2-hydroxyestrone and 16alpha-hydroxyestrone metabolism with flaxseed consumption: modification by COMT and CYP1B1 genotype. Cancer Epidemiol Biomarkers Prev. 2007;16(2):256–262.
47. Liu J, Sridhar J, Foroozesh M. Cytochrome P450 Family 1 Inhibitors and Structure-Activity Relationships. Molecules 2013;18(12):14470-14495.
48. Sies H, et al. Protection by flavanol-rich foods against vascular dysfunction and oxidative damage: 27th Hohenheim Consensus Conference. Adv Nutr. 2012;3(2):217–221.
49. UniProt (July 2019) Catechol O-methyltransferase. https://www.uniprot.org/uniprot/P21964 Accessed 22 August 2019.
50. Higdon J, Volpe S. (February 2019) Magnesium. https://lpi.oregonstate.edu/mic/minerals/magnesium Accessed 22 August 2019.
51. Patel K. (2019) S-adenosyl Methionine. https://examine.com/supplements/s-adenosyl-methionine/ Accessed 22 August 2019.
Andrea Gruszecki, ND, received her BA in ecology and evolutionary biology from the University of Connecticut, where she was exposed to a variety of research projects; her own research project examined the effects of diurnal cycles on Poeciliopsis species. Trained as a radiologic technologist and army medic, she spent the years prior to graduation working in urgent care and hospital settings, gaining valuable clinical experience. She received her doctorate in naturopathy from Southwest College of Naturopathic Medicine. Upon her graduation from SWCNM, she worked with patients at the Wellness Center in Norwalk, Connecticut, before starting her own naturopathic practice.
Her experiences in private practice evolved into an inclusive model of medicine for use by conventional and CAM providers, designed to allow cross-specialty communication among health care providers (“Forward into the Past: Reclaiming Our Roots Through an Inclusive Model of Medicine.” NDNR eNewsletter, June 2013). She has presented at a variety of venues, including the American Academy of Environmental Medicine, Integrative Medicine for Mental Health, International College of Integrative Medicine, and the California Naturopathic Doctors Association.
Dr. Gruszecki is a member of the consulting department at Meridian Valley Laboratory, where she may provide interpretive assistance with laboratory results, write interpretations, and create conference presentations.
