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Hypertensive Crisis Associated with High Dose Soy Isoflavone Supplementation

Isoflavones are gaining popularity as alternatives to hormone replacement therapy. However, few guidelines exist to inform the public as to an appropriate dose.

BMC Women's Health 2005
An Open Access  Case report
Published 23 June 2005

Abstract (provisional)

Isoflavones are gaining popularity as alternatives to hormone replacement therapy. However, few guidelines exist to inform the public as to an appropriate dose. This case involves a postmenopausal woman who experienced a hypertensive crisis while consuming a high-dose isoflavone supplement as part of a research protocol.

Case Presentation
The participant was part of a placebo-controlled crossover trial to investigate the potential synergism of the antioxidant activity of soy isoflavones and vitamin C. Upon entry into the study, this healthy, well-nourished, normotensive postmenopausal woman (51 years old), consumed the first of four randomly assigned treatments (500 mg vitamin C plus 5 mg/kg body weight soy isoflavones). During this treatment, the participant's systolic blood pressure spiked to a recorded 226/117 mmHg, necessitating medical intervention and discontinuation of study participation. Two plausible mechanisms for this hypertensive crisis are discussed.

Due to the availability and increasing popularity of soy supplements, practitioners should be aware of the potential side effects associated with their use. Practitioners counseling clients who are consuming soy isoflavone supplements should advise them that elevated blood pressure may be a potential side-effect to consider and monitor.

In recent years, isoflavones have increased in popularity as an alternative to conventional hormone replacement therapy for the relief of hot flashes and other symptoms associated with menopause. Currently, isoflavones are available as tablets, capsules, powders (particularly soy protein powders), drinks and bars [1] as well as a component of traditional soy foods. Typically, supplements provide 25–100 mg total isoflavones if consumed according to package directions [1]. Yet, due to the increasing variety of soy foods in the marketplace, consumers can easily consume 100 mg or more of total isoflavones each day from the diet alone. Although soy foods have been available for millennia, isoflavone supplements are relatively new and few drug/supplement or nutrient/supplement interactions have been identified [1]. However, consumers should be advised to use caution when taking isoflavone supplements because the potential for unidentified interactions does exist. This case study presents a postmenopausal woman who experienced an isoflavone/nutrient interaction, which resulted in a hypertensive crisis requiring medical intervention

Case Presentation
A 51-year-old postmenopausal non-Hispanic white woman was treated for a hypertensive crisis at a regional medical center in eastern Arizona. She had complained of symptoms for one week prior to admission, including light-headedness, headaches, and high blood pressure by self-measurement. Ten days prior to admission, the patient had been enrolled in a university-sponsored research trial designed to investigate the extent to which vitamin C and soy isoflavones, as supplements to a habitual diet, could provide antioxidant effects by reducing in vivo oxidative damage to cells, either alone or synergistically. During trial screening the patient reported typically consuming soy or soy products twice a week; no regular alcohol consumption; no history of hypertension or cardiovascular disease (although there was a family history of mild hypertension); no current medical supervision or care for any chronic health problems; no current use of over-the-counter or prescription medications and a routine exercise pattern of three times a week for 30–60 minutes. The participant weighed 175 pounds (79.5 kg), stood 5'8" (1.73 m), with a body mass index of 26.7 kg/m2.

Early in the research trial, the patient was randomized to receive 500 mg vitamin C plus 5 mg/kg body weight soy isoflavones. On trial day 3, the patient reported to the investigators that she felt "odd" and "light-headed." At the time, this was not attributed to the study-related supplements because the participant reported experiencing infrequent headaches for the past 20 years. On trial days 6 and 7 of the treatment period, the participant had her blood pressure checked by an automated machine; the readings were in the range of 140–150/92–98 mmHg vs. her usual BP of 120/82 mmHg. Due to this unexpected occurrence, the investigators requested that she stop consuming the supplements and drop out of the study. The incident was reported the university's Institutional Review Board Research Compliance Office, and the research trial was allowed to continue. Unbeknownst to the investigators, the participant chose to ignore the request to discontinue the supplements and continued to take the supplements on trial days 8 and 9. On trial day 9 she found her BP to be 159/110 mmHg. That night, she experienced an intense headache, a feeling of anxiety, and difficulty sleeping. Around midday on trial day 10, she stopped by a regional medical center to have her BP checked by a medical professional before going hiking. At that time, her BP was 226/117 mmHg; she reported that "my head feels like it is going to explode" and she was admitted to the emergency room. Laboratory analyses, including a complete blood count, metabolic panel and thyroid stimulating hormone test, were all within normal limits. A CT scan of the head showed no abnormalities or intracranial hemorrhages and a 12 lead EKG showed a normal sinus rhythm. At this time, the participant reported to the physician a 20-year history of chronic headaches that had resolved with better sleep habits and a higher fluid intake. The participant was then given 20 mg of the alpha1 and beta-blocker labetalol HCl via intravenous infusion (see Table 1). Subsequent to administration of the medication, the participant's blood pressure slowly dropped below critical levels, but did not reach normal limits. She was dismissed from the emergency room after 3 1/2 hours with a prescription for the non-selective beta-blocker propranolol HCl (Inderal LA), 80 mg once a day. She was told to discontinue the supplements that she was taking for the research trial.

The patient notified the trial investigator of the hypertensive event several days later. The hypertensive crisis was reported to the university's Institutional Review Board Research Compliance Office, and the research trial was allowed to continue with the stipulation that all participants submit to blood pressure monitoring weekly. Later that week, the participant's BP was measured by the primary investigator's staff and was still above normal limits. When the participant saw a cardiologist and her regular physician for further follow-up, no abnormalities in cardiac function, renal function or hormone levels were identified that could have led to the hypertensive crisis. The participant continued on antihypertensive medications for the next 12 months and was gradually able to decrease the dose of the medications over time.

One plausible explanation for the hypertensive crisis experienced by this participant is the inhibition of monoamine oxidase by the isoflavones (e.g., daidzin, daidzein) or their metabolites (e.g., equol). Rooke et al.[2] and Gao et al.[3] both reported that daidzin, the plant precursor of the mammalian metabolite daidzein, and some of its structural analogs can inhibit mitochondrial monoamine oxidase in vitro. Additionally, Dewar et al.[4] reported that equol, a mammalian metabolite of daidzein, was an effective inhibitor of rat liver monoamine oxidase in vitro. Since the soy isoflavone supplements used in the research trial consisted of 63% (178 mg aglycone units/g) genistein, 28% (79.1 mg aglycone units/g) daidzein and 9% (24.6 aglycone units/g) glycitein (percentages based on aglycone units), the daidzein in the supplement may have interacted with monoamine oxidase.

Monoamine oxidase is responsible for the deamination of monoamines, including serotonin, epinephrine, norepinephrine, dopamine and tyramine. Its inhibition will cause an increase in the blood levels of these compounds. Since tyramine acts as a vasoconstrictor, an increased tyramine level will cause an increase in blood pressure [5,6]. Review of the two-day food records recorded prior to the participant's entering the study in addition to dietary information obtained after the hypertensive event indicated the participant's normal diet typically contained multiple tyramine-containing foods. The participant confirmed that she had consumed several tyramine-containing foods during the study, including the day before and the day of her emergency room admission (Table 2). Thus, the high dose of supplemental isoflavones [397.5 mg isoflavones (aglycone units) containing approximately 111 mg daidzein (aglycone units)], in conjunction with her typical moderate to high tyramine diet, may have contributed to a monoamine oxidase inhibitor-type reaction. Although the studies by Rooke et al.[2], Gao et al. [3] and Dewar et al.[4] suggest such a reaction might be possible, we believe this is the first report published of a possible monoamine oxidase inhibitor reaction and subsequent blood pressure spike occurring in vivo due to intake of a soy isoflavone supplement.

A second plausible explanation for the hypertensive crisis experienced by this participant is an imbalance in the renin-angiotensin system, an important regulator of blood pressure, due to the administration of the isoflavones. Isoflavones are known to bind to both the α and β estrogen receptors and exert weak estrogenic effects in vivo [7,8]. Because angiotensinogen production by the liver is modulated by estrogens, the assumed increase in the serum isoflavone concentrations due to the high isoflavone intake may have stimulated an estrogenic response, thereby increasing hepatic angiotensinogen production and release into the plasma [9-11]. Once cleaved by renin, angiotensinogen becomes angiotensin I which is rapidly converted to angiotensin II by the angiotensin-converting enzyme [12]. Angiotensin II acts on the outer layer of the zona glomerulosa of the adrenal cortex, converting corticosterone to aldosterone, which subsequently increases renal sodium reabsorption as well as extracellular fluid and blood volume resulting in an increase in blood pressure [12]. Thus, the high dose of supplemental isoflavones consumed by this participant may have caused an imbalance in the renin-angiotensin system, the end result of which was the hypertensive crisis that the participant experienced.

Due to the availability and increasing popularity of soy supplements, practitioners should be aware of the potential side effects associated with their use. This case study reports two plausible reactions, a monoamine oxidase inhibitor-type reaction or an imbalance in the renin-angiotensin system, which may have occurred with consumption of a high-dose isoflavone supplement resulting in the participant experiencing a hypertensive crisis. Although this reaction occurred within the context of a research study, it is possible that similar reactions might occur in general population if the dosage guidelines listed on the soy isoflavone supplements are exceeded. Practitioners counseling clients who are consuming soy isoflavone supplements should advise them that elevated blood pressure may be a potential side-effect to consider and monitor

Competing interests
The author(s) declare that they have no competing interests.

Authors' contributions
AH participated in the design and coordination of the study and drafted the manuscript. IM participated in the design of the study, participated in conducting the laboratory analyses, and helped to draft the manuscript. CJ participated in the design of the study, performed the statistical analyses, and helped to draft the manuscript.

This study was funded by the Sustainable Technologies, Agribusiness and Resource Center, Arizona State University, Mesa, AZ 85212, USA.

Written consent was obtained from the patient for publication of the study.


  Blood Pressure     

Date  Time  Systolic  Diastolic  Heart Rate  Respirations  Notes  

March 10  1301  226  117  87  20   
 1310      12 lead EKG performed Blood drawn for laboratory analyses  
 1334  203  115  75  18   
 1339  190  110  70  20  Taken to CT  
 1345  178  112  78  16   
 1349  176  100  78  18   
 1354  177  111  71  12   
 1357  177  118  72  10   
 1359  187  106  70  18  Medicated via IV: Labetolol HCl 20 mg Pt. stated ↓ headache  
 1404  162  96  67  11   
 1409  159  94  74  16   
 1414  169  111  72  15   
 1419  177  108  72  17   
 1424  181  104  73  27   
 1429  163  93  69  13   
 1434  169  97  69  15   
 1439  170  111  72  22   
 1444  162  97  84  14   
 1449  168  104  70  13  Pt. stated headache gone  
 1454  171  104  65  12   
 1459  166  92  69  14   
 1504  190  106  74  18   
 1509  181  107  69  34   
 1514  177  106  76  13   
 1519  163  104  71  20   
 1524  178  108  70  14   
 1529  176  106  64  20   
 1534  168  102  89  9   
 1539  162  100  70  16   
 1544  168  102  68  14   
 1549  165  102  70  12  Medicated PO: Inderal LA 80 mg  
 1618  179  117  69  N/A   
 1630      Discharged to home  




1. Fragakis AS: The Health Professional's Guide to Popular Dietary Supplements.2nd edition. Chicago, IL , American Dietetic Association; 2003.

2. Rooke N, Li DJ, Li J, Keung WM: The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: a potential site of action of diadzin.J Med Chem 2000, 43:4169-4179. [PubMed Abstract] [Publisher Full Text]

3. Gao GY, Li DJ, Keung WM: Synthesis of potential antidipsotropic isoflavones: inhibitors of the mitochondiral monoamine oxidase-aldehyde dehydrogenase pathway.J Med Chem 2001, 44:3320-3328. [PubMed Abstract] [Publisher Full Text]

4. Dewar D, Glover V, Elsworth J, Sandler M: Equol and other compounds from bovine urine as monoamine oxidase inhibitors.J Neural Transm 1986, 65:147-150. [PubMed Abstract] [Publisher Full Text]

5. Physician's Desk Reference58th edition. Thompson Healthcare; 2004.

6. Pronsky ZM, Crowe JP: Food-drug interactions.In Krause's Food, Nutrition and Diet Therapy. 11th edition. Edited by: Mahan LK, Escott-Stump S. Philadelphia, PA , Saunders; 2004:455-474.

7. Setchell KDR: Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones.Am J Clin Nutr 1998, 68(suppl):1333S-46S.

8. Setchell KDR, Clerici C, Lephart ED, Cole SJ, Heenan C, Castellani D, Wolfe BE, Nechemias-Zimmer L, Brown NM, Lund TD, Handa RJ, Heubi JE: S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora.Am J Clin Nutr 2005, 81:1072-1079. [PubMed Abstract] [Publisher Full Text]

9. Dzau VJ, Herrmann HC: Hormonal control of angiotensinogen production.Life Sci 1982, 30:577-584. [PubMed Abstract] [Publisher Full Text]

10. Hong-Brown LQ, Deschepper CF: Regulation of the angiotensinogen gene by estrogens in rat liver and different brain regions.Proc Soc Exp Biol Med 1993, 203:467-473. [PubMed Abstract]

11. Stavreus-Evers A, Parini P, Freyschuss B, Elger W, Reddersen G, Sahlin L, Eriksson H: Estrogenic influence on the regulation of hepatic estrogen receptor-alpha and serum level of angiotensinogen in female rats.J Steroid Biochem Molec Biol 2001, 78:83-88. [PubMed Abstract] [Publisher Full Text]

12. Costanzo LS: Physiology.3rd edition. Baltimore, MD , Lippincott Williams & Wilkens; 2003.

BMC Women's Health 2005, 5:9 doi:10.1186/1472-6874-5-9

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472-6874/5/9

© 2005 Hutchins et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/2.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.