Hypertensive crisis associated with high dose soy isoflavone supplementation in a post-menopausal woman: a case report [ISRCTN98074661]
© Hutchins et al; licensee BioMed Central Ltd. 2005
Received: 30 November 2004
Accepted: 23 June 2005
Published: 23 June 2005
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.
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  as well as a component of traditional soy foods. Typically, supplements provide 25–100 mg total isoflavones if consumed according to package directions . 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 . 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.
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.
Vital signs and pertinent events during emergency room admission
12 lead EKG performed Blood drawn for laboratory analyses
Taken to CT
Medicated via IV: Labetolol HCl 20 mg Pt. stated ↓ headache
Pt. stated headache gone
Medicated PO: Inderal LA 80 mg
Discharged to home
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. and Gao et al. 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. 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.
Participant's Dietary Intake
Dinner on Day 9, 5:30 p.m.
*Yoplait fat free yogurt–12 ounces
Peanuts, salted–1/4 cup
Navel orange–1 medium
*Banana, ripe–1 medium
*Avocado, ripe–1 small
Potato chips–1 handful
Jelly beans–1/4 cup
*3 Musketeers bar–1/3 of bar
Vanilla ice cream–1/2 cup
Breakfast on Day 10, 8:00 a.m.
Eggs, scrambled–2 whole
Toast–1 slice with ~1 teaspoon margarine
* signifies tyramine-containing foods
Foods from participant's Typical Diet containing tyramine or other pressor agents[5,6]
Balsamic vinegar–1–2 teaspoons daily
Cheddar cheese–2–4 ounces daily
Mozzarella cheese–1 ounce daily
Yogurt–16 ounces daily
Dried beans or legumes–1/2 cup daily
Coffee–17–21 ounces daily
Bananas–1 every other day
Tamari sauce–1 tablespoon 2 times/week
Swiss cheese–2 ounces/week
Cured meats–1 time/week
Blue Cheese–2–3 times/month
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 . 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 . 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.
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.
- Fragakis AS: The Health Professional's Guide to Popular Dietary Supplements. 2003, Chicago, IL , American Dietetic Association, 2ndGoogle Scholar
- 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. 10.1021/jm990614i.View ArticlePubMedGoogle Scholar
- 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. 10.1021/jm0101390.View ArticlePubMedGoogle Scholar
- 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. 10.1007/BF01256490.View ArticlePubMedGoogle Scholar
- Physician's Desk Reference. 2004, Thompson Healthcare, 58th
- Pronsky ZM, Crowe JP: Food-drug interactions. Krause's Food, Nutrition and Diet Therapy. Edited by: Mahan LK, Escott-Stump S. 2004, Philadelphia, PA , Saunders, 455-474. 11thGoogle Scholar
- Setchell KDR: Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr. 1998, 68(suppl): 1333S-46S.Google Scholar
- 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.PubMedGoogle Scholar
- Dzau VJ, Herrmann HC: Hormonal control of angiotensinogen production. Life Sci. 1982, 30: 577-584. 10.1016/0024-3205(82)90272-7.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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. 10.1016/S0960-0760(01)00077-2.View ArticlePubMedGoogle Scholar
- Costanzo LS: Physiology. 2003, Baltimore, MD , Lippincott Williams & Wilkens, 3rdGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6874/5/9/prepub
This article is published under license to 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.